[Identifying the specific causes of kidney allograft loss: A population-based study].

PubMed

Lohéac, Charlotte; Aubert, Olivier; Loupy, Alexandre; Legendre, Christophe

2018-04-01

Results of kidney transplantation have been improving but long-term allograft survival remains disappointing. The objective of the present study was to identify the specific causes of renal allograft loss, to assess their incidence and long-term outcomes. A total of 4783 patients from four French centres, transplanted between January 2004 and January 2014 were prospectively included. A total of 9959 kidney biopsies (protocol and for cause) performed between January 2004 and March 2015 were included. Donor and recipient clinical and biological parameters as well as anti-HLA antibody directed against the donor were included. The main outcome was the long-term kidney allograft survival, including the study of the associated causes of graft loss, the delay of graft loss according to their causes and the determinants of graft loss. There were 732 graft losses during the follow-up period (median time: 4.51 years) with an identified cause in 95.08 %. Kidney allograft survival at 9 years post-transplant was 78 %. The causes of allograft loss were: antibody-mediated rejection (31.69 %), thrombosis (25.55 %), medical intercurrent disease (14.62 %), recurrence of primary renal disease (7.1 %), BK- or CMV-associated nephropathy (n=35, 4.78 %), T cell-mediated rejection (4.78 %), urological disease (2.46 %) and calcineurin inhibitor nephrotoxicity (1.09 %). The main causes of allograft loss were antibody-mediated rejection and thrombosis. These results encourage efforts to prevent and detect these complications earlier in order to improve allograft survival. Copyright © 2018 Association Société de néphrologie. Published by Elsevier Masson SAS. All rights reserved.

Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes

PubMed Central

Naesens, Maarten; Khatri, Purvesh; Li, Li; Sigdel, Tara K.; Vitalone, Matthew J.; Chen, Rong; Butte, Atul J.; Salvatierra, Oscar; Sarwal, Minnie M.

2015-01-01

The degree of progressive chronic histological damage is associated with long-term renal allograft survival. In order to identify promising molecular targets for timely intervention, we examined renal allograft protocol and indication biopsies from 120 low-risk pediatric and adolescent recipients by whole-genome microarray expression profiling. In data-driven analysis, we found a highly regulated pattern of adaptive and innate immune gene expression that correlated with established or ongoing histological chronic injury, and also with development of future chronic histological damage, even in histologically pristine kidneys. Hence, histologically unrecognized immunological injury at a molecular level sets the stage for the development of chronic tissue injury, while the same molecular response is accentuated during established and worsening chronic allograft damage. Irrespective of the hypothesized immune or nonimmune trigger for chronic allograft injury, a highly orchestrated regulation of innate and adaptive immune responses was found in the graft at the molecular level. This occurred months before histologic lesions appear, and quantitatively below the diagnostic threshold of classic T-cell or antibody-mediated rejection. Thus, measurement of specific immune gene expression in protocol biopsies may be warranted to predict the development of subsequent chronic injury in histologically quiescent grafts and as a means to titrate immunosuppressive therapy. PMID:21881554

Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes.

PubMed

Naesens, Maarten; Khatri, Purvesh; Li, Li; Sigdel, Tara K; Vitalone, Matthew J; Chen, Rong; Butte, Atul J; Salvatierra, Oscar; Sarwal, Minnie M

2011-12-01

The degree of progressive chronic histological damage is associated with long-term renal allograft survival. In order to identify promising molecular targets for timely intervention, we examined renal allograft protocol and indication biopsies from 120 low-risk pediatric and adolescent recipients by whole-genome microarray expression profiling. In data-driven analysis, we found a highly regulated pattern of adaptive and innate immune gene expression that correlated with established or ongoing histological chronic injury, and also with development of future chronic histological damage, even in histologically pristine kidneys. Hence, histologically unrecognized immunological injury at a molecular level sets the stage for the development of chronic tissue injury, while the same molecular response is accentuated during established and worsening chronic allograft damage. Irrespective of the hypothesized immune or nonimmune trigger for chronic allograft injury, a highly orchestrated regulation of innate and adaptive immune responses was found in the graft at the molecular level. This occurred months before histologic lesions appear, and quantitatively below the diagnostic threshold of classic T-cell or antibody-mediated rejection. Thus, measurement of specific immune gene expression in protocol biopsies may be warranted to predict the development of subsequent chronic injury in histologically quiescent grafts and as a means to titrate immunosuppressive therapy.

Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats.

PubMed

Mackenzie, H S; Azuma, H; Troy, J L; Rennke, H G; Tilney, N L; Brenner, B M

1996-03-01

Conventional renal transplantation, which substitutes a single allograft for two native kidneys, imposes an imbalance between nephron supply and the metabolic and excretory demands of the recipient. This discrepancy, which stimulates hyperfunction and hypertrophy of viable allograft nephrons, may be intensified by nephron loss through ischemia-reperfusion injury or acute rejection episodes occurring soon after transplantation. In other settings where less than 50% of the total renal mass remains, progressive glomerular injury develops through mechanisms associated with compensatory nephron hyperfiltration and hypertrophy. To determine whether responses to nephron loss contribute to chronic injury in renal allografts, nephron supply was restored to near-normal levels by transplanting Lewis recipients with two Fisher 344 kidneys (group 2A) compared with the standard single allograft F344 --> LEW rat model of late renal allograft failure (group 1A). At 20 weeks, indices of injury were observed in 1A but not 2A rats. These indices included proteinuria (1A: 45 +/- 13; 2A: 4.0 +/- 0.29 mg/day) and glomerulosclerosis (1A: 23 +/- 4.9%, 2A: 0.7 +/- 0.3%) (p < .05). Double-allograft recipients maintained near normal renal structure and function, whereas 1A rats showed evidence of compensatory hyperfiltration (single-nephron glomerular filtration rate of 63 +/- 10 versus 44 +/- 2.0 nl/min in 2A rats) and hypertrophy (mean glomerular volume of 2.64 +/- 0.15 versus 1.52 +/- 0.05 microns3 x 10(6) in 2A rats) (p < .05). Thus, we conclude that a major component of late allograft injury is attributable to processes associated with inadequate transplanted renal mass, a finding that has major implications for kidney transplantation biology and policy.

Liver fatty-acid-binding protein in heart and kidney allograft recipients in relation to kidney function.

PubMed

Przybylowski, P; Koc-Zorawska, E; Malyszko, J S; Kozlowska, S; Mysliwiec, M; Malyszko, J

2011-10-01

Mammalian intracellular fatty-acid-binding proteins (FABPs), a large multigene family, encode 14-kD proteins that are members of a superfamily of lipid-binding proteins. FABPs are tissue specific. Liver-type FABP (L-FABP) can be filtered through the glomerulus owing to its small molecular size, similar to cystatin C, but it is reabsorbed by proximal tubule epithelial cells like other small proteins. In the human kidney, L-FABP is expressed predominantly in proximal tubules. It had been suggested that the presence of L-FABP in urine reflects hypoxic conditions resulting from decreased peritubular capillary flow, serving as a marker of acute kidney injury. The aim of this study was to assess urinary L-FABP in 111 heart and 76 kidney transplant recipients in relation to kidney function. Complete blood count, urea, fasting glucose, creatinine, and the N-terminal fragment of brain natriuretic protein were studied by standard laboratory methods; L-FABP and cystatin C, by ELISA using commercially available kits. Kidney transplant recipients displayed significantly higher L-FABP than heart recipients. Upon univariate analysis, urinary L-FABP correlated, with serum creatinine, cystatin C and estimated glomerular filtration ratio (eGFR) in kidney allograft recipients. However, in heart transplant recipients it was not related to kidney function, as reflected by creatinine or eGFR; was strongly related to cystatin C (r=0.34; P<.001) and urinary creatinine (r=-0.29; P<.01), and NGAL (r=0.29; P<.01). Upon multiple regression analysis, the best predictor of urinary L-FABP in kidney allograft recipients, was eGFR whereas in heart recipients, no parameter independently predicted L-FABP. Successful heart transplantation is associated with kidney injury as reflected by a reduced eGFR; however, in this population, L-FABP did not serve as a marker of kidney function. In contrast, in kidney allograft recipients, L-FABP may be a potential early marker for impaired kidney function

Proliferative glomerulonephritis with monoclonal IgG deposits in two kidney allografts successfully treated with rituximab.

PubMed

Merhi, Basma; Patel, Nikunjkuma; Bayliss, George; Henriksen, Kammi J; Gohh, Reginald

2017-06-01

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposit (PGNMID), a recently described pathologic entity in native kidneys, has been recognized in kidney transplant patients, where it can present as either recurrent or de novo disease. There is no definitive treatment to date, in either population. Here, we present two cases of PGNMID in kidney allografts that illustrate the challenges of diagnostic approach and highlight the allograft outcome after treatment with rituximab as a potential treatment of this condition.

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts From Deceased Donors.

PubMed

Williams, Robert C; Opelz, Gerhard; McGarvey, Chelsea J; Weil, E Jennifer; Chakkera, Harini A

2016-05-01

Since the beginning of the technology, there has been active debate about the role of human leucocyte antigen (HLA) matching in kidney allograft survival. Recent studies have reported diminishing importance of HLA matching, which have, in turn, been challenged by reports that suggest the continuing importance of these loci. Given the controversies, we examined the effect of HLA compatibility on kidney allograft survival by studying all first adult kidney transplants in the United States from a deceased donor. Using the United Network for Organ Sharing data, we identified first deceased donor kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine the impact of HLA compatibility on kidney allograft survival. Study cohort included 189 141 first adult kidney alone transplants, with a total of 994 558 years of kidney allograft follow-up time. Analyses adjusted for recipient and donor characteristics demonstrated a 13% higher risk (hazard ratio, 1.13; 95% confidence interval, 1.06-1.21) with 1 mismatch and a 64% higher risk (hazard ratio, 1.64, 95% confidence interval, 1.56-1.73) with 6 mismatches. Dividing the mismatch categories into 27 ordered permutations, and testing their 57 within mismatch category differences, demonstrated that all but 1 were equal, independent of locus. A significant linear relationship of hazard ratios was associated with HLA mismatch and affects allograft survival even during the recent periods of increasing success in renal transplantation.

Proliferative glomerulonephritis with monoclonal IgG deposits in two kidney allografts successfully treated with rituximab

PubMed Central

Patel, Nikunjkuma; Bayliss, George; Henriksen, Kammi J.; Gohh, Reginald

2017-01-01

Abstract Proliferative glomerulonephritis with monoclonal immunoglobulin G deposit (PGNMID), a recently described pathologic entity in native kidneys, has been recognized in kidney transplant patients, where it can present as either recurrent or de novo disease. There is no definitive treatment to date, in either population. Here, we present two cases of PGNMID in kidney allografts that illustrate the challenges of diagnostic approach and highlight the allograft outcome after treatment with rituximab as a potential treatment of this condition. PMID:28616219

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide

PubMed Central

Williams, Robert C.; Opelz, Gerhard; Weil, E. Jennifer; McGarvey, Chelsea J.; Chakkera, Harini A.

2017-01-01

Background Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Methods Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. Results There were 66 596 first adult transplants from living donors with 348 960 years of follow-up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. Conclusions These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible. PMID:28573187

The Risk of Transplant Failure With HLA Mismatch in First Adult Kidney Allografts 2: Living Donors, Summary, Guide.

PubMed

Williams, Robert C; Opelz, Gerhard; Weil, E Jennifer; McGarvey, Chelsea J; Chakkera, Harini A

2017-05-01

Allografts from living donors survive longer than those from deceased donors but the role of HLA mismatching in living kidney donation is still in question. We examined the effect of HLA compatibility on kidney allograft survival from living donors by studying all first adult kidney transplants performed in the United States over 25 years. Using the United Network for Organ Sharing data, we identified first kidney transplants between October 1, 1987, and December 31, 2013. Recipients were classified by their number of HLA mismatches and stratified by donor origin. Cox multivariate regression analyses adjusting for recipient and donor transplant characteristics were performed to determine impact of HLA compatibility on kidney allograft survival for all living donors and for living related and living unrelated subsets. There were 66 596 first adult transplants from living donors with 348 960 years of follow-up. We found a linear relationship between HLA mismatch and allograft survival. In adjusted analyses, among all living donors, 1 mismatch conferred a 44% higher risk, whereas 6 mismatches conferred a twofold higher risk of allograft failure. When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors. Twenty-five years of transplant experience, stratified by donor source, was summarized and presented as a guide for allocation. These data reinforce the importance of optimizing HLA matching to further improve survival in first adult kidney allografts in the future, especially in living unrelated donations, when possible.

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts

PubMed Central

Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− mice were transplanted with complete MHC mismatched A/J kidney grafts and intra-graft inflammatory components were followed to rejection. B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients rejected kidney allografts by day 35 whereas 65% of allografts in wild type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8−/−/CCR5−/− recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. PMID:27165816

Kidney versus Islet Allograft Survival after Induction of Mixed Chimerism with Combined Donor Bone Marrow Transplantation

PubMed Central

Oura, Tetsu; Ko, Dicken S.C.; Boskovic, Svjetlan; O'Neil, John J.; Chipashvili, Vaja; Koulmanda, Maria; Hotta, Kiyohiko; Kawai, Kento; Nadazdin, Ognjenka; Smith, R. Neal; Cosimi, A. B.; Kawai, Tatsuo

2016-01-01

Background We have previously reported successful induction of transient mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates. In this study, we attempted to extend this tolerance induction approach to islet allografts. Methods A total of eight recipients underwent MHC mismatched combined islet and bone marrow (BM) transplantation after induction of diabetes by streptozotocin. Three recipients were treated after a nonmyeloablative conditioning regimen that includes low dose total body and thymic irradiation, horse ATG (Atgam), six doses of anti-CD154 monoclonal antibody (mAb) and a one month course of cyclosporine (CyA) (Islet-A). In Islet-B, anti-CD8 mAb was administered in place of CyA. In Islet-C, two recipients were treated with Islet-B but without Atgam. The results were compared with previously reported results of eight cynomolgus monkeys that received combined kidney and bone marrow transplantation (Kidney-A) following the same conditioning regimen used in Islet-A. Results The majority of Kidney/BM recipients achieved long-term renal allograft survival after induction of transient chimerism. However, prolonged islet survival was not achieved in similarly conditioned Islet/BM recipients (Islet-A), despite induction of comparable levels of chimerism. In order to rule out islet allograft loss due to calcineurin inhibitor (CNI) toxicity, three recipients were treated with anti-CD8 mAb in place of CNI. Although these recipients developed significantly superior mixed chimerism and more prolonged islet allograft survival (61, 103, and 113 days), islet function was lost soon after the disappearance of chimerism. In Islet-C recipients, neither prolonged chimerism nor islet survival was observed (30 and 40 days). Conclusion Significant improvement of mixed chimerism induction and islet allograft survival were achieved with a CNI-free regimen that includes anti-CD8 mAb. However, unlike the kidney allograft, islet allograft

Kidney Versus Islet Allograft Survival After Induction of Mixed Chimerism With Combined Donor Bone Marrow Transplantation.

PubMed

Oura, Tetsu; Ko, Dicken S C; Boskovic, Svjetlan; O'Neil, John J; Chipashvili, Vaja; Koulmanda, Maria; Hotta, Kiyohiko; Kawai, Kento; Nadazdin, Ognjenka; Smith, R Neal; Cosimi, A B; Kawai, Tatsuo

2016-01-01

We have previously reported successful induction of transient mixed chimerism and long-term acceptance of renal allografts in MHC mismatched nonhuman primates. In this study, we attempted to extend this tolerance induction approach to islet allografts. A total of eight recipients underwent MHC mismatched combined islet and bone marrow (BM) transplantation after induction of diabetes by streptozotocin. Three recipients were treated after a nonmyeloablative conditioning regimen that included low-dose total body and thymic irradiation, horse Atgam (ATG), six doses of anti-CD154 monoclonal antibody (mAb), and a 1-month course of cyclosporine (CyA) (Islet A). In Islet B, anti-CD8 mAb was administered in place of CyA. In Islet C, two recipients were treated with Islet B, but without ATG. The results were compared with previously reported results of eight cynomolgus monkeys that received combined kidney and BM transplantation (Kidney A) following the same conditioning regimen used in Islet A. The majority of kidney/BM recipients achieved long-term renal allograft survival after induction of transient chimerism. However, prolonged islet survival was not achieved in similarly conditioned islet/BM recipients (Islet A), despite induction of comparable levels of chimerism. In order to rule out islet allograft loss due to CyA toxicity, three recipients were treated with anti-CD8 mAb in place of CyA. Although these recipients developed significantly superior mixed chimerism and more prolonged islet allograft survival (61, 103, and 113 days), islet function was lost soon after the disappearance of chimerism. In Islet C recipients, neither prolonged chimerism nor islet survival was observed (30 and 40 days). Significant improvement of mixed chimerism induction and islet allograft survival were achieved with a CyA-free regimen that included anti-CD8 mAb. However, unlike the kidney allograft, islet allograft tolerance was not induced with transient chimerism. Induction of more

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.

PubMed

Rong, Song; Hueper, Katja; Kirsch, Torsten; Greite, Robert; Klemann, Christian; Mengel, Michael; Meier, Matthias; Menne, Jan; Leitges, Michael; Susnik, Nathan; Meier, Martin; Haller, Hermann; Shushakova, Nelli; Gueler, Faikah

2014-09-15

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H(2b) PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H(2d) recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI. Copyright © 2014 the American Physiological Society.

Timing of Pregnancy After Kidney Transplantation and Risk of Allograft Failure.

PubMed

Rose, C; Gill, J; Zalunardo, N; Johnston, O; Mehrotra, A; Gill, J S

2016-08-01

The optimal timing of pregnancy after kidney transplantation remains uncertain. We determined the risk of allograft failure among women who became pregnant within the first 3 posttransplant years. Among 21 814 women aged 15-45 years who received a first kidney-only transplant between 1990 and 2010 captured in the United States Renal Data System, n = 729 pregnancies were identified using Medicare claims. The probability of allograft failure from any cause including death (ACGL) at 1, 3, and 5 years after pregnancy was 9.6%, 25.9%, and 36.6%. In multivariate analyses, pregnancy in the first posttransplant year was associated with an increased risk of ACGL (hazard ratio [HR]: 1.18; 95% confidence interval [CI] 1.00, 1.40) and death censored graft loss (DCGL) (HR:1.25; 95% CI 1.04, 1.50), while pregnancy in the second posttransplant year was associated with an increased risk of DCGL (HR: 1.26; 95% CI 1.06, 1.50). Pregnancy in the third posttransplant year was not associated with an increased risk of ACGL or DCGL. These findings demonstrate a higher incidence of allograft failure after pregnancy than previously reported and that the increased risk of allograft failure extends to pregnancies in the second posttransplant year. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.

PubMed

Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

2016-06-01

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Male kidney allograft recipients at risk for urinary tract infection?

PubMed Central

Schuette-Nuetgen, Katharina; Vogl, Thomas; Dobrindt, Ulrich; Kahl, Barbara C.; Brand, Marcus; Pavenstädt, Hermann; Suwelack, Barbara

2017-01-01

Background Urinary tract infection (UTI) is the most common infection after renal transplantation (RTx). Although female sex is a well-known risk factor for the development of UTI after RTx, the role of the donor sex in this context remains unclear. Methods In this case control study 6,763 RTx cases were screened for UTI when presenting at our transplant outpatient clinics. 102 different RTx patients fulfilled the inclusion criteria and were compared to 102 controls. Data on renal function was prospectively followed for 12 months. Results were compared to a previous RTx cohort from our transplant center. Additionally, we assessed the immunological response of leukocytes from 58 kidney recipients and 16 controls to lipopolysaccharide stimulation. Result After identification by univariate analysis, multivariate logistic regression analysis indicated female sex, minor height, advanced age and male kidney allograft sex to be associated with the occurrence of UTI after RTx. Female recipients who received male grafts had the best renal function 12 months after presentation. However, leukocyte response of recipients to lipopolysaccharide was impaired irrespective of donor and recipient sex to the same extend. Conclusions We conclude from our data that male kidney allografts are associated with the occurrence of UTI after RTx but did not influence the response of leukocytes to lipopolysaccharide. Further prospective studies are needed to identify the underlying mechanisms of higher male kidney donor dependent UTI. PMID:29145515

Long-term tolerance to kidney allografts in a preclinical canine model.

PubMed

Kuhr, Christian S; Yunusov, Murad; Sale, George; Loretz, Carol; Storb, Rainer

2007-08-27

Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.

Expression of bone morphogenetic proteins 4, 6 and 7 is downregulated in kidney allografts with interstitial fibrosis and tubular atrophy.

PubMed

Furic-Cunko, Vesna; Kes, Petar; Coric, Marijana; Hudolin, Tvrtko; Kastelan, Zeljko; Basic-Jukic, Nikolina

2015-07-01

Bone morphogenetic proteins (BMPs) are pleiotropic growth factors. This paper investigates the connection between the expression pattern of BMPs in kidney allograft tissue versus the cause of allograft dysfunction. The expression pattern of BMP2, BMP4, BMP6 and BMP7 in 50 kidney allografts obtained by transplant nephrectomy is investigated. Immunohistochemical staining is semiquantitatively evaluated for intensity to identify the expression pattern of BMPs in normal and allograft kidney tissues. The expression of BMP4 is unique between different tubular cell types in grafts without signs of fibrosis. This effect is not found in specimens with high grades of interstitial fibrosis and tubular atrophy (IFTA). In samples with IFTA grades II and III, the BMP7 expression is reduced in a significant fraction of specimens relative to those without signs of IFTA. The expression pattern of BMP6 indicates that its activation may be triggered by the act of transplantation and subsequent reperfusion injury. The expression of BMP2 is strong in all types of tubular epithelial cells and does not differ between the compared allografts and control kidney specimens. The intensity and expression pattern of BMP4, BMP6 and BMP7 in transplanted kidney tissue are found to be dependent upon the length of the transplanted period, the clinical indication for transplant nephrectomy and signs of IFTA in kidney tissue.

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

PubMed Central

Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

2015-01-01

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

Urine Fibrosis Markers and Risk of Allograft Failure in Kidney Transplant Recipients: A Case-Cohort Ancillary Study of the FAVORIT Trial.

PubMed

Ix, Joachim H; Katz, Ronit; Bansal, Nisha; Foster, Meredith; Weiner, Daniel E; Tracy, Russell; Jotwani, Vasantha; Hughes-Austin, Jan; McKay, Dianne; Gabbai, Francis; Hsu, Chi-Yuan; Bostom, Andrew; Levey, Andrew S; Shlipak, Michael G

2017-03-01

Kidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown. Case-cohort study. The FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257). Using spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α 1 -microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide). Death-censored allograft failure. In models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure. We lack kidney biopsy data, BK titers, and HLA antibody status. Urine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR. Published by Elsevier Inc.

Value of Donor–Specific Anti–HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss

PubMed Central

Viglietti, Denis; Loupy, Alexandre; Vernerey, Dewi; Bentlejewski, Carol; Gosset, Clément; Aubert, Olivier; Duong van Huyen, Jean-Paul; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Zeevi, Adriana

2017-01-01

The diagnosis system for allograft loss lacks accurate individual risk stratification on the basis of donor–specific anti–HLA antibody (anti-HLA DSA) characterization. We investigated whether systematic monitoring of DSA with extensive characterization increases performance in predicting kidney allograft loss. This prospective study included 851 kidney recipients transplanted between 2008 and 2010 who were systematically screened for DSA at transplant, 1 and 2 years post-transplant, and the time of post–transplant clinical events. We assessed DSA characteristics and performed systematic allograft biopsies at the time of post–transplant serum evaluation. At transplant, 110 (12.9%) patients had DSAs; post-transplant screening identified 186 (21.9%) DSA-positive patients. Post–transplant DSA monitoring improved the prediction of allograft loss when added to a model that included traditional determinants of allograft loss (increase in c statistic from 0.67; 95% confidence interval [95% CI], 0.62 to 0.73 to 0.72; 95% CI, 0.67 to 0.77). Addition of DSA IgG3 positivity or C1q binding capacity increased discrimination performance of the traditional model at transplant and post-transplant. Compared with DSA mean fluorescence intensity, DSA IgG3 positivity and C1q binding capacity adequately reclassified patients at lower or higher risk for allograft loss at transplant (category–free net reclassification index, 1.30; 95% CI, 0.94 to 1.67; P<0.001 and 0.93; 95% CI, 0.49 to 1.36; P<0.001, respectively) and post-transplant (category–free net reclassification index, 1.33; 95% CI, 1.03 to 1.62; P<0.001 and 0.95; 95% CI, 0.62 to 1.28; P<0.001, respectively). Thus, pre– and post–transplant DSA monitoring and characterization may improve individual risk stratification for kidney allograft loss. PMID:27493255

Raman-based detection of hydroxyethyl starch in kidney allograft biopsies as a potential marker of allograft quality in kidney transplant recipients

NASA Astrophysics Data System (ADS)

Vuiblet, Vincent; Fere, Michael; Bankole, Ezechiel; Wynckel, Alain; Gobinet, Cyril; Birembaut, Philippe; Piot, Olivier; Rieu, Philippe

2016-09-01

In brain-dead donor resuscitation, hydroxyethyl starch (HES) use has been associated with presence of osmotic-nephrosis-like lesions in kidney transplant recipients. Our aim was to determine whether the presence of HES in protocol renal graft biopsies at three months (M3) after transplantation is associated with renal graft quality. According to the HES administered to the donor during the procurement procedure, two groups of patients were defined according graft exposition to HES: HES group, (N = 20) and control group (N = 6). Detection and relative quantification of HES was performed by Raman spectroscopy microimaging on M3 protocol renal graft biopsies. Statistical analyses were used to investigate the association between Raman data and graft characteristics. HES spectral signal was revealed negative in the control group, whereas it was positive in 40% of biopsies from the HES group. In the HES group, a stronger HES signal was associated with a lower risk of graft failure measured by the Kidney Donor Risk Index (KDRI) and was correlated with the allograft kidney function. Thus, HES accumulation in donor kidney, as probed by Raman biophotonic technique, is correlated with the quality of donor kidney and consequently the graft renal function and graft survival.

De novo immune complex deposition in kidney allografts: a series of 32 patients.

PubMed

Lloyd, Isaac E; Ahmed, Faris; Revelo, Monica P; Khalighi, Mazdak A

2018-01-01

Immune complex deposition in kidney allografts can include both recurrent and de novo processes. Recurrent glomerulonephritis is a well-recognized phenomenon and has been shown to be a common cause of allograft failure. De novo immune complex-mediated disease remains relatively poorly characterized, likely owing to the less frequent use of immunofluorescence and electron microscopy in the transplant setting. We performed a retrospective review of kidney allograft biopsies showing glomerular immune complex deposition. Cases with de novo deposits were identified and further organized into two groups depending on whether the immune complex deposition could be clinically and/or histologically classified. Thirty-two patients with de novo immune complex deposition were identified over a 7-year period. A broad range of immune complex-mediated injuries were observed, the majority (63%) of which could be readily classified either clinically or histologically. These included cases of membranous glomerulonephropathy, IgA nephropathy, infection-related glomerulonephritis and glomerulonephritis related to an underlying autoimmune process. A smaller subset of patients (37%) demonstrated immune complex deposition that was difficult to histologically or clinically classify. These patients typically showed mild mesangial immune complex deposition with co-dominant IgG and IgM staining by immunofluorescence microscopy. The presence of concurrent antibody-mediated rejection and donor-specific antibody positivity was significantly higher in the unclassifiable group. The significance of these deposits and their possible relationship to allograft rejection deserves further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

PubMed Central

Noordmans, Gerda A.; O’Brien, Maya R.; Ma, Jin; Zhao, Cathy Y.; Zhang, Geoff Y.; Kwan, Tony K.T.; Alexander, Stephen I.; Chadban, Steven J.

2012-01-01

Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4+CD25+FoxP3+ cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance. PMID:22878960

Impact of post-kidney transplant parathyroidectomy on allograft function

PubMed Central

Parikh, Samir; Nagaraja, Haikady; Agarwal, Anil; Samavedi, Srinivas; Von Visger, Jon; Nori, Uday; Andreoni, Kenneth; Pesavento, Todd; Singh, Neeraj

2013-01-01

Background The impact of parathyroidectomy on allograft function in kidney transplant patients is unclear. Methods We conducted a retrospective, observational study of all kidney transplant recipients from 1988 to 2008 who underwent parathyroidectomy for uncontrolled hyperparathyroidism (n = 32). Post-parathyroidectomy, changes in estimated glomerular filtration rate (eGFR) and graft loss were recorded. Cross-sectional associations at baseline between eGFR and serum calcium, phosphate, and parathyroid hormone (PTH), and associations between their changes within subjects during the first two months post-parathyroidectomy were assessed. Results Post-parathyroidectomy, the mean eGFR declined from 51.19 mL/min/1.73 m2 at parathyroidectomy to 44.78 mL/min/1.73 m2 at two months (p < 0.0001). Subsequently, graft function improved, and by 12 months, mean eGFR recovered to 49.76 mL/min/1.73 m2 (p = 0.035). Decrease in serum PTH was accompanied by a decrease in eGFR (p = 0.0127) in the first two months post-parathyroidectomy. Patients whose eGFR declined by ≥ 20% (group 1) in the first two months post-parathyroidectomy were distinguished from the patients whose eGFR declined by <20% (group 2). The two groups were similar except that group 1 had a higher baseline mean serum PTH compared with group 2, although not significant (1046.7 ± 1034.2 vs. 476.6 ± 444.9, p = 0.14). In group 1, eGFR declined at an average rate of 32% (p < 0.0001) during the first month post-parathyroidectomy compared with 7% (p = 0.1399) in group 2, and the difference between these two groups was significant (p = 0.0003). The graft function recovered in both groups by one yr. During median follow-up of 66.00 ± 49.45 months, 6 (18%) patients lost their graft with a mean time to graft loss from parathyroidectomy of 37.2 ± 21.6 months. The causes of graft loss were rejection (n = 2), pyelonephritis (n = 1) and chronic allograft nephropathy (n = 3). No graft loss occurred during the first-year post

IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury.

PubMed

Lefaucheur, Carmen; Viglietti, Denis; Bentlejewski, Carol; Duong van Huyen, Jean-Paul; Vernerey, Dewi; Aubert, Olivier; Verine, Jérôme; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Loupy, Alexandre; Zeevi, Adriana

2016-01-01

Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. Copyright © 2016 by the American Society of Nephrology.

Cross-cultural adaptation of the Kidney Transplant Questionnaire for Chinese adult kidney allograft recipients.

PubMed

Niu, Yujian; Zhang, Wenxin; Chen, Hong; Mao, Sha; Yue, Yang; Zhang, Hongying; Li, Li; Sun, Ping; Wang, Jianli; Zhu, Xiongwei

2017-06-01

To provide a disease-specific instrument for evaluating the health-related quality life of Chinese kidney allograft recipients. Cross-cultural adaptation of the Kidney Transplant Questionnaire (KTQ) was performed by forward translation of the original English version into Chinese, followed by back translation and evaluation of the Chinese version by health care professionals, language professionals, and the translators. A total of 297 patients (110 women and 187 men; mean age, 43.91 ± 11.38 y; average time since transplant, 40.36 ± 32.86 mo) completed the Chinese versions of the KTQ and 36-Item Short Form Health Survey, and the results were used to evaluate the validity and reliability of the Chinese KTQ. The Cronbach α values for all KTQ dimensions were satisfactory (physical symptoms, α = 0.876; fatigue, α = 0.896; uncertainty/fear, α = 0.686; appearance, α = 0.701; and emotions, α = 0.886) and similar to values reported for the English and Spanish versions. The correlation coefficients among the dimensions of the Chinese KTQ ranged from 0.26 to 0.69, and those between the KTQ and 36-Item Short Form Health Survey physical component summary and mental component summary subscales were low and moderate to high, respectively, except for the appearance dimension. A good fit of the data in the confirmatory factor analysis indicated that the individual items of the translated instrument indeed evaluated the intended concepts. The Chinese version of the KTQ was found to be similarly valid and reliable compared with the original version and, thus, can be used to evaluate health-related quality of life among Chinese adult kidney allograft recipients. © 2017 John Wiley & Sons, Ltd.

Mesenchymal Stem Cell Therapy Prevents Interstitial Fibrosis and Tubular Atrophy in a Rat Kidney Allograft Model

PubMed Central

Herrero, Esther; Torras, Joan; Ripoll, Elia; Flaquer, Maria; Gomà, Montse; Lloberas, Nuria; Anegon, Ignacio; Cruzado, Josep M.; Grinyó, Josep M.; Herrero-Fresneda, Immaculada

2012-01-01

In solid organ transplantation, mesenchymal stem cell (MSC) therapy is strongly emerging among other cell therapies due to the positive results obtained in vitro and in vivo as an immunomodulatory agent and their potential regenerative role. We aimed at testing whether a single dose of MSCs, injected at 11 weeks after kidney transplantation for the prevention of chronic mechanisms, enhanced regeneration and provided protection against the inflammatory and fibrotic processes that finally lead to the characteristic features of chronic allograft nephropathy (CAN). Either bone marrow mononuclear cells (BMCs) injection or no-therapy (NT) were used as control treatments. A rat kidney transplantation model of CAN with 2.5 h of cold ischemia was used, and functional, histological, and molecular parameters were assessed at 12 and 24 weeks after transplantation. MSC and BMC cell therapy preserves renal function at 24 weeks and abrogates proteinuria, which is typical of this model (NT24w: 68.9±26.5 mg/24 h, MSC24w: 16.6±2.3 mg/24 h, BMC24w: 24.1±5.3 mg/24 h, P<0.03). Only MSC-treated animals showed a reduction in interstitial fibrosis and tubular atrophy (NT24w: 2.3±0.29, MSC24w: 0.4±0.2, P<0.03), less T cells (NT: 39.6±9.5, MSC: 8.1±0.9, P<0.03) and macrophages (NT: 20.9±4.7, MSC: 5.9±1.7, P<0.05) infiltrating the parenchyma and lowered expression of inflammatory cytokines while increasing the expression of anti-inflammatory factors. MSCs appear to serve as a protection from injury development rather than regenerate the damaged tissue, as no differences were observed in Ki67 expression, and kidney injury molecule-1, Clusterin, NGAL, and hepatocyte growth factor expression were only up-regulated in nontreated animals. Considering the results, a single delayed MSC injection is effective for the long-term protection of kidney allografts. PMID:22494435

Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival

PubMed Central

De Serres, Sacha A.; Safa, Kassem; Bijol, Vanesa; Ueno, Takuya; Onozato, Maristela L.; Iafrate, A. John; Herter, Jan M.; Lichtman, Andrew H.; Mayadas, Tanya N.; Guleria, Indira; Rennke, Helmut G.; Najafian, Nader; Chandraker, Anil

2015-01-01

Progress in long-term renal allograft survival continues to lag behind the progress in short-term transplant outcomes. Dendritic cells are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to their presence in transplanted kidneys. We used dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin as a marker of dendritic cells in 105 allograft biopsy samples from 105 kidney transplant recipients. High dendritic cell density was associated with poor allograft survival independent of clinical variables. Moreover, high dendritic cell density correlated with greater T cell proliferation and poor outcomes in patients with high total inflammation scores, including inflammation in areas of tubular atrophy. We then explored the association between dendritic cells and histologic variables associated with poor prognosis. Multivariate analysis revealed an independent association between the densities of dendritic cells and T cells. In biopsy samples with high dendritic cell density, electron microscopy showed direct physical contact between infiltrating lymphocytes and cells that have the ultrastructural morphologic characteristics of dendritic cells. The origin of graft dendritic cells was sought in nine sex-mismatched recipients using XY fluorescence in situ hybridization. Whereas donor dendritic cells predominated initially, the majority of dendritic cells in late allograft biopsy samples were of recipient origin. Our data highlight the prognostic value of dendritic cell density in allograft biopsy samples, suggest a new role for these cells in shaping graft inflammation, and provide a rationale for targeting dendritic cell recruitment to promote long-term allograft survival. PMID:25855773

Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts.

PubMed

Heemann, U W; Azuma, H; Tullius, S G; Schmid, C; Philipp, T; Tilney, N L

1996-07-01

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that

Increased risk of kidney damage among Chinese adults with simple renal cyst.

PubMed

Kong, Xianglei; Ma, Xiaojing; Zhang, Chengyin; Su, Hong; Gong, Xiaojie; Xu, Dongmei

2018-05-04

The presence of simple renal cyst (SRC) has been related to hypertension, the early and long-term allograft function, and aortic disease, but the relationship with kidney damage was still controversial. Accordingly, we conducted a large sample cross-sectional study to explore the association of SRC with indicators of kidney damage among Chinese adults. A total of 42,369 adults (aged 45.8 ± 13.67 years, 70.6% males) who visited the Health Checkup Clinic were consecutively enrolled. SRC was assessed by ultrasonography according to Bosniak category. Multiple regression models were applied to explore the relationships between SRC and indicators of kidney damage [proteinuria (dipstick urine protein ≥ 1+) and decreased estimated glomerular filtration rate (DeGFR) < 60 ml/min/1.73 m 2 ]. Among all participants in the study, the prevalence of SRC was 10.5%. As a categorical outcome, participants with more 1 cyst and with 1 cyst had higher percentage of proteinuria [53 (5.3%) and 93 (2.7%) vs. 596 (1.6%), p < 0.001] and DeGFR [57 (5.7%) and 85 (2.5%) vs. 278 (0.7%), p < 0.001] compared with participants with no cyst. SRC significantly correlated with proteinuria [OR 1.59 (95% CI 1.30-1.95)] and DeGFR [OR 1.97 (95% CI 1.56-2.47)] after adjusting for potential confounders. Furthermore, the results also demonstrated that maximum diameter (per 1 cm increase), bilateral location, and multiple cysts significantly correlated with DeGFR in the multiple logistic regression analysis. The study revealed that SRC significantly correlated with kidney damage and special attention should be paid among Chinese adults with SRC.

Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation.

PubMed

Bergler, Tobias; Jung, Bettina; Bourier, Felix; Kühne, Louisa; Banas, Miriam C; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

2016-01-01

Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust

Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation

PubMed Central

Bourier, Felix; Kühne, Louisa; Banas, Miriam C.; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

2016-01-01

Objective Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Results Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. Conclusion The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis

Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

PubMed

Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

2015-09-03

Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

Immunomodulatory Strategies Directed Towards Tolerance of Vascularized Composite Allografts

PubMed Central

Michel, Sebastian G.; Villani, Vincenzo; Muraglia, Glenn M. La; Torabi, Radbeh; Leonard, David A.; Randolph, Mark A.; Colvin, Robert B.; Yamada, Kazuhiko; Madsen, Joren C.; Cetrulo, Curtis L.; Sachs, David H.

2015-01-01

Background Achieving tolerance of vascularized composite allografts (VCAs) would improve the risk-to-benefit ratio in patients who undergo this life-enhancing, though not life-saving, transplant. Kidney co-transplantation along with a short course of high-dose immunosuppression enables tolerance of heart allografts across a full MHC mismatch. In this study, we investigated whether tolerance of VCA across full MHC disparities could be achieved in animals already tolerant of heart and kidney allografts. Methods Miniature swine that were tolerant of heart and/or kidney allografts long-term underwent transplantation of myocutaneous VCA across the same MHC barrier. Prior to VCA transplant, Group 1 (n=3) underwent Class I-mismatched kidney transplantation; Group 2 (n=3) underwent two sequential Class I-mismatched kidney transplantations; Group 3 (n=2) underwent haploidentical MHC-mismatched heart/kidney transplantation; and Group 4 (n=2) underwent full MHC-mismatched heart/kidney transplantation. Results All three animals in Group 1 and two of three animals in Group 2 showed skin rejection ≤85 days; one animal in Group 2 showed prolonged skin survival >200 days. Animals in Groups 3 and 4 showed skin rejection ≤30 days and regained in vitro evidence of donor responsiveness. Conclusion This is the first pre-clinical study in which hearts, kidneys, and VCAs have been transplanted into the same recipient. Despite VCA rejection, tolerance of heart and kidney allografts was maintained. These results suggest that regulatory tolerance of skin is possible but not generally achieved by the same level of immunomodulation that is capable of inducing tolerance of heart and kidney allografts. Achieving tolerance of skin may require additional immunomodulatory therapies. PMID:25757218

HLA Amino Acid Polymorphisms and Kidney Allograft Survival

PubMed Central

Kamoun, Malek; McCullough, Keith P.; Maiers, Martin; Fernandez Vina, Marcelo A.; Li, Hongzhe; Teal, Valerie; Leichtman, Alan B.; Merion, Robert M.

2017-01-01

Background The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid (AA) mismatches (MMs) at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those MMs assessed at the antigenic (2-digit) specificity. Methods Data on 240 024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding AA polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen MMs. Results We show that estimated AA MMs at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen MMs with graft survival. A statistically significant linear relationship between the estimated number of AA MMs and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months after transplantation (hazard ratio, 1.30 per 15 DRB1 AA MM; P < 0.0001). Conclusions This study shows that independent of the well-known association of HLA antigen (2-digit specificity) MMs with kidney graft survival, estimated AA MMs at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of GF. PMID:28221244

Influence of hypernatremia and polyuria of brain-dead donors before organ procurement on kidney allograft function.

PubMed

Kazemeyni, Seyed Mohammad; Esfahani, Fatemah

2008-01-01

Polyuria and hypernatremia are common problems during the pretransplant care of brain-dead donors. They have not only important role in hemodynamic stability, but also may influence organ transplantation outcomes. The influence of donor hypernatremia in liver transplantation was reported. This study aimed to determine these effects on kidney allograft. We retrospectively studied on 57 transplanted kidney allografts from cadaveric donors. The effects of the urine output volume and serum level of sodium of the donors were on the recipients' serum creatinine levels 1 week after transplantation and at the last follow-up visit were assessed. Of the donors, 58% had polyuria and 45% had hypernatremia. The median pretransplant urine output of the donors was 130 mL/h (range, 35 mL/h to 450 mL/h), and their mean serum sodium level was 152.0 +/- 13.0 mEq/L. Serum creatinine concentrations in the recipients at the 1st posttransplant week correlated significantly with the recipients' age (r = 0.355, P = .02) and the donors' urine output volume (r = 0.329, P = .04). The serum creatinine measured in the last follow-up visit significantly correlated only with the donors' serum sodium levels (r = 0.316, P = .02) and the donors' age (r = 0.306, P = .02). Multivariate regression analysis showed that the donors' serum levels of sodium and potassium were the predictors of the last measured serum creatinine level. Polyuria and hypernatremia in brain-dead donors are frequent. Elevated serum level of sodium and polyuria in the donor can have adverse effects on kidney allograft function.

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

PubMed Central

Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C.; Khadayate, Sanjay; Mas, Valeria R.; Nitsch, Dorothea D.; Wang, Zhen; Norman, Jill T.; Wilcox, Christopher S.; Wheeler, David C.; Leiper, James

2015-01-01

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule–specific Ddah1 knockout (Ddah1PT−/−) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1PT−/− mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. PMID:25855779

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.

PubMed

Tomlinson, James A P; Caplin, Ben; Boruc, Olga; Bruce-Cobbold, Claire; Cutillas, Pedro; Dormann, Dirk; Faull, Peter; Grossman, Rebecca C; Khadayate, Sanjay; Mas, Valeria R; Nitsch, Dorothea D; Wang, Zhen; Norman, Jill T; Wilcox, Christopher S; Wheeler, David C; Leiper, James

2015-12-01

Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1(PT-/-)) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1(PT-/-) mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function. Copyright © 2015 by the American Society of Nephrology.

Association of vitamin D binding protein polymorphism with long-term kidney allograft survival in Hispanic kidney transplant recipients.

PubMed

Vu, Don; Sakharkar, Prashant; Tellez-Corrales, Eglis; Shah, Tariq; Hutchinson, Ian; Min, David I

2013-02-01

Polymorphism of genes encoding components of the vitamin D pathway including vitamin D receptor (VDR) and vitamin D binding protein (VDBP), have been widely explored due to the complex role played by vitamin D in renal transplant outcomes. In this study, we investigated whether polymorphisms of genes encoding VDR and VDBP were associated with allograft survival or acute rejection (AR) among a Hispanic kidney transplant population. A total of 502 Hispanic renal allograft recipients at the St. Vincent Medical Center between 2001 and 2010 were genotyped for four different single nucleotide polymorphisms of VDR: FokI C>T (rs2228570), BsmI G>A (rs1544410), ApaI T>G (rs7975232), and TaqI T>C (rs731236). We also performed genotyping for one common polymorphism in the VDBP gene (rs4588). Survival was significantly improved for patients who were homozygous GG for the rs4588 G>T allele in the VDBP gene (GG vs. GT + TT, OR = 0.63, p = 0.02) while GT genotype was associated with a higher risk of graft loss (GT vs. GG + TT, OR = 1.67, p = 0.01). We found no association for polymorphic markers in VDR with allograft survival and AR. The frequency of the haplotype GTCG (in the order of VDR FokI C>T, BsmI G>A, ApaI T>G, and TaqI T>C), was significantly different in the patients with graft rejection compared to the control (p = 0.007) while ACCA haplotype was found to be associated with graft loss (p = 0.02). Hence, the VDBP G>T polymorphism (rs4588) and two haplotypes (GTCG and ACCA) of VDR appear to be associated with renal allograft outcomes among Hispanic allograft recipients.

Comparing glycaemic benefits of Active Versus passive lifestyle Intervention in kidney Allograft Recipients (CAVIAR): study protocol for a randomised controlled trial.

PubMed

Wilcox, Joanne; Waite, Chantelle; Tomlinson, Lyndsey; Driscoll, Joanne; Karim, Asra; Day, Edward; Sharif, Adnan

2016-08-22

Lifestyle modification is widely recommended to kidney allograft recipients post transplantation due to the cardiometabolic risks associated with immunosuppression including new-onset diabetes, weight gain and cardiovascular events. However, we have no actual evidence that undertaking lifestyle modification protects from any adverse outcomes post transplantation. The aim of this study is to compare whether a more proactive versus passive interventional approach to modify lifestyle is associated with superior outcomes post kidney transplantation. We designed this prospective, single-centre, open-label, randomised controlled study to compare the efficacy of active versus passive lifestyle intervention for kidney allograft recipients early post transplantation. A total of 130 eligible patients, who are stable, nondiabetic and between 3 and 24 months post kidney transplantation, will be recruited. Randomisation is being undertaken by random block permutations into passive (n = 65, leaflet guidance only) versus active lifestyle modification (n = 65, supervised intervention) over a 6-month period. Supervised intervention is being facilitated by two dietitians during the 6-month intervention period to provide continuous lifestyle intervention guidance, support and encouragement. Both dietitians are accredited with behavioural intervention skills and will utilise motivational aids to support study recruits randomised to active intervention. The primary outcome is change in abnormal glucose metabolism parameters after 6 months of comparing active versus passive lifestyle intervention. Secondary outcomes include changes in a wide array of cardiometabolic parameters, kidney allograft function and patient-reported outcome measures. Long-term tracking of patients via data linkage to electronic patient records and national registries will facilitate long-term comparison of outcomes after active versus passive lifestyle intervention beyond the 6-month intervention

Depletion of CD8 Memory T Cells for Induction of Tolerance of a Previously Transplanted Kidney Allograft

PubMed Central

Koyama, I.; Nadazdin, O.; Boskovic, S.; Ochiai, T.; Smith, R. N.; Sykes, M.; Sogawa, H.; Murakami, T.; Strom, T. B.; Colvin, R. B.; Sachs, D. H.; Benichou, G.; Cosimi, A. B.; Kawai, T.

2013-01-01

Heterologous immunologic memory has been considered a potent barrier to tolerance induction in primates. Induction of such tolerance for a previously transplanted organ may be more difficult, because specific memory cells can be induced and activated by a transplanted organ. In the current study, we attempted to induce tolerance to a previously transplanted kidney allograft in nonhuman primates. The conditioning regimen consisted of low dose total body irradiation, thymic irradiation, antithymocyte globulin, and anti- CD154 antibody followed by a brief course of a calcineurin inhibitor. This regimen had been shown to induce mixed chimerism and allograft tolerance when kidney transplantation (KTx) and donor bone marrow transplantation (DBMT) were simultaneously performed. However, the same regimen failed to induce mixed chimerism when delayed DBMT was performed after KTx. We found that significant levels of memory T cells remained after conditioning, despite effective depletion of naïve T cells. By adding humanized anti-CD8 monoclonal antibody (cM-T807), CD8 memory T cells were effectively depleted and these recipients successfully achieved mixed chimerism and tolerance. The current studies provide ‘proof of principle’ that the mixed chimerism approach can induce renal allograft tolerance, even late after organ transplantation if memory T-cell function is adequately controlled. PMID:17286617

Outcome of organs procured from donors on extracorporeal membrane oxygenation support: an analysis of kidney and liver allograft data.

PubMed

Carter, Timothy; Bodzin, Adam S; Hirose, Hitoshi; West, Sharon; Hasz, Richard; Maley, Warren R; Cavarocchi, Nicholas C

2014-07-01

Extracorporeal membrane oxygenation has become rescue therapy for adults with overwhelming cardiac and/or respiratory failure. Not all patients are saved, creating a new cohort of potential organ donors. This study examines the outcomes of liver and kidney allografts procured from donors on extracorporeal membrane oxygenation (ECMO). A retrospective review was conducted through the local organ procurement organization. Donors on ECMO prior to notification were classified into donation after brain death (DBD) and donation after cardiac death (DCD). We compared short-term outcome data against published standards. Between 1995 and 2012, 97 organs were procured from 41 donors supported on ECMO. There were 68 kidneys donated, 51 were transplanted and 17 discarded. Excluding extended criteria donors, 29 DBD and 13 DCD kidneys were transplanted from donors supported on ECMO. Delayed graft function occurred in 34% of DBD kidneys and 38% of DCD kidneys. Kidney allograft survival at one yr was 93%. Twenty-four livers were procured, nine discarded, and 15 transplanted. Ninety-three percent of liver transplant recipients were alive with graft function at one yr. Donation after brain death kidneys procured from donors on ECMO perform similarly to non-ECMO organs with regard to delayed graft function (DGF), one-yr graft survival and function. Livers from ECMO donors have a higher discard rate than non-ECMO donors, but function similarly at six months and one yr. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Relationship of Serum Klotho Level With ACE Gene Polymorphism in Stable Kidney Allograft Recipients.

PubMed

Zaare Nahandi, Maryam; Ardalan, Mohamad Reza; Banagozar Mohamadi, Ali; Ghorbani Haghjo, Amir; Jabbarpor Bonyadi, Morteza; Mohamadian, Tahere

2017-03-01

The kidney is the main source of serum Klotho production. Immunosuppressive agents could affect the kidney in this regard. The effect of the ACE gene polymorphism on Klotho production is a less studied area. This study aimed to assess serum Klotho and ACE gene in a group of stable kidney transplant recipients. In a cross-sectional study, 30 kidney transplant recipients with stable allograft function and 27 healthy young individuals were assessed for their serum Klotho levels. The ACE gene polymorphisms were studied in both groups. Klotho level was higher in kidney transplant recipients than the controls, but the difference was not significant (2.76 ± 2.41 ng/mL versus 2.01 ± 1.41 ng/mL, respectively). In both groups, serum Klotho level was higher in those with the I>I polymorphism, the men, those with higher glomerular filtration rate, and younger individuals, but the differences did not reach a significant level. Higher body mass index was significantly associated with lower serum Klotho level in both groups. Klotho level after kidney transplantation meets the range in healthy individuals, and it is not affected by the ACE gene polymorphism.

The mode of sensitization and its influence on allograft outcomes in highly sensitized kidney transplant recipients.

PubMed

Redfield, Robert R; Scalea, Joseph R; Zens, Tiffany J; Mandelbrot, Didier A; Leverson, Glen; Kaufman, Dixon B; Djamali, Arjang

2016-10-01

We sought to determine whether the mode of sensitization in highly sensitized patients contributed to kidney allograft survival. An analysis of the United Network for Organ Sharing dataset involving all kidney transplants between 1997 and 2014 was undertaken. Highly sensitized adult kidney transplant recipients [panel reactive antibody (PRA) ≥98%] were compared with adult, primary non-sensitized and re-transplant recipients. Kaplan-Meier survival analyses were used to determine allograft survival rates. Cox proportional hazards regression analyses were conducted to determine the association of graft loss with key predictors. Fifty-three percent of highly sensitized patients transplanted were re-transplants. Pregnancy and transfusion were the only sensitizing event in 20 and 5%, respectively. The 10-year actuarial graft survival for highly sensitized recipients was 43.9% compared with 52.4% for non-sensitized patients, P < 0.001. The combination of being highly sensitized by either pregnancy or blood transfusion increased the risk of graft loss by 23% [hazard ratio (HR) 1.230, confidence interval (CI) 1.150-1.315, P < 0.001], and the combination of being highly sensitized from a prior transplant increased the risk of graft loss by 58.1% (HR 1.581, CI 1.473-1.698, P < 0.001). The mode of sensitization predicts graft survival in highly sensitized kidney transplant recipients (PRA ≥98%). Patients who are highly sensitized from re-transplants have inferior graft survival compared with patients who are highly sensitized from other modes of sensitization. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Compliance with lifestyle recommendations in kidney allograft recipients.

PubMed

Kobus, G; Małyszko, J; Małyszko, J S; Puza, E; Bachórzewska-Gajewska, H; Myśliwiec, M

2011-10-01

Many factors affect long-term graft and patient survival. Compliance with lifestyle recommendation may be an important factor. Lifestyle modifications may play a therapeutic and protective role against graft failure and possible death. The aim of this work was to assess compliance with lifestyle recommendations among 110 kidney allograft recipients. All patients were asked to complete a questionnaire regarding life style, frequency of outpatient visits, self-control, diet, physical activity and addictions. The mean age of the population was 48.79±13.18 years, and their mean time after transplantation was 69±44.5 years with a mean serum creatinine value of 1.45±0.7 mg/dL. Physicians were the major source of information (40%) for patients while in the hospital; nurses informed patients in only 5.5% of cases. The majority of patients (97.5%) attended regular outpatient clinic visits. A similar percentage of subjects regularly measured their blood pressure at home. One-fifth of the patient wrote a self-control diary. Only 55.5% of patients knew the immunosuppressive regimen, including the doses of the medications. An overweight condition was diagnosed in 39%, with obesity in 22%; 16% of the patients were smokers; one-fourth of the patients drank alcohol at least several times a month; 85.3% of patients did not change their diet after kidney transplantation; and one-half of the patients (64.2%) were not aware of dietary recommendations after kidney transplantation. The majority of patients regularly attended the outpatient clinic and ingested immunosuppressive medications. However, their knowledge regarding diet, cancer prophylaxis, and self-control was insufficient. Therefore, there is a need to introduce more intense organizational and educational activities to improve patient knowledge. Copyright © 2011 Elsevier Inc. All rights reserved.

Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

PubMed

Kim, J K; Yuen, D A; Leung, G; Jothy, S; Zaltzman, J; Ramesh Prasad, G V; Prabhudesai, V; Mnatzakanian, G; Kirpalani, A

2017-09-01

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient. Copyright © 2017 Elsevier Inc. All rights reserved.

Utility in Treating Kidney Failure in End-Stage Liver Disease With Simultaneous Liver-Kidney Transplantation.

PubMed

Cheng, Xingxing S; Stedman, Margaret R; Chertow, Glenn M; Kim, W Ray; Tan, Jane C

2017-05-01

Simultaneous liver-kidney (SLK) transplantation plays an important role in treating kidney failure in patients with end-stage liver disease. It used 5% of deceased donor kidney transplanted in 2015. We evaluated the utility, defined as posttransplant kidney allograft lifespan, of this practice. Using data from the Scientific Registry of Transplant Recipients, we compared outcomes for all SLK transplants between January 1, 1995, and December 3, 2014, to their donor-matched kidney used in kidney-alone (Ki) or simultaneous pancreas kidney (SPK) transplants. Primary outcome was kidney allograft lifespan, defined as the time free from death or allograft failure. Secondary outcomes included death and death-censored allograft failure. We adjusted all analyses for donor, transplant, and recipient factors. The adjusted 10-year mean kidney allograft lifespan was higher in Ki/SPK compared with SLK transplants by 0.99 years in the Model for End-stage Liver Disease era and 1.71 years in the pre-Model for End-stage Liver Disease era. Death was higher in SLK recipients relative to Ki/SPK recipients: 10-year cumulative incidences 0.36 (95% confident interval 0.33-0.38) versus 0.19 (95% confident interval 0.17-0.21). SLK transplantation exemplifies the trade-off between the principles of utility and medical urgency. With each SLK transplantation, about 1 year of allograft lifespan is traded so that sicker patients, that is, SLK transplant recipients, are afforded access to the organ. These data provide a basis against which benefits derived from urgency-based allocation can be measured.

Utility in Treating Kidney Failure in End-Stage Liver Disease With Simultaneous Liver-Kidney Transplantation

PubMed Central

Cheng, Xingxing S.; Stedman, Margaret R.; Chertow, Glenn M.; Kim, W. Ray; Tan, Jane C.

2017-01-01

Background Simultaneous liver-kidney (SLK) transplantation plays an important role in treating kidney failure in patients with end-stage liver disease. It used 5% of deceased donor kidney transplanted in 2015. We evaluated the utility, defined as posttransplant kidney allograft lifespan, of this practice. Methods Using data from the Scientific Registry of Transplant Recipients, we compared outcomes for all SLK transplants between January 1, 1995, and December 3, 2014, to their donor-matched kidney used in kidney-alone (Ki) or simultaneous pancreas kidney (SPK) transplants. Primary outcome was kidney allograft lifespan, defined as the time free from death or allograft failure. Secondary outcomes included death and death-censored allograft failure. We adjusted all analyses for donor, transplant, and recipient factors. Results The adjusted 10-year mean kidney allograft lifespan was higher in Ki/SPK compared with SLK transplants by 0.99 years in the Model for End-stage Liver Disease era and 1.71 years in the pre-Model for End-stage Liver Disease era. Death was higher in SLK recipients relative to Ki/SPK recipients: 10-year cumulative incidences 0.36 (95% confident interval 0.33-0.38) versus 0.19 (95% confident interval 0.17-0.21). Conclusions SLK transplantation exemplifies the trade-off between the principles of utility and medical urgency. With each SLK transplantation, about 1 year of allograft lifespan is traded so that sicker patients, that is, SLK transplant recipients, are afforded access to the organ. These data provide a basis against which benefits derived from urgency-based allocation can be measured. PMID:28437790

Targeting Sirtuin-1 prolongs murine renal allograft survival and function

PubMed Central

Levine, Matthew H.; Wang, Zhonglin; Xiao, Haiyan; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R.; Hancock, Wayne W.; Beier, Ulf H.

2016-01-01

Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory (Treg) cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ Treg suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1 specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration. PMID:27083279

Peritransplant Soluble CD30 as a Risk Factor for Slow Kidney Allograft Function, Early Acute Rejection, Worse Long-Term Allograft Function, and Patients' Survival.

PubMed

Trailin, Andriy V; Ostapenko, Tetyana I; Nykonenko, Tamara N; Nesterenko, Svitlana N; Nykonenko, Olexandr S

2017-01-01

We aimed to determine whether serum soluble CD30 (sCD30) could identify recipients at high risk for unfavorable early and late kidney transplant outcomes. Serum sCD30 was measured on the day of kidney transplantation and on the 4th day posttransplant. We assessed the value of these measurements in predicting delayed graft function, slow graft function (SGF), acute rejection (AR), pyelonephritis, decline of allograft function after 6 months, and graft and patient survival during 5 years of follow-up in 45 recipients. We found the association between low pretransplant serum levels of sCD30 and SGF. The absence of significant decrease of sCD30 on the 4th day posttransplant was characteristic for SGF, early AR (the 8th day-6 months), late AR (>6 months), and early pyelonephritis (the 8th day-2 months). Lower pretransplant and posttransplant sCD30 predicted worse allograft function at 6 months and 2 years, respectively. Higher pretransplant sCD30 was associated with higher frequency of early AR, and worse patients' survival, but only in the recipients of deceased-donor graft. Pretransplant sCD30 also allowed to differentiate patients with early pyelonephritis and early AR. Peritransplant sCD30 is useful in identifying patients at risk for unfavorable early and late transplant outcomes.

Peritransplant Soluble CD30 as a Risk Factor for Slow Kidney Allograft Function, Early Acute Rejection, Worse Long-Term Allograft Function, and Patients' Survival

PubMed Central

Ostapenko, Tetyana I.; Nykonenko, Tamara N.; Nesterenko, Svitlana N.; Nykonenko, Olexandr S.

2017-01-01

Background We aimed to determine whether serum soluble CD30 (sCD30) could identify recipients at high risk for unfavorable early and late kidney transplant outcomes. Methods Serum sCD30 was measured on the day of kidney transplantation and on the 4th day posttransplant. We assessed the value of these measurements in predicting delayed graft function, slow graft function (SGF), acute rejection (AR), pyelonephritis, decline of allograft function after 6 months, and graft and patient survival during 5 years of follow-up in 45 recipients. Results We found the association between low pretransplant serum levels of sCD30 and SGF. The absence of significant decrease of sCD30 on the 4th day posttransplant was characteristic for SGF, early AR (the 8th day–6 months), late AR (>6 months), and early pyelonephritis (the 8th day–2 months). Lower pretransplant and posttransplant sCD30 predicted worse allograft function at 6 months and 2 years, respectively. Higher pretransplant sCD30 was associated with higher frequency of early AR, and worse patients' survival, but only in the recipients of deceased-donor graft. Pretransplant sCD30 also allowed to differentiate patients with early pyelonephritis and early AR. Conclusions Peritransplant sCD30 is useful in identifying patients at risk for unfavorable early and late transplant outcomes. PMID:28694560

Pre-transplant and post-transplant soluble CD30 for prediction and diagnosis of acute kidney allograft rejection.

PubMed

Nafar, Mohsen; Farrokhi, Farhat; Vaezi, Mohammad; Entezari, Amir-Ebrahim; Pour-Reza-Gholi, Fatemeh; Firoozan, Ahmad; Eniollahi, Behzad

2009-01-01

Serum levels of soluble CD30 (sCD30) have been considered as a predictor of acute kidney allograft rejection. We have evaluated the pre-transplant and post-transplant levels of sCD30 with the aim of determining its value in predicting and diagnosing kidney rejection. We measured sCD30 serum levels before kidney transplantation, 5 days post-operatively, and at creatinine elevation episodes. The predictive value of sCD30 for diagnosing acute rejection (AR) within the first 6 post-operative months was assessed in 203 kidney recipients from living donors. Pre-transplant and post-operative levels of serum sCD30 were 58.10 +/- 52.55 and 51.55 +/- 49.65 U/ml, respectively (P = 0.12). Twenty-three patients experienced biopsy-proven acute rejection, and 28 had acute allograft dysfunction due to non-immunologic diseases. The pre-transplant sCD30 level was not different between patients with and without AR. However, post-transplant sCD30 was higher in the AR group. The median serum level of post-transplant sCD30 was 52 U/ml in the AR group and 26.3 U/ml in a control group (P < 0.001). The relative changes of sCD30 on day 5 were higher in patients with AR (P = 0.003). Based on post-transplant sCD30 levels, we were able to differentiate between kidney recipients who experienced an AR within 6 months post-surgery and those without an AR (cutoff value 41 U/ml; sensitivity 70%; specificity 71.7%). The level of sCD30 during periods of elevated serum creatinine was not independently associated with the diagnosis of AR. Post-transplant sCD30 levels and their relative changes are higher in patients experiencing AR. We propose further studies on the post-transplant trend of this marker for the prediction of AR.

Do Alloreactivity and Prolonged Cold Ischemia Cause Different Elementary Lesions in Chronic Allograft Nephropathy?

PubMed Central

Herrero-Fresneda, Immaculada; Torras, Joan; Cruzado, Josep M.; Condom, Enric; Vidal, August; Riera, Marta; Lloberas, Nuria; Alsina, Jeroni; Grinyo, Josep M.

2003-01-01

This study assesses the individual contributions of the nonalloreactive factor, cold ischemia (CI), and alloreactivity to late functional and structural renal graft changes, and examines the effect of the association of both factors on the progression of chronic allograft nephropathy. Lewis rats acted as receptors of kidneys from either Lewis or Fischer rats. For CI, kidneys were preserved for 5 hours. The rats were divided into four groups: Syn, syngeneic graft; SynI, syngeneic graft and CI; Allo, allogeneic graft; AlloI, allogeneic graft and CI. Renal function was assessed every 4 weeks for 24 weeks. Grafts were evaluated for acute inflammatory response at 1 week and for chronic histological damage at 24 weeks. Only when CI and allogenicity were combined did immediate posttransplant mortality occur, while survivors showed accelerated renal insufficiency that induced further mortality at 12 weeks after transplant. Solely ischemic rats developed renal insufficiency. Renal structural damage in ischemic rats was clearly tubulointerstitial, while significant vasculopathy and glomerulosclerosis appeared only in the allogeneic groups. There was increased infiltration of macrophages and expression of mRNA-transforming growth factor-β1 in the ischemic groups, irrespective of the allogeneic background. The joint association of CI plus allogenicity significantly increased cellular infiltration at both early and late stages, aggravating tubulointerstitial and vascular damage considerably. In summary, CI is mainly responsible for tubulointerstitial damage, whereas allogenicity leads to vascular lesion. The association of both factors accelerates and aggravates the progression of experimental chronic allograft nephropathy. PMID:12507896

Estrogens and progression of diabetic kidney damage.

PubMed

Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Elliot, Sharon J

2011-01-01

It is generally accepted that estrogens affect and modulate the development and progression of chronic kidney diseases (CKD) not related to diabetes. Clinical studies have indeed demonstrated that the severity and rate of progression of renal damage tends to be greater among men, compared with women. Experimental studies also support the notion that female sex is protective and male sex permissive, for the development of CKD in non-diabetics, through the opposing actions of estrogens and testosterone. However, when we consider diabetes-induced kidney damage, in the setting of either type 1 or type 2 diabetes, the contribution of gender to the progression of renal disease is somewhat uncertain. Previous studies on the effects of estrogens in the pathogenesis of progressive kidney damage have primarily focused on mesangial cells. More recently, data on the effects of estrogens on podocytes, the cell type whose role may include initiation of progressive diabetic renal disease, became available. The aim of this review will be to summarize the main clinical and experimental data on the effects of estrogens on the progression of diabetes-induced kidney injury. In particular, we will highlight the possible biological effects of estrogens on podocytes, especially considering those critical for the pathogenesis of diabetic kidney damage.

Variation in Dialysis Exposure Prior to Nonpreemptive Living Donor Kidney Transplantation in the United States and Its Association With Allograft Outcomes.

PubMed

Gill, John S; Rose, Caren; Joffres, Yayuk; Landsberg, David; Gill, Jagbir

2018-05-01

The impact of dialysis exposure before nonpreemptive living donor kidney transplantation on allograft outcomes is uncertain. Retrospective cohort study. Adult first-time recipients of kidney-only living donor transplants in the United States who were recorded within the Scientific Registry of Transplant Recipients for 2000 to 2016. Duration of pretransplantation dialysis exposure. Kidney transplant failure from any cause including death, death-censored transplant failure, and death with allograft function. Among the 77,607 living donor transplant recipients studied, longer pretransplantation dialysis exposure was independently associated with progressively higher risk for transplant failure from any cause, including death beginning 6 months after transplantation. Compared with patients with 0.1 to 3.0 months of dialysis exposure, the HR for transplant failure from any cause including death increased from 1.16 (95% CI, 1.07-1.31) among patients with 6.1 to 9.0 months of dialysis exposure to 1.60 (95% CI, 1.43-1.79) among patients with more than 60.0 months of dialysis exposure. Pretransplantation dialysis exposure varied markedly among centers; median exposures were 11.0 and 18.9 months for centers in the 10th and 90th percentiles of dialysis exposure, respectively. Centers with the highest proportions of living donor transplantations had the shortest pretransplantation dialysis exposures. In multivariable analysis, patients of black race, with low income, with nonprivate insurance, with less than high school education, and not working for income had longer pretransplantation dialysis exposures. Dialysis exposure in patients with these characteristics also varied 2-fold between transplantation centers. Why longer dialysis exposure is associated with transplant failure could not be determined. Longer pretransplantation dialysis exposure in nonpreemptive living donor kidney transplantation is associated with increased risk for allograft failure. Pretransplantation

Spectroscopic photoacoustics for assessing ischemic kidney damage

NASA Astrophysics Data System (ADS)

Berndl, Elizabeth S. L.; He, Xiaolin; Yuen, Darren A.; Kolios, Michael C.

2018-02-01

Ischemic reperfusion injuries (IRIs) are caused by return of blood to a tissue or organ after a period without oxygen or nutrients. Damage in the microvasculature causes an inflammatory response and heterogeneous scarring, which is associated with an increase in collagen in the extracellular matrix. Although most often associated with heart attacks and strokes, IRI also occurs when blood reperfuses a transplanted organ. Currently, monitoring for IRI is limited to biopsies, which are invasive and sample a limited area. In this work, we explored photoacoustic (PA) biomarkers of scarring. IRI events were induced in mice (n=2) by clamping the left renal artery, then re-establishing flow. At 53 days post-surgery, kidneys were saline perfused and cut in half laterally. One half was immediately imaged with a VevoX system (Fujifilm-VisualSonics, Toronto) in two near infrared ranges - 680 to 970 nm (NIR), and 1200 to 1350 nm (NIR II). The other half was decellularized and then imaged at NIR and NIR II. Regions of interest were manually identified and analyzed for each kidney. For both cellularized and decellularized samples, the PA signal ratio based on irradiation wavelengths of 715:930 nm was higher in damaged kidneys than for undamaged kidneys (p < 0.0001 for both). Damaged kidneys had ROIs with spectra indicating the presence of collagen in the NIR II range, while healthy kidneys did not. Collagen rich spectra were more apparent in decellularized kidneys, suggesting that in the cellularized samples, other components may be contributing to the signal. PA imaging using spectral ratios associated with collagen signatures may provide a non-invasive tool to determine areas of tissue damage due to IRIs.

Treatment options for renal cell carcinoma in renal allografts: a case series from a single institution.

PubMed

Swords, Darden C; Al-Geizawi, Samer M; Farney, Alan C; Rogers, Jeffrey; Burkart, John M; Assimos, Dean G; Stratta, Robert J

2013-01-01

Renal cell carcinoma (RCC) is more common in renal transplant and dialysis patients than the general population. However, RCC in transplanted kidneys is rare, and treatment has previously consisted of nephrectomy with a return to dialysis. There has been recent interest in nephron-sparing procedures as a treatment option for RCC in allograft kidneys in an effort to retain allograft function. Four patients with RCC in allograft kidneys were treated with nephrectomy, partial nephrectomy, or radiofrequency ablation. All of the patients are without evidence of recurrence of RCC after treatment. We found nephron-sparing procedures to be reasonable initial options in managing incidental RCCs diagnosed in functioning allografts to maintain an improved quality of life and avoid immediate dialysis compared with radical nephrectomy of a functioning allograft. However, in non-functioning renal allografts, radical nephrectomy may allow for a higher chance of cure without the loss of transplant function. Consequently, radical nephrectomy should be utilized whenever the allograft is non-functioning and the patient's surgical risk is not prohibitive. © 2013 John Wiley & Sons A/S.

Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.

PubMed

Freedman, B I; Julian, B A; Pastan, S O; Israni, A K; Schladt, D; Gautreaux, M D; Hauptfeld, V; Bray, R A; Gebel, H M; Kirk, A D; Gaston, R S; Rogers, J; Farney, A C; Orlando, G; Stratta, R J; Mohan, S; Ma, L; Langefeld, C D; Hicks, P J; Palmer, N D; Adams, P L; Palanisamy, A; Reeves-Daniel, A M; Divers, J

2015-06-01

Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Renal Allograft Outcome After Simultaneous Heart and Kidney Transplantation.

PubMed

Grupper, Avishay; Grupper, Ayelet; Daly, Richard C; Pereira, Naveen L; Hathcock, Matthew A; Kremers, Walter K; Cosio, Fernando G; Edwards, Brooks S; Kushwaha, Sudhir S

2017-08-01

Chronic kidney disease frequently accompanies end-stage heart failure and may result in consideration of simultaneous heart and kidney transplantation (SHKT). In recent years, there has been a significant increase in SHKT. This single-center cohort consisted of 35 patients who underwent SHKT during 1996 to 2015. The aim of this study was to review factors that may predict better long-term outcome after SKHT. Thirteen patients (37%) had delayed graft function (DGF) after transplant (defined as the need for dialysis during the first 7 days after transplant), which was significantly associated with mechanical circulatory support device therapy and high right ventricular systolic pressure before transplant. Most of the recipients had glomerular filtration rate (GFR) ≥50 ml/min/1.73 m 2 at 1 and 3 years after transplant (21 of 26 [81%] and 20 of 21 [95%], respectively). Higher donor age was associated with reduced 1-year GFR (p = 0.017), and higher recipient pretransplant body mass index was associated with reduced 3-year GFR (p = 0.008). There was a significant association between DGF and reduced median GFR at 1 and 3 years after transplant (p <0.005). Patient survival rates at 6 months, 1, and 3 years after transplant were 97%, 91%, and 86% respectively. In conclusions, our data support good outcomes after SHKT. Mechanical circulatory support device therapy and pulmonary hypertension before transplant are associated with DGF, which is a risk factor for poor long-term renal allograft function. Copyright © 2017 Elsevier Inc. All rights reserved.

Incidental kidney stones: a single center experience with kidney donor selection

PubMed Central

Kim, Irene K.; Tan, Jane C.; Lapasia, Jessica; Elihu, Arvand; Busque, Stephan; Melcher, Marc L.

2014-01-01

The presence of kidney stones has been a relative contraindication for living donation. With the widespread use of more sensitive imaging techniques as part of the routine living donor workup, kidney stones are more frequently detected, and their clinical significance in this setting is largely unknown. Records from 325 potential kidney donors who underwent MRA or CT-angiography were reviewed; 294 proceeded to donation. The prevalence of kidney stones found incidentally during donor evaluation was 7.4% (24 of 325). Sixteen donors with stones proceeded with kidney donation. All incidental calculi were nonobstructing and small (median 2 mm; range 1–9 mm). Eleven recipients were transplanted with allografts containing stones. One recipient developed symptomatic nephrolithasis after transplantation. This recipient was found to have newly formed stones secondary to hyperoxaluria, suggesting a recipient-driven propensity for stone formation. The remaining ten recipients have stable graft function, postoperative ultrasound negative for nephrolithiasis, and no sequelae from stones. No donor developed symptomatic nephrolithiasis following donation. Judicious use of allografts with small stones in donors with normal metabolic studies may be acceptable, and careful follow-up in recipients of such allografts is warranted. PMID:22168332

Survival of Kidney Allograft of Donors after Circulatory Death Is Similar to Donors after Brain Death: Experience in a Regional Program.

PubMed

Gentil, M A; Castro, P; Ballesteros, L; Gracia-Guindo, M C; Cabello, M; Mazuecos, M A; Rodriguez-Benot, A; Gonzalez-Corvillo, C; Borrego, J; Ortega, A O; Alonso, M

2015-11-01

Donors after circulatory death (DCD) are an increasingly crucial source of organs to maintain deceased donor kidney transplant activity when faced with a standstill in donors after brain death (DBD). We analyzed the influence on graft survival since the use of DCD organs was implemented in Andalusia (2010-2014). We compared 164 kidney transplants from DCD (83 Maastricht type II and 81 type III) and 1488 DBD transplants in recipients over the age of 18, excluding combined transplants. DCD were more frequently men from the A blood group who were younger (48.9 ± 11 vs 55.2 ± 15 years old for DBD, P < .001). Kidneys from DCD were implanted in younger recipients (51.2 ± 11 vs 53.5 ± 13 years old for DBD, P = .03), more frequently in men from blood group A who spent less time in renal replacement therapy (39.8 vs 51.5 months), in a lower proportion of immunized recipients and re-transplant patients, and had worse HLA-DR compatibility. DCD presented a proportion of primary nonfunctional allografts and an initial need for dialysis of 8.8% and 69.6% vs 5.5% and 29.6% for DBD (P < .001). DCD allograft recipient survival was 96% and 96% at the first and third year respectively, vs 96% and 93% with a DBD graft (NS). Survival of the graft was 91% and 86% at the 1(st) and 3(rd) years, vs 90% and 86% with a DBD allograft (NS). No significant difference was found between Maastricht type II and III. DCD were related to lower graft survival versus DBD under the age of 50 (n = 445), 86% vs 92% (P = .02) in the third year, but were similar to DBD from age 50 to 59 (n = 407) and higher than DBD over age 60 (n = 636), 80% at the 3(rd) year (NS). The survival of DCD recipients was not different than DBD in those under 60 and was significantly better than DBD at or over the age of 60 (96% vs 87% in the 3(rd) year, P = .036). In the multivariable survival study (Cox, covariates of influence previously demonstrated in our region) DCD are not a significant survival prognosis

MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao

Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, andmore » chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.« less

Poly[ADP-ribose] polymerase-1 expression is related to cold ischemia, acute tubular necrosis, and delayed renal function in kidney transplantation.

PubMed

O'Valle, Francisco; Del Moral, Raimundo G M; Benítez, María del Carmén; Martín-Oliva, David; Gómez-Morales, Mercedes; Aguilar, David; Aneiros-Fernández, José; Hernández-Cortés, Pedro; Osuna, Antonio; Moreso, Francesc; Serón, Daniel; Oliver, Francisco J; Del Moral, Raimundo G

2009-09-28

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN). Nuclear PARP-1 immunohistochemical expression was studied in 326 paraffin-embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury. PARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p = 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function.

Cyclosporine A and azathioprine are equipotent in chronic kidney allograft rejection.

PubMed

Hamar, P; Liu, S; Viklický, O; Szabó, A; Múller, V; Heemann, U

2000-04-15

Chronic rejection is the major cause of graft loss after kidney transplantation. Various immunosuppressive protocols have been used to ameliorate this process. We investigated whether cyclosporin A- (CyA) or azathioprine- (Aza) based immunosuppression is better able to slow the progression of chronic rejection. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats. Recipients received CyA (1.5 mg/kg/day, s.c.) for 10 days, and were treated from day 11 with either CyA (1.5 mg/kg)+pred (0.15 mg/kg) (C+P),Aza (2 mg/kg)+pred (A+P), vehicle+pred (P), or vehicle alone (controls) (n = 8/group). Proteinuria was regularly assessed and grafts were harvested for morphological, immunohistological, and molecular biological analysis at week 24. By week 12 proteinuria had increased to significant levels. At week 24, proteinuria was significantly lower and creatinine clearance was significantly higher in C+P and A+P, than in P or controls. Morphological analysis supported these functional results: at week 24, glomerulopathy, tubular atrophy and intimal proliferation (as assessed according to the BANFF score) were less pronounced in C+P and A+P, as compared with P or controls. These morphological parameters were accompanied by a reduced infiltration of ED-1+ macrophages and CD-5+ T lymphocytes. In P or controls the synthesis of IL-2Ralpha mRNA was markedly elevated at this time. In parallel to the reduced cellular infiltration, IL-2Ralpha mRNA expression was markedly inhibited, both, in C+P and A+P. There were no significant differences between C+P and A+P regarding the parameters studied. In conclusion, both C+P and A+P reduced the infiltration of activated T lymphocytes, and the pace of chronic kidney allograft rejection. The outcome of C+P and A+P based therapy did not differ significantly.

Pre-Treatment with Curcumin Ameliorates Cisplatin-Induced Kidney Damage by Suppressing Kidney Inflammation and Apoptosis in Rats.

PubMed

Soetikno, Vivian; Sari, Shinta Dewi Permata; Ul Maknun, Lulu; Sumbung, Nielda Kezia; Rahmi, Deliana Nur Ihsani; Pandhita, Bashar Adi Wahyu; Louisa, Melva; Estuningtyas, Ari

2018-06-26

In addition to oxidative stress, inflammation and apoptosis have an important role in the pathogenesis of cisplatin-induced kidney damage. This study aimed to investigate the molecular mechanisms of protective effects of curcumin against cisplatin-induced kidney inflammation and apoptosis in rats. Eighteen rats were equally divided into three groups; normal (0.5% CMC-Na), cisplatin (CDPP) (7 mg/kg i.p.), and cisplatin+curcumin (CMN100) groups. Curcumin was given at a dose of 100 mg/kg orally for nine days, starts one week before giving a single dose of cisplatin. Kidney and plasma were taken for analysis. Cisplatin challenged rats demonstrated kidney injury as shown by reduced creatinine clearance, increased of plasma BUN, plasma creatinine, and kidney MDA, decreased of kidney GSH levels, and kidney histopathology alterations. Also, cisplatin increased ERK1/2 phosphorylation and NF-κB expression, which subsequently increased mRNA expression of TNF-α, IL-6, KIM-1, NGAL, and Bax/Bcl-2 ratio as well as decreased mRNA expression of IL-10 in kidney tissues. Pre-treatment with curcumin significantly ameliorated inflammation and apoptosis induced by cisplatin. In addition, curcumin downregulated Ctr1 and OCT2 drug transporters as compared to cisplatin group. Histopathological examination furthers confirmed the kidney damage protection effect of curcumin. These data indicate that curcumin has nephroprotective properties against cisplatin-induced kidney damage in rats and this effect is associated with its anti-inflammatory and anti-apoptosis profiles, in addition to its antioxidant. Hence, curcumin may be useful for preventing kidney damage against cisplatin administration. © Georg Thieme Verlag KG Stuttgart · New York.

Expression of GSK-3β in renal allograft tissue and its significance in pathogenesis of chronic allograft dysfunction.

PubMed

Yan, Qiang; Wang, Baoyao; Sui, Weiguo; Zou, Guimian; Chen, Huaizhou; Xie, Shenping; Zou, Hequn

2012-01-13

To explore the expression of Glycogen synthase kinase 3 beta (GSK-3β) in renal allograft tissue and its significance in the pathogenesis of chronic allograft dysfunction. Renal allograft biopsy was performed in all of the renal allograft recipients with proteinuria or increased serum creatinine level who came into our hospital from January 2007 to December 2009. Among them 28 cases was diagnosed as chronic allograft dysfunction based on pahtological observation, including 21 males with a mean age of 45 ± 10 years old and 7 females with a mean age of 42 ± 9 years old. The time from kidney transplantation to biopsy were 1-9 (3.5) years. Their serum creatinine level were 206 ± 122 umol/L. Immunohistochemical assay and computer-assisted genuine color image analysis system (imagepro-plus 6.0) were used to detect the expression of GSK-3β in the renal allografts of 28 cases of recipients with chronic allograft dysfunction. Mean area and mean integrated optical density of GSK-3β expression were calculated. The relationship between expression level of GSK-3β and either the grade of inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft was analyzed. Five specimens of healthy renal tissue were used as controls. The expression level of the GSK-3β was significantly increased in the renal allograft tissue of recipients with chronic allograft dysfunction, compared to normal renal tissues, and GSK-3β expression became stronger along with the increasing of the grade of either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy in renal allograft tissue. There might be a positive correlation between either inflammatory cell infiltration or interstitial fibrosis/tubular atrophy and high GSK-3β expression in renal allograft tissue. The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/9924478946162998.

Functional MRI detects perfusion impairment in renal allografts with delayed graft function.

PubMed

Hueper, Katja; Gueler, Faikah; Bräsen, Jan Hinrich; Gutberlet, Marcel; Jang, Mi-Sun; Lehner, Frank; Richter, Nicolas; Hanke, Nils; Peperhove, Matti; Martirosian, Petros; Tewes, Susanne; Vo Chieu, Van Dai; Großhennig, Anika; Haller, Hermann; Wacker, Frank; Gwinner, Wilfried; Hartung, Dagmar

2015-06-15

Delayed graft function (DGF) after kidney transplantation is not uncommon, and it is associated with long-term allograft impairment. Our aim was to compare renal perfusion changes measured with noninvasive functional MRI in patients early after kidney transplantation to renal function and allograft histology in biopsy samples. Forty-six patients underwent MRI 4-11 days after transplantation. Contrast-free MRI renal perfusion images were acquired using an arterial spin labeling technique. Renal function was assessed by estimated glomerular filtration rate (eGFR), and renal biopsies were performed when indicated within 5 days of MRI. Twenty-six of 46 patients had DGF. Of these, nine patients had acute rejection (including borderline), and eight had other changes (e.g., tubular injury or glomerulosclerosis). Renal perfusion was significantly lower in the DGF group compared with the group with good allograft function (231 ± 15 vs. 331 ± 15 ml·min(-1)·100 g(-1), P < 0.001). Living donor allografts exhibited significantly higher perfusion values compared with deceased donor allografts (P < 0.001). Renal perfusion significantly correlated with eGFR (r = 0.64, P < 0.001), resistance index (r = -0.57, P < 0.001), and cold ischemia time (r = -0.48, P < 0.01). Furthermore, renal perfusion impairment early after transplantation predicted inferior renal outcome and graft loss. In conclusion, noninvasive functional MRI detects renal perfusion impairment early after kidney transplantation in patients with DGF. Copyright © 2015 the American Physiological Society.

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

PubMed

Freedman, Barry I; Pastan, Stephen O; Israni, Ajay K; Schladt, David; Julian, Bruce A; Gautreaux, Michael D; Hauptfeld, Vera; Bray, Robert A; Gebel, Howard M; Kirk, Allan D; Gaston, Robert S; Rogers, Jeffrey; Farney, Alan C; Orlando, Giuseppe; Stratta, Robert J; Mohan, Sumit; Ma, Lijun; Langefeld, Carl D; Bowden, Donald W; Hicks, Pamela J; Palmer, Nicholette D; Palanisamy, Amudha; Reeves-Daniel, Amber M; Brown, W Mark; Divers, Jasmin

2016-01-01

Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors. The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed. Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant. Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Poly[ADP-Ribose] Polymerase-1 Expression Is Related To Cold Ischemia, Acute Tubular Necrosis, and Delayed Renal Function In Kidney Transplantation

PubMed Central

O'Valle, Francisco; Del Moral, Raimundo G. M.; Benítez, María del Carmén; Martín-Oliva, David; Gómez-Morales, Mercedes; Aguilar, David; Aneiros-Fernández, José; Hernández-Cortés, Pedro; Osuna, Antonio; Moreso, Francesc; Serón, Daniel; Oliver, Francisco J.; Del Moral, Raimundo G.

2009-01-01

Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN). Materials and Methods Nuclear PARP-1 immunohistochemical expression was studied in 326 paraffin-embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury. Results PARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p = 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function. PMID:19784367

Integrated Kidney Exosome Analysis for the Detection of Kidney Transplant Rejection.

PubMed

Park, Jongmin; Lin, Hsing-Ying; Assaker, Jean Pierre; Jeong, Sangmoo; Huang, Chen-Han; Kurdi, A; Lee, Kyungheon; Fraser, Kyle; Min, Changwook; Eskandari, Siawosh; Routray, Sujit; Tannous, Bakhos; Abdi, Reza; Riella, Leonardo; Chandraker, Anil; Castro, Cesar M; Weissleder, Ralph; Lee, Hakho; Azzi, Jamil R

2017-11-28

Kidney transplant patients require life-long surveillance to detect allograft rejection. Repeated biopsy, albeit the clinical gold standard, is an invasive procedure with the risk of complications and comparatively high cost. Conversely, serum creatinine or urinary proteins are noninvasive alternatives but are late markers with low specificity. We report a urine-based platform to detect kidney transplant rejection. Termed iKEA (integrated kidney exosome analysis), the approach detects extracellular vesicles (EVs) released by immune cells into urine; we reasoned that T cells, attacking kidney allografts, would shed EVs, which in turn can be used as a surrogate marker for inflammation. We optimized iKEA to detect T-cell-derived EVs and implemented a portable sensing system. When applied to clinical urine samples, iKEA revealed high level of CD3-positive EVs in kidney rejection patients and achieved high detection accuracy (91.1%). Fast, noninvasive, and cost-effective, iKEA could offer new opportunities in managing transplant recipients, perhaps even in a home setting.

HEMATOPOIETIC STEM CELL INFUSION/TRANSPLANTATION FOR INDUCTION OF ALLOGRAFT TOLERANCE

PubMed Central

Granados, Jose M. Marino; Benichou, Gilles; Kawai, Tatsuo

2015-01-01

Purpose of review This review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent findings Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Summary Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, as well as to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications. PMID:25563992

Clinical utility of histological features of polyomavirus allograft nephropathy.

PubMed

Gaber, Lillian W; Egidi, M Francesca; Stratta, Robert J; Lo, Agnes; Moore, Linda W; Gaber, A Osama

2006-07-27

The purpose of this study was to determine if histological features of polyomavirus allograft nephropathy (PVAN) are associated with the clinical presentation and outcomes of PVAN. We examined the histological features of initial and follow-up biopsies of 20 kidney and kidney-pancreas transplant recipients with PVAN during a time prior to routine surveillance. The subjects' demographics, clinical characteristics, and outcomes were compared based upon classification of histological features of PVAN on initial biopsy. Diabetes mellitus (45%) and a history of tacrolimus-induced nephrotoxicity (35%) appeared to be prevalent in subjects with PVAN. Although histological severity of PVAN did not predict or correlate with the clinical course of PVAN, subjects with pattern C on initial PVAN biopsy presented later posttransplant, had higher serum creatinine level at presentation, and had significant allograft deterioration at follow-up than subjects with either pattern A or B on initial biopsy. Resolution of PVAN was noted in 60% of follow-up biopsies and occurred more frequently in subjects with pattern B on initial biopsy. Most subjects developed chronic allograft nephropathy after PVAN and viral clearance did not abrogate the progression to chronic allograft nephropathy. These data indicate that histologic patterns of PVAN may have clinical correlation to disease presentation and prognosis.

Histomorphological Assessment of Phlebitis in Renal Allografts

PubMed Central

Jurčić, Vesna; Jeruc, Jera; Marić, Stela; Ferluga, Dušan

2007-01-01

Aim To evaluate the histomorphological features of veins in normal and transplanted kidneys. Methods Between 1992 and 1997 at the Institute of Pathology in Ljubljana, we semiquantitatively evaluated histomorphological changes in veins in nephrectomy specimens of 29 renal allografts with rejection and in 31 control kidneys. The structure of different segments of renal veins was additionally analyzed. Results Small interlobular veins were composed of endothelium and basement membrane, similar to capillaries, while the walls of large interlobular and arcuate veins had smooth muscle cell bundles forming the medial layer, similar to large extrarenal veins. In the control group, only focal mononuclear infiltration around small interlobular veins was found (8/31). In rejected kidney allografts, the veins were frequently infiltrated with inflammatory cells, predominantly T lymphocytes and macrophages (29/29). Other changes included thrombosis (16/29), fibrinoid necrosis (7/29), and sclerosis (9/29), and in one case an intimal lipid deposition. Conclusion This study, performed on whole explanted kidney specimens, revealed that rejection vasculitis often involved extrarenal and intrarenal veins, showing a whole spectrum of histopathological changes similar to those in arteries. Since large intrarenal veins have a muscle wall, we believe that the term »rejection phlebitis« could be used in renal transplant pathology. PMID:17589975

Urinary Angiogenin Reflects the Magnitude of Kidney Injury at the Infrahistologic Level

PubMed Central

Tavernier, Quentin; Mami, Iadh; Rabant, Marion; Karras, Alexandre; Laurent-Puig, Pierre; Chevet, Eric; Thervet, Eric; Anglicheau, Dany

2017-01-01

The ribonuclease angiogenin is a component of the mammalian stress response that is secreted by renal epithelial cells on activation of the inositol–requiring enzyme 1α (IRE1α)–active spliced X–box binding protein 1 (sXBP1) axis and instrumental to the adaptation to AKI associated with endoplasmic reticulum stress. To determine whether the amount of angiogenin in urine of individuals with a kidney injury reflects the magnitude of the lesions and provides information on the risk of organ failure, we examined individuals referred for a kidney injury and determined the biochemical characteristics of urinary angiogenin and its diagnostic and prognostic values. Urinary angiogenin did not correlate with the urinary concentrations of high molecular weight proteins and correlated only weakly with low molecular weight proteins, suggestive of tubular production. In a cohort of 242 kidney transplant recipients with acute allograft dysfunction, higher urinary angiogenin concentrations at the time of the biopsy associated with worse renal function and higher proteinuria but did not correlate with histologic lesions as defined in the Banff classification. Kidney transplant recipients with urinary angiogenin amounts in the highest 50% had a risk of graft failure 3.59 times as high (95% confidence interval, 1.12 to 15.94) as that of patients with amounts in the lowest 50%. Finally, the amount of urinary angiogenin reflected the activity of the IRE1α-XBP1 axis in allografts. Our approach identified urinary angiogenin as a noninvasive indicator of the extent of tissue damage, independent of the histologic lesions, and a risk predictor of kidney allograft failure. PMID:27436854

Allograft replacement for absent native tissue.

PubMed

Chaudhury, Salma; Wanivenhaus, Florian; Fox, Alice J; Warren, Russell F; Doyle, Maureen; Rodeo, Scott A

2013-03-01

Structural instability due to poor soft tissue quality often requires augmentation. Allografts are important biological substitutes that are used for the symptomatic patient in the reconstruction of deficient ligaments, tendons, menisci, and osteochondral defects. Interest in the clinical application of allografts has arisen from the demand to obtain stable anatomy with restoration of function and protection against additional injury, particularly for high-demand patients who participate in sports. Traditionally, allografts were employed to reinforce weakened tissue. However, they can also be employed to substitute deficient or functionally absent tissue, particularly in the sports medicine setting. This article presents a series of 6 cases that utilized allografts to restore functionally deficient anatomic architecture, rather than just simply augmenting the degenerated or damaged native tissue. Detailed discussions are presented of the use of allografts as a successful treatment strategy to replace functionally weakened tissue, often after failed primary repairs.

Allograft Replacement for Absent Native Tissue

PubMed Central

Chaudhury, Salma; Wanivenhaus, Florian; Fox, Alice J.; Warren, Russell F.; Doyle, Maureen; Rodeo, Scott A.

2013-01-01

Context: Structural instability due to poor soft tissue quality often requires augmentation. Allografts are important biological substitutes that are used for the symptomatic patient in the reconstruction of deficient ligaments, tendons, menisci, and osteochondral defects. Interest in the clinical application of allografts has arisen from the demand to obtain stable anatomy with restoration of function and protection against additional injury, particularly for high-demand patients who participate in sports. Traditionally, allografts were employed to reinforce weakened tissue. However, they can also be employed to substitute deficient or functionally absent tissue, particularly in the sports medicine setting. Objective: This article presents a series of 6 cases that utilized allografts to restore functionally deficient anatomic architecture, rather than just simply augmenting the degenerated or damaged native tissue. Detailed discussions are presented of the use of allografts as a successful treatment strategy to replace functionally weakened tissue, often after failed primary repairs. PMID:24427387

Early application of Met-RANTES ameliorates chronic allograft nephropathy.

PubMed

Song, Erwei; Zou, Hequn; Yao, Yousheng; Proudfoot, Amanda; Antus, Balazs; Liu, Shanying; Jens, Lutz; Heemann, Uwe

2002-02-01

Initial insults to kidney allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to chronic allograft nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal allografts from long-term deterioration. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 microg/day, 200 microg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis. Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-B (PDGF-B). Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

Clinical Courses of Graft Failure Caused by Chronic Allograft Dysfunction in Kidney Transplantation.

PubMed

Fujiwara, T; Teruta, S; Tsudaka, S; Ota, K; Matsuda, H

Chronic allograft dysfunction (CAD) is a main cause of graft failure in kidney transplantation. We retrospectively analyzed 279 kidney transplant recipients who survived with a functioning graft for at least 2 years. CAD was defined as chronic graft deterioration, excluding other specific causes. We defined the pattern of decline in estimated glomerular filtration rate (eGFR), as follows: (1) "plateau" was defined as decline in eGFR ≤2 mL/min/1.73 m 2 /year; "long plateaus" were those lasting more than 5 years; (2) "rapid decline" was a decrease in eGFR ≥20 mL/min/1.73 m 2 /year. Patients diagnosed with CAD were categorized according to the occurrence of rapid decline and/or long plateau as follows: group 1, neither rapid decline nor long plateau; group 2, rapid decline only; group 3, long plateau only; and group 4, both rapid decline and long plateau. From a total of 81 graft losses, 51 (63%) failed because of CAD, with a median of 9.4 years. Sixteen patients belonged to group 1, 14 to group 2, 12 to group 3, and nine to group 4. Mean graft survival times in the four groups were 7.7 ± 1.1, 6.1 ± 3.1, 16.2 ± 2.5, and 10.8 ± 3.6 years, respectively (P < .001). There were significant differences among groups in donor age, year of transplantation, mean eGFR at baseline, and acute rejection rate after transplantation. The results indicate that this cohort of kidney transplant recipients who had CAD comprised subgroups with different clinical courses. Copyright © 2016 Elsevier Inc. All rights reserved.

Sulphonylurea drugs reduce hypoxic damage in the isolated perfused rat kidney.

PubMed

Engbersen, R; Moons, M M; Wouterse, A C; Dijkman, H B; Kramers, C; Smits, P; Russel, F G

2000-08-01

Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3+/-1.5 for hypoxic perfusions vs 4.9+/-1.6 for normoxic perfusions, mean +/- s.e. mean, P<0.05), which could be completely restored by 200 microM tolbutamide (5.7+/-0.4 for tolbutamide vs 14.3+/-1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220+/-100 mU for tolbutamide vs. 1220+/-160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 microM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations.

Ischemic acute kidney injury and klotho in renal transplantation.

PubMed

Panah, Fatemeh; Ghorbanihaghjo, Amir; Argani, Hassan; Asadi Zarmehri, Maryam; Nazari Soltan Ahmad, Saeed

2018-05-01

Post-transplant ischemic acute kidney injury (AKI), secondary to ischemia reperfusion injury (IRI), is a major problem influencing on the short and long term graft and patient survival. Many molecular and cellular modifications are observed during IRI, for example, tissue damage result production of reactive oxygen species (ROS), cytokines, chemokines, and leukocytes recruitment which are activated by NF-κB (nuclear factor kappa B) signaling pathway. Therefore, inhibiting these processes can significantly protect renal parenchyma from tissue damage. Klotho protein, mainly produced in distal convoluted tubules (DCT), is an anti-senescence protein. There is increasing evidence to confirm a relationship between Klotho levels and renal allograft function. Many studies have also demonstrated that expression of the Klotho gene would be down regulated with IRI, so it will be used as an early biomarker for acute kidney injury after renal transplantation. Other studies suggest that Klotho may have a renoprotective effect for attenuating of kidney injury. In this review, we will discuss pathophysiology of IRI-induced acute kidney injury and its relation with klotho level in renal transplantation procedure. Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Aβ Damages Learning and Memory in Alzheimer's Disease Rats with Kidney-Yang Deficiency

PubMed Central

Qi, Dongmei; Qiao, Yongfa; Zhang, Xin; Yu, Huijuan; Cheng, Bin; Qiao, Haifa

2012-01-01

Previous studies demonstrated that Alzheimer's disease was considered as the consequence produced by deficiency of Kidney essence. However, the mechanism underlying the symptoms also remains elusive. Here we report that spatial learning and memory, escape, and swimming capacities were damaged significantly in Kidney-yang deficiency rats. Indeed, both hippocampal Aβ 40 and 42 increases in Kidney-yang deficiency contribute to the learning and memory impairments. Specifically, damage of synaptic plasticity is involved in the learning and memory impairment of Kidney-yang deficiency rats. We determined that the learning and memory damage in Kidney-yang deficiency due to synaptic plasticity impairment and increases of Aβ 40 and 42 was not caused via NMDA receptor internalization induced by Aβ increase. β-Adrenergic receptor agonist can rescue the impaired long-term potential (LTP) in Kidney-yang rats. Taken together, our results suggest that spatial learning and memory inhibited in Kidney-yang deficiency might be induced by Aβ increase and the decrease of β 2 receptor function in glia. PMID:22645624

Sulphonylurea drugs reduce hypoxic damage in the isolated perfused rat kidney

PubMed Central

Engbersen, Richard; Moons, Miek M; Wouterse, Alfons C; Dijkman, Henry B; Kramers, Cees; Smits, Paul; Russel, Frans G M

2000-01-01

Sulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 μM) and glibenclamide (10 μM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min. Hypoxic perfusions resulted in an increased fractional excretion of glucose (FE % glucose 14.3±1.5 for hypoxic perfusions vs 4.9±1.6 for normoxic perfusions, mean±s.e.mean, P<0.05), which could be completely restored by 200 μM tolbutamide (5.7±0.4 for tolbutamide vs 14.3±1.5 for untreated hypoxic kidneys, P<0.01). Furthermore, tolbutamide reduced the total amount of LDH excreted in the urine (220±100 mU for tolbutamide vs 1220±160 mU for untreated hypoxic kidneys, P<0.01). Comparable results were obtained with glibenclamide (10 μM). In agreement with the effect on functional parameters, ultrastructural analysis of proximal tubules showed increased brush border preservation in tolbutamide treated kidneys compared to untreated hypoxic kidneys. We conclude that glibenclamide and tolbutamide are both able to reduce hypoxic damage to proximal tubules in the isolated perfused rat kidney when applied in the appropriate concentrations. PMID:10928974

Kidneys at Higher Risk of Discard: Expanding the Role of Dual Kidney Transplantation

PubMed Central

Tanriover, B.; Mohan, S.; Cohen, D. J.; Radhakrishnan, J.; Nickolas, T. L.; Stone, P. W.; Tsapepas, D. S.; Crew, R. J.; Dube, G. K.; Sandoval, P. R.; Samstein, B.; Dogan, E.; Gaston, R. S.; Tanriover, J. N.; Ratner, L. E.; Hardy, M. A.

2014-01-01

Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI) >85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80–90% and >90%). Kidneys with KDPI >90% were associated with increased odds of discard (OR = 1.99, 95% CI 1.74–2.29) compared to ones with KDPI <80%. DKTs of KDPI >90% were associated with lower overall allograft failure (HR = 0.74, 95% CI 0.62–0.89) and better patient survival (HR = 0.79, 95% CI 0.64–0.98) compared to single ECD kidneys with KDPI >90%. Kidneys at higher risk of discard may be offered in the up-front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile. PMID:24472195

Comparison of peritoneal dialysis and hemodialysis after kidney transplant failure.

PubMed

Kang, G W; Jang, M H; Hwang, E A; Park, S B; Han, S Y

2013-10-01

Patients with a failed kidney transplant represent a unique chronic kidney disease population that is increasing in number and is at high risk of morbidity and mortality. Among transplant-naïve patients, those treated with peritoneal dialysis (PD) show an early survival advantage compared with those treated with hemodialysis (HD). But any advantage of PD after allograft failure is unknown. The aim of this study was to investigate the clinical outcomes of patients with failed allografts according to the type of dialysis modality. We reviewed medical records of patients who initiated dialysis after kidney transplant failure from November 1982 to May 2011. Demographics features, clinical data, and survival outcomes were compared between PD and HD patients who had experienced allograft failure. The 182 patients with failed allografts showed the most common cause to be chronic rejection. The median duration of function before allograft failure was 74.0 months. After allograft failure, 145 (79.7%) patients returned to HD and 37 (20.3%) to PD. Twenty-three patients (12.6%) died over the median 69.1 months duration of follow-up. During the observation period, 16 HD (11%) and 7 PD (8.9%) patients died. The survival rates of PD patients at 1 year were 91.2% and 84.4%, respectively, at 1 and 3 years, and those of HD patients 94.8% and 88.9%. There was no significant difference in the survivals of the 2 groups. The study suggests that the outcome of patients starting PD after kidney transplant failure was similar to those starting HD. Therefore, PD can be regarded to be a good treatment option for patients returning to dialysis after kidney transplant failure. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Plasma levels of soluble CD30 in kidney graft recipients as predictors of acute allograft rejection.

PubMed

Ayed, K; Abdallah, T B; Bardi, R; Abderrahim, E; Kheder, A

2006-09-01

In renal transplant recipients elevated soluble serum CD30 levels are associated with increased rejection and graft loss. We sought to determine the sCD30 plasma levels before and after kidney transplantation and to assess whether sCD30 was a predictive factor of immunological risk. sCD30 plasma levels were determined by an enzyme-linked immunosorbent assay assay in 52 kidney graft recipients before as well as 7, 15, and 21 days after transplantation. Eighteen patients developed acute allograft rejection (group I) and 34 patients showed uneventful courses (group II). Before transplantation sCD30 plasma levels were elevated in both groups (mean: 162.6 +/- 89.5 U/mL). After transplantation, group I recipients with acute rejection showed higher relative levels of plasma sCD30 on days 7 and 15 (120.8 +/- 74.6 U/mL and 210.6 +/- 108.7 U/mL respectively) compared with group II patients without rejection (95 +/- 45 U/mL and 59.4 +/- 31.6 U/mL), a difference that was significant for group I (P = .0003) and not significant for group II (P = .09). On day 21, sCD30 decreased in the two groups but remained higher among group I patients (120.6 +/- 92.7 U/mL). HLA antibodies were positive in 18 patients (34.6%) with 9 (50%) experiencing at last one episode of acute rejection. Among 34 patients negative for anti-HLA antibodies, nine displayed acute rejection only (26.4%), a difference that was not significant (P > .05). If we consider 100 U/mL as the minimum predictive level for allograft rejection, our results suggested that levels of sCD30 should be taken into consideration with the presence of HLA-antibodies detectable before and after transplantation, especially in patients with more than three HLA mismatches [RR = 3.20 (0.94 < RR < 10.91)]. These data suggested that measurement of plasma sCD30 is a useful procedure for the recognition of rejection in its earliest stages.

Mucormycosis (zygomycosis) of renal allograft

PubMed Central

Gupta, Krishan L.; Joshi, Kusum; Kohli, Harbir S.; Jha, Vivekanand; Sakhuja, Vinay

2012-01-01

Fungal infection is relatively common among renal transplant recipients from developing countries. Mucormycosis, also known as zygomycosis, is one of the most serious fungal infections in these patients. The most common of presentation is rhino-cerebral. Isolated involvement of a renal allograft is very rare. A thorough search of literature and our medical records yielded a total of 24 cases with mucormycosis of the transplanted kidney. There was an association with cytomegalovirus (CMV) infection and anti-rejection treatment in these patients and most of these transplants were performed in the developing countries from unrelated donors. The outcome was very poor with an early mortality in 13 (54.5%) patients. Renal allograft mucormycosis is a relatively rare and potentially fatal complication following renal transplantation. Early diagnosis, graft nephrectomy and appropriate antifungal therapy may result in an improved prognosis for these patients. PMID:26069793

Febuxostat for the Prevention of Recurrent 2,8-dihydroxyadenine Nephropathy due to Adenine Phosphoribosyltransferase Deficiency Following Kidney Transplantation.

PubMed

Nanmoku, Koji; Kurosawa, Akira; Shinzato, Takahiro; Shimizu, Toshihiro; Kimura, Takaaki; Yagisawa, Takashi

2017-01-01

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that results in irreversible renal damage due to 2,8-dihydroxyadenine (DHA) nephropathy. A 28-year-old man underwent living-related kidney transplantation for chronic kidney disease of unknown etiology. Numerous spherical brownish crystals observed in his urinary sediment on postoperative day 3 and were observed within the tubular lumen of renal allograft biopsy specimens on postoperative day 7. After a genetic diagnosis, febuxostat treatment was started on postoperative day 7, with the dosage gradually increased to 80 mg/day until complete the disappearance of 2,8-DHA crystals. Febuxostat prevented secondary 2,8-DHA nephropathy after kidney transplantation.

Febuxostat for the Prevention of Recurrent 2,8-dihydroxyadenine Nephropathy due to Adenine Phosphoribosyltransferase Deficiency Following Kidney Transplantation

PubMed Central

Nanmoku, Koji; Kurosawa, Akira; Shinzato, Takahiro; Shimizu, Toshihiro; Kimura, Takaaki; Yagisawa, Takashi

2017-01-01

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that results in irreversible renal damage due to 2,8-dihydroxyadenine (DHA) nephropathy. A 28-year-old man underwent living-related kidney transplantation for chronic kidney disease of unknown etiology. Numerous spherical brownish crystals observed in his urinary sediment on postoperative day 3 and were observed within the tubular lumen of renal allograft biopsy specimens on postoperative day 7. After a genetic diagnosis, febuxostat treatment was started on postoperative day 7, with the dosage gradually increased to 80 mg/day until complete the disappearance of 2,8-DHA crystals. Febuxostat prevented secondary 2,8-DHA nephropathy after kidney transplantation. PMID:28566603

Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction.

PubMed

Bombas, A; Stein-Oakley, A N; Baxter, K; Thomson, N M; Jablonski, P

1999-01-01

Non-allogeneic factors such as increased nephron "workload" may contribute to chronic renal allograft rejection. Reducing dietary protein from 20% to 8% was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, "tolerised" by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-beta1 mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8% lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage.

Prolonged Allograft Survival in a Patient With Chronic Immunosuppression: A Case Report and Systematic Review.

PubMed

Vyas, Krishna S; Burns, Chase; Ryan, Dylan T; Wong, Lesley

2017-06-01

A 41-year-old man with past medical history of kidney-liver transplantation requiring chronic immunosuppression presented 2 years posttransplant with a necrotizing soft tissue infection of his right thigh. Serial debridement to remove necrotic tissue was performed, and a Matrix HD Allograft Fenestrated (RTI Surgical, Alachua, FL) was applied. At 5-months post grafting, the patient demonstrated fully vascularized and intact skin. Under normal circumstances, a cadaveric allograft sloughs over several weeks and is not usually considered a permanent solution for wound closure. A systematic review of transplant patients on chronic immunosuppression with skin allografts demonstrates the potential for the indefinite survival of an allograft. Necrotizing soft tissue infections can definitively be treated using serial debridement and allograft transplantation in the chronically immunosuppressed.

Basal damage and oxidative DNA damage in children with chronic kidney disease measured by use of the comet assay.

PubMed

Aykanat, Banu; Demircigil, Gonca Cakmak; Fidan, Kibriya; Buyan, Necla; Gulleroglu, Kaan; Baskin, Esra; Bayrakci, Umut Selda; Sepici, Aylin; Buyukkaragoz, Bahar; Karakayali, Hamdi; Haberal, Mehmet; Burgaz, Sema

2011-10-09

One consequence of chronic kidney disease (CKD) is an elevated risk for cancer. There is sufficient evidence to conclude that there is an increased incidence of at least some cancers in kidney-dialysis patients. Cancer risk after kidney transplantation has mainly been attributed to immunosuppressive therapy. There are no data evaluating DNA damage in children with CKD, in dialysis patients, or following kidney transplantation. In this study, the comet assay and the enzyme-modified comet assay - with the use of endonuclease III (Endo III) and formamidopyrimidine glycosylase (FPG) enzymes - were conducted to investigate the basal damage and the oxidative DNA damage as a result of treatment in peripheral blood lymphocytes of children. Children at various stages of treatment for kidney disease, including pre-dialysis patients (PreD) (n=17), regular hemodialysis patients (HD) (n=15), and those that received kidney transplants (Tx) (n=17), comprised the study group. They were compared with age- and gender-matched healthy children (n=20) as a control group. Our results show that the %DNA intensity, a measure of basal damage, was significantly increased in children with CKD (mean ± SD) (5.22 ± 1.57) and also in each of the PreD, HD, and Tx groups [(4.92 ± 1.23), (4.91 ± 1.35), and (5.79 ± 1.94), respectively, vs the healthy children (2.74 ± 2.91) (p<0.001). Significant increases in oxidative DNA damage were only found in the FPG-sensitive sites for the PreD and Tx groups, compared with control and HD groups (p<0.05), suggesting that basal DNA damage was more evident for the PreD, HD, and Tx groups. The findings of the present study indicate a critical need for further research on genomic damage with different endpoints and also for preventive measures and improvements in treatment of pediatric patients, in order to improve their life expectancy. 2011 Elsevier B.V. All rights reserved.

A case of rhabdomyolysis after kidney transplantation successfully managed with intensive continuous dialysis.

PubMed

Shahbazov, Rauf; Fox, Michael; Alejo, Jennifer L; Anjum, Malik A; Azari, Feredun; Doyle, Alden; Agarwal, Avinash; Brayman, Kenneth L

2018-04-01

Rhabdomyolysis is characterized by muscle cell death which can result in acute kidney injury from pigment nephropathy. We present a patient who developed rhabdomyolysis immediately after deceased donor kidney transplantation surgery and was managed with continuous renal replacement therapy that resulted in successful salvage of the kidney allograft. Patients who develop acute kidney failure requiring renal replacement therapy generally have a poor prognosis. It is worth noting that while continuous veno-venous hemofiltration (CVVHF) offers greater volume support and continuous clearance compared to hemodialysis (HD), recent studies have demonstrated no clinically significant improvement in clinical outcome between the two. Perhaps CVVHF is a better modality compared to HD in this setting to prevent further insult from pigment nephropathy to an allograft. A combination of early diagnosis and intensive continuous renal replacement therapy can be used for allograft salvage in a patient with rhabdomyolysis in the immediate post-kidney transplant period.

Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.

PubMed

Kuo, Elbert; Bharat, Ankit; Shih, Jennifer; Street, Tyler; Norris, Jenyi; Liu, Wei; Parks, William; Walter, Michael; Patterson, G Alexander; Mohanakumar, T

2006-10-01

Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection. Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts. Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio. Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.

Independent Risk Factors for Urinary Tract Infection and for Subsequent Bacteremia or Acute Cellular Rejection: A Single Center Report of 1166 Kidney Allograft Recipients

PubMed Central

Lee, John R.; Bang, Heejung; Dadhania, Darshana; Hartono, Choli; Aull, Meredith J.; Satlin, Michael; August, Phyllis; Suthanthiran, Manikkam; Muthukumar, Thangamani

2013-01-01

Background Urinary tract infection (UTI) is a frequent, serious complication in kidney allograft recipients. Methods We reviewed the records of 1166 kidney allograft recipients who received their allografts at our institution between January 2005 to December 2010 and determined the incidence of UTI during the first three months after transplantation (early UTI). We utilized Cox proportional hazard models to determine the risk factors for early UTI and whether early UTI was an independent risk factor for subsequent bacteremia or acute cellular rejection (ACR). Results UTI, defined as ≥105 bacterial colony forming units per milliliter of urine, developed in 247 (21%) of the 1166 recipients. Independent risk factors for the first episode of UTI were: female gender (hazard ratio [HR]: 2.9, 95% Confidence Intervals (CI): 2.2–3.7, P<0.001), prolonged use of Foley catheter (HR: 3.9, 95% CI: 2.8–5.4, P<0.001), ureteral stent (HR 1.4, 95% CI: 1.1–1.8, P=0.01), age (HR: 1.1, 95% CI: 1.0–1.2, P=0.03), and delayed graft function (HR:1.4, 95% CI: 1.0–1.9, P=0.06). Trimethoprim/sulfamethoxazole prophylaxis was associated with a reduced risk of UTI (HR: 0.6, 95% CI: 0.3–0.9, P=0.02). UTI was an independent risk factor for subsequent bacteremia (HR: 2.4, 95% CI: 1.2–4.8, P=0.01). Untreated, but not treated, UTI was associated with an increased risk of ACR (HR: 2.8, 95% CI: 1.3–6.2, P=0.01). Conclusions Female gender, prolonged use of Foley catheter, ureteral stent, age, and delayed graft function are independent risk factors for early UTI. UTI is independently associated with the development of bacteremia, and untreated UTI is associated with subsequent ACR. PMID:23917724

Independent risk factors for urinary tract infection and for subsequent bacteremia or acute cellular rejection: a single-center report of 1166 kidney allograft recipients.

PubMed

Lee, John R; Bang, Heejung; Dadhania, Darshana; Hartono, Choli; Aull, Meredith J; Satlin, Michael; August, Phyllis; Suthanthiran, Manikkam; Muthukumar, Thangamani

2013-10-27

Urinary tract infection (UTI) is a frequent, serious complication in kidney allograft recipients. We reviewed the records of 1166 kidney allograft recipients who received their allografts at our institution between January 2005 and December 2010 and determined the incidence of UTI during the first 3 months after transplantation (early UTI). We used Cox proportional hazards models to determine the risk factors for early UTI and whether early UTI was an independent risk factor for subsequent bacteremia or acute cellular rejection (ACR). UTI, defined as 10 or more bacterial colony-forming units/mL urine, developed in 247 (21%) of the 1166 recipients. Independent risk factors for the first episode of UTI were female gender (hazard ratio [HR], 2.9; 95% confidence intervals [CI], 2.2-3.7; P<0.001), prolonged use of Foley catheter (HR, 3.9; 95% CI, 2.8-5.4; P <0.001), ureteral stent (HR, 1.4; 95% CI, 1.1-1.8; P=0.01), age (HR, 1.1; 95% CI, 1.0-1.2; P=0.03), and delayed graft function (HR, 1.4; 95% CI, 1.0-1.9; P=0.06). Trimethoprim/sulfamethoxazole prophylaxis was associated with a reduced risk of UTI (HR, 0.6; 95% CI, 0.3-0.9; P=0.02). UTI was an independent risk factor for subsequent bacteremia (HR, 2.4; 95% CI, 1.2-4.8; P=0.01). Untreated UTI, but not treated UTI, was associated with an increased risk of ACR (HR, 2.8; 95% CI, 1.3-6.2; P=0.01). Female gender, prolonged use of Foley catheter, ureteral stent, age, and delayed graft function are independent risk factors for early UTI. UTI is independently associated with the development of bacteremia, and untreated UTI is associated with subsequent ACR.

Kidney damage in extracorporeal shock wave lithotripsy: a numerical approach for different shock profiles.

PubMed

Weinberg, Kerstin; Ortiz, Michael

2009-08-01

In shock-wave lithotripsy--a medical procedure to fragment kidney stones--the patient is subjected to hypersonic waves focused at the kidney stone. Although this procedure is widely applied, the physics behind this medical treatment, in particular the question of how the injuries to the surrounding kidney tissue arise, is still under investigation. To contribute to the solution of this problem, two- and three-dimensional numerical simulations of a human kidney under shock-wave loading are presented. For this purpose a constitutive model of the bio-mechanical system kidney is introduced, which is able to map large visco-elastic deformations and, in particular, material damage. The specific phenomena of cavitation induced oscillating bubbles is modeled here as an evolution of spherical pores within the soft kidney tissue. By means of large scale finite element simulations, we study the shock-wave propagation into the kidney tissue, adapt unknown material parameters and analyze the resulting stress states. The simulations predict localized damage in the human kidney in the same regions as observed in animal experiments. Furthermore, the numerical results suggest that in first instance the pressure amplitude of the shock wave impulse (and not so much its exact time-pressure profile) is responsible for damaging the kidney tissue.

Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka.

PubMed

Nanayakkara, Shanika; Komiya, Toshiyuki; Ratnatunga, Neelakanthi; Senevirathna, S T M L D; Harada, Kouji H; Hitomi, Toshiaki; Gobe, Glenda; Muso, Eri; Abeysekera, Tilak; Koizumi, Akio

2012-05-01

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.

The Lymphatic Phenotype of Lung Allografts in Patients With Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome.

PubMed

Traxler, Denise; Schweiger, Thomas; Schwarz, Stefan; Schuster, Magdalena Maria; Jaksch, Peter; Lang, Gyoergy; Birner, Peter; Klepetko, Walter; Ankersmit, Hendrik Jan; Hoetzenecker, Konrad

2017-02-01

Chronic lung allograft dysfunction (CLAD), presenting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) is the major limiting factor of long-term survival in lung transplantation. Its pathogenesis is still obscure. In BOS, persistent alloimmune injury and chronic airway inflammation are suggested. One of the main tasks of the lymphatic vessel (LV) system is the promotion of immune cell trafficking. The formation of new LVs has been shown to trigger chronic allograft rejection in kidney transplants. We therefore sought to address the role of lymphangiogenesis in CLAD. Formalin-fixed paraffin-embedded tissue samples of 22 patients receiving a lung retransplantation due to BOS or RAS were collected. Lymphatic vessel density (LVD) was determined by immunohistochemical staining for podoplanin. Lung tissue obtained from 13 non-CLAD patients served as control. The impact of LVD on graft survival was assessed. Lymphatic vessel density in CLAD patients did not differ from those in control subjects (median number of LVs per bronchiole: 4.75 (BOS), 6.47 (RAS), 4.25 (control), P = 0.97). Moreover, the number of LVs was not associated with regions of cellular infiltrates (median number of LVs per bronchiole: with infiltrates, 5.00 (BOS), 9.00 (RAS), 4.00 (control), P = 0.62; without infiltrates, 4.5 (BOS), 0.00 (RAS), 4.56 (control), P = 0.74). Lymphatic vessel density did not impact the time to development of BOS or RAS in lung transplantation (low vs high LVD: 38.5 vs 86.0 months, P = 0.15 [BOS]; 60.5 vs 69.5 months, P = 0.80 [RAS]). Unlike chronic organ failure in kidney transplantation, lymphangiogenesis is not altered in CLAD patients. Our findings highlight unique immunological processes leading to BOS and RAS.

ARFI-based tissue elasticity quantification and kidney graft dysfunction: first clinical experiences.

PubMed

Stock, K F; Klein, B S; Cong, M T Vo; Regenbogen, C; Kemmner, S; Büttner, M; Wagenpfeil, S; Matevossian, E; Renders, L; Heemann, U; Küchle, C

2011-01-01

Beyond the medical history, the clinical exam and lab findings, non-invasive ultrasound parameters such as kidney size and Doppler values (e.g. the resistive index) are important tools assisting clinical decision making in the monitoring of renal allografts. The gold standard for the diagnosis of renal allograft dysfunction remains the renal biopsy; while an invasive procedure, the justifiable necessity for this derives from its definitive nature a requirement beyond the synopses of all non-invasive tools. "Acoustic Radiation Force Impulse Imaging"(ARFI)-quantification is a novel ultrasound-based technology measuring tissue elasticity properties. So far experience related to this new method has not been reported in renal transplant follow-up. The purpose of this study was to evaluate changes in ARFI-measurements between clinically stable renal allografts and biopsy-proven transplant dysfunction. We employed "Virtual Touch™ tissue quantification" (Siemens Acuson, S2000) for the quantitative measurement of tissue stiffness in the cortex of transplant kidneys. We performed initial baseline and later disease-evaluative ultrasound examinations in 8 renal transplant patients in a prospective study design. Patients were first examined during stable allograft function with a routine post-transplant renal ultrasound protocol. A second follow-up examination was carried out on subsequent presentation with transplant dysfunction prior to allograft biopsy and histological evaluation. All patiens were examined using ARFI-quantification (15 measurements/kidney). Resistive indices (RI) were calculated using pulsed-wave Doppler ultrasound, and transplant kidney size was measured on B-mode ultrasound images. All biopsies were evaluated histologically by a reference nephropathologist unaware of the results of the ultrasound studies. Histopathological diagnoses were based on biopsy results, taking clinical and laboratory findings into account. Finally we calculated the relative

Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney.

PubMed

Cano-Europa, Edgar; Blas-Valdivia, Vanessa; Franco-Colin, Margarita; Gallardo-Casas, Carlos Angel; Ortiz-Butrón, Rocio

2011-01-01

It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T₄ injection (20 μg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T₄ showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T₄ completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole. Copyright © 2009 Elsevier GmbH. All rights reserved.

DNA damage response in nephrotoxic and ischemic kidney injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan, Mingjuan; Tang, Chengyuan

DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death. Targeting DDR for kidney protection in AKI therefore reliesmore » on a thorough elucidation of the DDR pathways in various forms of AKI.« less

Transplantectomy is associated with presensitization with donor-reactive T cells and graft failure after kidney retransplantation: a cohort study.

PubMed

Schachtner, Thomas; Otto, Natalie M; Stein, Maik; Reinke, Petra

2018-05-01

The number of kidney transplant recipients (KTRs) being waitlisted for a subsequent transplantation has disproportionately increased to almost 25%. Evidence for the optimal management of the failed allograft, however, remains inconsistent. We studied 111 KTRs who underwent their second kidney transplantation from 1998 to 2015. In 51/111 KTRs (46%) the failed allograft was removed and in 60/111 (54%) the failed allograft was retained. KTRs with primary non-function and allograft loss <12  months of the first failed allograft were excluded from analysis. Samples were collected before transplantation and at  1  month posttransplantation and donor-reactive T cells were measured using an interferon-γ enzyme-linked immunosorbent spot assay. KTRs with the previous allograft removed showed significantly higher rates of acute cellular rejection compared with KTRs with the previous allograft retained [27/51 KTRs (53%) versus 18/60 KTRs (30%); P = 0.019]. KTRs with the previous allograft removed showed significantly inferior death-censored allograft survival compared with KTRs with the previous allograft retained (P = 0.022). Here, KTRs with the previous allograft removed showed significantly higher donor-reactive T cells pretransplantation compared with KTRs with the previous allograft retained (P = 0.012). Interestingly, no differences were observed for the presence of panel reactive antibodies and for the development of de novo donor-specific antibodies. Our data suggest higher cellular presensitization among KTRs with the previous allograft removed, which is associated with higher rates of acute cellular rejection and inferior allograft survival. Immunological mechanisms that may account for these differences may include prolonged maintenance immunosuppression to save urine output in KTRs with the first kidney allograft retained and cellular presensitization after withdrawal of maintenance immunosuppression, which lead to allograft rejection and

MitoQ blunts mitochondrial and renal damage during cold preservation of porcine kidneys.

PubMed

Parajuli, Nirmala; Campbell, Lia H; Marine, Akira; Brockbank, Kelvin G M; Macmillan-Crow, Lee Ann

2012-01-01

Cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation but damage occurs during the preservation episode. It is well established that oxidant production increases during cold renal preservation and mitochondria are a key target for injury. Our laboratory has demonstrated that cold storage of renal cells and rat kidneys leads to increased mitochondrial superoxide levels and mitochondrial electron transport chain damage, and that addition of Mitoquinone (MitoQ) to the preservation solutions blunted this injury. In order to better translate animal studies, the inclusion of large animal models is necessary to develop safe preclinical protocols. Therefore, we tested the hypothesis that addition of MitoQ to cold storage solution preserves mitochondrial function by decreasing oxidative stress, leading to less renal tubular damage during cold preservation of porcine kidneys employing a standard criteria donor model. Results showed that cold storage significantly induced oxidative stress (nitrotyrosine), renal tubular damage, and cell death. Using High Resolution Respirometry and fresh porcine kidney biopsies to assess mitochondrial function we showed that MitoQ significantly improved complex II/III respiration of the electron transport chain following 24 hours of cold storage. In addition, MitoQ blunted oxidative stress, renal tubular damage, and cell death after 48 hours. These results suggested that MitoQ decreased oxidative stress, tubular damage and cell death by improving mitochondrial function during cold storage. Therefore this compound should be considered as an integral part of organ preservation solution prior to transplantation.

MitoQ Blunts Mitochondrial and Renal Damage during Cold Preservation of Porcine Kidneys

PubMed Central

Parajuli, Nirmala; Campbell, Lia H.; Marine, Akira; Brockbank, Kelvin G. M.; MacMillan-Crow, Lee Ann

2012-01-01

Cold preservation has greatly facilitated the use of cadaveric kidneys for transplantation but damage occurs during the preservation episode. It is well established that oxidant production increases during cold renal preservation and mitochondria are a key target for injury. Our laboratory has demonstrated that cold storage of renal cells and rat kidneys leads to increased mitochondrial superoxide levels and mitochondrial electron transport chain damage, and that addition of Mitoquinone (MitoQ) to the preservation solutions blunted this injury. In order to better translate animal studies, the inclusion of large animal models is necessary to develop safe preclinical protocols. Therefore, we tested the hypothesis that addition of MitoQ to cold storage solution preserves mitochondrial function by decreasing oxidative stress, leading to less renal tubular damage during cold preservation of porcine kidneys employing a standard criteria donor model. Results showed that cold storage significantly induced oxidative stress (nitrotyrosine), renal tubular damage, and cell death. Using High Resolution Respirometry and fresh porcine kidney biopsies to assess mitochondrial function we showed that MitoQ significantly improved complex II/III respiration of the electron transport chain following 24 hours of cold storage. In addition, MitoQ blunted oxidative stress, renal tubular damage, and cell death after 48 hours. These results suggested that MitoQ decreased oxidative stress, tubular damage and cell death by improving mitochondrial function during cold storage. Therefore this compound should be considered as an integral part of organ preservation solution prior to transplantation. PMID:23139796

Effects of Zinc Supplementation on DNA Damage in Rats with Experimental Kidney Deficiency.

PubMed

Yegin, Sevim Çiftçi; Dede, Semiha; Mis, Leyla; Yur, Fatmagül

2017-04-01

This study was carried out to determine the effect of zinc on oxidative DNA damage in rats with experimental acute and chronic kidney deficiency. Six groups of five Wistar-Albino rats each were assigned as controls (C), acute kidney deficiency (AKD), zinc-supplemented (+Zn), acute kidney deficiency, zinc-supplemented (AKD + Zn), chronic kidney deficiency (CKD) and zinc-supplemented chronic kidney deficiency (CKD + Zn). The levels of 8-Oxo-2'-deoxyguanosine (8-OHdG) were determined, being the lowest in the CKD group (p < 0.05), higher in the C group than those of rats with CKD but lower than that of all the other groups (p < 0.05). There were no significant differences between the controls and the CKD + Zn group, or between the AKD and the +Zn groups. Among all groups, the highest 8-OHdG level was found in the AKD + Zn group (p < 0.05). DNA damage was greater in acute renal failure than in rats with chronic renal failure. The DNA damage in the zinc group was significantly higher than in the controls.

Gynecologic symptoms and sexual function in female kidney allograft recipients.

PubMed

Karayalcin, R; Genc, V; Oztuna, D; Huseynova, N; Ersoz, S

2010-09-01

There is little information in the literature about changing menstrual patterns, sexuality, and fertility after kidney transplantation. The purpose of this study was to describe gynecologic symptoms, menstrual characteristics, sexual functions, details of pregnancies and gynecologic care before and after women underwent renal transplantation. A detailed Turkish questionnaire was prepared for gynecologic evaluation. Fifty women of reproductive age who underwent renal transplantation took part in this study. The questionnaires were filled out at the time of the postoperative follow-up. The mean age and body mass index of all study participants at the time of interview was 33.9 years (range, 18-52) and 23.5 kg/m(2) (range, 16.5-33.3), respectively. There were no differences between bleeding between periods, heavy period, painful period, and period duration before and after transplantation. Eight women left active working life after grafting on their own accord. Thirteen women ceased sexual activity after transplantation. None of the women reported pregnancy after grafting. A total of 98% of women reported that they were never instructed about regular gynecologic care. We found that restrictions in the lives of women with transplanted kidneys included ceasing sexual activity and leaving active working life and that these were due to fear of possible organ damage. Women with transplanted kidneys must be informed about posttransplant sex life and the requirement for regular examinations by a gynecologist. Hence, close collaborations should be formed between patients, primary care physicians, and gynecologists. 2010 Elsevier Inc. All rights reserved.

Histologic damage of lung allografts according to magnitude of acute rejection in the re-isotransplant model.

PubMed

Marui, Tsutomu; Iwata, Hisashi; Shirahashi, Koyo; Matsumoto, Shinsuke; Mizuno, Yoshimasa; Matsui, Masafumi; Takemura, Hirofumi

2008-06-01

Graft damage due to acute rejection has been reported as one of the risk factors in the chronic stage of cardiac and renal allografts. This study was designed to elucidate the histologic changes of grafts after ongoing acute allograft rejection was discontinued in models of lung re-isotransplantation. WKAH rat lungs were orthotopically transplanted into F344 recipients. Three days (3A group) and 5 days (5A group) after the first allotransplantation, the grafts were re-isotransplanted back into the WKAH rats (3RA and 5RA groups, respectively). Five days (5I group) after the first isotransplantation, the grafts were re-isotransplanted back into the WKAH rats (5RI group). The grafts were removed 30 and 60 days after re-isotransplantation and assessed histologically. Typical acute allograft rejection developed in the 3A and 5A groups, and the changes were reduced after re-isotransplantation, although they remained significantly greater in the 5RA group than in the 3RA and 5RI groups. For intimal hyperplasia, the graft score 60 days after re-isotransplantation in the 5RA group was significantly higher than in the 5RI and 3RA groups. The changes in airway inflammation were significantly greater in the 5RA group than in the 3RA and 5RI groups at 60 days. Peribronchiolar fibrosis was significantly more frequent in the 5RA and 3RA groups than in the 5RI group. Acute rejection and airway inflammation corresponded to the magnitude of rejection before retransplantation. Significant intimal hyperplasia developed in severe acute rejection, and peribronchiolar fibrosis occurred after the first acute rejection.

Important risk factors of allograft survival in cadaveric renal transplantation. A study of 426 patients.

PubMed Central

Diethelm, A G; Blackstone, E H; Naftel, D C; Hudson, S L; Barber, W H; Deierhoi, M H; Barger, B O; Curtis, J J; Luke, R G

1988-01-01

Multiple risk factors contribute to the allograft survival of patients who have cadaveric renal transplantation. A retrospective review of 19 such factors in 426 patients identified race, DR match, B + DR match, number of transplants, and preservation time to have a significant influence. The parametric analysis confirmed the effect to be primarily in the early phase, i.e., first 6 months. All patients received cyclosporine with other methods of immunosuppression resulting in an overall 1-year graft survival rate of 66%. The overall 1-year graft survival rate in the white race was 73% and in the black race was 57% (p = 0.002). Allograft survival and DR match showed white recipients with a 1 DR match to have 75% survival at 1 year compared with 57% in the black patient (p = 0.009). If HLA B + DR match was considered, the white recipient allograft survival increased to 76%, 84%, and 88% for 1, 2, and 3 match kidneys by parametric analysis. Patients receiving first grafts had better graft survival (68%) than those undergoing retransplantation (58%) (p = 0.05). Organ preservation less than 12 hours influenced allograft survival with a 78% 1-year survival rate compared with 63% for kidneys with 12-18 hours of preservation. Despite the benefits of B + DR typing, short preservation time, and first transplants to the white recipient, the allograft survival in the black recipient remained uninfluenced by these parameters. PMID:3288138

Quantification of vascular damage in acute kidney injury with fluorine magnetic resonance imaging and spectroscopy.

PubMed

Moore, Jeremy K; Chen, Junjie; Pan, Hua; Gaut, Joseph P; Jain, Sanjay; Wickline, Samuel A

2018-06-01

To design a fluorine MRI/MR spectroscopy approach to quantify renal vascular damage after ischemia-reperfusion injury, and the therapeutic response to antithrombin nanoparticles (NPs) to protect kidney function. A total of 53 rats underwent 45 min of bilateral renal artery occlusion and were treated at reperfusion with either plain perfluorocarbon NPs or NPs functionalized with a direct thrombin inhibitor (PPACK:phenyalanine-proline-arginine-chloromethylketone). Three hours after reperfusion, kidneys underwent ex vivo fluorine MRI/MR spectroscopy at 4.7 T to quantify the extent and volume of trapped NPs, as an index of vascular damage and ischemia-reperfusion injury. Microscopic evaluation of structural damage and NP trapping in non-reperfused renal segments was performed. Serum creatinine was quantified serially over 7 days. The damaged renal cortico-medullary junction trapped a significant volume of NPs (P = 0.04), which correlated linearly (r = 0.64) with the severity of kidney injury 3 h after reperfusion. Despite global large vessel reperfusion, non-reperfusion in medullary peritubular capillaries was confirmed by MRI and microscopy, indicative of continuing hypoxia due to vascular compromise. Treatment of animals with PPACK NPs after acute kidney injury did not accelerate kidney functional recovery. Quantification of ischemia-reperfusion injury after acute kidney injury with fluorine MRI/MR spectroscopy of perfluorocarbon NPs objectively depicts the extent and severity of vascular injury and its linear relationship to renal dysfunction. The lack of kidney function improvement after early posttreatment thrombin inhibition confirms the rapid onset of ischemia-reperfusion injury as a consequence of vascular damage and non-reperfusion. The prolongation of medullary ischemia renders cortico-medullary tubular structures susceptible to continued necrosis despite restoration of large vessel flow, which suggests limitations to acute interventions after

Long-term allograft and patient outcomes of kidney transplant recipients with and without incident cancer – a population cohort study

PubMed Central

Lim, Wai H.; Badve, Sunil V.; Wong, Germaine

2017-01-01

The excess risk for cancer in kidney transplant recipients is substantial, but the allograft and patient survivals after cancer development are under-studied. This is a population-based cohort study of all primary live and deceased donor kidney transplant recipients in Australia and New Zealand between 1990-2012. The risks of overall graft loss and death with a functioning graft in kidney transplant recipients with and without incident cancer were determined using adjusted Cox regression analysis, with incident cancer considered as a time-varying covariate in the models. In those with incident cancer, types and cancer stage at diagnoses were reported. Of 12,545 transplant recipients followed for a median of 6.9 years (91,380 patient-years), 1184 (9.4%) developed incident cancers at a median of 5.8 years post-transplant. Digestive, kidney and urinary tract cancers were the most common cancer types, although digestive and respiratory tract cancers were more aggressive, with 40% reported as advanced cancers at time of cancer diagnosis. Cancer-related deaths accounted for approximately 80% of recipients with a prior cancer history. Compared with recipients with no prior cancer, the adjusted hazard ratios (HR) for overall graft loss and death with functioning graft were 4.34 (95%CI 3.90, 4.82; p<0.001) and 9.53 (95%CI 8.30, 10.95; <0.001) among those with a prior cancer. Incident cancer after kidney transplantation is a significant risk factor for death with a functioning graft, with the majority of deaths attributed to cancer. A greater understanding of the barriers to screening and treatment approaches following cancer diagnosis may lead to improve survival in kidney transplant recipients with cancer. PMID:29100424

Protective effects of FTY720 on chronic allograft nephropathy by reducing late lymphocytic infiltration.

PubMed

Wang, Minghui; Liu, Shanying; Ouyang, Nengtai; Song, Erwei; Lutz, Jens; Heemann, Uwe

2004-09-01

Lymphocytic infiltration is obvious throughout early and late stages of chronic allograft nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney allografts, but the contribution of late infiltration to long-term allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of chronic allograft nephropathy. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis. FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts. FTY720 ameliorated chronic allograft nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.

Selected Mildly Obese Donors Can Be Used Safely in Simultaneous Pancreas and Kidney Transplantation.

PubMed

Alhamad, Tarek; Malone, Andrew F; Lentine, Krista L; Brennan, Daniel C; Wellen, Jason; Chang, Su-Hsin; Chakkera, Harini A

2017-06-01

Donor obesity, defined as donor body mass index (D-BMI) of 30 kg/m or greater, has been associated with increased risk of technical failure and poor pancreas allograft outcomes. Many transplant centers establish a threshold of D-BMI of 30 kg/m to decline donor offers for pancreas transplantation. However, no previous studies differentiate the impact of mild (D-BMI, 30-35 kg/m) versus severe obesity (D-BMI, ≥35 kg/m) on pancreas allograft outcomes. We examined Organ Procurement Transplant Network database records for 9916 simultaneous pancreas-kidney transplants (SPKT) performed between 2000 and 2013. We categorized donor body mass index (D-BMI) into 4 groups: 20 to 25 (n = 5724), 25 to 30 (n = 3303), 30 to 35 (n = 751), and 35 to 50 kg/m (n= 138). Associations of D-BMI with pancreas and kidney allograft failure were assessed by multivariate Cox regression adjusted for recipient, donor, and transplant factors. Compared with D-BMI 20 to 25 kg/m, only D-BMI 35 to 50 kg/m was associated with significantly higher pancreas allograft [adjusted hazard ratio [aHR], 1.37; 95% confidence interval (CI], 1.04-1.79] and kidney allograft (aHR, 1.36; CI, 1.02-1.82) failure over the study period (13 years). Donor BMI 30 to 35 kg/m did not impact pancreas allograft (aHR, 0.99; CI, 0.86-1.37) or kidney allograft (aHR, 0.98; CI, 0.84-1.15) failure. Similar patterns were noted at 3 months, and 1, 5, and 10 years posttransplant. These data support that pancreata from mildly obese donors (BMI, 30-35 kg/m) can be safely used for transplantation, with comparable short-term and long-term outcomes as organs from lean donors. Consideration of pancreata from obese donors may decrease the pancreas discard rate.

Sirolimus in kidney transplant donors and clinical and histologic improvement in recipients: rat model.

PubMed

Cicora, F; Lausada, N; Vasquez, D N; Cicora, P; Zalazar, G; Gonzalez, P; Palti, G; Raimondi, C

2010-01-01

Ischemia-reperfusion (I/R) injury is one of the risk factors for delayed graft function, acute rejection episodes, and impaired long-term allograft survival after kidney transplantation. This antigen-independent inflammatory process produces tissue damage. Isogeneic transplantation in a rat model is a useful method for study of nonimmunologic risk factors for kidney damage. To study the effect of sirolimus on I/R injury using only 1 dose of the drug in the donor. Eighteen rats were allocated to 3 groups of 6 rats each: sham group, control group, and rapamycin group. Improved renal function and systemic inflammatory response were observed in the rapamycin group compared with the control group (Deltaurea, Deltacreatinine, and DeltaC3, all P < .01). The number of apoptotic nuclei in the renal medulla in the control group was higher than in the rapamycin group (P < .01). Tubular damage was less severe in the rapamycin group compared with the control group (P < .01). Complement 3 and tumor necrosis factor-alpha expression in the kidney samples were significantly decreased when rapamycin was given to the donor rats (P > .01). Bcl-2 protein was upregulated in the rapamycin group compared with the control group (P < .01). Administration of rapamycin in donors attenuates the I/R injury process after kidney transplantation in a rat model.

Effects of mechanical ventilation on gene expression profiles in renal allografts from brain dead rats.

PubMed

Hottenrott, Maximilia C; Krebs, Joerg; Pelosi, Paolo; Luecke, Thomas; Rocco, Patricia R M; Sticht, Carsten; Breedijk, Annette; Yard, Benito; Tsagogiorgas, Charalambos

2017-12-01

Pathophysiological changes of brain death (BD) are impairing distal organ function and harming potential renal allografts. Whether ventilation strategies influence the quality of renal allografts from BD donors has not been thoroughly studied. 28 adult male Wistar rats were randomly assigned to four groups: 1) no brain death (NBD) with low tidal volume/low positive endexpiratory pressure (PEEP) titrated to minimal static elastance of the respiratory system (LVT/OLPEEP); 2) NBD with high tidal volume/low PEEP (HVT/LPEEP); 3) brain death (BD) with LVT/OLPEEP; and 4) BD with HVT/LPEEP. We hypothesized that HVT/LPEEP in BD leads to increased interleukin 6 (IL-6) gene expression and impairs potential renal allografts after six hours of mechanical ventilation. We assessed inflammatory cytokines in serum, genome wide gene expression profiles and quantitative PCR (qPCR) in kidney tissue. The influence of BD on renal gene-expression profiles was greater than the influence of the ventilation strategy. In BD, LVT ventilation did not influence the inflammatory parameters or kidney function in our experimental model. Copyright © 2017. Published by Elsevier B.V.

Azilsartan improves glycemic status and reduces kidney damage in zucker diabetic fatty rats.

PubMed

Hye Khan, Md Abdul; Neckář, Jan; Haines, Jasmine; Imig, John D

2014-08-01

Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, demonstrates antihypertensive and organ protective effects in hypertension. We investigated the efficacy of AZL-M to ameliorate metabolic syndrome and kidney damage associated with type 2 diabetes using Zucker diabetic fatty (ZDF) rats. ZDF rats were treated with vehicle or AZL-M for 8 weeks. Zucker diabetic lean (ZDL) rats were used as controls. Urine and plasma samples were collected for biochemical analysis, and kidney tissues were used for histopathological and immunohistopathological examination at the end of the 8-week protocol. ZDF rats were diabetic with hyperglycemia and impaired glucose tolerance, and AZL-M ameliorated the diabetic phenotype. ZDF rats were hypertensive compared with ZDL rats (181±6 vs. 129±7mm Hg), and AZL-M decreased blood pressure in ZDF rats (116±7mm Hg). In ZDF rats, there was marked renal damage with elevated proteinuria, albuminuria, nephrinuria, 2-4-fold higher tubular cast formation, and glomerular injury compared with ZDL rats. AZL-M treatment reduced renal damage in ZDF rats. ZDF rats demonstrated renal inflammation and oxidative stress with elevated urinary monocyte chemoattractant protein 1 excretion, renal infiltration of macrophages, and elevated kidney malondialdehyde levels. AZL-M reduced oxidative stress and inflammation in ZDF rats. Overall, we demonstrate that AZL-M attenuates kidney damage in type 2 diabetes. We further demonstrate that anti-inflammatory and antioxidative activities of AZL-M contribute to its kidney protective action. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Primary vascularization of allografts governs their immunogenicity and susceptibility to tolerogenesis

PubMed Central

Kant, Cavit D.; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Connolly, Sarah E; Germana, Sharon; Winn, Henry J.; LeGuern, Christian; Tocco, Georges; Benichou, Gilles

2013-01-01

We investigated the influence of allograft primary vascularization on alloimmunity, rejection and tolerance in mice. First, we showed that fully allogeneic primarily vascularized and conventional skin transplants were rejected at the same pace. Remarkably, however, short-term treatment of mice with anti-CD40L antibodies achieved long-term survival of vascularized skin and cardiac transplants but not conventional skin grafts. Non-vascularized skin transplants triggered vigorous direct and indirect pro-inflammatory type 1 T cell responses (IL-2 and γIFN) while primarily-vascularized skin allografts failed to trigger a significant indirect alloresponse. Similar lack of indirect alloreactivity was also observed after placement of different vascularized organ transplants including hearts and kidneys while hearts placed under the skin (non-vascularized) triggers potent indirect alloresponses. Altogether, these results suggest that primary vascularization of allografts is associated with lack of indirect T cell alloreactivity. Finally, we show that long-term survival of vascularized skin allografts induced by anti-CD40L antibodies was associated with a combined lack of indirect alloresponse and a shift of the direct alloresponse towards a type 2 cytokine (IL-4, IL-10) secretion pattern but no activation/expansion of regulatory T cells. Therefore, primary vascularization of allografts governs their immunogenicity and tolerogenicity. PMID:23833234

Immunological and inflammatory mapping of vascularized composite allograft rejection processes in a rat model

PubMed Central

Friedman, Or; Carmel, Narin; Sela, Meirav; Abu Jabal, Ameen; Inbal, Amir; Ben Hamou, Moshe; Krelin, Yakov; Gur, Eyal

2017-01-01

Background Hand and face vascularized composite allotransplantation (VCA) is an evolving and challenging field with great opportunities. During VCA, massive surgical damage is inflicted on both donor and recipient tissues, which may contribute to the high VCA rejection rates. To segregate between the damage-induced and rejection phase of post-VCA responses, we compared responses occurring up to 5 days following syngeneic versus allogeneic vascularized groin flap transplantations, culminating in transplant acceptance or rejection, respectively. Methods The immune response elicited upon transplantation of a syngeneic versus allogeneic vascularized groin flap was compared at Post-operative days 2 or 5 by histology, immunohistochemistry and by broad-scope gene and protein analyses using quantitative real-time PCR and Multiplex respectively. Results Immune cell infiltration began at the donor-recipient interface and paralleled expression of a large group of wound healing-associated genes in both allografts and syngrafts. By day 5 post-transplantation, cell infiltration spread over the entire allograft but remained confined to the wound site in the syngraft. This shift correlated with upregulation of IL-18, INFg, CXCL9, 10 and 11, CCL2, CCL5, CX3CL1 and IL-10 in the allograft only, suggesting their role in the induction of the anti-alloantigen adaptive immune response. Conclusions High resemblance between the cues governing VCA and solid organ rejection was observed. Despite this high resemblance we describe also, for the first time, a damage induced inflammatory component in VCA rejection as immune cell infiltration into the graft initiated at the surgical damage site spreading to the entire allograft only at late stage rejection. We speculate that the highly inflammatory setting created by the unique surgical damage during VCA may enhance acute allograft rejection. PMID:28746417

Thalidomide Ameliorates Inflammation and Vascular Injury but Aggravates Tubular Damage in the Irradiated Mouse Kidney

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scharpfenecker, Marion, E-mail: m.scharpfenecker@nki.nl; Floot, Ben; Russell, Nicola S.

Purpose: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. Methods and Materials: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, andmore » 40 weeks after irradiation. Results: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. Conclusions: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.« less

Inhibition of WISE preserves renal allograft function.

PubMed

Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven; Ge, Xupeng; Lee, Jae; Jurisch, Anke; Zhang, Li; You, Andrew; Fitzpatrick, Vincent D; Williams, Alexia; Valente, Eliane G; Pretorius, Jim; Stevens, Jennitte L; Tipton, Barbara; Winters, Aaron G; Graham, Kevin; Harriss, Lindsey; Baker, Daniel M; Damore, Michael; Salimi-Moosavi, Hossein; Gao, Yongming; Elkhal, Abdallah; Paszty, Chris; Simonet, W Scott; Richards, William G; Tullius, Stefan G

2013-01-01

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction.

PubMed

Shino, Michael Y; Weigt, S Samuel; Li, Ning; Palchevskiy, Vyacheslav; Derhovanessian, Ariss; Saggar, Rajan; Sayah, David M; Gregson, Aric L; Fishbein, Michael C; Ardehali, Abbas; Ross, David J; Lynch, Joseph P; Elashoff, Robert M; Belperio, John A

2013-11-01

After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process. Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology. Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates. There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD. DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands.

Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates.

PubMed

Oura, T; Hotta, K; Lei, J; Markmann, J; Rosales, I; Dehnadi, A; Kawai, K; Ndishabandi, D; Smith, R-N; Cosimi, A B; Kawai, T

2017-03-01

The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet-kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti-interleukin-6 receptor mAb and anti-tumor necrosis factor-α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Comprehensive morphometric analysis of mononuclear cell infiltration during experimental renal allograft rejection.

PubMed

Hoffmann, Ute; Bergler, Tobias; Jung, Bettina; Steege, Andreas; Pace, Claudia; Rümmele, Petra; Reinhold, Stephan; Krüger, Bernd; Krämer, Bernhard K; Banas, Bernhard

2013-01-01

The role of specific subtypes of infiltrating cells in acute kidney allograft rejection is still not clear and was so far not examined by different analyzing methods under standardized conditions of an experimental kidney transplantation model. Immunohistochemical staining of CD3, CD20 and CD68 was performed in rat allografts, in syngeneically transplanted rats and in control rats with a test duration of 6 and 28 days. The detailed expression and localization of infiltrating cells were analyzed manually in different kidney compartments under light microscope and by the two different morphometric software programs. Data were correlated with the corresponding kidney function as well as with histopathological classification. The information provided by the morphometric software programs on the infiltration of the specific cell types after renal transplantation was in accordance with the manual analysis. Morphometric methods were solid to analyze reliably the induction of cellular infiltrates after renal transplantation. By manual analysis we could clearly demonstrate the detailed localization of the specific cell infiltrates in the different kidney compartments. Besides infiltration of CD3 and CD68 infiltrating cells, a robust infiltration of CD20 B-cells in allogeneically transplanted rats, even at early time points after transplantation was detected. Additionally an MHC class I expression could reliable be seen in allogeneically transplanted rats. The infiltration of B-cells and the reliable antigen presentation might act as a silent subclinical trigger for subsequent chronic rejection and premature graft loss. Copyright © 2012 Elsevier B.V. All rights reserved.

Disinfection of human skin allografts in tissue banking: a systematic review report.

PubMed

Johnston, C; Callum, J; Mohr, J; Duong, A; Garibaldi, A; Simunovic, N; Ayeni, O R

2016-12-01

The use of skin allografts to temporarily replace lost or damaged skin is practiced worldwide. Naturally occurring contamination can be present on skin or can be introduced at recovery or during processing. This contamination can pose a threat to allograft recipients. Bacterial culture and disinfection of allografts are mandated, but the specific practices and methodologies are not dictated by standards. A systematic review of literature from three databases found 12 research articles that evaluated bioburden reduction processes of skin grafts. The use of broad spectrum antibiotics and antifungal agents was the most frequently identified disinfection method reported demonstrating reductions in contamination rates. It was determined that the greatest reduction in the skin allograft contamination rates utilized 0.1 % peracetic acid or 25 kGy of gamma irradiation at lower temperatures.

Soluble CD30 correlates with clinical but not subclinical renal allograft rejection.

PubMed

Hirt-Minkowski, Patricia; Roth, Michèle; Hönger, Gideon; Amico, Patrizia; Hopfer, Helmut; Schaub, Stefan

2013-01-01

Soluble CD30 (sCD30) has been proposed as a promising noninvasive biomarker for clinical renal allograft rejection, but its diagnostic characteristics regarding detection of subclinical rejection have not been assessed. We investigated sCD30 in 146 consecutive kidney allograft recipients under tacrolimus-mycophenolate-based immunosuppression having 250 surveillance biopsies at 3 and 6 months as well as 52 indication biopsies within the first year post-transplant. Allograft histology results were classified as (i) acute Banff score zero or interstitial infiltrates only, (ii) tubulitis t1, (iii) tubulitis t2-3 and (iv) isolated vascular compartment inflammation. sCD30 correlated well with the extent of clinical (P < 0.0001), but not subclinical tubulointerstitial rejection (P = 0.06). To determine diagnostic characteristics of sCD30, histological groups were assigned to two categories: no relevant inflammation (i.e. acute Banff score zero and interstitial infiltrates only) versus all other pathologies (tubulitis t1-3 and isolated vascular compartment inflammation). For clinical allograft inflammation, AUC was 0.87 (sensitivity 89%, specificity 79%; P = 0.0006); however, for subclinical inflammation, AUC was only 0.59 (sensitivity 50%, specificity 69%; P = 0.47). In conclusion, sCD30 correlated with clinical, but not subclinical renal allograft rejection limiting its clinical utility as a noninvasive rejection screening biomarker in patients with stable allograft function receiving tacrolimus-mycophenolate-based immunosuppression. © 2012 The Authors Transplant International © 2012 European Society for Organ Transplantation.

Microbiota metabolites: Pivotal players of cardiovascular damage in chronic kidney disease.

PubMed

Cosola, Carmela; Rocchetti, Maria Teresa; Cupisti, Adamasco; Gesualdo, Loreto

2018-04-01

In chronic kidney disease (CKD), cardiovascular (CV) damage is present in parallel which leads to an increased risk of CV disease. Both traditional and non-traditional risk factors contribute to CV damage in CKD. The systemic role of the microbiota as a central player in the pathophysiology of many organs is progressively emerging in the literature: the microbiota is indeed involved in a complex, bi-directional network between many organs, including the kidney and heart connection, although many of these relationships still need to be elucidated through in-depth mechanistic studies. The aim of this review is to provide evidence that microbiota metabolites influence non-traditional risk factors, such as inflammation and endothelial dysfunction in CKD-associated CV damage. Here, we report our current understanding and hypotheses on the gut-kidney and gut-heart axes and provide details on the potential mechanisms mediated by microbial metabolites. More specifically, we summarize some novel hypotheses linking the microbiota to blood pressure regulation and hypertension. We also emphasise the idea that the nutritional management of CKD should be redesigned and include the new findings from research on the intrinsic plasticity of the microbiota and its metabolites in response to food intake. The need is felt to integrate the classical salt and protein restriction approach for CKD patients with foods that enhance intestinal wellness. Finally, we discuss the new perspectives, especially the importance of taking care of the microbiota in order to prevent the risk of developing CKD and hypertension, as well as the still not tested but very promising CKD innovative treatments, such as postbiotic supplementation and bacteriotherapy. This interesting area of research offers potential complementary approaches to the management of CKD and CV damage assuming that the causal mechanisms underlying the gut-kidney and gut-heart axes are clarified. This will pave the way to the design

ANTIBACTERIAL ACTIVITY OF BONE ALLOGRAFTS: COMPARISON OF A NEW VANCOMYCIN-TETHERED ALLOGRAFT WITH ALLOGRAFT LOADED WITH ADSORBED VANCOMYCIN

PubMed Central

Ketonis, Constantinos; Barr, Stephanie; Shapiro, Irving M.; Parvizi, Javad; Adams, Christopher S.; Hickok, Noreen J.

2010-01-01

Bacterial contamination of bone allograft is a significant complication of orthopaedic surgery. To address this issue, we have engineered a method for covalently modifying bone allograft tissue with the antibiotic vancomycin. The goal of this investigation was to compare the biocidal properties of this new allograft material with those of vancomycin physisorbed onto graft material. The duration of antibiotic release from the vancomycin-modified allograft matrix was determined and no elution was observed. In contrast, the adsorbed antibiotic showed a peak elution at 24 h that then decreased over several days. We next used an S. aureus disk diffusion assay to measure the activity of the eluted vancomycin. Again we found that no active antibiotic was eluted from the covalently–modified allograft. Similarly, when the vancomycin-modified allograft morsel was used in the assay, no measurable elution was observed; amounts of antibiotic released from the adsorbed samples inhibited S. aureus growth for 4-7 days. Probably the most telling property of the allograft was that after two weeks, the tethered-allograft was able to resist bacterial colonization. Unlike the elution system in which vancomycin was depleted over the course of days-weeks, the antibiotic on the allograft was stably bound even after 300 days, while its biocidal activity remained undiminished for 60 days. This finding was in stark contrast to the antibiotic impregnated allograft which was readily colonized by bacteria. Finally we chose to evaluate three indicators of cell function: expression of a key transcription factor, expression of selected transcripts, and assessment of cell morphology. Since the tethered antibiotic appeared to have little or no effect on any of these activities, it was concluded that the stable, tethered antibiotic prevented bacterial infection while not modifying bone cell function. PMID:21035576

The role of fetal-maternal microchimerism as a natural-born healer in integrity improvement of maternal damaged kidney.

PubMed

Kajbafzadeh, Abdol-Mohammad; Sabetkish, Shabnam; Sabetkish, Nastaran

2018-01-01

To identify the fetal stem cell (FSC) response to maternal renal injury with emphasis on renal integrity improvement and Y chromosome detection in damaged maternal kidney. Eight non-green fluorescent protein (GFP) transgenic Sprague- Dawley rats were mated with GFP-positive transgenic male rats. Renal damage was induced on the right kidney at gestational day 11. The same procedure was performed in eight non-pregnant rats as control group. Three months after delivery, right nephrectomy was performed in order to evaluate the injured kidney. The fresh perfused kidneys were stained with anti-GFP antibody. Polymerase chain reaction (PCR) assay was also performed for the Y chromosome detection. Cell culture was performed to detect the GFP-positive cells. Technetium-99m-DMSA renal scan and single-photon emission computed tomography (SPECT) were performed after renal damage induction and 3 months later to evaluate the improvement of renal integrity. The presence of FSCs was confirmed by immune histochemical staining as well as immunofluorescent imaging of the damaged part. Gradient PCR of female rat purified DNA demonstrated the presence of Y-chromosome in the damaged maternal kidney. Moreover, the culture of kidney cells showed GPF- positive cells by immunofluorescence microscopy. The acute renal scar was repaired and the integrity of damaged kidney reached to near normal levels in experimental group as shown in DMSA scan. However, no significant improvement was observed in control group. FSC seems to be the main mechanism in repairing of the maternal renal injury during pregnancy as indicated by Y chromosome and GFP-positive cells in the sub-cultured medium. Copyright® by the International Brazilian Journal of Urology.

Donor-specific hypo-responsiveness occurs in simultaneous liver-kidney transplant recipients after the first year.

PubMed

Taner, Timucin; Gustafson, Michael P; Hansen, Michael J; Park, Walter D; Bornschlegl, Svetlana; Dietz, Allan B; Stegall, Mark D

2018-06-01

Kidney allografts of patients who undergo simultaneous liver-kidney transplantation incur less immune-mediated injury, and retain better function compared to other kidney allografts. To characterize the host alloimmune responses in 28 of these patients, we measured the donor-specific alloresponsiveness and phenotypes of peripheral blood cells after the first year. These values were then compared to those of 61 similarly immunosuppressed recipients of a solitary kidney or 31 recipients of liver allografts. Four multicolor, non-overlapping flow cytometry protocols were used to assess the immunophenotypes. Mixed cell cultures with donor or third party cells were used to measure cell proliferation and interferon gamma production. Despite a significant overlap, simultaneous liver-kidney transplant recipients had a lower overall frequency of circulating CD8 + , activated CD4 + and effector memory T cells, compared to solitary kidney transplant recipients. Simultaneous liver-kidney transplant recipient T cells had a significantly lower proliferative response to the donor cells compared to solitary kidney recipients (11.9 vs. 42.9%), although their response to third party cells was unaltered. The frequency of interferon gamma producing alloreactive T cells in simultaneous liver-kidney transplant recipients was significantly lower than that of solitary kidney transplant recipients. Flow cytometric analysis of the mixed cultures demonstrated that both alloreactive CD4 + and CD8 + compartments of the simultaneous liver-kidney transplant recipient circulating blood cells were smaller. Thus, the phenotypic and functional characteristics of the circulating blood cells of the simultaneous liver-kidney transplant recipients resembled those of solitary liver transplant recipients, and appear to be associated with donor-specific hypo-alloresponsiveness. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Early Focal Segmental Glomerulosclerosis as a Cause of Renal Allograft Primary Nonfunction

PubMed Central

Griffin, Emma J.; Thomson, Peter C.; Kipgen, David; Clancy, Marc; Daly, Conal

2013-01-01

Background. Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS. Case Report. A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail. Discussion. Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered. PMID:23781382

Continuous monitoring of kidney transplant perfusion with near-infrared spectroscopy.

PubMed

Malakasioti, Georgia; Marks, Stephen D; Watson, Tom; Williams, Fariba; Taylor-Allkins, Mariesa; Mamode, Nizam; Morgan, Justin; Hayes, Wesley N

2018-05-11

Current reliance on clinical, laboratory and Doppler ultrasound (DUS) parameters for monitoring kidney transplant perfusion in the immediate post-operative period in children risks late recognition of allograft hypoperfusion and vascular complications. Near-infrared spectroscopy (NIRS) is a real-time, non-invasive technique for monitoring tissue oxygenation percutaneously. NIRS monitoring of kidney transplant perfusion has not previously been validated to the gold standard of DUS. We examined whether NIRS tissue oxygenation indices can reliably assess blood flow in established paediatric kidney transplants. Paediatric kidney transplant recipients ages 1-18 years with stable allograft function were eligible. Participants underwent routine DUS assessment of kidney transplant perfusion, including resistive index (RI) and peak systolic velocity at the upper and lower poles. NIRS data [tissue oxygenation index (TOI%)] were recorded for a minimum of 2 min with NIRS sensors placed on the skin over upper and lower allograft poles. Twenty-nine subjects with a median age of 13.3 (range 4.8-17.8) years and a median transplant vintage of 26.5 months participated. Thirteen (45%) were female and 20 (69%) were living donor kidney recipients. NIRS monitoring was well tolerated by all, with 96-100% valid measurements. Significant negative correlations were observed between NIRS TOI% and DUS RI at both the upper and lower poles (r = -0.4 and -0.6, P = 0.04 and 0.001, respectively). Systolic blood pressure but not estimated glomerular filtration rate also correlated with NIRS TOI% (P = 0.01). NIRS indices correlate well with DUS perfusion and haemodynamic parameters in established paediatric kidney transplant recipients. Further studies are warranted to extend NIRS use for continuous real-time monitoring of early post-transplant perfusion status.

Evaluation of renal allografts function early after transplantation using intravoxel incoherent motion and arterial spin labeling MRI.

PubMed

Ren, Tao; Wen, Cheng-Long; Chen, Li-Hua; Xie, Shuang-Shuang; Cheng, Yue; Fu, Ying-Xin; Oesingmann, Niels; de Oliveira, Andre; Zuo, Pan-Li; Yin, Jian-Zhong; Xia, Shuang; Shen, Wen

2016-09-01

To evaluate renal allografts function early after transplantation using intravoxel incoherent motion (IVIM) and arterial spin labeling (ASL) MRI. This prospective study was approved by the local ethics committee, and written informed consent was obtained from all participants. A total of 82 participants with 62 renal allograft recipients (2-4weeks after kidney transplantation) and 20 volunteers were enrolled to be scanned using IVIM and ASL MRI on a 3.0T MR scanner. Recipients were divided into two groups with either normal or impaired function according to the estimated glomerular filtration rate (eGFR) with a threshold of 60ml/min/1.73m(2). The apparent diffusion coefficient (ADC) of pure diffusion (ADCslow), the ADC of pseudodiffusion (ADCfast), perfusion fraction (PF), and renal blood flow (RBF) of cortex were compared among three groups. The correlation of ADCslow, ADCfast, PF and RBF with eGFR was evaluated. The receiver operating characteristic (ROC) curve and binary logistic regression analyses were performed to assess the diagnostic efficiency of using IVIM and ASL parameters to discriminate allografts with impaired function from normal function. P<0.05 was considered statistically significant. In allografts with normal function, no significant difference of mean cortical ADCslow, ADCfast, and PF was found compared with healthy controls (P>0.05). Cortical RBF in allografts with normal function was statistically lower than that of healthy controls (P<0.001). Mean cortical ADCslow, ADCfast, PF and RBF were lower for allografts with impaired function than that with normal function (P<0.05). Mean cortical ADCslow, ADCfast, PF and RBF showed a positive correlation with eGFR (all P<0.01) for recipients. The combination of IVIM and ASL MRI showed a higher area under the ROC curve (AUC) (0.865) than that of ASL MRI alone (P=0.02). Combined IVIM and ASL MRI can better evaluate the diffusion and perfusion properties for allografts early after kidney transplantation

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications.

PubMed

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2017-02-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular injury, and/or rejection creates permissive conditions for the expression of cryptic autoantigens, allowing these autoantibodies to bind antigenic targets and further enhance vascular inflammation and renal dysfunction. Antiperlecan/LG3 antibodies and antiangiotensin II type 1 receptor antibodies have been found before transplant in patients with de novo transplants and portend negative long-term outcome in patients with renal transplants. Here, we review mounting evidence suggesting an important role for autoantibodies to cryptic antigens as novel accelerators of kidney dysfunction and acute or chronic allograft rejection. Copyright © 2017 by the American Society of Nephrology.

Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options.

PubMed

Kim, Miae; Martin, Spencer T; Townsend, Keri R; Gabardi, Steven

2014-07-01

Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients. © 2014 Pharmacotherapy Publications, Inc.

Peripheral blood sampling for the detection of allograft rejection: biomarker identification and validation.

PubMed

Heidt, Sebastiaan; San Segundo, David; Shankar, Sushma; Mittal, Shruti; Muthusamy, Anand S R; Friend, Peter J; Fuggle, Susan V; Wood, Kathryn J

2011-07-15

Currently, acute allograft rejection can only be detected reliably by deterioration of graft function confirmed by allograft biopsy. A huge drawback of this method of diagnosis is that substantial organ damage has already taken place at the time that rejection is diagnosed. Discovering and validating noninvasive biomarkers that predict acute rejection, and chronic allograft dysfunction, is of great importance. Many studies have investigated changes in the peripheral blood in an attempt to find biomarkers that reflect changes in the graft directly or indirectly. Herein, we will review the promises and limitations of the peripheral blood biomarkers that have been described in the literature so far.

Diabetic Kidney Problems

MedlinePlus

... too high. Over time, this can damage your kidneys. Your kidneys clean your blood. If they are damaged, waste ... in your blood instead of leaving your body. Kidney damage from diabetes is called diabetic nephropathy. It ...

Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression

PubMed Central

Wang, Xiaojie; Hao, Jianqiang; Leung, Gigi; Breitkopf, Trisia; Wang, Eddy; Kwong, Nicole; Akhoundsadegh, Noushin; Warnock, Garth L.; Shapiro, Jerry; McElwee, Kevin J.

2015-01-01

Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1) or fibroblasts (FB, group 2) under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P < 0.001) without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation. PMID:26000314

Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury

PubMed Central

Maejima, Ikuko; Takahashi, Atsushi; Omori, Hiroko; Kimura, Tomonori; Takabatake, Yoshitsugu; Saitoh, Tatsuya; Yamamoto, Akitsugu; Hamasaki, Maho; Noda, Takeshi; Isaka, Yoshitaka; Yoshimori, Tamotsu

2013-01-01

Diverse causes, including pathogenic invasion or the uptake of mineral crystals such as silica and monosodium urate (MSU), threaten cells with lysosomal rupture, which can lead to oxidative stress, inflammation, and apoptosis or necrosis. Here, we demonstrate that lysosomes are selectively sequestered by autophagy, when damaged by MSU, silica, or the lysosomotropic reagent L-Leucyl-L-leucine methyl ester (LLOMe). Autophagic machinery is recruited only on damaged lysosomes, which are then engulfed by autophagosomes. In an autophagy-dependent manner, low pH and degradation capacity of damaged lysosomes are recovered. Under conditions of lysosomal damage, loss of autophagy causes inhibition of lysosomal biogenesis in vitro and deterioration of acute kidney injury in vivo. Thus, we propose that sequestration of damaged lysosomes by autophagy is indispensable for cellular and tissue homeostasis. PMID:23921551

Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury.

PubMed

Maejima, Ikuko; Takahashi, Atsushi; Omori, Hiroko; Kimura, Tomonori; Takabatake, Yoshitsugu; Saitoh, Tatsuya; Yamamoto, Akitsugu; Hamasaki, Maho; Noda, Takeshi; Isaka, Yoshitaka; Yoshimori, Tamotsu

2013-08-28

Diverse causes, including pathogenic invasion or the uptake of mineral crystals such as silica and monosodium urate (MSU), threaten cells with lysosomal rupture, which can lead to oxidative stress, inflammation, and apoptosis or necrosis. Here, we demonstrate that lysosomes are selectively sequestered by autophagy, when damaged by MSU, silica, or the lysosomotropic reagent L-Leucyl-L-leucine methyl ester (LLOMe). Autophagic machinery is recruited only on damaged lysosomes, which are then engulfed by autophagosomes. In an autophagy-dependent manner, low pH and degradation capacity of damaged lysosomes are recovered. Under conditions of lysosomal damage, loss of autophagy causes inhibition of lysosomal biogenesis in vitro and deterioration of acute kidney injury in vivo. Thus, we propose that sequestration of damaged lysosomes by autophagy is indispensable for cellular and tissue homeostasis.

Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis.

PubMed

Gosset, Clément; Viglietti, Denis; Rabant, Marion; Vérine, Jérôme; Aubert, Olivier; Glotz, Denis; Legendre, Christophe; Taupin, Jean-Luc; Duong Van-Huyen, Jean-Paul; Loupy, Alexandre; Lefaucheur, Carmen

2017-09-01

Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16-2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11-2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell-mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus-associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA-associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of

Antibody-Mediated Rejection of the Kidney after Simultaneous Pancreas-Kidney Transplantation

PubMed Central

Pascual, Julio; Samaniego, Milagros D.; Torrealba, José R.; Odorico, Jon S.; Djamali, Arjang; Becker, Yolanda T.; Voss, Barbara; Leverson, Glen E.; Knechtle, Stuart J.; Sollinger, Hans W.; Pirsch, John D.

2008-01-01

The prevalence, risk factors, and outcome of antibody-mediated rejection (AMR) of the kidney after simultaneous pancreas-kidney transplantation are unknown. In 136 simultaneous pancreas-kidney recipients who were followed for an average of 3.1 yr, 21 episodes of AMR of the kidney allograft were identified. Eight episodes occurred early (≤90 d) after transplantation, and 13 occurred later. Histologic evidence of concomitant acute cellular rejection was noted in 12 cases; the other nine had evidence only of humoral rejection. In 13 cases, clinical rejection of the pancreas was diagnosed simultaneously, and two of these were biopsy proven and were positive for C4d immunostaining. Multivariate analysis identified only one significant risk factor: Female patients were three times more likely to experience AMR. Nearly all early episodes resolved with treatment and did not predict graft loss, but multivariate Cox models revealed that late AMR episodes more than tripled the risk for kidney and pancreas graft loss; therefore, new strategies are needed to prevent and to treat late AMR in simultaneous pancreas-kidney transplant recipients. PMID:18235091

Macrophages: Contributors to Allograft Dysfunction, Repair or Innocent Bystanders?

PubMed Central

Mannon, Roslyn B.

2012-01-01

Purpose of this review Macrophages are members of the innate immune response. However, their role in the adaptive immune response is not known. The purpose of this review is to highlight our current understanding of macrophage structure and function and how they may participate in allograft injury. Recent Findings Studies in acute kidney injury models identify macrophages as key mediators of inflammatory injury while more recent studies indicate that they may play a reparative role, depending on phenotype—M1 or M2 type macrophages. Mregs, generated in vitro, appear to have immune suppressive abilities and a unique phenotype. In solid organ transplant, the emphasis of studies has been on acute or chronic injury. These data are derived from animal models using depletion of macrophages or antagonizing their activation and inflammatory responses. The relative contribution of macrophage phenotype in transplantation has not been explored. Summary These studies suggest that macrophages play an injurious role in acute cellular allograft rejection, as well as in chronic injury. Infiltration of an allograft with macrophages is also associated with worse graft function and poor prognosis. Further studies are needed to understand the mechanisms of macrophage mediated injury, explore their potential reparative role and determine if they or their functional products are biomarkers of poor graft outcomes. PMID:22157320

Macrophages: contributors to allograft dysfunction, repair, or innocent bystanders?

PubMed

Mannon, Roslyn B

2012-02-01

Macrophages are members of the innate immune response. However, their role in the adaptive immune response is not known. The purpose of this review is to highlight our current understanding of macrophage structure and function and how they may participate in allograft injury. Studies in acute kidney injury models identify macrophages as key mediators of inflammatory injury, while more recent studies indicate that they may play a reparative role, depending on phenotype - M1 or M2 type macrophages. Mregs, generated in vitro, appear to have immune suppressive abilities and a unique phenotype. In solid-organ transplant, the emphasis of studies has been on acute or chronic injury. These data are derived from animal models using depletion of macrophages or antagonizing their activation and inflammatory responses. The relative contribution of macrophage phenotype in transplantation has not been explored. These studies suggest that macrophages play an injurious role in acute cellular allograft rejection, as well as in chronic injury. Infiltration of an allograft with macrophages is also associated with worse graft function and poor prognosis. Further studies are needed to understand the mechanisms of macrophage-mediated injury, explore their potential reparative role, and determine if they or their functional products are biomarkers of poor graft outcomes.

Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft.

PubMed

Alejandro, V; Scandling, J D; Sibley, R K; Dafoe, D; Alfrey, E; Deen, W; Myers, B D

1995-02-01

Postischemic filtration failure in experimental animals results primarily from depression of the transcapillary hydraulic pressure difference (delta P), a quantity that cannot be determined in humans. To circumvent this limitation we determined the GFR and each of its remaining determinants in transplanted kidneys. Findings in 12 allografts that exhibited subsequent normofiltration (group 1) were compared with those in 11 allografts that exhibited persistent hypofiltration (group 2). Determinations were made intraoperatively in the exposed graft after 1-3 h of reperfusion. GFR (6 +/- 2 vs 29 +/- 5 ml/min) and renal plasma flow by Doppler flow meter (140 +/- 30 vs 315 +/- 49 ml/min) were significantly lower in group 2 than group 1. Morphometric analysis of glomeruli obtained by biopsy and a structural hydrodynamic model of viscous flow revealed the glomerular ultrafiltration coefficient to be similar, averaging 3.5 +/- 0.6 and 3.1 +/- 0.2 ml/(min.mmHg) in group 2 vs 1, respectively. Corresponding values for plasma oncotic pressure were also similar, averaging 19 +/- 1 vs 21 +/- 1 mmHg. We next used a mathematical model of glomerular ultrafiltration and a sensitivity analysis to calculate the prevailing range for delta P from the foregoing measured quantities. This revealed delta P to vary from only 20-21 mmHg in group 2 vs 34-45 mmHg in group 1 (P < 0.001). Further morphometric analysis revealed the diameters of Bowman's space and tubular lumens, as well as the percentage of tubular cells that were necrotic or devoid of brush border, to be similar in the two groups. We thus conclude (a) that delta P depression is the predominant cause of hypofiltration in this form of postischemic injury; and (b) that afferent vasoconstriction rather than tubular obstruction is the proximate cause of the delta P depression.

The Basics of Renal Allograft Pathology.

PubMed

Troxell, Megan L; Houghton, Donald C

2014-09-01

Renal allograft biopsy provides critical information in the management of renal transplant patients, and must be analyzed in close collaboration with the clinical team. The histologic correlates of acute T-cell mediated rejection are interstitial inflammation, tubulitis, and endothelialitis; polyomavirus nephropathy is a potential mimic. Evidence of antibody-mediated rejection includes C4d deposition; morphologic acute tissue injury; and donor specific antibodies. Acute tubular injury/necrosis is a reversible cause of impaired graft function, especially in the immediate post-transplant period. Drug toxicity, recurrent disease, chronic injury, and other entities affecting both native and transplant kidneys must also be evaluated. Copyright © 2014 Elsevier Inc. All rights reserved.

Factors Predicting Meniscal Allograft Transplantation Failure

PubMed Central

Parkinson, Ben; Smith, Nicholas; Asplin, Laura; Thompson, Peter; Spalding, Tim

2016-01-01

any time. Conclusion: This study showed that the presence of severe cartilage damage at the time of MAT and medial allografts were significantly predictive of failure. Surgeons and patients should use this information when considering the risks and benefits of surgery. PMID:27583257

[Surgical overview on kidney and pancreas transplantation].

PubMed

Capocasale, Enzo; Berardinelli, Luisa; Beretta, Claudio; Berloco, Pasquale; Boggi, Ugo; Boschiero, Luigino; Bretto, Piero; Carmellini, Mario; Citterio, Franco; Concone, Giacomo; De Carlis, Luciano; De Rosa, Paride; Del Gaudio, Massimo; Di Sandro, Stefano; Di Tonno, Pasquale; Faenza, Alessandro; Famulari, Antonio; Giacomoni, Alessandro; Giovannoni, Massimo; Iaria, Maurizio; Lauterio, Andrea; Lasaponara, Fedele; Mazzoni, Maria Patrizia; Nicita, Giulio; Orsenigo, Elena; Parolini, Danilo Carlo; Pietrabissa, Andrea; Pinna, Antonio Daniele; Pisani, Franco; Ravaioli, Matteo; Rigotti, Paolo; Romagnoli, Jacopo; Rossetti, Ornella; Secchi, Antonio; Socci, Carlo; Vistoli, Fabio

2016-01-01

The main purpose of this paper, written by a group of Italian expert transplant surgeons, is to provide clinical support and to help through the decision-making process over pre-transplant surgical procedures in potential kidney recipients, as well as selection of pancreas transplant candidates and perioperative management of kidney recipient. Current topics such as different approaches in minimally invasive donor nephrectomy, methods of graft preservation and treatment of failed allograft were addressed.

The outcomes of simultaneous liver and kidney transplantation using donation after cardiac death organs.

PubMed

Alhamad, Tarek; Spatz, Christin; Uemura, Tadahiro; Lehman, Eric; Farooq, Umar

2014-12-15

There has been a remarkable increase in simultaneous liver and kidney transplantations (SLK). As organ demand has increased, so has the use of donation after cardiac death (DCD). However, little is known about the outcomes of DCD in SLK. We performed a retrospective analysis using the United Network for Organ Sharing database to compare the outcomes of DCD SLK to donation after brain death (DBD) and determine the impact of donor and recipient factors on allograft and patient survival. Between 2002 and 2011, a total of 3,026 subjects received SLK from DBD and 98 from DCD. Kidney, liver, and patient survival from DCD donors were inferior to DBD at 1, 3, and 5 years (P=0.0056, P=0.0035, and P=0.0205, respectively). With the use of the Cox model, DCD was a significant risk factor for kidney and liver allograft failure and patient mortality. Recipient factors that were associated with worse allograft and patient outcomes included black race, diabetes, being on a ventilator, hospitalization, delayed graft function, hepatocellular carcinoma, and intensive care unit stay. Older age of the donor was also associated with worse outcomes. Despite the decreased allograft and patient survival compared with DBD, DCD SLK provides an acceptable option for SLK, with a survival probability of more than 50% at 5 years.

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

PubMed Central

Pellegrini, Giovanni; Siwowska, Klaudia; Haller, Stephanie; Antoine, Daniel J.; Schibli, Roger; Kipar, Anja; Müller, Cristina

2017-01-01

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage. PMID:28635637

Photoacoustic imaging for assessing ischemic kidney damage in vivo

NASA Astrophysics Data System (ADS)

Berndl, Elizabeth S. L.; He, Xiaolin; Yuen, Darren A.; Kolios, Michael C.

2018-02-01

Ischemic reperfusion injuries (IRIs) occur after blood returns to a tissue or organ after a period without oxygen or nutrients, which causes an inflammatory response leading to heterogeneous scarring of the nearby tissue and vasculature. This is associated with long-term decreases blood flow, and necrosis. Although most commonly associated with heart attacks and strokes, IRIs are also a side effect of organ transplants, when the organ is reperfused in the recipient's body after being transported from the donor to the transplant hospital. Currently, the optimal method of monitoring for IRI is limited to biopsies, which are invasive and poorly monitor the spatial heterogeneity of the damage. To non-invasively identify changes in kidneys, the left renal artery in mice (n=3) was clamped for 45 minutes to create an IRI event. Both kidneys of each animal were monitored using photoacoustics (PA) with the VevoLAZR system (Fujifilm-VisualSonics, Toronto) three, four and eight weeks after surgery. IRI-treated kidneys show increased picosirius red staining, indicative of collagen (0.601 vs 0.042, p < 0.0001), decreased size as assessed by cross-sectional area (7.8 mm2 vs 35.9 mm2 , p < 0.0001), and decreased oxygen saturation (sO2; 62% vs 77%, p = 0.02). Analysis of the photoacoustic data shows that a two-point metric, the 715:930 nm ratio of the whole kidney (1.05 vs 0.57, p = 0.049) and the optical spectral slope (OSS) (0.8 * 10-3 vs 3.0 * 10-3, p = 0.013) are both able to differentiate between IRI-treated and healthy kidneys. These data suggest that photoacoustics can be used as a non-invasive method to observe in vivo changes in the kidney due to IRI.

Varied dose exposures to ultrafine particles in the motorcycle smoke cause kidney cell damages in male mice.

PubMed

Wardoyo, Arinto Y P; Juswono, Unggul P; Noor, Johan A E

2018-01-01

Ultrafine particles (UFPs) are one of motorcycle exhaust emissions which can penetrate the lung alveoli and deposit in the kidney. This study was aimed to investigate mice kidney cell physical damage (deformation) due to motorcycle exhaust emission exposures. The motorcycle exhaust emissions were sucked from the muffler with the rate of 33 cm 3 /s and passed through an ultrafine particle filter system before introduced into the mice exposure chamber. The dose concentration of the exhaust emissions was varied by setting the injected time of the 20s, 40s, 60s, 80s, and 100s. The mice were exposed to the smoke in the chamber for 100 s twice a day. The impact of the ultrafine particles on the kidney was observed by identifying the histological image of the kidney cell deformation using a microscope. The exposure was conducted for 10 days. The kidney observations were carried out on day 11. The results showed that there was a significant linear correlation between the total concentration of ultrafine particles deposited in the kidneys and the physical damage percentages. The increased concentrations of ultrafine particles caused larger cell deformation to the kidneys.

Splicing alterations in human renal allografts: detection of a new splice variant of protein kinase Par1/Emk1 whose expression is associated with an increase of inflammation in protocol biopsies of transplanted patients.

PubMed

Hueso, Miguel; Beltran, Violeta; Moreso, Francesc; Ciriero, Eva; Fulladosa, Xavier; Grinyó, Josep Maria; Serón, Daniel; Navarro, Estanis

2004-05-24

Protein kinase Emk1/Par1 (GenBank accession no. X97630) has been identified as a regulator of the immune system homeostasis. Since immunological factors are critical for the development of chronic allograft nephropathy (CAN), we reasoned that expression of Par1/Emk1 could be altered in kidney allografts undergoing CAN. In this paper, we have analysed the association among renal allograft lesions and expression of Par1/Emk1, studied by RT-PCR on total RNA from 51 protocol biopsies of transplanted kidneys, five normal kidneys, and five dysfunctional allografts. The most significant result obtained has been the detection of alterations in the normal pattern of alternative splicing of the Par1/Emk1 transcript, alterations that included loss of expression of constitutively expressed isoforms, and the inclusion of a cryptic exon to generate a new Emk1 isoform (Emk1C). Expression of Emk1C was associated with an increase in the extension of the interstitial infiltrate (0.88+/-0.33 in Emk1C([+]) vs. 0.41+/-0.50 in Emk1C([-]); P<0.011), and with a trend to display higher interstitial scarring (0.66+/-0.70 vs. 0.29+/-0.52; P=0.09) in protocol biopsies when evaluated according to the Banff schema. Moreover, a higher mean arterial pressure (MAP) was also observed (110+/-11 vs. 99+/-11 mm Hg; P=0.012). From these results we propose that Par1/Emk1 could have a role in the development of CAN in kidney allografts.

Revitalization of biostatic tissue allografts: new perspectives in tissue transplantology.

PubMed

Olender, E; Uhrynowska-Tyszkiewicz, I; Kaminski, A

2011-10-01

Biostatic (nonvital) tissue allografts have been used for temporary replacement as well as to trigger, stimulate, and ensure space for the regeneration of a recipient's own tissues. Examples of biostatic allografts routinely used in clinic are bone, tendons, skin, and amniotic membrane. A characteristic feature of biostatic allografts is the lack of living cells. In the recipient's body, biostatic allografts function as scaffolds as well as sources of growth, differentiation, and chemotactic factors. After implantation, recipient cells migrate onto the graft, colonize it, and initiate synthesis of extracellular matrix, thereby regenerating the structure of the lost or damaged tissue. The allograft gradually degrades before being remodeled and substituted by the recipient's new tissue. However, this process is not always effective due to a lack of reaction by recipient cells. New concepts have proposed seeding recipient cells onto the allograft prior to implantation, that is, biostatic allografts that are revitalized ex vivo. The aim of this presentation was to review scientific publications to provide essential information on the revitalization of biostatic allografts, as a rising trend in tissue transplantology. Biostatic allografts show the following advantages: they are human-derived, nontoxic, biocompatible, and, in some cases, already display the desired shape. The process of introducing cells into the biostatic graft is described as "revitalization." The cells used in the process are recipient autologous elements that are either differentiated or progenitor elements. Cells are seeded onto the graft directly after retrieval or after propagation in culture. Revitalized biostatic allografts can be used orthotopically for the regeneration of the same tissue they have been retrieved from or heterotopically wherein the graft retrieved from a different tissue is used as a carrier for cells typical for the tissue to be regenerated. Examples of orthotopic use include

Ginger extract protects rat's kidneys against oxidative damage after chronic ethanol administration.

PubMed

Shirpoor, Aireza; Rezaei, Farzaneh; Fard, Amin Abdollahzade; Afshari, Ali Taghizadeh; Gharalari, Farzaneh Hosseini; Rasmi, Yousef

2016-12-01

Chronic alcohol ingestion is associated with pronounced detrimental effects on the renal system. In the current study, the protective effect of ginger extract on ethanol-induced damage was evaluated through determining 8-OHdG, cystatin C, glomerular filtration rate, and pathological changes such as cell proliferation and fibrosis in rats' kidneys. Male wistar rats were randomly divided into three groups and were treated as follows: (1) control, (2) ethanol and (3) ginger extract treated ethanolic (GETE) groups. After a six weeks period of treatment, the results revealed proliferation of glomerular and tubular cells, fibrosis in glomerular and peritubular and a significant rise in the level of 8-OHdG, cystatin C, plasma urea and creatinine. Moreover, compared to the control group, the ethanol group showed a significant decrease in the urine creatinine and creatinine clearance. In addition, significant amelioration of changes in the structure of kidneys, along with restoration of the biochemical alterations were found in the ginger extract treated ethanolic group, compared to the ethanol group. These findings indicate that ethanol induces kidneys abnormality by oxidative DNA damage and oxidative stress, and that these effects can be alleviated using ginger as an antioxidant and anti-inflammatory agent. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

BK-virus nephropathy and simultaneous C4d positive staining in renal allografts.

PubMed

Honsová, E; Lodererová, A; Viklický, O; Boucek, P

2005-10-01

The role of antibodies in rejection of transplanted kidneys was the subject of debate at the last two Banff meetings and in medical journals. Diffuse C4d positive staining of peritubular capillaries (PTCs) was recognized as a marker of antibody-mediated rejection and this morphological feature was included in the updated Banff schema. At the same time polyomavirus infection of the renal allografts has been reported more frequently and is emerging as an important cause of renal allograft dysfunction and graft loss. At the present time, BK-virus nephropathy (BKN) represents the most common viral disease affecting renal allografts. BKN was identified in 6 patients in 12 biopsies and 2 graft nephrectomy specimens of 1115 biopsies between September 2000 and December 2003. Definite virus identification was done by immunohistochemistry. The reason for graft nephrectomies was graft failure due to BKN in a recipient after kidney-pancreas transplantation with good function of his pancreas graft and the necessity of continuing immunosuppression. Detection of C4d deposits was performed by immunofluorescence or by immunohistochemistry. In graftectomy samples C4d detection was performed by immunohistochemistry and retrospectively in all cases of BKN. Focal C4d positive PTCs and BKN were found simultaneously in 9 of 12 needle biopsies and in both graft nephrectomy samples. Detection of C4d by immunohistochemistry disclosed focal C4d positive staining in kidney tissue but diffuse in the sites where BK-virus inclusions in tubular epithelial cells were found. The complement system is part of the host defense response and is crucial to our natural ability to ward off infection. In cases of BKN, virus likely gains access to the bloodstream through injured tubular walls and via PTCs. Vascular endothelium in the PTCs represents a potential target antigen for alloresponse, and simultaneously possibly represents an imprint of complement activation or complement production in the places

Two-Stage, In Silico Deconvolution of the Lymphocyte Compartment of the Peripheral Whole Blood Transcriptome in the Context of Acute Kidney Allograft Rejection

PubMed Central

Shannon, Casey P.; Balshaw, Robert; Ng, Raymond T.; Wilson-McManus, Janet E.; Keown, Paul; McMaster, Robert; McManus, Bruce M.; Landsberg, David; Isbel, Nicole M.; Knoll, Greg; Tebbutt, Scott J.

2014-01-01

Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially

Risk of Infection After Allograft Anterior Cruciate Ligament Reconstruction: Are Nonprocessed Allografts More Likely to Get Infected? A Cohort Study of Over 10,000 Allografts.

PubMed

Yu, Anthony; Prentice, Heather A; Burfeind, William E; Funahashi, Tadashi; Maletis, Gregory B

2018-03-01

Allograft tissue is frequently used in anterior cruciate ligament reconstruction (ACLR). It is often irradiated and/or chemically processed to decrease the risk of disease transmission, but some tissue is aseptically harvested without further processing. Irradiated and chemically processed allograft tissue appears to have a higher risk of revision, but whether this processing decreases the risk of infection is not clear. To determine the incidence of deep surgical site infection after ACLR with allograft in a large community-based sample and to evaluate the association of allograft processing and the risk of deep infection. Cohort study; Level of evidence, 3. The authors conducted a cohort study using the Kaiser Permanente Anterior Cruciate Ligament Reconstruction Registry. Primary isolated unilateral ACLR with allograft were identified from February 1, 2005 to September 30, 2015. Ninety-day postoperative deep infections were identified via an electronic screening algorithm and then validated through chart review. Logistic regression was used to evaluate the likelihood of 90-day postoperative deep infection per allograft processing method: processed (graft treated chemically and/or irradiated) or nonprocessed (graft not irradiated or chemically processed). Of 10,190 allograft cases, 8425 (82.7%) received a processed allograft, and 1765 (17.3%) received a nonprocessed allograft. There were 15 (0.15%) deep infections during the study period: 4 (26.7%) coagulase-negative Staphylococcus, 4 (26.7%) methicillin-sensitive Staphylococcus aureus, 1 (6.7%) Peptostreptococcus micros, and 6 (40.0%) with no growth. There was no difference in the likelihood for 90-day deep infection for processed versus nonprocessed allografts (odds ratio = 1.36, 95% CI = 0.31-6.04). The overall incidence of deep infection after ACLR with allograft tissue was very low (0.15%), suggesting that the methods currently employed by tissue banks to minimize the risk of infection are effective. In this

Incidence and Risk Factors for Cytomegalovirus Infection in Patients With Kidney Transplantation: A Single-Center Experience.

PubMed

Feng, S; Yang, J; Wang, W; Hu, X; Liu, H; Qian, X; Feng, D; Zhang, X

2016-10-01

Cytomegalovirus (CMV) infection is deemed to be a major cause of morbidity and mortality in patients after kidney transplantation. The purpose of this study was to analyze the incidence of CMV infection and risk factors for CMV infection in our center, to help in determination of its impact on the kidney function in this patient population, and to provide new ideas for the prevention and treatment of CMV infection. A total of 319 kidney transplant recipients from our center were studied between January 2000 and December 2015. The CMV viral load in each kidney transplant patients was monitored with the use of CMV quantitative nucleic acid testing (CMV-QNAT). Laboratory data and other medical records were also collected. The incidence of CMV infection was 8.8% in our studied patients. The patients within 3 to 6 months and 5 to 10 years after transplantation had a higher risk of CMV infection. CMV infection was probably correlated with lower white blood cell counts but elevated hemoglobin, serum creatinine, blood urea nitrogen, potassium, and estimated glomerular filtration rate (eGFR). Anti-CMV immunoglobulin (Ig)G and history of allograft rejection were also associated with CMV infection. In multivariate regression analysis, white blood cells, eGFR, anti-CMV IgG, and history of allograft rejection were the independent risk factors associated with CMV infection in kidney transplantation patients. CMV infection was an important complication after kidney transplantation, particularly in these patients with allograft impairment. Copyright © 2016 Elsevier Inc. All rights reserved.

Comparison of Aerobic Preservation by Venous Systemic Oxygen Persufflation or Oxygenated Machine Perfusion of Warm-Ischemia-Damaged Porcine Kidneys.

PubMed

Kalenski, Julia; Mancina, Elina; Paschenda, Pascal; Beckers, Christian; Bleilevens, Christian; Tóthová, Ľubomíra; Boor, Peter; Gross, Dominik; Tolba, René H; Doorschodt, Benedict M

2016-01-01

The global shortage of donor organs for transplantation has necessitated the expansion of the organ pool through increased use of organs from less ideal donors. Venous systemic oxygen persufflation (VSOP) and oxygenated machine perfusion (OMP) have previously demonstrated beneficial results compared to cold storage (CS) in the preservation of warm-ischemia-damaged kidney grafts. The aim of this study was to compare the efficacy of VSOP and OMP for the preservation of warm-ischemia-damaged porcine kidneys using the recently introduced Ecosol preservation solution compared to CS using Ecosol or histidine-tryptophan-ketoglutarate solution (HTK). Kidneys from German Landrace pigs (n = 5/group) were retrieved and washed out with either Ecosol or HTK after 45 min of clamping of the renal pedicle. As controls, kidneys without warm ischemia, cold stored for 24 h in HTK, were employed. Following 24 h of preservation by VSOP, OMP, CS-Ecosol, or CS-HTK, renal function and damage were assessed during 1 h using the isolated perfused porcine kidney model. During reperfusion, urine production was significantly higher in the VSOP and OMP groups than in the CS-HTK group; however, only VSOP could demonstrate lower urine protein concentrations and fractional excretion of sodium, which did not differ from the non-warm-ischemia-damaged control group. VSOP, CS-Ecosol, and controls showed better maintenance of the acid-base balance than CS-HTK. Reduced lipid peroxidation, as reflected in postreperfusion tissue thiobarbituric acid-reactive substance levels, was observed in the VSOP group compared to the OMP group, and the VSOP and CS-Ecosol groups had concentrations similar to the controls. The ratio of reduced to oxidized glutathione was higher in the VSOP, OMP, and CS-Ecosol groups than in the CS-HTK group and controls, with a higher ratio in the VSOP than in the OMP group. VSOP was associated with mitigation of oxidative stress in comparison to OMP and CS. Preservation of warm-ischemia-damaged

Renal Allograft Function Is a Risk Factor of Left Ventricular Remodeling After Kidney Transplantation.

PubMed

Koo, T Y; Ahn, C; Yang, J

2017-06-01

Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplantation (KT) patients. The prevalence of left ventricular hypertrophy increases with the progression of renal insufficiency. We investigated the association between the progression of renal insufficiency and left ventricular hypertrophy after KT. We reviewed KT patients at Seoul National University Hospital from January 1973 to December 2009. The creatinine elevation ratio (CER, the percentage change in the creatinine level from 1 month to 5 years after transplant) was calculated as follows: (creatinine level at 5 years minus creatinine level at 1 month)/creatinine level at 1 month × 100. The study population was classified into a high-CER group (CER ≥25%) and low-CER group (CER <25%). Mean left ventricular mass index (LVMI) values were 135.7 and 134.7 g/m 2 before KT and 101.7 and 123.7 g/m 2 at 5 years after KT in the low-CER and high-CER groups, respectively. The LVMI before or 1 year after KT was not different between the 2 groups, but the LVMI at 5 years post-transplant was higher in the high-CER group than in the low-CER group. The LVMI increased after its initial decrease in the high-CER group, whereas its reduction was maintained in the low-CER group during the 5 years after KT (P = .009, repeated-measures analysis of variance). These data suggest that deterioration of renal allograft function is associated with left ventricular remodeling after KT. Copyright © 2017 Elsevier Inc. All rights reserved.

Association between Delayed graft function (DGF) biomarkers and long-term outcomes after living donor kidney transplantation.

PubMed

Sahraei, Zahra; Mehdizadeh, Mona; Salamzadeh, Jamshid; Nafar, Mohsen; Eshraghi, Azadeh

2018-05-21

The Association between preoperative Urine Neutrophil Gelatinase-associated Lipocalin (uNGAL) and interlukin-18 (uIL-18) with poor 1-year allograft function has been shown in deceased-donor kidney transplant recipients previously, and also these markers could predict 3-month allograft function. However, it is unknown whether there is any association between these postoperative biomarkers with important recipient outcomes beyond this time in live-donor transplants. NGAL and IL-18 four and 24 hours were measured in live-donor kidney transplant recipients after transplantation. The relationships between changes in these markers with clinical outcomes as well as kidney function were examined at 1 month and 2 years. Also, the association between delayed graft function with clinical outcome and serum creatinine (SrCr) were evaluated during this period. The Mean age for kidney recipients was 23.9 years. There was significant interaction between uNGAL 24 hr (pvalue=0.01) and uIL-18 four and 24 hr after transplantation (pvalue=0.04, 0.03; respectively) with patients' outcome after 1 month and changes in uNGAL with outcomes after 2 years (pvalue= 0.04). Changes in urine NGAL postoperative is associated with worse outcome 2 years after kidney transplantation, suggesting its potential role for identifying patients that are at high risk for diminished allograft function, outcome and survival. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[The diagnostic importance of the new marker KIM-1 in kidney damage].

PubMed

Marchewka, Zofia; Płonka, Joanna

2013-07-24

In recent years, the rapid development of scientific research led to the introduction of strategies based on new markers that allow for estimation of the latent disease period before the clinical symptoms of actual kidney failure are revealed. The experimental tests carried out on animals and cell lines derived from the proximal tubule have made possible the detection of genes that are induced early after hypoxia. The protein products of these genes can be considered as useful markers for the diagnosis of renal failure. The induction of gene KIM-1 (called Kidney Injury Molecule-1) results in the formation of protein that can be considered as a diagnostic marker. This work describes the data on the structure, biological function and importance of determining the concentrations of KIM-1 in the diagnosis of drug-induced toxicity and kidney damage.

The mitochondria-targeted antioxidants and remote kidney preconditioning ameliorate brain damage through kidney-to-brain cross-talk.

PubMed

Silachev, Denis N; Isaev, Nikolay K; Pevzner, Irina B; Zorova, Ljubava D; Stelmashook, Elena V; Novikova, Svetlana V; Plotnikov, Egor Y; Skulachev, Vladimir P; Zorov, Dmitry B

2012-01-01

Many ischemia-induced neurological pathologies including stroke are associated with high oxidative stress. Mitochondria-targeted antioxidants could rescue the ischemic organ by providing specific delivery of antioxidant molecules to the mitochondrion, which potentially suffers from oxidative stress more than non-mitochondrial cellular compartments. Besides direct antioxidative activity, these compounds are believed to activate numerous protective pathways. Endogenous anti-ischemic defense may involve the very powerful neuroprotective agent erythropoietin, which is mainly produced by the kidney in a redox-dependent manner, indicating an important role of the kidney in regulation of brain ischemic damage. The goal of this study is to track the relations between the kidney and the brain in terms of the amplification of defense mechanisms during SkQR1 treatment and remote renal preconditioning and provide evidence that the kidney can generate signals inducing a tolerance to oxidative stress-associated brain pathologies. We used the cationic plastoquinone derivative, SkQR1, as a mitochondria-targeted antioxidant to alleviate the deleterious consequences of stroke. A single injection of SkQR1 before cerebral ischemia in a dose-dependent manner reduces infarction and improves functional recovery. Concomitantly, an increase in the levels of erythropoietin in urine and phosphorylated glycogen synthase kinase-3β (GSK-3β) in the brain was detected 24 h after SkQR1 injection. However, protective effects of SkQR1 were not observed in rats with bilateral nephrectomy and in those treated with the nephrotoxic antibiotic gentamicin, indicating the protective role of humoral factor(s) which are released from functional kidneys. Renal preconditioning also induced brain protection in rats accompanied by an increased erythropoietin level in urine and kidney tissue and P-GSK-3β in brain. Co-cultivation of SkQR1-treated kidney cells with cortical neurons resulted in enchanced

Regulatory dendritic cell infusion prolongs kidney allograft survival in nonhuman primates.

PubMed

Ezzelarab, M B; Zahorchak, A F; Lu, L; Morelli, A E; Chalasani, G; Demetris, A J; Lakkis, F G; Wijkstrom, M; Murase, N; Humar, A; Shapiro, R; Cooper, D K C; Thomson, A W

2013-08-01

We examined the influence of regulatory dendritic cells (DCreg), generated from cytokine-mobilized donor blood monocytes in vitamin D3 and IL-10, on renal allograft survival in a clinically relevant rhesus macaque model. DCreg expressed low MHC class II and costimulatory molecules, but comparatively high levels of programmed death ligand-1 (B7-H1), and were resistant to pro-inflammatory cytokine-induced maturation. They were infused intravenously (3.5-10 × 10(6) /kg), together with the B7-CD28 costimulation blocking agent CTLA4Ig, 7 days before renal transplantation. CTLA4Ig was given for up to 8 weeks and rapamycin, started on Day -2, was maintained with tapering of blood levels until full withdrawal at 6 months. Median graft survival time was 39.5 days in control monkeys (no DC infusion; n = 6) and 113.5 days (p < 0.05) in DCreg-treated animals (n = 6). No adverse events were associated with DCreg infusion, and there was no evidence of induction of host sensitization based on circulating donor-specific alloantibody levels. Immunologic monitoring also revealed regulation of donor-reactive memory CD95(+) T cells and reduced memory/regulatory T cell ratios in DCreg-treated monkeys compared with controls. Termination allograft histology showed moderate combined T cell- and Ab-mediated rejection in both groups. These findings justify further preclinical evaluation of DCreg therapy and their therapeutic potential in organ transplantation. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

Outcomes of Renal Allograft Recipients With Hepatitis C.

PubMed

Carpio, R; Pamugas, G E; Danguilan, R; Que, E

2016-04-01

Studies on the effect of hepatitis C virus (HCV) infection showed decreased graft survival compared to HCV-negative matched patients. It was also identified as an independent risk factor for graft loss and mortality in kidney transplantation patients. This study was designed to evaluate the 10-year graft and patient outcomes of renal allograft recipients with HCV infection at the National Kidney and Transplant Institute. This is a retrospective study of patients who underwent renal transplantation with HCV infection and a group who were HCV-negative in the same post-transplantation period. Data were gathered from the in-patient and out-patient clinic records. Patient survival was significantly lower in the HCV-positive than in the HCV-negative group. The mean duration of patient survival was 154.95 (+4.95) months (12 years and 10 months) in HCV-negative patients compared to 141 (+6.52) months (11 years and 9 months) in the HCV-positive group (P = .05). Graft survival did not differ significantly between HCV-positive and HCV-negative recipients (P = .734). The mean duration of graft survival was 137 (+7.68) months (11 years and 5 months) in HCV-negative patients compared to 130 (+6.84) months (10 years and 10 months) in HCV-positive patients. Short- and long-term outcomes including biopsy-proven acute rejection, transplant glomerulopathy, chronic allograft nephropathy, renal function, and proteinuria were similar in both groups. Rejection, glomerulopathy, and renal function were similar in both groups. HCV progression was also observed in patients with detectable HCV-RNA 6 months before transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes

PubMed Central

Habib, Samy L.; Liang, Sitai

2014-01-01

Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have explored one of the mechanisms by which diabetes accelerates tumorigenesis in the kidney. Kidney cancer tissue from patients with diabetes showed a higher activity of Akt and decreased in total protein of tuberin compared to kidney cancer patient without diabetes or diabetes alone. In addition, a significant increase in phospho-Akt/tuberin expression was associated with an increase in Ki67 expression and activation of mTOR in kidney tumor with or without diabetes compared to diabetes alone. In addition, decrease in tuberin expression resulted in a significant decrease in protein expression of OGG1 and increased in oxidative DNA damage, 8-oxodG in kidney tissues from patients with cancer or cancer+diabetes. Importantly, these data showed that the majority of the staining of Akt/tuberin/p70S6K phosphorylation was more prominently in the tubular cells. In addition, accumulation of oxidative DNA damage is localized only in the nucleus of tubular cells within the cortex region. These data suggest that Akt/tuberin/mTOR pathway plays an important role in the regulation DNA damage and repair pathways that may predispose diabetic kidneys to pathogenesis of renal cell carcinoma. PMID:24797175

Allograft integration in a rabbit transgenic model for anterior cruciate ligament reconstruction.

PubMed

Bachy, M; Sherifi, I; Zadegan, F; Petite, H; Vialle, R; Hannouche, D

2016-04-01

Tissue engineering strategies include both cell-based and cell homing therapies. Ligamentous tissues are highly specialized and constitute vital components of the musculoskeletal system. Their damage causes significant morbidity and loss in function. The aim of this study is to analyze tendinous graft integration, cell repopulation and ligamentization by using GFP+/- allografts in GFP+/- transgenic New Zealand white (NZW) rabbits. Graft implantation was designed to closely mimic anterior cruciate ligament (ACL) repair surgery. Allografts were implanted in 8 NZW rabbits and assessed at 5 days, 3 weeks and 6 weeks through: (1) arthroCT imaging, (2) morphological analysis of the transplanted allograft, (3) histological analysis, (4) collagen type I immunochemistry, and (5) GFP cell tracking. Collagen remodeling was appreciated at 3 and 6 weeks. Graft repopulation with host cells, chondrocyte-like cells at the tendon-bone interface and graft corticalization in the bone tunnels were noticed at 3 weeks. By contrast we noticed a central necrosis aspect in the allografts intra-articularly at 6 weeks with a cell migration towards the graft edge near the synovium. Our study has served to gain a better understanding of tendinous allograft bone integration, ligamentization and allograft repopulation. We believe that both cell-based therapies and cell homing therapies are beneficial in ligament tissue engineering. Future studies may elucidate whether cell repopulation occurs with pre-differentiated or progenitor cells. We believe that both cell-based therapies and cell homing therapies are beneficial in ligament tissue engineering. Level V (animal study). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Osteochondral allograft.

PubMed

Torrie, Arissa M; Kesler, William W; Elkin, Joshua; Gallo, Robert A

2015-12-01

Over the past decade, osteochondral allograft transplantation has soared in popularity. Advances in storage techniques have demonstrated improved chondrocyte viability at longer intervals and allowed for potential of increased graft availability. Recent studies have stratified outcomes according to location and etiology of the chondral or osteochondral defect. Unipolar lesions generally have favorable outcomes with promising 10-year survival rates. Though those undergoing osteochondral allograft transplantation often require reoperation, patient satisfaction remains high.

Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.

PubMed

Lin, Huan-Tang; Liu, Fu-Chao; Lin, Jr-Rung; Pang, See-Tong; Yu, Huang-Ping

2018-06-04

Most patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients. Retrospective nationwide cohort study. Data retrieved from the Taiwan National Health Insurance Research Database. The National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation. The pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model. There were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant

Oxidative Stress as a Mechanism Involved in Kidney Damage After Subchronic Exposure to Vanadium Inhalation and Oral Sweetened Beverages in a Mouse Model.

PubMed

Espinosa-Zurutuza, Maribel; González-Villalva, Adriana; Albarrán-Alonso, Juan Carlos; Colín-Barenque, Laura; Bizarro-Nevares, Patricia; Rojas-Lemus, Marcela; López-Valdéz, Nelly; Fortoul, Teresa I

Kidney diseases have notably increased in the last few years. This is partially explained by the increase in metabolic syndrome, diabetes, and systemic blood hypertension. However, there is a segment of the population that has neither of the previous risk factors, yet suffers kidney damage. Exposure to atmospheric pollutants has been suggested as a possible risk factor. Air-suspended particles carry on their surface a variety of fuel combustion-related residues such as metals, and vanadium is one of these. Vanadium might produce oxidative stress resulting in the damage of some organs such as the kidney. Additionally, in countries like Mexico, the ingestion of sweetened beverages is a major issue; whether these beverages alone are responsible for direct kidney damage or whether their ingestion promotes the progression of an existing renal damage generates controversy. In this study, we report the combined effect of vanadium inhalation and sweetened beverages ingestion in a mouse model. Forty CD-1 male mice were distributed in 4 groups: control, vanadium inhalation, 30% sucrose in drinking water, and vanadium inhalation plus sucrose 30% in drinking water. Our results support that vanadium inhalation and the ingestion of 30% sucrose induce functional and histological kidney damage and an increase in oxidative stress biomarkers, which were higher in the combined effect of vanadium plus 30% sucrose. The results also support that the ingestion of 30% sucrose alone without hyperglycemia also produces kidney damage.

Urine protein profiling identified alpha-1-microglobulin and haptoglobin as biomarkers for early diagnosis of acute allograft rejection following kidney transplantation.

PubMed

Stubendorff, Beatrice; Finke, Stephanie; Walter, Martina; Kniemeyer, Olaf; von Eggeling, Ferdinand; Gruschwitz, Torsten; Steiner, Thomas; Ott, Undine; Wolf, Gunter; Wunderlich, Heiko; Junker, Kerstin

2014-12-01

Early diagnosis of acute rejection and effective immunosuppressive therapy lead to improvement in graft survival following kidney transplantation. In this study, we aimed to establish a urinary protein profile suitable to distinguish between patients with rejection and stable graft function and to predict acute rejection based on postoperatively collected urine samples. A further objective was to identify candidate proteins for the use as biomarkers in clinical practice. Urine samples of 116 kidney recipients were included. Rejection was proven by biopsy (n = 58), and stable transplant function was monitored for at least 2 years (n = 58). Postoperative urine samples were collected between 3rd and 10th day following transplantation. Urinary protein profiles were obtained by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Protein identification and validation were performed using multiplex fluorescence 2DE, peptide mass fingerprinting and enzyme-linked immunosorbent assay. A protein profile including four mass peaks differentiated acute rejection from stable transplants at the time point of rejection and at the postoperative state with 73 % sensitivity and 88 % specificity. Alpha-1-microglobulin (A1MG) and Haptoglobin (Hp) were identified as putative rejection biomarkers. Protein levels were significantly higher in postoperative urine from patients with rejection (A1MG 29.13 vs. 22.06 μg/ml, p = 0.001; Hp 628.34 vs. 248.57 ng/ml, p = 0.003). The combination of both proteins enabled the diagnosis of early rejection with 85 % sensitivity and 80 % specificity. Protein profiling using mass spectrometry is suitable for noninvasive detection of rejection-specific changes following kidney transplantation. A specific protein profile enables the prediction of early acute allograft rejection in the immediate postoperative period. A1MG and Hp appear to be reliable rejection biomarkers.

Sodium fluoride induces apoptosis in the kidney of rats through caspase-mediated pathways and DNA damage.

PubMed

Song, Guo Hua; Gao, Ji Ping; Wang, Chun Fang; Chen, Chao Yang; Yan, Xiao Yan; Guo, Min; Wang, Yu; Huang, Fu Bing

2014-09-01

Long-term excessive sodium fluoride (NaF) intake can cause many bone diseases and nonskeletal fluorosis. The kidneys are the primary organs involved in the excretion and retention of NaF. The objective of the present study was to determine the effects of NaF treatment on renal cell apoptosis, DNA damage, and the protein expression levels of cytosolic cytochrome C (Cyt C) and cleaved caspases 9, 8, and 3 in vivo. Male Sprague-Dawley rats were divided randomly into four groups (control, low fluoride, medium fluoride, and high fluoride) and administered 0, 50, 100, and 200 mg/L of NaF, respectively, via drinking water for 120 days. Histopathological changes in the kidneys were visualized using hematoxylin and eosin staining. Renal cell apoptosis was examined using flow cytometry, and renal cell DNA damage was detected using the comet assay. Cytosolic Cyt C and cleaved caspases 9, 8, and 3 protein expression levels were visualized using immunohistochemistry and Western blotting. The results showed that NaF treatment increased apoptosis and DNA damage. In addition, NaF treatment increased the protein expression levels of cytosolic Cyt C and cleaved caspases 9, 8, and 3. These results indicated that NaF induces apoptosis in the kidney of rats through caspase-mediated pathway, and DNA damage may be involved in this process.

Post-transplantation nephroptosis causing recurrent episodes of acute renal failure and hypertension secondary to intermittent vascular torsion of intraperitoneal renal allograft

PubMed Central

Dosch, Austin R.; Pahl, Madeleine; Reddy, Uttam; Foster, Clarence E.

2017-01-01

Abstract Nephroptosis is a rare complication in renal transplantation, but one with significant associated risk. Due to non-specific clinical features, there may be a substantial delay in diagnosis and loss of the transplanted kidney due to renal pedicle thrombosis. We present a case of post-transplantation nephroptosis after simultaneous pancreas and kidney transplant, which resulted in accelerated hypertension and reversible acute kidney injury >1 year after transplantation. Prompt detection of this rare entity leading to expeditious surgical intervention is necessary to preserve viability of the renal allograft. PMID:28560019

Effect of Long-Term Systolic Blood Pressure Trajectory on Kidney Damage in the Diabetic Population: A Prospective Study in a Community-Based Chinese Cohort.

PubMed

Li, Jian-Chao; Tian, Jun; Wu, Shou-Ling; Wang, Zhi-Jun; Zhang, Xiao-Fei; Jia, Dao; Ding, Rong-Jing; Xiao, Xiong-Fu; Fan, Yu-Bo; Hu, Da-Yi

2018-05-20

Previous studies have shown that hypertension is an important factor contributing to the occurrence and progression of diabetic kidney damage. However, the relationship between the patterns of blood pressure (BP) trajectory and kidney damage in the diabetic population remains unclear. This prospective study investigated the effect of long-term systolic BP (SBP) trajectory on kidney damage in the diabetic population based on an 8-year follow-up community-based cohort. This study included 4556 diabetic participants among 101,510 participants. BP, estimated glomerular filtration rate (eGFR), and urinary protein were measured every 2 years from 2006 to 2014. SBP trajectory was identified by the censored normal modeling. Five discrete SBP trajectories were identified according to SBP range and the changing pattern over time. Kidney damage was evaluated through eGFR and urinary protein value. A multivariate logistic regression model was used to analyze the influence of different SBP trajectory groups on kidney damage. We identified five discrete SBP trajectories: low-stable group (n = 864), moderate-stable group (n = 1980), moderate increasing group (n = 609), elevated decreasing group, (n = 679), and elevated stable group (n = 424). The detection rate of kidney damage in the low-stable group (SBP: 118-124 mmHg) was the lowest among the five groups. The detection rate of each kidney damage index was higher in the elevated stable group (SBP: 159-172 mmHg) compared with the low-stable group. For details, the gap was 4.14 (11.6% vs. 2.8%) in eGFR <60 ml·min -1 ·1.73 m -2 and 3.66 (17.2% vs. 4.7%), 3.38 (25.0% vs. 7.4%), and 1.8 (10.6% vs. 5.9%) times in positive urinary protein, eGFR <60 ml·min -1 ·1.73 m -2 and/or positive urinary protein, and eGFR decline ≥30%, respectively (P < 0.01). An elevated stable SBP trajectory is an independent risk factor for kidney damage in the diabetic population.

Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients.

PubMed

Sofue, Tadashi; Inui, Masashi; Hara, Taiga; Nishijima, Yoko; Moriwaki, Kumiko; Hayashida, Yushi; Ueda, Nobufumi; Nishiyama, Akira; Kakehi, Yoshiyuki; Kohno, Masakazu

2014-01-01

Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU. Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups. The FX group showed significantly greater decreases in serum uric acid (-2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96-10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m(2) versus 47±19 mL/min/1.73 m(2)), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m(2) versus -0.2±6.9 mL/min/1.73 m(2) per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%). Treatment with febuxostat sufficiently

Gender bias in Iranian living kidney transplantation program: a national report.

PubMed

Taheri, Saeed; Alavian, Seyed M; Einollahi, Behzad; Nafar, Mohsen

2010-01-01

Strong challenges exist about living kidney transplantation practices worldwide. One of these concerns is based on the observation that in many places women constitute the majority of living kidney donors but the minority of recipients. We studied this issue in Iran by using national data for kidney transplantation. Data of the Iranian national registry for kidney transplantation which comprises data of all renal transplantations performed in the country during a 22 yr period were included in the study. Data of 16,672 living donors (living related [LR]=16%, living unrelated [LUR]=86%) were analyzed. Males received 62.2% of all kidney transplants. From 16,672 living donors, 20% and 80% were women and men, respectively. Recipients were more likely to receive kidney allograft from their own gender groups (p<0.05). In living related donations, mothers, brothers and sons were significantly more often donors than their counterparts of opposite gender. In contrast with previous reports from other countries, this study of Iranian national data revealed that in Iran, most related and unrelated living kidney donors are male and the percentage of recipients who are female exceeds the percentage of donors who are female. Considering previous reports from other countries, our findings suggest that Iran is the only country in which females are more likely to be recipients of a kidney allograft than donors. The reason for the predominance of male kidney donors in Iran is probably multifactorial and associated with economical, social and cultural issues. The financial incentives paid to living unrelated donors may be an attraction for males to donate a kidney although, even in living related donations, males constitute the majority of donors. © 2009 John Wiley & Sons A/S.

Acute Kidney Failure

MedlinePlus

... through your urine Impaired blood flow to the kidneys Diseases and conditions that may slow blood flow ... anaphylaxis) Severe burns Severe dehydration Damage to the kidneys These diseases, conditions and agents may damage the ...

Nerve Damage From Bone Allografts and Xenografts-A Case Series.

PubMed

Pogrel, M Anthony

2017-07-01

The concept of socket preservation by placing a particulate bone allograft or xenograft into a tooth socket or on the alveolar ridge after tooth removal remains a somewhat controversial topic. The concept is that it will preserve the ridge from resorption and such that subsequent implant insertion will be easier, with fewer complications. However, one particular issue is that these materials, although not directly neurotoxic, appear to be an irritant to the nerves if they come in contact with them. We present a case series demonstrating this complication. Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Regulatory dendritic cell infusion prolongs kidney allograft survival in non-human primates

PubMed Central

Ezzelarab, M.; Zahorchak, A.F.; Lu, L.; Morelli, A.E.; Chalasani, G.; Demetris, A.J.; Lakkis, F.G.; Wijkstrom, M.; Murase, N.; Humar, A.; Shapiro, R.; Cooper, D.K.C.; Thomson, A.W.

2014-01-01

We examined the influence of regulatory dendritic cells (DCreg), generated from cytokine-mobilized donor blood monocytes in vitamin D3 and IL-10, on renal allograft survival in a clinically-relevant rhesus macaque model. DCreg expressed low MHC class II and costimulatory molecules, but comparatively high levels of programmed death ligand-1 (B7-H1), and were resistant to pro-inflammatory cytokine-induced maturation. They were infused intravenously (3.5–10×106/kg), together with the B7-CD28 costimulation blocking agent CTLA4Ig, 7 days before renal transplantation. CTLA4Ig was given for up to 8 weeks and rapamycin, started on day −2, was maintained with tapering of blood levels until full withdrawal at 6 months. Median graft survival time was 39.5 days in control monkeys (no DC infusion; n=6) and 113.5 days (p< 0.05) in DCreg-treated animals (n=6). No adverse events were associated with DCreg infusion, and there was no evidence of induction of host sensitization based on circulating donor-specific alloantibody levels. Immunologic monitoring also revealed regulation of donor-reactive memory CD95+ T cells and reduced memory/regulatory T cell ratios in DCreg-treated monkeys compared with controls. Termination allograft histology showed moderate combined T cell- and Ab-mediated rejection in both groups. These findings justify further pre-clinical evaluation of DCreg therapy and their therapeutic potential in organ transplantation. PMID:23758811

Deceased-Donor Smoking History Is Associated With Increased Recipient Mortality After Kidney Transplant: A Population-Cohort Study.

PubMed

Gillott, Holly; Jackson Spence, Francesca; Tahir, Sanna; Hodson, James; Nath, Jay; Sharif, Adnan

2018-05-16

Historical data have suggested that donor smoking is associated with detrimental clinical outcomes for recipients of kidneys from deceased donors. However, the effects of smoking status of a kidney donor on the outcomes of the recipient in a contemporary setting of immunosuppression and transplant practice have not yet been ascertained. This retrospective, population-cohort study analyzed data of all deceased-donor kidney-alone transplant procedures performed in the United Kingdom between April 2001 and April 2013. Our study included 11?199 deceased-donor kidney allograft recipients, with median follow-up of 46 months posttransplant. In our cohort, 5280 deceased donors (47.1%) had a documented history of smoking. Deceased donors with versus those without smoking history were more likely to be younger (mean age of 48 vs 50 years; P < .001), be of white ethnicity (96.6% vs 95.3%; P < .001), and have brain death before donation (77.1% vs 74.9%; P = .006). On unadjusted survival analyses, overall patient survival was significantly shorter in patients who received kidney allografts from deceased donors with smoking history (hazard ratio of 1.12, 95% confidence interval, 1.00-1.25; P = .044). No significant association was seen for death-censored or overall graft survival. Our multivariate survival analyses showed that, after accounting for confounding factors, the effects of donor smoking status remained significant for patient survival (hazard ratio of 1.16, 95% CI, 1.03-1.29; P =.011) but not graft survival. This population-cohort study suggests that deceased-donor kidneys from smokers contribute to an increased risk of death for kidney allograft recipients. These study findings imply donor smoking history should be factored into the risk stratification decision for recipient selection to optimize decision making; however, further clarification and validation of these data are warranted.

Associations among environmental exposure to manganese, neuropsychological performance, oxidative damage and kidney biomarkers in children.

PubMed

Nascimento, Sabrina; Baierle, Marília; Göethel, Gabriela; Barth, Anelise; Brucker, Natália; Charão, Mariele; Sauer, Elisa; Gauer, Bruna; Arbo, Marcelo Dutra; Altknecht, Louise; Jager, Márcia; Dias, Ana Cristina Garcia; de Salles, Jerusa Fumagalli; Saint' Pierre, Tatiana; Gioda, Adriana; Moresco, Rafael; Garcia, Solange Cristina

2016-05-01

Environmental exposure to manganese (Mn) results in several toxic effects, mainly neurotoxicity. This study investigated associations among Mn exposure, neuropsychological performance, biomarkers of oxidative damage and early kidney dysfunction in children aged 6-12 years old. Sixty-three children were enrolled in this study, being 43 from a rural area and 20 from an urban area. Manganese was quantified in blood (B-Mn), hair (H-Mn) and drinking water using inductively coupled plasma mass spectrometry (ICP-MS). The neuropsychological functions assessed were attention, perception, working memory, phonological awareness and executive functions - inhibition. The Intelligence quotient (IQ) was also evaluated. The biomarkers malondialdehyde (MDA), protein carbonyls (PCO), δ-aminolevulinate dehydratase (ALA-D), reactivation indexes with dithiothreitol (ALA-RE/DTT) and ZnCl2 (ALA-RE/ZnCl2), non-protein thiol groups, as well as microalbuminuria (mALB) level and N-acetyl-β-D-glucosaminidase (NAG) activity were assessed. The results demonstrated that Mn levels in blood, hair and drinking water were higher in rural children than in urban children (p<0.01). Adjusted for potential confounding factors, IQ, age, gender and parents' education, significant associations were observed mainly between B-Mn and visual attention (β=0.649; p<0.001). Moreover, B-Mn was negatively associated with visual perception and phonological awareness. H-Mn was inversely associated with working memory, and Mn levels from drinking water with written language and executive functions - inhibition. Rural children showed a significant increase in oxidative damage to proteins and lipids, as well as alteration in kidney function biomarkers (p<0.05). Moreover, significant associations were found between B-Mn, H-Mn and Mn levels in drinking water and biomarkers of oxidative damage and kidney function, besides between some oxidative stress biomarkers and neuropsychological tasks (p<0.05). The findings of this

Tertiary Excess of Fibroblast Growth Factor 23 and Hypophosphatemia Following Kidney Transplantation

PubMed Central

Seeherunvong, Wacharee; Wolf, Myles

2010-01-01

Hypophosphatemia due to inappropriate urinary phosphate wasting is a frequent metabolic complication of the early period following kidney transplantation. Although previously considered to be caused by tertiary hyperparathyroidism, recent evidence suggests a primary role for persistently elevated circulating levels of the phosphorus-regulating hormone, fibroblast growth factors 23 (FGF23). In the setting of a healthy renal allograft, markedly increased FGF23 levels from the dialysis period induce renal phosphate wasting and inhibition of calcitriol production, which contribute to hypophosphatemia. While such tertiary FGF23 excess and resultant hypophosphatemia typically abates within the first few weeks to months post-transplant, some recipients manifest persistent renal phosphate wasting. Furthermore, increased FGF23 levels have been associated with increased risk of kidney disease progression, cardiovascular disease and death outside of the transplant setting. Whether tertiary FGF23 excess is associated with adverse transplant outcomes is unknown. In this article, we review the physiology of FGF23, summarize its relationship with hypophosphatemia after kidney transplantation, and speculate on its potential impact on long term outcomes of renal allograft recipients. PMID:20946192

Haloperidol-loaded lipid-core polymeric nanocapsules reduce DNA damage in blood and oxidative stress in liver and kidneys of rats

NASA Astrophysics Data System (ADS)

Roversi, Katiane; Benvegnú, Dalila M.; Roversi, Karine; Trevizol, Fabíola; Vey, Luciana T.; Elias, Fabiana; Fracasso, Rafael; Motta, Mariana H.; Ribeiro, Roseane F.; dos S. Hausen, Bruna; Moresco, Rafael N.; Garcia, Solange C.; da Silva, Cristiane B.; Burger, Marilise E.

2015-04-01

Haloperidol (HP) nanoencapsulation improves therapeutic efficacy, prolongs the drug action time, and reduces its motor side effects. However, in a view of HP toxicity in organs like liver and kidneys in addition to the lack of knowledge regarding the toxicity of polymeric nanocapsules, our aim was to verify the influence of HP-nanoformulation on toxicity and oxidative stress markers in the liver and kidneys of rats, also observing the damage caused in the blood. For such, 28 adult male Wistar rats were designated in four experimental groups ( n = 7) and treated with vehicle (C group), free haloperidol suspension (FH group), blank nanocapsules suspension (B-Nc group), and haloperidol-loaded lipid-core nanocapsules suspension (H-Nc group). The nanocapsules formulation presented the size of approximately 250 nm. All suspensions were administered to the animals (0.5 mg/kg/day-i.p.) for a period of 28 days. Our results showed that FH caused damage in the liver, evidenced by increased lipid peroxidation, plasma levels of aspartate aminotransferase, and alanine aminotransferase, as well as decreased cellular integrity and vitamin C levels. In kidneys, FH treatment caused damage to a lesser extent, observed by decreased activity of δ-aminolevulinate dehydratase (ALA-D) and levels of VIT C. In addition, FH treatment was also related to a higher DNA damage index in blood. On the other hand, animals treated with H-Nc and B-Nc did not show damage in liver, kidneys, and DNA. Our study indicates that the nanoencapsulation of haloperidol was able to prevent the sub-chronic toxicity commonly observed in liver, kidneys, and DNA, thus reflecting a pharmacological superiority in relation to free drug.

Intragraft vascular occlusive sickle crisis with early renal allograft loss in occult sickle cell trait.

PubMed

Kim, Lisa; Garfinkel, Marc R; Chang, Anthony; Kadambi, Pradeep V; Meehan, Shane M

2011-07-01

Early renal allograft failure due to sickle cell trait is rare. We present clinical and pathologic findings in 2 cases of early renal allograft failure associated with renal vein thrombosis and extensive erythrocyte sickling. Hemoglobin AS was identified in retrospect. In case 1, a 41-year-old female recipient of a deceased donor renal transplant developed abdominal pain and acute allograft failure on day 16, necessitating immediate nephrectomy. In case 2, the transplanted kidney in a 58-year-old female recipient was noted to be mottled blue within minutes of reperfusion. At 24 hours, the patient was oliguric; and the graft was removed. Transplant nephrectomies had diffuse enlargement with diffuse, nonhemorrhagic, cortical, and medullary necrosis. Extensive sickle vascular occlusion was evident in renal vein branches; interlobar, interlobular, and arcuate veins; vasa recta; and peritubular capillaries. The renal arteries had sickle vascular occlusion in case 1. Glomeruli had only focal sickle vascular occlusion. The erythrocytes in sickle vascular occlusion had abundant cytoplasmic filaments by electron microscopy. Acute rejection was not identified in either case. Protein C and S levels, factor V Leiden, and lupus anticoagulant assays were within normal limits. Hemoglobin analysis revealed hemoglobin S of 21.8% and 25.6%, respectively. Renal allograft necrosis with intragraft sickle crisis, characterized by extensive vascular occlusive erythrocyte sickling and prominent renal vein thrombosis, was observed in 2 patients with sickle cell trait. Occult sickle cell trait may be a risk factor for early renal allograft loss. Copyright © 2011 Elsevier Inc. All rights reserved.

Ultrasonography parameters and histopathology findings in transplanted kidney.

PubMed

Rigler, A A; Vizjak, A; Ferluga, D; Kandus, A; Buturović-Ponikvar, J

2013-05-01

Until now studies have shown conflicting results about morphologic and hemodynamic parameters in predicting histopathology results in renal graft malfunction. We sought to analyze whether parenchymal thickness relative to graft length and resistive index (RI) measured by ultrasonography can predict histopathology findings on renal biopsy. We retrospectively analyzed 72 deceased donor renal allograft biopsies and respective allograft ultrasounds, performed on 68 patients (57% men) with mean age of 50 years (range, 21-73), with kidney graft dysfunction in 2010 and 2011. Parenchymal thickness relative to graft length and RI were compared with different histopathology diagnoses: Acute rejection, chronic rejection, chronic kidney changes, acute tubular necrosis (ATN), and other diagnoses. The mean value of the RI and of the parenchymal thickness/graft length ratio (parenchyma size index [PSI]) was 0.81 ± 0.10 (SD) and 1.48 ± 0.27 (SD), respectively. Enlarged PSI was significantly higher in ATN (mean 1.72 ± 0.26) compared with no ATN (mean 1.39 ± 0.23; P < .001), and lower when chronic changes were present (mean 1.40 ± 0.25 for chronic changes vs mean 1.62 ± 0.28 for no chronic changes; P = .004). In the group without ATN, PSI was enlarged in acute graft rejection compared with no graft rejection (mean 1.50 ± 0.24 vs 1.24 ± 0.13, respectively; P < .001), whereas in the whole group, including ATN, PSI showed no differentiating power for acute rejection (P = .526). RI was significantly higher in ATN than without it (mean 0.91 ± 0.10 vs 0.79 ± 0.08, respectively; P < .001), whereas the RI was not increased (but was actually lower) in acute graft rejection compared with no graft rejection, neither in the whole group (mean 0.81 ± 0.09 vs 0.82 ± 0.12, respectively; P = .611). Enlarged parenchymal thickness/graft length ratio on ultrasonography was observed in ATN and acute allograft rejection. The RI was increased in ATN, but not in acute allograft rejection

Kidney Diseases

MedlinePlus

... until you go to the bathroom. Most kidney diseases attack the nephrons. This damage may leave kidneys ... medicines. You have a higher risk of kidney disease if you have diabetes, high blood pressure, or ...

Boldine Improves Kidney Damage in the Goldblatt 2K1C Model Avoiding the Increase in TGF-β.

PubMed

Gómez, Gonzalo I; Velarde, Victoria

2018-06-25

Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS, such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats ( n = 5/group) were treated with boldine (50 mg/kg/day, gavage) for six weeks after 2K1C surgery (pressure ≥ 180 mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. Alpha-smooth muscle actin (α-SMA) and Col III were used as markers of kidney damage; ED-1 and osteopontin (OPN) were used as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced the UProt/UCrea ratio, plasma TBARS, and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1, and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic.

Early Allograft Dysfunction After Liver Transplantation Is Associated With Short- and Long-Term Kidney Function Impairment.

PubMed

Wadei, H M; Lee, D D; Croome, K P; Mai, M L; Golan, E; Brotman, R; Keaveny, A P; Taner, C B

2016-03-01

Early allograft dysfunction (EAD) after liver transplantation (LT) is related to ischemia-reperfusion injury and may lead to a systemic inflammatory response and extrahepatic organ dysfunction. We evaluated the effect of EAD on new-onset acute kidney injury (AKI) requiring renal replacement therapy within the first month and end-stage renal disease (ESRD) within the first year post-LT in 1325 primary LT recipients. EAD developed in 358 (27%) of recipients. Seventy-one (5.6%) recipients developed AKI and 38 (2.9%) developed ESRD. Compared with those without EAD, recipients with EAD had a higher risk of AKI and ESRD (4% vs. 9% and 2% vs. 6%, respectively, p < 0.001 for both). Multivariate logistic regression analysis showed an independent relationship between EAD and AKI as well as ESRD (odds ratio 3.5, 95% confidence interval 1.9-6.4, and odds ratio 3.1, 95% confidence interval 11.9-91.2, respectively). Patients who experienced both EAD and AKI had inferior 1-, 3-, 5-, and 10-year patient and graft survival compared with those with either EAD or AKI alone, while those who had neither AKI nor EAD had the best outcomes (p < 0.001). Post-LT EAD is a risk factor for both AKI and ESRD and should be considered a target for future intervention to reduce post-LT short- and long-term renal dysfunction. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Should fractures in massive intercalary bone allografts of the lower limb be treated with ORIF or with a new allograft?

PubMed

Aponte-Tinao, Luis A; Ayerza, Miguel A; Muscolo, D Luis; Farfalli, Germán L

2015-03-01

Massive bone allografts have been used for limb salvage of bone tumor resections as an alternative to endoprostheses, although they have different outcomes and risks. There is no general consensus about when to use these alternatives, but when it is possible to save the native joints after the resection of a long bone tumor, intercalary allografts offer some advantages despite complications, such as fracture. The management and outcomes of this complication deserve more study. The purposes of this study were to (1) analyze the fracture frequency in a group of patients treated with massive intercalary bone allografts of the femur and tibia; (2) compare the results of allografts treated with open reduction and internal fixation (ORIF) with those treated with resection and repeat allograft reconstruction; and (3) determine the likelihood that treatment of a fracture resulted in a healed intercalary reconstruction. We reviewed patients treated with intercalary bone allografts between 1991 and 2011. During this period, patients were generally treated with intercalary allografts when after tumor resection at least 1 cm of residual epiphysis remained to allow fixation of the osteotomy junction. To obtain a homogeneous group of patients, we excluded allograft-prosthesis composites and osteoarticular and hemicylindrical intercalary allografts from this study. We analyzed the fracture rate of 135 patients reconstructed with segmental intercalary bone allografts of the lower extremities (98 femurs and 37 tibias). In patients whose grafts fractured were treated either by internal fixation or a second allograft, ORIF generally was attempted but after early failures in femur fractures, these fractures were treated with a second allograft. Using a chart review, we ascertained the frequency of osseous union, complications, and reoperations after the treatment of fractured intercalary allografts. Followup was at a mean of 101 months (range, 24-260 months); of the original 135

NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease.

PubMed

Nickolas, Thomas L; Forster, Catherine S; Sise, Meghan E; Barasch, Nicholas; Solá-Del Valle, David; Viltard, Melanie; Buchen, Charles; Kupferman, Shlomo; Carnevali, Maria Luisa; Bennett, Michael; Mattei, Silvia; Bovino, Achiropita; Argentiero, Lucia; Magnano, Andrea; Devarajan, Prasad; Mori, Kiyoshi; Erdjument-Bromage, Hediye; Tempst, Paul; Allegri, Landino; Barasch, Jonathan

2012-09-01

The type and the extent of tissue damage inform the prognosis of chronic kidney disease (CKD), but kidney biopsy is not a routine test. Urinary tests that correlate with specific histological findings might serve as surrogates for the kidney biopsy. We used immunoblots and ARCHITECT-NGAL assays to define the immunoreactivity of urinary neutrophil gelatinase-associated lipocalin (NGAL) in CKD, and we used mass spectroscopy to identify associated proteins. We analyzed kidney biopsies to determine whether specific pathological characteristics associated with the monomeric NGAL species. Advanced CKD urine contained the NGAL monomer as well as novel complexes of NGAL. When these species were separated, we found a significant correlation between the NGAL monomer and glomerular filtration rate (r=-0.53, P<0.001), interstitial fibrosis (mild vs. severe disease; mean 54 vs. 167 μg uNGAL/g Cr, P<0.01), and tubular atrophy (mild vs. severe disease; mean 54 vs. 164 μg uNGAL/g Cr, P<0.01). Monospecific assays of the NGAL monomer demonstrated a correlation with histology that typifies progressive, severe CKD.

Matrix metalloproteinases in kidney homeostasis and diseases

PubMed Central

Tan, Roderick J.

2012-01-01

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that have been increasingly linked to both normal physiology and abnormal pathology in the kidney. Collectively able to degrade all components of the extracellular matrix, MMPs were originally thought to antagonize the development of fibrotic diseases solely through digestion of excessive matrix. However, increasing evidence has shown that MMPs play a wide variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP dysregulation in a multitude of renal diseases including acute kidney injury, diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic allograft nephropathy. The goal of this review is to summarize current findings regarding the role of MMPs in kidney diseases as well as the mechanisms of action of this family of proteases. PMID:22492945

The PROCARE consortium: toward an improved allocation strategy for kidney allografts.

PubMed

Otten, H G; Joosten, I; Allebes, W A; van der Meer, A; Hilbrands, L B; Baas, M; Spierings, E; Hack, C E; van Reekum, F; van Zuilen, A D; Verhaar, M C; Bots, M L; Seelen, M A J; Sanders, J S F; Hepkema, B G; Lambeck, A J; Bungener, L B; Roozendaal, C; Tilanus, M G J; Vanderlocht, J; Voorter, C E; Wieten, L; van Duijnhoven, E; Gelens, M; Christiaans, M; van Ittersum, F; Nurmohamed, A; Lardy, N M; Swelsen, W T; van Donselaar-van der Pant, K A M I; van der Weerd, N C; Ten Berge, I J M; Bemelman, F J; Hoitsma, A J; de Fijter, J W; Betjes, M G H; Roelen, D L; Claas, F H J

2014-10-01

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the

Metformin use in kidney transplant recipients in the United States: an observational study.

PubMed

Stephen, Jenise; Anderson-Haag, Teresa L; Gustafson, Sally; Snyder, Jon J; Kasiske, Bertram L; Israni, Ajay K

2014-01-01

Although metformin is contraindicated in patients with increased serum creatinine levels (≥1.5 mg/dl in men, ≥1.4 mg/dl in women) in the United States, its use has not been systematically examined in kidney transplant recipients. We aimed to determine the frequency of metformin use and its associations among kidney transplant recipients, and to assess allograft and patient survival associated with metformin use. In this retrospective cohort study, we linked Scientific Registry of Transplant Recipients data for all incident kidney transplants 2001-2012 and national pharmacy claims (n = 46,914). We compared recipients having one or more pharmacy claims for a metformin-containing product (n = 4,609) and recipients having one or more claims for a non-metformin glucose-lowering agent (n = 42,305). On average, metformin claims were filled later after transplant and were associated with higher estimated glomerular filtration rates before the first claim. Median serum creatinine (mg/dl) levels before the first claim were lower in recipients with metformin claims than in those with non-metformin claims (1.3 [interquartile range 1.0-1.7] vs. 1.6 [1.2-2.5], respectively; p < 0.0001). Metformin was associated with lower adjusted hazards for living donor (0.55, 95% confidence interval 0.38-0.80; p = 0.002) and deceased donor (0.55, 0.44-0.70; p < 0.0001) allograft survival at 3 years posttransplant, and with lower mortality. Despite metformin being contraindicated in renal dysfunction, many kidney transplant recipients receive it, and it is not associated with worse patient or allograft survival. © 2015 S. Karger AG, Basel.

Preimplant Histologic Acute Tubular Necrosis and Allograft Outcomes

PubMed Central

Hall, Isaac E.; Reese, Peter P.; Weng, Francis L.; Schröppel, Bernd; Doshi, Mona D.; Hasz, Rick D.; Reitsma, William; Goldstein, Michael J.; Hong, Kwangik

2014-01-01

Background and objectives The influence of deceased-donor AKI on post-transplant outcomes is poorly understood. The few published studies about deceased-donor preimplant biopsy have reported conflicting results regarding associations between AKI and recipient outcomes. Design, setting, participants, & measurements This multicenter study aimed to evaluate associations between deceased-donor biopsy reports of acute tubular necrosis (ATN) and delayed graft function (DGF), and secondarily for death-censored graft failure, first adjusting for the kidney donor risk index and then stratifying by donation after cardiac death (DCD) status. Results Between March 2010 and April 2012, 651 kidneys (369 donors, 4 organ procurement organizations) were biopsied and subsequently transplanted, with ATN reported in 110 (17%). There were 262 recipients (40%) who experienced DGF and 38 (6%) who experienced graft failure. DGF occurred in 45% of kidneys with reported ATN compared with 39% without ATN (P=0.31) resulting in a relative risk (RR) of 1.13 (95% confidence interval [95% CI], 0.9 to 1.43) and a kidney donor risk index–adjusted RR of 1.11 (95% CI, 0.88 to 1.41). There was no significant difference in graft failure for kidneys with versus without ATN (8% versus 5%). In stratified analyses, the adjusted RR for DGF with ATN was 0.97 (95% CI, 0.7 to 1.34) for non-DCD kidneys and 1.59 (95% CI, 1.23 to 2.06) for DCD kidneys (P=0.02 for the interaction between ATN and DCD on the development of DGF). Conclusions Despite a modest association with DGF for DCD kidneys, this study reveals no significant associations overall between preimplant biopsy-reported ATN and the outcomes of DGF or graft failure. The potential benefit of more rigorous ATN reporting is unclear, but these findings provide little evidence to suggest that current ATN reports are useful for predicting graft outcomes or deciding to accept or reject allograft offers. PMID:24558049

Kidney transplantation outcomes in African-, Hispanic- and Caucasian-Americans with lupus.

PubMed

Contreras, G; Mattiazzi, A; Schultz, D R; Guerra, G; Ladino, M; Ortega, L M; Garcia-Estrada, M; Ramadugu, P; Gupta, C; Kupin, W L; Roth, D

2012-01-01

African-American recipients of kidney transplants with lupus have high allograft failure risk. We studied their risk adjusting for: (1) socio-demographic factors: donor age, gender and race-ethnicity; recipient age, gender, education and insurance; donor-recipient race-ethnicity match; (2) immunologic factors: donor type, panel reactive antibodies, HLA mismatch, ABO blood type compatibility, pre-transplant dialysis, cytomegalovirus risk and delayed graft function (DGF); (3) rejection and recurrent lupus nephritis (RLN). Two thousand four hundred and six African-, 1132 Hispanic-, and 2878 Caucasian-Americans were followed for 12 years after transplantation. African- versus Hispanic- and Caucasian-Americans received more kidneys from deceased donors (71.6%, 57.3% and 55.1%) with higher two HLA loci mismatches for HLA-A (50%, 39.6% and 32.4%), HLA-B (52%, 42.8% and 35.6%) and HLA-DR (30%, 24.5% and 21.1%). They developed more DGF (19.5%, 13.6% and 13.4%). More African- versus Hispanic- and Caucasian-Americans developed rejection (41.7%, 27.6% and 35.9%) and RLN (3.2, 1.8 and 1.8%). 852 African-, 265 Hispanic-, and 747 Caucasian-Americans had allograft failure (p < 0.0001). After adjusting for transplant era, socio-demographic-immunologic differences, rejection and RLN, the increased hazard ratio for allograft failure of African- compared with Caucasian-Americans became non-significant (1.26 [95% confidence interval 0.78-2.04]). African-Americans with lupus have high prevalence of risk factors for allograft failure that can explain poor outcomes.

Pre- and Posttransplant IgA Anti-Fab Antibodies to Predict Long-term Kidney Graft Survival.

PubMed

Amirzargar, M A; Amirzargar, A; Basiri, A; Hajilooi, M; Roshanaei, G; Rajabi, G; Solgi, G

2015-05-01

Immunologic factors are reliable markers for allograft monitoring, because of their seminal role in rejection process. One of these factors is the immunoglobulin (Ig)A anti-Fab of the IgG antibody. This study aimed to evaluate the predictive value of pre- and posttransplant levels of this marker for kidney allograft function and survival. Sera samples of 59 living unrelated donor kidney recipients were collected before and after transplantation (days 7, 14, and 30) and investigated for IgA anti-Fab of IgG antibody levels using enzyme-linked immunosorbent assay in relation with allograft outcome. Among 59 patients, 15 cases (25%) including 10 with acute rejection and 5 with chronic rejection episodes showed graft failure during a mean of 5 years of follow-up. High posttransplant levels of IgA anti-Fab antibodies were observed more frequently in patients with stable graft function (SGF) compared with patients with graft failure (P = 2 × 10(-6)). None of patients with acute or chronic rejection episodes had high levels of IgA anti-Fab antibodies at day 30 posttransplant compared with the SGF group (P = 10(-6) and P = .01, respectively). In addition, high levels of IgA anti-Fab antibody correlated with lesser concentration of serum creatinine at 1 month posttransplantation (P = .01). Five-year graft survival was associated with high levels of pre- and posttransplant IgA anti-Fab antibodies (P = .02 and P = .003, respectively). Our findings indicate the protective effect of higher levels of IgA anti-Fab antibodies regarding to kidney allograft outcomes and long-term graft survival. Copyright © 2015 Elsevier Inc. All rights reserved.

[Causes of death with a functioning graft among kidney allograft recipients].

PubMed

Vega, Jorge; Videla, Christian; Borja, Hernán; Goecke, Helmuth; Martínez, Felipe; Betancour, Pablo

2012-03-01

Death with a functioning graft (DWGF) is now one of the main causes of renal transplant (RTx) loss. To determine whether the causes of DWGF, characteristics of donors and recipients and complications of RTx have changed in the last two decades. Cooperative study of a cohort of 418 kidney grafts performed between 1968 and 2010. Patients were divided into two groups according to whether their kidney transplants were performed between 1968 and 1992 (Group 1) or 1993 and 2010 (Group 2). Sixty eight patients experienced DWGF. Infections were the leading cause of DWGF in both groups (38 and 41%, respectively), followed by cardiovascular diseases (24 and 23% respectively), gastrointestinal disorders (21 and 26% respectively) and cancer (17 and 10% respectively). There were no significant differences in causes of death between the two groups according to the time elapsed since the renal transplantation. In patients in Group 1, the interval between diagnosis of renal failure and dialysis (HD) and the interval between the start of HD and kidney transplantation were significantly lower than in Group 2. The former had also an increased number of acute rejections in the first five years of kidney transplantation (p < 0.001). In Group 2, patients more often received their kidneys from deceased donors, had previous kidney transplantation, higher rate of antibodies to a panel of lymphocytes and an increased incidence of cardiovascular disorders after five years of RTx. The proportion of graft loss due to DWGF has increased over the last 2 decades, but its causes have not changed significantly. Infections are the most common causes of DWGF followed by cardiovascular and digestive diseases.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats

PubMed Central

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-01-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at −80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully

Does sterilization with fractionated electron beam irradiation prevent ACL tendon allograft from tissue damage?

PubMed

Schmidt, T; Grabau, D; Grotewohl, J H; Gohs, U; Pruß, A; Smith, M; Scheffler, S; Hoburg, A

2017-02-01

Allografts are frequently used for anterior cruciate ligament (ACL) reconstruction. However, due to the inherent risk of infection, a method that achieves complete sterilization of grafts is warranted without impairing their biomechanical properties. Fractionation of electron beam (FEbeam) irradiation has been shown to maintain similar biomechanical properties compared to fresh-frozen allografts (FFA) in vitro. Therefore, aim of this study was to evaluate the biomechanical properties and early remodelling of grafts that were sterilized with fractionated high-dose electron beam irradiation in an in vivo sheep model. ACL reconstruction was performed in 18 mature merino mix sheep. Sixteen were reconstructed with allografts sterilized with FEbeam irradiation (8 × 3.4 kGy) and two with FFA. Eight FFA from prior studies with identical surgical reconstruction and biomechanical and histological analyzes served as controls. Half of the animals were sacrificed at 6 and 12 weeks, and biomechanical testing was performed. Anterior-posterior laxity (APL) was assessed with an AP drawer test at 60° flexion, and load to failure testing was carried out. Histological evaluation of mid-substance samples was performed for descriptive analysis, cell count, crimp and vessel density. For statistical analysis a Kruskal-Wallis test was used for overall group comparison followed by a Mann-Whitney U test for pairwise comparison of the histological and biomechanical parameters. Biomechanical testing showed significantly decreased stiffness in FEbeam compared to FFA at both time points (p ≤ 0.004). APL was increased in FEbeam compared to FFA, which was significant at 6 weeks (p = 0.004). Median of failure loads was decreased in FEbeam grafts, with 12 reconstructions already failing during cyclic loading. Vessel density was decreased in FEbeam compared to FFA at both time points, with significant differences at 12 weeks (p = 0.015). Crimp length was significantly shorter in

Outcomes of Solid Organ Transplants After Simultaneous Solid Organ and Vascularized Composite Allograft Procurements: A Nationwide Analysis.

PubMed

Aycart, Mario A; Alhefzi, Muayyad; Sharma, Gaurav; Krezdorn, Nicco; Bueno, Ericka M; Talbot, Simon G; Carty, Matthew J; Tullius, Stefan G; Pomahac, Bohdan

2017-06-01

Current knowledge of the impact of facial vascularized composite allograft (VCA) procurement on the transplantation outcomes of the concomitantly recovered solid organs is limited to isolated case reports and short-term results. Here we report on a nationwide analysis of facial allograft donor surgery experience and long-term outcomes of the concomitantly recovered solid organs and their recipients. There were 10 facial VCA procurements in organ donors between December 2008 and October 2014. We identified the population of subjects who received solid organs from these 10 donors using the Scientific Registry of Transplant Recipients. We retrospectively reviewed operative characteristics, intraoperative parameters, and postoperative outcomes. Six of 10 donor surgeries were performed at outside institutions, all on brain-dead donors. Mean operative duration for facial VCA recovery was 6.9 hours (range, 4-13.25 hours). A total of 36 solid organs were recovered and transplanted into 35 recipients. Survival rates for kidney and liver recipients were 100% and 90% at a median follow-up of 33 and 27.5 months, respectively (range, 6-72 months). Graft survival rates for kidneys and livers were 15 of 16 (94%) and 9 of 10 (90%), respectively. Recipient and graft survival rates for hearts and lungs were 75% (n = 4) and 100% (n = 3) at mean follow-up time of 14.75 and 16 months, respectively. A liver recipient died at 22 months from unknown causes and a heart recipient died of leukemia at 10 months. Facial VCA procurement does not appear to adversely affect the outcomes of transplant recipients of concomitantly recovered solid organ allografts.

Kidney transplant outcomes from older deceased donors: a paired kidney analysis by the European Renal Association-European Dialysis and Transplant Association Registry.

PubMed

Pippias, Maria; Jager, Kitty J; Caskey, Fergus; Casula, Anna; Erlandsson, Helen; Finne, Patrik; Heaf, James; Heinze, Georg; Hoitsma, Andries; Kramar, Reinhard; Lempinen, Marko; Magaz, Angela; Midtvedt, Karsten; Mumford, Lisa L; Pascual, Julio; Prütz, Karl G; Sørensen, Søren S; Traynor, Jamie P; Massy, Ziad A; Ravanan, Rommel; Stel, Vianda S

2017-12-05

As the median age of deceased kidney donors rises, updated knowledge of transplant outcomes from older deceased donors in differing donor-recipient age groups is required. Using ERA-EDTA Registry data we determined survival outcomes of kidney allografts donated from the same older deceased donor (55-70 years), and transplanted into one recipient younger and one recipient of similar age to the donor. The recipient pairs were divided into two groups: group 1; younger (median age: 52 years) and older (60 years) and group 2; younger (41 years) and older (60 years). A total of 1410 adults were transplanted during 2000-2007. Compared to the older recipients, the mean number of functioning graft years at 10 years was 6 months longer in the group 1 and group 2 younger recipients (P < 0.001). Ten-year graft survival was 54% and 40% for the group 1 younger and older recipients, and 60% and 49% for the group 2 younger and older recipients. Paired Cox regression analyses showed a lower risk of graft failure (group 1 younger; adjusted relative risk [RRa]:0.57, 95% CI:0.41-0.79, and group 2 younger; RRa:0.63, 95% CI:0.47-0.85) in younger recipients. Outcomes from older deceased donor allografts transplanted into differing donor-recipient age groups are better than previously reported. These allografts remain a valuable transplant resource, particularly for similar-aged recipients. © 2017 Steunstichting ESOT.

Diffuse vascular damage in a transplanted kidney: an indication for nuclear magnetic resonance?

PubMed

Burdese, M; Consiglio, V; Mezza, E; Savio, D; Guarena, C; Rossetti, M; Messina, M; Soragna, G; Suriani, C; Rabbia, C; Segoloni, G P; Piccoli, G B

2005-06-01

Vascular lesions are an increasing challenge after renal transplantation due to the wider indications for recipients and acceptance criteria for donors. Diagnostic approach and prognostic interpretation are still matter of controversy. The case reported herein may summarize some of the issues in this regard. A 54-year-old woman, on renal replacement therapy since 1974, and a kidney graft recipient from 1975 to 1999, received a second graft in 2001. The donor age was 65 years (cold ischemia 22 hours; two mismatches). The early posttransplant follow-up was characterized by delayed graft function, hypertension, and diabetes. During the initial hypertension workup, renal graft ultrasound (US) Doppler demonstrated increased vascular resistances, stable over time (resistance index 0.74 to 0.77); renal scintiscan displayed homogeneously parenchymoa and angio-magnetic resonance imaging (MRI), an homogeneous parenchymal vascularization. Initial immunosuppression with tacrolimus and steroids was modulated by adding mycophenolate mofetil to taper tacrolimus (to reduce nephrotoxicity and hypertension). Despite this, kidney function slowly deteriorated; serum creatinine reached 3 to 3.5 mg/dL by the second year. After a severe hypertensive crisis with unchanged scintiscan and US doppler examinations, angio-MRI revealed the almost complete disappearance of parenchymal enhancement beyond the lobar arteries. A renal biopsy confirmed the severe vascular damage. The patient was switched to rapamycine and a low-dose of an angiotension converting enzyme (ACE) inhibitor. She did relatively well (serum creatinine 2.2 to 3 mg/dL) for 6 months, when rapid functional impairment forced her to restart hemodialysis. This case, almost paradigmatic of the problems occurring when the rigid vasculature of long-term dialysis patients is matched with "marginal kidneys," suggests that MRI may be a sensible good to define vascular damage in the grafted kidney.

Sustained Pyridoxine Response in Primary Hyperoxaluria Type 1 Recipients of Kidney Alone Transplant

PubMed Central

Lorenz, Elizabeth C; Lieske, John C; Seide, Barbara M; Meek, Alicia M; Olson, Julie B; Bergstralh, Eric J; Milliner, Dawn S

2015-01-01

Combined kidney liver transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) given that it removes the hepatic source of oxalate production and improves renal allograft survival. However, PH1 patients homozygous for the G170R mutation can develop normal urine oxalate levels with pyridoxine therapy and may be candidates for kidney alone transplant. We examined the efficacy of pyridoxine therapy following kidney alone transplant in five patients homozygous for G170R transplanted between 9/1999 and 7/2013. All patients were maintained on pyridoxine post-transplant. Median age at transplant was 39 years (range 33–67 years). Median follow-up post-transplant was 8.5 years (range 0.2–13.9 years). At the end of follow-up, 4 grafts were functioning. One graft failed 13.9 years post-transplant due to recurrent oxalate nephropathy following an acute medical illness. After tissue oxalate stores had cleared, post-transplant urine oxalate levels were < 0.5 mmol/24 hr the majority of times checked. Calcium oxalate crystals were noted in only 3/13 allograft biopsies. This series suggests that a subgroup of PH1 patients demonstrate sustained response to pyridoxine therapy following kidney alone transplant. Therefore, pyridoxine combined with kidney alone transplantation should be considered for PH1 patients with a homozygous G170R mutation. PMID:24797341

[Pedal bypass using venous allograft].

PubMed

Pluháčková, H; Staffa, R; Konečný, Z; Kříž, Z; Vlachovský, R

Pedal or distal crural bypass surgery for limb salvage is a method with very good long-term results. For patients in whom a suitable autologous venous graft is not available, the use of a venous allograft is an alternative procedure. A 68 years old man with ischaemic disease of lower extremities and gangrene of the left foot was admitted to our Centre in August 2014. He underwent percutaneous transluminal angioplasty of crural arteries of his left lower extremity. This, however, failed to improve peripheral circulation. The patient was then indicated for pedal or distal crural vascular reconstruction. Since no suitable autologous vein was available, distal bypass surgery using a donor graft remained the only option for limb salvage. Amputation of the toes on the left foot due to gangrene was necessary. Subsequently, femoro-pedal bypass to the left common plantar artery was performed using a great saphenous vein allograft. The post-operative course was without complications, the pedal bypass was patent and toe amputation was with good healing. The patient remained in follow-up care. A good outcome of vascular reconstruction with an allograft depends on the availability of a suitable allograft and good patient compliance with post-operative care. In the case presented here, the pedal bypass grafting by means of an allograft helped to save the patients limb. pedal bypass venous allograft limb salvage.

Acute kidney failure

MedlinePlus

Kidney failure; Renal failure; Renal failure - acute; ARF; Kidney injury - acute ... There are many possible causes of kidney damage. They include: ... cholesterol (cholesterol emboli) Decreased blood flow due to very ...

Rabbit Trochlear Model of Osteochondral Allograft Transplantation

PubMed Central

To, Nhat; Curtiss, Shane; Neu, Corey P; Salgado, Christopher J; Jamali, Amir A

2011-01-01

Allografting and autografting of osteochondral tissues is a promising strategy to treat articular cartilage lesions in damaged joints. We developed a new model of fresh osteochondral allografting using the entire rabbit trochlea. The objective of the current study was to demonstrate that this model would achieve reproducible graft–host healing and maintain normal articular cartilage histologic, immunolocalization, and biochemical characteristics after transplantation under diverse storage and transplantation conditions. New Zealand white (n = 8) and Dutch belted (n = 8) rabbits underwent a 2-stage transplantation operation using osteochondral grafts that had been stored for 2 or 4 wk. Trochlear grafts harvested from the left knee were transplanted to the right knee as either autografts or allografts. Grafts were fixed with 22-gauge steel wire or 3-0 nylon suture. Rabbits were euthanized for evaluation at 1, 2, 4, 6, and 12 wk after transplantation. All grafts that remained in vivo for at least 4 wk demonstrated 100% interface healing by microCT. Trabecular bridging was present at the host–graft interface starting at 2 wk after transplantation, with no significant difference in cartilage histology between the various groups. The combined histology scores indicated minimal evidence of osteoarthritis. Immunostaining revealed that superficial zone protein was localized at the surface of all transplants. The rabbit trochlear model met our criteria for a successful model in regard to the ease of the procedure, low rate of surgical complications, relatively large articular cartilage surface area, and amount of host–graft bone interface available for analysis. PMID:22330350

Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients

PubMed Central

Sofue, Tadashi; Inui, Masashi; Hara, Taiga; Nishijima, Yoko; Moriwaki, Kumiko; Hayashida, Yushi; Ueda, Nobufumi; Nishiyama, Akira; Kakehi, Yoshiyuki; Kohno, Masakazu

2014-01-01

Background Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU. Methods Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups. Results The FX group showed significantly greater decreases in serum uric acid (−2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96–10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m2 versus 47±19 mL/min/1.73 m2), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m2 versus −0.2±6.9 mL/min/1.73 m2 per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%). Conclusion

Kidney Biopsy Adequacy: A Metric-based Study.

PubMed

Ferrer, German; Andeen, Nicole K; Lockridge, Joseph; Norman, Douglas; Foster, Bryan R; Houghton, Donald C; Troxell, Megan L

2018-06-05

There are differences in renal biopsy yield related to on-site evaluation, tissue division, and operator, among others. To understand these variations, we collected adequacy-associated data (%cortex, glomeruli, arteries, length) from consecutive native and allograft kidney biopsies over a 22-month period. In total, 1332 biopsies (native: 873, allograft: 459) were included, 617 obtained by nephrologists, 663 by radiologists, and 559 with access to on-site division. Proceduralists with access to on-site evaluation had significantly lower inadequacy rates and better division of tissue for light microscopy (LM), immunofluorescence, and electron microscopy than those without access to on-site evaluation. Radiologists in our region were significantly less likely to have access to on-site evaluation than nephrologists. On multivariate analysis for native kidney biopsies, the effect of having a radiologist perform the biopsy and having access to on-site division were both significant predictors of obtaining greater calculated amount of cortex for LM. Despite the trend for radiologists to obtain more tissue in general, biopsies from nephrologists contained a greater percentage of cortex and were more likely to be considered adequate for LM (native kidney inadequacy rate for LM: 1.11% vs. 5.41%, P=0.0086). Biopsies in which inadequate or marginal cortical tissue was submitted for LM had only minor decreases in the amount of cortex submitted for immunofluorescence and electron microscopy, revealing an opportunity for improved specimen triaging when limited tissue is obtained. In conclusion, both on-site evaluation/division and proceduralist significantly affect quantitative kidney biopsy metrics, which in turn affects the pathologist's ability to render an accurate diagnosis with appropriate prognostic information for the patient and treating nephrologist.

Characterization of skin allograft use in thermal injury.

PubMed

Fletcher, John L; Caterson, E J; Hale, Robert G; Cancio, Leopoldo C; Renz, Evan M; Chan, Rodney K

2013-01-01

This study provides objective data on the practice of allograft usage in severely burned patients. Furthermore, gaps in our knowledge are identified, and areas for further research are delineated. Using an institutional review board-approved protocol, active duty military patients injured while deployed in support of overseas contingency operations and treated at our burn center between March 2003 and December 2010 were identified. Their electronic medical records were reviewed for allograft use, TBSA burned, injury severity score, anatomic distribution of burns, operative burden, length of stay, transfusions, and outcome. Among 844 patients, 112 (13.3%) received allograft and 732 (86.7%) did not. The amount of allograft used per patient varied and was not normally distributed (median, 23.5; interquartile range, 69.5). Patients received allograft skin an average of 12.75 times during their admission. Allografted patients sustained severe burns (μ, 53.8% TBSA); most were transfused (71.2%) and grafted frequently, averaging every 7.45 days. Most commonly, allograft was placed on the extremities (66.5%) followed by the trunk (44.2%); however, the vast majority of allografted patients also had concomitant burns of the head (91.1%) and hands (87.5%). All-cause mortality among the allografted patients was 19.1%. In conclusion, allograft is commonly used in the surgical treatment of severe burns. Although there are no anatomic limitations to allograft placement, there are distinct patterns of use. Given the role of allograft in the acute management of large burns, there is need for further investigation of its effect on mortality, morbidity, and antigenicity.

Evaluation of posttransplantation soluble CD30 for diagnosis of acute renal allograft rejection.

PubMed

Pelzl, Steffen; Opelz, Gerhard; Daniel, Volker; Wiesel, Manfred; Süsal, Caner

2003-02-15

Posttransplantation measurement of soluble CD30 (sCD30) may be useful for identifying kidney graft recipients at risk of impending graft rejection in the early posttransplantation period. We measured plasma sCD30 levels and evaluated the levels in relation to the diagnosis of rejection. Receiver operating characteristic curves demonstrated that on posttransplantation days 3 to 5, sCD30 allowed a differentiation of recipients who subsequently developed acute allograft rejection (n=25) from recipients with an uncomplicated course (n=20, P<0.0001) (area under the receiver operating characteristic curve 0.96, specificity 100%, sensitivity 88%) and recipients with acute tubular necrosis in the absence of rejection (n=11, P=0.001) (area under the receiver operating characteristic curve 0.85, specificity 91%, sensitivity 72%). sCD30 measured on posttransplantation days 3 to 5 offers a noninvasive means for differentiating patients with impending acute allograft rejection from patients with an uncomplicated course or with acute tubular necrosis.

Efficacy of vitamin C against liver and kidney damage induced by paraquat toxicity.

PubMed

Awadalla, Eatemad A

2012-07-01

Paraquat has been demonstrated to be a highly toxic compound for humans and animals and many cases of acute poisoning and death have been reported over the past few decades. The current experiment aimed to examine if vitamin C (ascorbic acid) alleviates the morphological changes induced by paraquat (PQ) administration in the liver and kidney of male albino rats. Male adult rats received paraquat (PQ) (1.5 mg/kg body weight) daily for three weeks. Vitamin C (VC) at a dose of 20 mg/kg body weight was given concomitantly with PQ to rats. Animals were divided into three groups in this experiment (control, PQ and PQ+VC). The morphopathological manifestations were investigated in tissues from liver and kidney. As expected, PQ administration induced marked changes in the morphological structure of the liver and kidney in PQ demonstrated animals. Importantly, vitamin C administration restored PQ-induced changes in the studied organs. Vitamin C administration attenuated the morphological damages induced by PQ in the liver and kidney of experimental animals. Our results suggest an antitoxic effect of vitamin C against paraquat. Copyright © 2010 Elsevier GmbH. All rights reserved.

Current organ allocation disadvantages kidney alone recipients over combined organ recipients.

PubMed

Martin, Michael S; Hagan, Michael E; Granger, Darla K

2016-03-01

The United Network for Organ Sharing began including the Kidney Donor Profile Index (KDPI) March 26, 2012 and began a new allocation scheme December 1, 2014. Kidney donors from our organ procurement organization from March 2012 to December 2014 were reviewed. The KDPIs of all 919 kidney only transplants were compared with all 102 kidney/extrarenal transplants. The average KDPI for kidney alone allografts was 47 (range 1 to 100) (standard deviation = 25.83) vs 27 for kidney/extrarenal kidneys (range 1 to 82) (standard deviation = 20.16) (P < .001, t test). Multivariate analysis including in- vs out-of-state recipient, donor body mass index, and donation after cardiac death vs brain-dead donor showed significantly lower KDPI for kidney/extrarenal transplants. Kidney/extrarenal organs have decreased graft survival compared with kidneys transplanted alone. In this sample, 21% of lower KDPI kidneys were allocated as kidney/extrarenal organs. This disadvantages those waiting for a kidney alone. Attention to the outcomes of kidneys transplanted with extrarenal organs is needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Successful 4th kidney transplantation: a case report from Iran.

PubMed

Nourbala, Mohammad Hossein; Ghadian, Alireza; Einollahi, Behzad; Azarabadi, Mehdi

2013-05-21

Kidney transplantation is generally considered the best option for most patients with end-stage renal disease requiring renal replacement therapy, even for patients with graft failure. Here, we describe a case of a 49-year-old man who received his 1st kidney transplant the United Kingdom from his brother when he was 18 years old in. Thirty-one year after the first transplant, he underwent successful 4th living-unrelated kidney transplantation with no serious complications at our transplant center. He continued to have excellent allograft function and his latest serum creatinine 33 months after his 4th transplant was 1.2 mg/dL. To our knowledge, this is the first case of 4th kidney transplantation from Iran.

Circumocular exanthema associated with chronic rejection after kidney transplantation.

PubMed

Morishita, Yoshiyuki; Umino, Tetsuo; Kobayashi, Takahisa; Miyata, Yukio; Kusano, Eiji

2010-12-01

A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross-reacted with unknown pathogens on the skin and contributed to inflammation.

Tissue-associated self-antigens containing exosomes: Role in allograft rejection.

PubMed

Sharma, Monal; Ravichandran, Ranjithkumar; Bansal, Sandhya; Bremner, Ross M; Smith, Michael A; Mohanakumar, T

2018-06-15

Exosomes are extracellular vesicles that express self-antigens (SAgs) and donor human leukocyte antigens. Tissue-specific exosomes can be detected in the circulation following lung, heart, kidney and islet cell transplantations. We collected serum samples from patients who had undergone lung (n = 30), heart (n = 8), or kidney (n = 15) transplantations to isolate circulating exosomes. Exosome purity was analyzed by Western blot, using CD9 exosome-specific markers. Tissue-associated lung SAgs, collagen V (Col-V) and K-alpha 1 tubulin (Kα1T), heart SAgs, myosin and vimentin, and kidney SAgs, fibronectin and collagen IV (Col-IV), were identified using western blot. Lung transplant recipients diagnosed with bronchiolitis obliterans syndrome had exosomes with higher expression of Col-V (4.2-fold) and Kα1T (37.1-fold) than stable. Exosomes isolated from heart transplant recipients diagnosed with coronary artery vasculopathy had a 3.9-fold increase in myosin and a 4.7-fold increase in vimentin compared with stable. Further, Kidney transplant recipients diagnosed with transplant glomerulopathy had circulating exosomes with a 2-fold increased expression of fibronectin and 2.5-fold increase in Col-IV compared with stable. We conclude that circulating exosomes with tissue associated SAgs have the potential to be a noninvasive biomarker for allograft rejection. Copyright © 2018. Published by Elsevier Inc.

Clinical relevance of pre and post-transplant immune markers in kidney allograft recipients: anti-HLA and MICA antibodies and serum levels of sCD30 and sMICA.

PubMed

Solgi, Ghasem; Furst, Daniel; Mytilineos, Joannis; Pourmand, Gholamreza; Amirzargar, Ali Akbar

2012-03-01

This retrospective study aims to determine the prognostic values of HLA and MICA antibodies, serum levels of sCD30 and soluble form of MHC class I related chain A (sMICA) in kidney allograft recipients. Sera samples of 40 living unrelated donor kidney recipients were tested by ELISA and Flow beads techniques for the presence of anti HLA and MICA antibodies and the contents of sCD30 and sMICA. HLA and MICA antibody specification was performed by LABScreen single antigen beads to determine whether the antibodies were directed against donor mismatches. Within first year post operatively 9 of 40 patients (22.5%) showed acute rejection episodes (ARE) that four of them lost their grafts compared to 31 functioning transplants (P=0.001). The presence of HLA antibodies before and after transplantation was significantly associated with ARE (P=0.01 and P=0.02 respectively). Sensitization to HLA class II antigens pre-transplant was strongly associated with higher incidence of ARE (P=0.004). A significant correlation was found between ARE and appearance of non-donor specific antibodies (P=0.02). HLA antibody positive patients either before or after transplantation showed lower graft survival rates than those without antibodies during three years follow-up (P=0.04 and P=0.02). Anti-MICA antibodies were observed in 8/40(20%) and 5/40(12.5%) of patients pre and post-transplant respectively. Coexistence of HLA and MICA antibodies was shown in 2 of 4 cases with graft loss. A significant increased level of sCD30 at day 14 (P=0.001) and insignificant decreased levels of sMICA pre and post operatively were detected in rejecting transplants compared to functioning graft group. Our findings support the view that monitoring of HLA and MICA antibodies as well as sCD30 levels early after transplant has predictive value for early and late allograft dysfunctions and the presence of these factors are detrimental to graft function and survival. Copyright © 2012 Elsevier B.V. All rights

Allografts for Ligament Reconstruction: Where Are We Now?

PubMed

Wydra, Frank B; York, Philip J; Johnson, Christopher R; Silvestri, Lorenzo

The use of musculoskeletal allografts by orthopedic surgeons continues to rise. The process of procuring and sterilizing allografts is evolving with much consideration to limiting the spread of infectious diseases and preserving tissue integrity. Research involving the application of allografts, particularly for ligament repair, is quite active, necessitating an update for the practicing orthopedist. Avoiding donor site morbidities is one of the most commonly cited advantages of allografts over autografts. There is controversy amongst studies for allografts in terms of their biological incorporation and clinical outcomes compared to autografts. This article focuses on reviewing the most current literature and usage of allograft tissue for ligamentous reconstruction amongst orthopedic surgeons today. It includes an in-depth analysis of the current processing, handling, and safety standards employed today, in addition to the advantages and disadvantages of allograft use.

Clostridium difficile colitis in patients after kidney and pancreas–kidney transplantation

PubMed Central

Keven, K.; Basu, A.; Re, L.; Tan, H.; Marcos, A.; Fung, J.J.; Starzl, T.E.; Simmons, R.L.; Shapiro, R.

2010-01-01

Limited data exist about Clostridium difficile colitis (CDC) in solid organ transplant patients. Between 1/1/99 and 12/31/02, 600 kidney and 102 pancreas–kidney allograft recipients were transplanted. Thirty-nine (5.5%) of these patients had CDC on the basis of clinical and laboratory findings. Of these 39 patients, 35 have information available for review. CDC developed at a median of 30 days after transplantation, and the patients undergoing pancreas–kidney transplantation had a slightly higher incidence of CDC than recipients of kidney alone (7.8% vs. 4.5%, P> 0.05). All but one patient presented with diarrhea. Twenty-four patients (64.9%) were diagnosed in the hospital, and CDC occurred during first hospitalization in 14 patients (40%). Treatment was with oral metronidazole (M) in 33 patients (94%)and M + oral vancomycin (M + V) in 2 patients. Eight patients had recurrent CDC, which occurred at a median of 30 days (range 15–314) after the first episode. Two patients (5.7%) developed fulminant CDC, presented with toxic megacolon, and underwent colectomy. One of them died; the other patient survived after colectomy. CDC should be considered as a diagnosis in transplant patients with history of diarrhea after antibiotic use, and should be treated aggressively before the infection becomes complicated. PMID:15225221

[Changes in body composition according to kidney damage in patients with type 2 diabetes mellitus].

PubMed

Medina-Escobedo, Martha; Romero-Campos, Sandra; Sansores-España, Delia; Viveros-Cortés, Angel; Villanueva-Jorge, Salha

2013-01-01

To know the relationship between total body composition and the stage of kidney damage, according to the K/DOQI classification, in patients with type 2 diabetes mellitus (T2DM). Under a correlation design, adults with T2DM were studied. Age, evolution time, fat and lean mass, fat percentage, total water, body index mass (BMI), creatinine clearance by Cockroft-Gault (CrCCG), glucose, HbA1c, proteinuria and microalbuminuria were determined. T test to compare independent means and Spearman correlation were used. The study included 60 men (23.4%) and 196 women (76.6%). There were no differences by gender when comparing age, BMI, duration of T2DM, blood glucose and HbA1c. The analysis showed a direct relationship between BMI (r = 0.281), the amount of fat mass (r = 0.360), lean tissue (r = 0.158), and water (r = 0.176) with the CrCCG (p < 0.0001). The biggest change in body composition, due to fat mass, was observed in chronic kidney disease stages 1-3, in which BMI had a good correlation with fat mass (r = 0.80, p < 0.001). Fat mass is inversely related to the stage of kidney damage in patients with T2DM.

Biomarkers-a potential route for improved diagnosis and management of ongoing renal damage.

PubMed

Oberbauer, R

2008-12-01

Currently, the identification and validation of biomarkers of kidney injury is among the top priorities of many diagnostic biotechnology companies as well as academic research institutes. Specifically, in renal transplantation, validated biomarkers of tissue injury with good discriminatory power between the various renal compartments and the underlying pathophysiology are desired, because sequential allograft biopsies are limited in number and cannot be used as a screening tool. Given the high demands on these markers, it is not surprising that none of those currently under evaluation has been thoroughly validated for a specific entity. Published biomarker candidates for early tubular damage include neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, soluble CD30, perforin, and granzyme B. Recently, C4d flow panel reactive antibodies were evaluated as biomarkers for humoral alloimmune responses. Additional biomarkers such as FOXP3 and kidney injury molecule 1 have been studied in the maintenance phase of renal transplantation. Given the complex prerequisites, it is not surprising that no biomarker panel has been sufficiently validated for clinical use. However, in the near future a biomarker for use as an indicator of renal tubule cell injury will be available. Troponin T or transaminase of the kidney may then at least be used to differentiate between functional renal failure (equivalent to a rise in creatinine) and intrinsic kidney injury.

Vascular Damage and Kidney Transplant Outcomes: An Unfriendly and Harmful Link.

PubMed

Hernández, Domingo; Triñanes, Javier; Armas, Ana María; Ruiz-Esteban, Pedro; Alonso-Titos, Juana; Duarte, Ana; González-Molina, Miguel; Palma, Eulalia; Salido, Eduardo; Torres, Armando

2017-07-01

Kidney transplant (KT) is the treatment of choice for most patients with chronic kidney disease, but this has a high cardiovascular mortality due to traditional and nontraditional risk factors, including vascular calcification. Inflammation could precede the appearance of artery wall lesions, leading to arteriosclerosis and clinical and subclinical atherosclerosis in these patients. Additionally, mineral metabolism disorders and activation of the renin-angiotensin system could contribute to this vascular damage. Thus, understanding the vascular lesions that occur in KT recipients and the pathogenic mechanisms involved in their development could be crucial to optimize the therapeutic management and outcomes in survival of this population. This review focuses on the following issues: (1) epidemiological data framing the problem; (2) atheromatosis in KT patients: subclinical and clinical atheromatosis, involving ischemic heart disease, congestive heart failure, stroke and peripheral vascular disease; (3) arteriosclerosis and vascular calcifications; and (4) potential pathogenic mechanisms and their therapeutic targets. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

13-cis Retinoic Acid Inhibits Development and Progression of Chronic Allograft Nephropathy

PubMed Central

Adams, Judith; Kiss, Eva; Arroyo, Ana B.V.; Bonrouhi, Mahnaz; Sun, Qiang; Li, Zhen; Gretz, Norbert; Schnitger, Anna; Zouboulis, Christos C.; Wiesel, Manfred; Wagner, Jürgen; Nelson, Peter J.; Gröne, Hermann-Josef

2005-01-01

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344→Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1α/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-β1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 × 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-κB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy. PMID:15972972

Effect of Replacing Race with Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index

PubMed Central

Julian, B. A.; Gaston, R. S.; Brown, W. M.; Reeves-Daniel, A. M.; Israni, A. K.; Schladt, D. P.; Pastan, S. O.; Mohan, S.; Freedman, B. I.; Divers, J.

2016-01-01

Renal allografts from deceased African Americans with two apolipoprotein L1 gene (APOL1) renal-risk variants fail sooner than kidneys from donors with fewer variants. Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied 10-fold cross-validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross-validation was repeated 10,000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current-KDRI score for all donors was 1.4930 versus mean revised-KDRI score 1.2518 for 529 donors with 0/1 variant and 1.8527 for 93 donors with 2 variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence/absence of 2 APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85-90% of kidneys offered, and enhances the link between donor quality and recipient need. PMID:27862962

Autophagy and kidney inflammation.

PubMed

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-06-03

Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases.

The effect of hypericum perforatum on kidney ischemia/reperfusion damage.

PubMed

Cakir, Murat; Duzova, Halil; Baysal, Işil; Gül, Cemile Ceren; Kuşcu, Gülbahar; Kutluk, Fatma; Çakin, Hilal; Şeker, Şifanur; İlbeği, Esranur; Uslu, Seda; Avci, Umut; Demir, Samet; Akinci, Cihan; Atli, Sercan

2017-11-01

It has been revealed in recent studies that Hypericum Perforatum (HP) is influential on cancer, inflammatory diseases, bacterial and viral diseases, and has neuroprotective and antioxidant properties. In this study, we investigated the effect of HP, which is known to have antioxidant and anti-inflammatory effects, on kidney I/R damage. Male Sprague-Dawley rats were divided into three groups, and each of the groups had eight rats: The Control Group; the Ischemia/Reperfusion (I/R) Group; and the IR + HP Group which was treated with 50 mg/kg of HP. The right kidneys of the rats were removed, and the left kidney developed ischemia during the 45th min, and reperfusion occurred in the following 3rd h. The histopathological findings and also the level of Malondialdehyde (MDA), Glutathione (GSH) and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) enzyme activations in the renal tissues were measured. Blood Urea Nitrogen (BUN), Creatinin (Cre) from serum samples were determined. The levels of BUN, Cre, and kidney tissue MDA increased at a significant level, and the SOD, CAT, and GSH-PX enzyme activity decreased at a significant level in the I/R group, compared with the Control Group (p < 0.05). In the I/R + HP group, the levels of MDA decreased at a significant level compared to the I/R group, while the SOD, CAT, and GSH-PX activity increased (p < 0.05). In histopathological examinations, it was observed that the tubular dilatation and epithelial desquamation regressed in the IR + HP Group when compared with the I/R Group. It has been shown with the histological and biochemical results in this study that HP is protective against acute renal I/R.

A biomechanical cadaveric study comparing superior capsule reconstruction using fascia lata allograft with human dermal allograft for irreparable rotator cuff tear.

PubMed

Mihata, Teruhisa; Bui, Christopher N H; Akeda, Masaki; Cavagnaro, Matthew A; Kuenzler, Michael; Peterson, Alexander B; McGarry, Michelle H; Itami, Yasuo; Limpisvasti, Orr; Neo, Masashi; Lee, Thay Q

2017-12-01

Biomechanical and clinical success of the superior capsule reconstruction (SCR) using fascia lata (FL) grafts has been reported. In the United States, human dermal (HD) allograft has been used successfully for SCRs; however, the biomechanical characteristics have not been reported. Eight cadaveric shoulders were tested in 5 conditions: (1) intact; (2) irreparable supraspinatus tear; (3) SCR using FL allograft with anterior and posterior suturing; (4) SCR using HD allograft with anterior and posterior suturing; and (5) SCR using HD allograft with posterior suturing. Rotational range of motion, superior translation, glenohumeral joint force, and subacromial contact were measured at 0°, 30°, and 60° of glenohumeral abduction in the scapular plane. Graft dimensions before and after testing were also recorded. Biomechanical parameters were compared using a repeated-measures analysis of variance with Tukey post hoc test, and graft dimensions were compared using a Student t-test (P < .05). Irreparable supraspinatus tear significantly increased superior translation, superior glenohumeral joint force, and subacromial contact pressure, which were completely restored with the SCR FL allografts. Both SCR HD allograft repairs partially restored superior translation and completely restored subacromial contact and superior glenohumeral joint force. The HD allografts significantly elongated by 15% during testing, whereas the FL allograft lengths were unchanged. Single-layered HD SCR allografts partially restored superior glenohumeral stability, whereas FL allograft SCR completely restored the superior glenohumeral stability. This may be due to the greater flexibility of the HD allograft, and the SCR procedure used was developed on the basis of FL grafts. Published by Elsevier Inc.

Impact of Tacrolimus Compared With Cyclosporin on the Incidence of Acute Allograft Rejection in Human Immunodeficiency Virus-Positive Kidney Transplant Recipients.

PubMed

Gathogo, Esther; Harber, Mark; Bhagani, Sanjay; Levy, Jeremy; Jones, Rachael; Hilton, Rachel; Davies, Graham; Post, Frank A

2016-04-01

Kidney transplantation (KT) of human immunodeficiency virus (HIV)-positive patients has transformed the management of end-stage kidney disease in this population. Although favourable outcomes have been reported, patients experience high rates of acute allograft rejection (AR). We examined factors associated with AR in the first year after KT, with particular emphasis on the choice of calcineurin inhibitor (CNI) immunosuppressive therapy. We conducted a national observational cohort study of HIV/KT in the United Kingdom. Patients were included if HIV positive at KT, transplanted in the United Kingdom between January 2005 and December 2013, and did not experience primary graft failure. Kaplan-Meier methods were used to estimate host/graft survival and cumulative incidence of biopsy proven AR. Logrank tests were used to compare survival, and Cox proportional hazard models to examine factors associated with AR. Our study analyzed the incidence of AR in the first year after KT in 78 HIV-positive patients of whom 31 initiated cyclosporin (CsA) and 47 tacrolimus (Tac) based immunosuppression. AR was observed in 28 patients (36%) after a median of 2.6 (interquartile range, 0.5-5.9) months. The cumulative incidence of AR at 1 year was 58% and 21% among patients on CsA and Tac, respectively (P =0.003). Choice of CNI was the only factor significantly associated with AR (hazard ratio for Tac vs CsA 0.25 [95% confidence interval, 0.11-0.57], P = 0.001). Subtherapeutic CNI concentrations were common in the first 12 weeks after KT. Our data suggest that Tac may be the preferred CNI for use in KT in people living with HIV.

Pancreatic Anastomosis Leak 15 Years after Simultaneous Pancreas-Kidney Transplantation from Late-Onset Allograft Cytomegalovirus Duodenal Ulcers Presenting with Gross Hematuria

PubMed Central

Tantisattamo, Ekamol; Chung, Heath; Okado, Manami

2013-01-01

Cytomegalovirus (CMV) infection is one of the most important causes of morbidity and mortality in solid organ transplantation. It can present with hematuria, the most common urological complication in the early post-simultaneous pancreas-kidney (SPK) transplant period. In SPK transplantation, CMV infection usually occurs 1 month after transplantation. We report an instance of bladder-drained SPK transplant presenting with recurrent gross hematuria from CMV infected duodenal graft ulcers 15 years after preserved well-functioning grafts. Serum quantitative Polymerase Chain Reaction (qPCR) for CMV was negative. Postmortem duodenal graft staining for CMV was positive, and revealed the cause of the inciting ulcer. To our knowledge, our patient is the first reported case of very late onset invasive CMV disease causing duodenal graft ulcers 15 years after transplantation, as previously reported cases of posttransplant CMV disease occurred only as late as 18 months. In addition, the absence of correlation between CMV viremia and CMV-infected duodenal allograft in SPK transplant has not been reported. Our case demonstrates that CMV viral load is -unreliable to diagnose invasive CMV disease, and tissue biopsy should be obtained to avoid missed diagnosis causing high morbidity and mortality. PMID:24349888

Successful liver allografts in mice by combination with allogeneic bone marrow transplantation.

PubMed Central

Nakamura, T; Good, R A; Yasumizu, R; Inoue, S; Oo, M M; Hamashima, Y; Ikehara, S

1986-01-01

Successful liver allografts were established by combination with allogeneic bone marrow transplantation. When liver tissue of BALB/c (H-2d) or C57BL/6J (H-2b) mice was minced and grafted under the kidney capsules of C3H/HeN (H-2k) mice, it was rejected. However, when C3H/HeN mice were irradiated and reconstituted with T-cell-depleted BALB/c or BALB/c nu/nu bone marrow cells, or with fetal liver cells of BALB/c mice, they accepted both donor (stem-cell)-type (BALB/c) and host (thymus)-type (C3H/HeN) liver tissue. Assays for both mixed-lymphocyte reaction and induction of cytotoxic T lymphocytes revealed that the newly developed T cells were tolerant of both donor (stem-cell)-type and host (thymus)-type major histocompatibility complex determinants. We propose that liver allografts combined with bone marrow transplantation should be considered as a viable therapy for patients with liver disease such as liver cirrhosis and hepatoma. Images PMID:3520575

Dual growth factor delivery from biofunctionalized allografts: Sequential VEGF and BMP-2 release to stimulate allograft remodeling.

PubMed

Sharmin, Farzana; McDermott, Casey; Lieberman, Jay; Sanjay, Archana; Khan, Yusuf

2017-05-01

Autografts have been shown to stimulate osteogenesis, osteoclastogenesis, and angiogenesis, and subsequent rapid graft incorporation. Large structural allografts, however, suffer from limited new bone formation and remodeling, both of which are directly associated with clinical failure due to non-unions, late graft fractures, and infections, making it a priority to improve large structural allograft healing. We have previously shown the osteogenic ability of a polymer-coated allograft that delivers bone morphogenetic protein-2 both in vitro and in vivo through both burst release and sustained release kinetics. In this study, we have demonstrated largely sequential delivery of bone morphogenetic protein-2 and vascular endothelial growth factor from the same coated allograft. Release data showed that loading both growth factors onto a polymeric coating with two different techniques resulted in short-term (95% release within 2 weeks) and long-term (95% release within 5 weeks) delivery kinetics. We have also demonstrated how released VEGF, traditionally associated with angiogenesis, can also provide a stimulus for allograft remodeling via resorption. Bone marrow derived mononuclear cells were co-cultured with VEGF released from the coated allograft and showed a statistically significant (p < 0.05) and dose dependent increase in the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts. Functionality of these osteoclasts was assessed quantitatively and qualitatively by evaluating resorption pit area from both osteo-assay plates and harvested bone. Data indicated a statistically significant higher resorption area from the cells exposed to VEGF released from the allografts over controls (p < 0.05). These results indicate that by using different loading protocols temporal control can be achieved when delivering multiple growth factors from a polymer-coated allograft. Further, released VEGF can also stimulate osteoclastogenesis that may

Acute urinary retention secondary to a urethral calculus in a bladder-drained kidney pancreas transplant patient - a metallic clip nidus.

PubMed

Smith, J B K; Sairam, K; Olsburgh, J

2009-01-01

Urological expertise is usually required for the management of any urological complications of bladder-drained pancreatic allografts whether they are the result of simultaneous pancreas-kidney transplants, pancreas after kidney transplants, or pancreas transplants alone. This study presents a case of urinary retention secondary to prostatic urethra calculus impaction, the nidus of which was found to be metallic staples from the donor duodenal segment of a pancreatic allograft. Knowledge of the pre-transplant benchwork gave a high index of suspicion to the urological sequelae of this case and, in particular, the presence of calculi should suggest a metal clip nidus. We examine the methods of exocrine pancreatic drainage, donor duodenum preparation and case management.

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

PubMed Central

Chapman, Jeremy R.; Coates, Patrick T.; Lewis, Joshua R.; Russ, Graeme R.; Watson, Narelle; Holdsworth, Rhonda; Wong, Germaine

2016-01-01

Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). Conclusions HLA

Cytokines in the regulation of allograft rejection.

PubMed

Huber, C; Irschick, E

1988-01-01

Stimulation of T lymphocytes with alloantigen leads to release of both IL-2 and IFN-gamma. IL-2 enhances clonal expansion of alloantigen-activated T cells. This permits it to overcome acquired allograft tolerance which, at the efferent limb of the cellular immune response, is caused by reduced clone size of donor-specific cytotoxic lymphocyte precursor cells. Cells exhibiting a low constitutive expression of class I MHC antigenes are refractory to lysis by cytotoxic T cells. This second type of tolerance located at the level of the allogeneic target cells can be easily broken by exogenous IFN-gamma, which increases the density of class I MHC antigens. There is suggestive evidence for enhanced endogenous production of lymphokines during rejection of cardiac allografts in mice and men. Rejection episodes are also associated with increased expression of class I and elevated frequency of class II MHC antigen-positive cells in the cardiac transplants. Whereas early immune recognition of histoincompatible grafts is primarily related to the presence of genetic barriers between donor and recipient, the further amplification of alloreactivity is driven by the release of antigen-unspecific lymphokines. Production of endogenous lymphokines can be modified by a variety of means: methylprednisone, ciclosporin and specific antibodies against lymphokines or their receptors represent effective inhibitors of this amplification mechanism which can finally lead to irreversible graft damage. It is well established in clinical experience that infectious complications subsequent to allografting may precipitate rejection or graft-vs.-host disease. Our finding of increased endogenous IFN-gamma levels during infections, in particular in those caused by cytomegalovirus, provides an explanation for this association.(ABSTRACT TRUNCATED AT 250 WORDS)

Autophagy and kidney inflammation

PubMed Central

Kimura, Tomonori; Isaka, Yoshitaka; Yoshimori, Tamotsu

2017-01-01

ABSTRACT Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. It is noteworthy that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy. In this mode, autophagy suppresses inflammation to protect the kidney. Systemic inflammation also affects the kidney via pro-inflammatory cytokines and infiltration of inflammatory cells, and autophagy also has a regulatory role in systemic inflammation. This review focuses on the roles of autophagy in kidney diseases and aging through inflammation, and discusses the potential usage of autophagy as an inflammatory modulator for the treatment of kidney diseases. PMID:28441075

Dose-effect relationship between drinking water fluoride levels and damage to liver and kidney functions in children.

PubMed

Xiong, Xianzhi; Liu, Junling; He, Weihong; Xia, Tao; He, Ping; Chen, Xuemin; Yang, Kedi; Wang, Aiguo

2007-01-01

Although a dose-effect relationship between water fluoride levels and damage to liver and kidney functions in animals has been reported, it was not demonstrated in humans. To evaluate the effects of drinking water fluoride levels on the liver and kidney functions in children with and without dental fluorosis, we identified 210 children who were divided into seven groups with 30 each based on different drinking water fluoride levels in the same residential area. We found that the fluoride levels in serum and urine of these children increased as the levels of drinking water fluoride increased. There were no significant differences in the levels of total protein (TP), albumin (ALB), aspartate transamine (AST), and alanine transamine (ALT) in serum among these groups. However, the activities of serum lactic dehydrogenase (LDH), urine N-acetyl-beta-glucosaminidase (NAG), and urine gamma-glutamyl transpeptidase (gamma-GT) in children with dental fluorosis and having water fluoride of 2.15-2.96 mg/L and in children having water fluoride of 3.15-5.69 mg/L regardless of dental fluorosis were significantly higher than children exposed to water fluoride of 0.61-0.87 mg/L in a dose-response manner. In contrast to children with dental fluorosis and having water fluoride of 2.15-2.96 and 3.10-5.69 mg/L, serum LDH activity of children without dental fluorosis but exposed to the same levels of water fluoride as those with dental fluorosis were also markedly lower, but the activities of NAG and gamma-GT in their urine were not. Therefore, our results suggest that drinking water fluoride levels over 2.0mg/L can cause damage to liver and kidney functions in children and that the dental fluorosis was independent of damage to the liver but not the kidney. Further studies on the mechanisms and significance underlying damage to the liver without dental fluorosis in the exposed children are warranted.

Eucalyptus globulus extract protects upon acetaminophen-induced kidney damages in male rat

PubMed Central

Dhibi, Sabah; Mbarki, Sakhria; Elfeki, Abdelfettah; Hfaiedh, Najla

2014-01-01

Plants have historically been used in treating many diseases. Eucalyptus globules, a rich source of bioactive compounds, and have been shown to possess antioxidative properties. The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of Eucalyptus globulus extract upon acetaminophen-induced damages in kidney. Our study is realized in the Department of Biology, Faculty of Sciences of Sfax (Tunisia). 32 Wistar male rats; were divided into 4 batches: a control group (n=8), a group of rats treated with acetaminophen (goomg/kg) by intraperitoneal injection during 4 days (n=8), a group receiving Eucalyptus globulus extract (130 mg of dry leaves/kg/day) in drinking water during 42 days after 2 hours of acetaminophen administration (during 4 days) (n=8) and group received only Eucalyptus (n=8) during 42 days. After 6 weeks, animals from each group were rapidly sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, acetaminophen poisoning resulted in an oxidative stress evidenced by statistically significant losses in the activities of catalase (CAT), superoxide-dismutase (SOD), glutathione-peroxidase (GPX) activities and an increase in lipids peroxidation level in renal tissue of acetaminophen-treated group compared with the control group. Acetaminophen also caused kidney damage as evident by statistically significant (p<0.05) increase in levels of creatinine and urea and decreased levels of uric acid and proteins in blood. Histological analysis demonstrated alteration of proximal tubules, atrophy of the glomerule and dilatation of urinary space. Previous administration of plant extract is found to alleviate this acetaminophen-induced damage. PMID:24856382

Chronic Kidney Disease

MedlinePlus

You have two kidneys, each about the size of your fist. Their main job is to filter your blood. They remove wastes and ... help control blood pressure, and make hormones. Chronic kidney disease (CKD) means that your kidneys are damaged ...

Cutaneous exposure to lewisite causes acute kidney injury by invoking DNA damage and autophagic response.

PubMed

Srivastava, Ritesh K; Traylor, Amie M; Li, Changzhao; Feng, Wenguang; Guo, Lingling; Antony, Veena B; Schoeb, Trenton R; Agarwal, Anupam; Athar, Mohammad

2018-06-01

Lewisite (2-chlorovinyldichloroarsine) is an organic arsenical chemical warfare agent that was developed and weaponized during World Wars I/II. Stockpiles of lewisite still exist in many parts of the world and pose potential environmental and human health threat. Exposure to lewisite and similar chemicals causes intense cutaneous inflammatory response. However, morbidity and mortality in the exposed population is not only the result of cutaneous damage but is also a result of systemic injury. Here, we provide data delineating the pathogenesis of acute kidney injury (AKI) following cutaneous exposure to lewisite and its analog phenylarsine oxide (PAO) in a murine model. Both agents caused renal tubular injury, characterized by loss of brush border in proximal tubules and tubular cell apoptosis accompanied by increases in serum creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Interestingly, lewisite exposure enhanced production of reactive oxygen species (ROS) in the kidney and resulted in the activation of autophagic and DNA damage response (DDR) signaling pathways with increased expression of beclin-1, autophagy-related gene 7, and LC-3A/B-II and increased phosphorylation of γ-H 2 A.X and checkpoint kinase 1/2, respectively. Terminal deoxyribonucleotide-transferase-mediated dUTP nick-end labeling-positive cells were detected in renal tubules along with enhanced proapoptotic BAX/cleaved caspase-3 and reduced antiapoptotic BCL 2 . Scavenging ROS by cutaneous postexposure application of the antioxidant N-acetyl-l-cysteine reduced lewisite-induced autophagy and DNA damage. In summary, we provide evidence that topical exposure to lewisite causes AKI. The molecular mechanism underlying these changes involves ROS-dependent activation of autophagy and DDR pathway associated with the induction of apoptosis.

[Kidney transplant experience at the Specialty Hospital Bernardo Sepulveda National Medical Center Century XXI, Mexican Institute of Social Security].

PubMed

Gracida-Juárez, Carmen; Espinoza-Pérez, Ramón; Cancino-López, Jorge David; Ibarra-Villanueva, Araceli; Cedillo-López, Urbano; Villegas-Anzo, Fernando; Martínez-Alvarez, Julio

2011-09-01

The first kidney transplant in Mexico was done on October 22, 1963 at the General Hospital of National Medical Center (CMN) of the Mexican Institute of Social Security. After the earthquake in 1985, the transplantation activity was continued at the Specialty Hospital of National Medical Center Century XXI. Our program has a continue activity for almost 48 years and a total of 2019 kidney transplants from October 1963 to December 2010. We describe our experience in 20 years. Retrospective cohort study that includes all kidney transplants performed in the period from January 1991 to December 2010. Descriptive statistics were used. The survival analysis was performed using the Kaplan Meier method. We show the patient survival, graft survival censored for death with functional graft and total graft survival (uncensored). We analyzed a total of 1544 kidney transplants. The percentage of living donor was 82.9 vs. deceased donor of 17.1%. Patient survival at 1, 5, 10, 15 and 20 years was 95.0, 91.8, 87.2, 81.1 and 70.1%, respectively; allograft survival rate censored for death with functional allograft at 1, 5, 10, 15 and 20 years was 93.0, 86.2, 76.2, 63.7 and 50.9%, respectively. Our Transplant center also take care of around 1300 living donors in the long term, looking for morbidities as risk factors for the unique kidney as metabolic syndrome, diabetes, hypertension and others. In our program, the main source of renal allografts was living donors. Our transplant center has to increase the organ procurement from deceased donors. An important contribution of our center has been the long follow up of living donors according to international consensus.

Cytokines in single layer amnion allografts compared to multilayer amnion/chorion allografts for wound healing.

PubMed

Koob, Thomas J; Lim, Jeremy J; Zabek, Nicole; Massee, Michelle

2015-07-01

Human amniotic membrane allografts have proven effective at improving healing of cutaneous wounds. The mechanism of action for these therapeutic effects is poorly understood but is thought to involve the resident growth factors present in near term amniotic tissue. To determine the relative cytokine contribution of the amnion and chorion in amniotic allografts, the content of 18 cytokines involved in wound healing were measured in samples of PURION® Processed dehydrated amnion, chorion, and amnion/chorion membrane (dHACM) grafts by multiplex enzyme-linked immunosorbent assay array. Both amnion and chorion contained similar amounts of each factor when normalized per dry weight; however, when calculated per surface area of tissue applied to a wound, amnion contained on average only 25% as much of each factor as the chorion. Therefore, an allograft containing both amnion and chorion would contain four to five times more cytokine than a single layer amnion allograft alone. Both single layer amnion and multilayer allografts containing amnion and chorion are currently marketed for wound repair. To examine the role of tissue processing technique in cytokine retention, cytokine contents in representative dehydrated single layer wound care products were measured. The results demonstrated that cytokine content varied significantly among the allografts tested, and that PURION® Processed single layer amnion grafts contained more cytokines than other single layer products. These results suggest that PURION® Processed dHACM contains substantially more cytokines than single layer amnion products, and therefore dHACM may be more effective at delivering growth factors to a healing wound than amnion alone. © 2014 Wiley Periodicals, Inc.

Kidney Failure

MedlinePlus

Healthy kidneys clean your blood by removing excess fluid, minerals, and wastes. They also make hormones that keep your ... strong and your blood healthy. But if the kidneys are damaged, they don't work properly. Harmful ...

The roles and potential therapeutic implications of CXCL4 and its variant CXCL4L1 in the pathogenesis of chronic liver allograft dysfunction.

PubMed

Li, Jing; Liu, Bin; Yan, Lu-nan; Lau, Wan-yee

2015-02-01

Chronic liver allograft dysfunction is the leading cause of patient morbidity and late allograft loss after liver transplantation. The pathogenesis of chronic liver allograft dysfunction remains unknown. Recent studies have demonstrated that CXCL4 and its variant CXCL4L1 are involved in organ damage induced through inflammatory and immune responses throughout all stages of liver transplantation. CXCL4 and CXCL4L1 are low-molecular-weight proteins that have been implicated in hematopoiesis, angiostasis, organ fibrogenesis, mitogenesis, tumor growth and metastasis. The purpose of this review is to discuss the current status and future developments of research into the roles of CXCL4 and CXCL4L1 in the pathogenesis of chronic liver allograft dysfunction. The potential utilization of CXCL4 and CXCL4L1 as therapeutic targets for chronic liver allograft dysfunction will also be discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of the Purinergic Inhibitor Oxidized ATP in a Model of Islet Allograft Rejection

PubMed Central

Vergani, Andrea; Fotino, Carmen; D’Addio, Francesca; Tezza, Sara; Podetta, Michele; Gatti, Francesca; Chin, Melissa; Bassi, Roberto; Molano, Ruth D.; Corradi, Domenico; Gatti, Rita; Ferrero, Maria E.; Secchi, Antonio; Grassi, Fabio; Ricordi, Camillo; Sayegh, Mohamed H.; Maffi, Paola; Pileggi, Antonello; Fiorina, Paolo

2013-01-01

The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function. PMID:23315496

Rationale of mesenchymal stem cell therapy in kidney injury.

PubMed

Cantaluppi, Vincenzo; Biancone, Luigi; Quercia, Alessandro; Deregibus, Maria Chiara; Segoloni, Giuseppe; Camussi, Giovanni

2013-02-01

Numerous preclinical and clinical studies suggest that mesenchymal stem cells, also known as multipotent mesenchymal stromal cells (MSCs), may improve pathologic conditions involving different organs. These beneficial effects initially were ascribed to the differentiation of MSCs into organ parenchymal cells. However, at least in the kidney, this is a very rare event and the kidney-protective effects of MSCs have been attributed mainly to paracrine mechanisms. MSCs release a number of trophic, anti-inflammatory, and immune-modulatory factors that may limit kidney injury and favor recovery. In this article, we provide an overview of the biologic activities of MSCs that may be relevant for the treatment of kidney injury in the context of a case vignette concerning a patient at high immunologic risk who underwent a second kidney transplantation followed by the development of ischemia-reperfusion injury and acute allograft rejection. We discuss the possible beneficial effect of MSC treatment in the light of preclinical and clinical data supporting the regenerative and immunomodulatory potential of MSCs. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Kidney Transplantation: The Challenge of Human Leukocyte Antigen and Its Therapeutic Strategies.

PubMed

Alelign, Tilahun; Ahmed, Momina M; Bobosha, Kidist; Tadesse, Yewondwossen; Howe, Rawleigh; Petros, Beyene

2018-01-01

Kidney transplantation remains the treatment of choice for end-stage renal failure. When the immune system of the recipient recognizes the transplanted kidney as a foreign object, graft rejection occurs. As part of the host immune defense mechanism, human leukocyte antigen (HLA) is a major challenge for graft rejection in transplantation therapy. The impact of HLA mismatches between the donor and the potential recipient prolongs the time for renal transplantation therapy, tethered to dialysis, latter reduces graft survival, and increases mortality. The formation of pretransplant alloantibodies against HLA class I and II molecules can be sensitized through exposures to blood transfusions, prior transplants, and pregnancy. These preformed HLA antibodies are associated with rejection in kidney transplantation. On the other hand, the development of de novo antibodies may increase the risk for acute and chronic rejections. Allograft rejection results from a complex interplay involving both the innate and the adaptive immune systems. Thus, further insights into the mechanisms of tissue rejection and the risk of HLA sensitization is crucial in developing new therapies that may blunt the immune system against transplanted organs. Therefore, the purpose of this review is to highlight facts about HLA and its sensitization, various mechanisms of allograft rejection, the current immunosuppressive approaches, and the directions for future therapy.

Kidney Transplantation: The Challenge of Human Leukocyte Antigen and Its Therapeutic Strategies

PubMed Central

Ahmed, Momina M.; Bobosha, Kidist; Tadesse, Yewondwossen; Howe, Rawleigh; Petros, Beyene

2018-01-01

Kidney transplantation remains the treatment of choice for end-stage renal failure. When the immune system of the recipient recognizes the transplanted kidney as a foreign object, graft rejection occurs. As part of the host immune defense mechanism, human leukocyte antigen (HLA) is a major challenge for graft rejection in transplantation therapy. The impact of HLA mismatches between the donor and the potential recipient prolongs the time for renal transplantation therapy, tethered to dialysis, latter reduces graft survival, and increases mortality. The formation of pretransplant alloantibodies against HLA class I and II molecules can be sensitized through exposures to blood transfusions, prior transplants, and pregnancy. These preformed HLA antibodies are associated with rejection in kidney transplantation. On the other hand, the development of de novo antibodies may increase the risk for acute and chronic rejections. Allograft rejection results from a complex interplay involving both the innate and the adaptive immune systems. Thus, further insights into the mechanisms of tissue rejection and the risk of HLA sensitization is crucial in developing new therapies that may blunt the immune system against transplanted organs. Therefore, the purpose of this review is to highlight facts about HLA and its sensitization, various mechanisms of allograft rejection, the current immunosuppressive approaches, and the directions for future therapy. PMID:29693023

A cost-effective method for femoral head allograft procurement for spinal arthrodesis: an alternative to commercially available allograft.

PubMed

Brown, Desmond A; Mallory, Grant W; Higgins, Dominique M; Abdulaziz, Mohammed; Huddleston, Paul M; Nassr, Ahmad; Fogelson, Jeremy L; Clarke, Michelle J

2014-07-01

A cost-effective procurement process for harvesting, storing, and using femoral head allografts is described. A brief review of the literature on the use of these allografts and a discussion of costs are provided. To describe a cost-effective method for the harvesting, storage, and use of femoral heads from patients undergoing total hip arthroplasty at our institution as a source of allograft bone. Spine fusion surgery uses a large proportion of commercially available bone grafts and bone substitutes. As the number of such surgical procedures performed in the United States continues to rise, these materials are at a historically high level of demand, which is projected to continue. Iliac crest bone autograft has historically been the standard of care, although this may be losing favor due to potential donor site morbidity. Although many substitutes are effective in promoting arthrodesis, their use is limited because of cost. Femoral heads are harvested under sterile conditions during total hip arthroplasty. The patient is tested per Food and Drug Administration regulations, and the tissue sample is cultured. The tissue is frozen and quarantined for a 6-month minimum pending repeat testing of donors and subsequently released for use. The relative cost-effectiveness of this tissue as a source of allograft bone is discussed. The average femoral head allograft is 54 to 56 mm in diameter and yields 50 cm of bone graft, with an average cost of US $435 for processing of the tissue resulting in a cost of US $8.70 per cm of allograft produced. Average production costs are significantly lower than those for other commonly available commercial bone grafts and substitutes. Femoral head allograft is a cost-effective alternative to commercially available allografts and bone substitutes. The method of procurement, storage, and use described could be adopted by other institutions in an effort to mitigate cost and increase supply. N/A.

High variation of individual soluble serum CD30 levels of pre-transplantation patients: sCD30 a feasible marker for prediction of kidney allograft rejection?

PubMed

Altermann, Wolfgang; Schlaf, Gerald; Rothhoff, Anita; Seliger, Barbara

2007-10-01

Previous studies have suggested that the pre-transplant levels of the soluble CD30 molecule (sCD30) represent a non-invasive tool which can be used as a biomarker for the prediction of kidney allograft rejections. In order to evaluate the feasibility of sCD30 for pre-transplantation monitoring the sera of potential kidney recipients (n = 652) were collected four times in a 3 months interval. Serum from healthy blood donors (n = 203) served as controls. The sCD30 concentrations of all samples were determined using a commercially available ELISA. This strategy allowed the detection of possible variations of individual sCD30 levels over time. Heterogeneous sCD30 concentrations were found in the samples obtained from individual putative kidney transplant recipients when quarterly measured over 1 year. Total 95% of serum samples obtained from healthy controls exhibited sCD30 values <30 U/ml, whereas most recipients displayed higher serum levels (>30 U/ml). Total 524 patients (80.4%) constantly exhibited serum concentrations of <100 U/ml during the period investigated, whereas 109 patients (16.7%) showed variations by exceeding the proposed 'cut off' of 100 U/ml for one to three times. The frequency of samples exhibiting sCD30 values >100 U/ml was significantly lower than that previously reported. The high degree of variation does not allow the stratification of patients into high and low immunological risk groups based on a single sCD30 value > 100 U/ml. Due to the heterogeneity of sCD30 levels during time course and the high values of SD, its implementation as a pre-transplant marker cannot be justified to generate special provisions for the organ allocation to patients with single sCD30 values > 100 U/ml.

Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms.

PubMed

Royer, Pierre-Joseph; Olivera-Botello, Gustavo; Koutsokera, Angela; Aubert, John-David; Bernasconi, Eric; Tissot, Adrien; Pison, Christophe; Nicod, Laurent; Boissel, Jean-Pierre; Magnan, Antoine

2016-09-01

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. Chronic lung allograft dysfunction manifests as bronchiolitis obliterans syndrome or the recently described restrictive allograft syndrome. Although numerous risk factors have been identified so far, the physiopathological mechanisms of CLAD remain poorly understood. We investigate here the immune mechanisms involved in the development of CLAD after lung transplantation. We explore the innate or adaptive immune reactions induced by the allograft itself or by the environment and how they lead to allograft dysfunction. Because current literature suggests bronchiolitis obliterans syndrome and restrictive allograft syndrome as 2 distinct entities, we focus on the specific factors behind one or the other syndromes. Chronic lung allograft dysfunction is a multifactorial disease that remains irreversible and unpredictable so far. We thus finally discuss the potential of systems-biology approach to predict its occurrence and to better understand its underlying mechanisms.

Allograft materials in phalloplasty: a comparative analysis.

PubMed

Solomon, Mark P; Komlo, Caroline; Defrain, Molly

2013-09-01

Allograft use has increased recently with the rising use of allograft materials in breast surgery. There are few data that compare the performance of the various allograft materials in this application, despite marketing efforts by the manufacturers to present one allograft material as superior to another. Phalloplasty is a procedure that uses allografts for penis girth augmentation. Preparation of these grafts differs with each manufacturer. We report our experience with 3 different types of allografts for this procedure. This allows for the comparison of these materials in their performance with a single model. Forty-seven patients who underwent penis girth enhancement with allograft material were reviewed. All patients underwent circumferential grafting to the shaft of the penis at the level of Buck's fascia. Graft materials included AlloDerm (n = 9), Belladerm (n = 20), and Repriza (n = 21). Charts were reviewed for material type, presence and type of infection, wound exposure, and graft loss with attention to the type of allograft material that was used. Follow-up ranged from 1 to 120 months with an average of 11.25 months. Infection, defined as an open wound with graft exposure, occurred in 20 (42%) of 47 patients. Of these, graft exposure only occurred in 17 (36%) patients, whereas 3 (6%) patients sustained total graft loss. Graft exposure or loss occurred in 3 patients who had AlloDerm, 9 patients with Belladerm, and 8 patients with Repriza. No patients with AlloDerm sustained graft loss, whereas 2 patients with Belladerm and 1 patient with Repriza sustained graft loss. There were no statistical differences among these graft types with regard to infection or graft loss. Three different brands of allograft material were used in 1 surgical procedure and followed up for their performance with regard to exposure and infection. In this model, there is no difference in the rate of infection in these materials despite their different methods of preparation

Structural allograft reconstruction of the foot and ankle after tumor resections.

PubMed

Ayerza, M A; Piuzzi, N S; Aponte-Tinao, L A; Farfalli, G L; Muscolo, D L

2016-08-01

Structural allografts have been used to correct deformities or to fill bone defects secondary to tumor excisions, trauma, osteochondral lesions, or intercalary arthrodesis. However, the quality of published evidence supporting the use of allograft transplantation in foot and ankle surgery has been reported as fair. The purpose of this study was to report the overall survival of structural allograft in the foot and ankle after tumor resection, and the survival according to the type of allograft and the complication rates in the medium to long term. From January 1989 to June 2011, 44 structural allograft reconstructions of the foot and ankle were performed in 42 patients (28 men and 14 women) due to musculoskeletal tumor resections. Mean age at presentation was 27 years. Mean follow-up was 53 months. Demographic data, diagnosis, site of the neoplasm, operations performed, operative complications, outcomes after surgery, date of last follow-up evaluation, and local recurrences were reviewed for all patients. Regarding the type of 44 allograft reconstructions, 16 were hemicylindrical allografts (HA), 12 intercalary allografts (IA), 10 osteoarticular allografts (OA), and 6 were total calcaneal allograft (CA). The overall allograft survival rate, as calculated with the Kaplan-Meier method, at 5 and 10 years was 79 % (95 % CI 64-93 %). When allocated by type of allograft reconstruction the specific allograft survival at 5 and 10 years was: 83 % for CA, 80 % for HA, 77 % for OA, and 75 % for IA. The complications rate for this series was 36 % including: articular failure, local recurrence, infection, fracture and nonunion. This study showed that structural allograft reconstruction in the foot and ankle after tumor resection may be durable with a 79 % survival rate at 5 and 10 years. The two types of allografts that showed better survival rate were hemicylindrical allografts (80 %) and calcaneus allografts (83 %). The highest complication rates occurred

Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats.

PubMed

Zhao, Hailin; Luo, Xianghong; Zhou, Zhaowei; Liu, Juying; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

2014-01-01

Chronic allograft nephropathy (CAN) is a common finding in kidney grafts with functional impairment. Prolonged hypothermic storage-induced ischemia-reperfusion injury is associated with the early onset of CAN. As the noble gas xenon is clinically used as an anesthetic and has renoprotective properties in a rodent model of ischemia-reperfusion injury, we studied whether early treatment with xenon could attenuate CAN associated with prolonged hypothermic storage. Exposure to xenon enhanced the expression of insulin growth factor-1 (IGF-1) and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. Xenon treatment before or after hypothermia-hypoxia decreased cell apoptosis and cell inflammation after reoxygenation. The xenon-induced HK-2 cell proliferation was abolished by blocking the IGF-1 receptor, mTOR, and HIF-1α individually. In the Fischer-to-Lewis rat allogeneic renal transplantation model, xenon exposure of donors before graft retrieval or recipients after engraftment enhanced tubular cell proliferation and decreased tubular cell death and cell inflammation associated with ischemia-reperfusion injury. Compared with control allografts, xenon treatment significantly suppressed T-cell infiltration and fibrosis, prevented the development of CAN, and improved renal function. Thus, xenon treatment promoted recovery from ischemia-reperfusion injury and reduced susceptibility to the subsequent development of CAN in allografts.

Ipsilateral versus Contralateral Placement of the Pancreas Allograft in Pancreas after Kidney Transplant Recipients.

PubMed

Yin, Hang; Arpali, Emre; Leverson, Glen E; Sollinger, Hans W; Kaufman, Dixon B; Odorico, Jon S

2018-06-28

In a diabetic, uremic kidney transplant recipient that may receive a future pancreas after kidney (PAK) transplant, the kidney is typically implanted on the left side in anticipation of the subsequent pancreas transplant on the right side. In this study, we sought to determine if ipsilateral PAK (iPAK) is as safe as contralateral PAK (cPAK). 115 PAK transplants (iPAK n=57, cPAK n=58) were performed from 1997-2010 and results were compared between the groups. Kidney graft survival and pancreas graft survival was similar between the two groups. Kidney graft function according to serum creatinine and eGFR was not different between the cPAK and iPAK groups and there were no episodes of kidney graft thrombosis in either group. Subgroup analyses focusing on donor source, also did not show worse outcomes for graft survivals in iPAK group when compared to cPAK group. Pancreas and kidney graft survival in PAK transplants is unaffected by the surgical procedure and iPAK is safe. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

PTH promotes allograft integration in a calvarial bone defect

PubMed Central

Sheyn, Dmitriy; Yakubovich, Doron Cohn; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M.; Gazit, Dan; Gazit, Zulma

2013-01-01

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and micro–computed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in Allograft + PTH–treated mice comparing to Allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the Allograft + PTH–treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment. PMID:24131143

PTH promotes allograft integration in a calvarial bone defect.

PubMed

Sheyn, Dmitriy; Cohn Yakubovich, Doron; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M; Gazit, Dan; Gazit, Zulma

2013-12-02

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and microcomputed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in allograft + PTH treated mice comparing to allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the allograft + PTH treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment.

CMV allograft pancreatitis: diagnosis, treatment, and histological features.

PubMed

Klassen, D K; Drachenberg, C B; Papadimitriou, J C; Cangro, C B; Fink, J C; Bartlett, S T; Weir, M R

2000-05-15

Cytomegalovirus (CMV) infection is a common problem in solid organ transplant recipients. CMV infection of pancreas allografts is not, however, well described. We report the clinical presentation, histologic findings, treatment, and outcome in four patients with CMV allograft pancreatitis. These patients presented 18 weeks to 44 months after transplantation with elevated serum amylase and lipase and were suspected to have acute rejection. Percutaneous pancreas allograft biopsy specimens showed evidence of tissue invasive CMV infection. One patient had simultaneous CMV infection and acute rejection. Prolonged treatment with ganciclovir resulted in clinical and histologic resolution of the CMV disease. Rejection was successfully treated. Primary CMV infection in seronegative recipients seemed to be a risk factor. Three patients maintain normal allograft function; one patient lost function due to chronic rejection. The histology of tissue-invasive CMV pancreas allograft infection and its differentiation from acute rejection is described. Prompt diagnosis and prolonged therapy with antiviral agents can result in maintenance of allograft function.

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney.

PubMed

Kelsen, Silvia; He, Xiaochen; Chade, Alejandro R

2012-08-15

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution

Early superoxide scavenging accelerates renal microvascular rarefaction and damage in the stenotic kidney

PubMed Central

Kelsen, Silvia; He, Xiaochen

2012-01-01

Renal artery stenosis (RAS), the main cause of chronic renovascular disease (RVD), is associated with significant oxidative stress. Chronic RVD induces renal injury partly by promoting renal microvascular (MV) damage and blunting MV repair in the stenotic kidney. We tested the hypothesis that superoxide anion plays a pivotal role in MV dysfunction, reduction of MV density, and progression of renal injury in the stenotic kidney. RAS was induced in 14 domestic pigs and observed for 6 wk. Seven RAS pigs were chronically treated with the superoxide dismutase mimetic tempol (RAS+T) to reduce oxidative stress. Single-kidney hemodynamics and function were quantified in vivo using multidetector computer tomography (CT) and renal MV density was quantified ex vivo using micro-CT. Expression of angiogenic, inflammatory, and apoptotic factors was measured in renal tissue, and renal apoptosis and fibrosis were quantified in tissue sections. The degree of RAS and blood pressure were similarly increased in RAS and RAS+T. Renal blood flow (RBF) and glomerular filtration rate (GFR) were reduced in the stenotic kidney (280.1 ± 36.8 and 34.2 ± 3.1 ml/min, P < 0.05 vs. control). RAS+T kidneys showed preserved GFR (58.5 ± 6.3 ml/min, P = not significant vs. control) but a similar decreases in RBF (293.6 ± 85.2 ml/min) and further decreases in MV density compared with RAS. These changes were accompanied by blunted angiogenic signaling and increased apoptosis and fibrosis in the stenotic kidney of RAS+T compared with RAS. The current study shows that tempol administration provided limited protection to the stenotic kidney. Despite preserved GFR, renal perfusion was not improved by tempol, and MV density was further reduced compared with untreated RAS, associated with increased renal apoptosis and fibrosis. These results suggest that a tight balance of the renal redox status is necessary for a normal MV repair response to injury, at least at the early stage of RVD, and raise caution

Autograft versus Allograft for Cervical Spinal Fusion

PubMed Central

Brodke, Darrel S.; Youssef, Jim A.; Meisel, Hans-Jörg; Dettori, Joseph R.; Park, Jong-Beom; Yoon, S. Tim; Wang, Jeffrey C.

2017-01-01

Study Design Systematic review. Objective To compare the effectiveness and safety between iliac crest bone graft (ICBG), non-ICBG autologous bone, and allograft in cervical spine fusion. To avoid problems at the donor site, various allograft materials have been used as a substitute for autograft. However, there are still questions as to the comparative effectiveness and safety of cadaver allograft compared with autologous ICBG. Methods A systematic search of multiple major medical reference databases was conducted to identify studies evaluating spinal fusion in patients with cervical degenerative disk disease using ICBG compared with non-ICBG autograft or allograft or non-ICBG autograft compared with allograft in the cervical spine. Radiographic fusion, patient-reported outcomes, and functional outcomes were the primary outcomes of interest. Adverse events were evaluated for safety. Results The search identified 13 comparative studies that met our inclusion criteria: 2 prospective cohort studies and 11 retrospective cohort studies. Twelve cohort studies compared allograft with ICBG autograft during anterior cervical fusion and demonstrated with a low evidence level of support that there are no differences in fusion percentages, pain scores, or functional results. There was insufficient evidence comparing patients receiving allograft with non-ICBG autograft for fusion, pain, revision, and functional and safety outcomes. No publications directly comparing non-ICBG autograft with ICBG were found. Conclusion Although the available literature suggests ICBG and allograft may have similar effectiveness in terms of fusion rates, pain scores, and functional outcomes following anterior cervical fusion, there are too many limitations in the available literature to draw any significant conclusions. No individual study provided greater than class III evidence, and when evaluating the overall body of literature, no conclusion had better than low evidence support. A prospective

Sequential kidney/islet transplantation using prednisone-free immunosuppression.

PubMed

Kaufman, Dixon B; Baker, Marshall S; Chen, Xiaojuan; Leventhal, Joseph R; Stuart, Frank P

2002-08-01

Islet transplantation is becoming established as a treatment option for type I diabetes in select patients. Individuals with type I diabetes who have previously received a successful kidney allograft may be good candidates for islet transplantation. They have already assumed the risks of chronic immunosuppression, so the added procedural risk of a subsequent islet transplant would be minimal. Furthermore, because of the preimmunosuppressed state it is possible that islet-after-kidney transplantation may result in a more efficient early islet engraftment. Consequently, insulin independence might be achieved with significantly fewer islets than the approximately 8-10,000 islet equivalents/kg/b.w. currently required. A mass that usually demands two or more cadaveric donors. A case of successful islet-after-kidney transplantation is described using the steroid-free Edmonton immunosuppression protocol. Characteristics of the final islet product are: a) islet equivalents: 265,888 (4100 islet equivalents/kg/b.w.); b) islet purity: 75-80%; c) viability: >95% (trypan blue exclusion); and d) mean islet potency (static low-high glucose challenge): 4.16 +/- 1.91-fold increase. Post-transplant the patient's hypoglycemic episodes abated. Exogenous insulin requirements were eliminated at week 12 post-transplant as basal and Ensure (Abbott Laboratories, Abbott Park, IL, USA) oral glucose stimulated C-peptide levels peaked and stabilized. Twenty-four-hour continuous glucose monitoring confirmed moment-to-moment glycemic control, and periodic nonfasting finger stick glucose determinations over the next month confirmed glycemia was controlled. Hemoglobin A1c levels declined from a pretransplant level of 6.9% to 5.3%. Renal allograft function remained changed.

Proteomic and phosphoproteomic analysis of renal cortex in a salt-load rat model of advanced kidney damage

PubMed Central

Jiang, Shaoling; He, Hanchang; Tan, Lishan; Wang, Liangliang; Su, Zhengxiu; Liu, Yufeng; Zhu, Hongguo; Zhang, Menghuan; Hou, Fan Fan; Li, Aiqing

2016-01-01

Salt plays an essential role in the progression of chronic kidney disease and hypertension. However, the mechanisms underlying pathogenesis of salt-induced kidney damage remain largely unknown. Here, Sprague-Dawley rats, that underwent 5/6 nephrectomy (5/6Nx, a model of advanced kidney damage) or sham operation, were treated for 2 weeks with a normal or high-salt diet. We employed aTiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for proteomic and phosphoproteomic profiling of the renal cortex. We found 318 proteins differentially expressed in 5/6Nx group relative to sham group, and 310 proteins significantly changed in response to salt load in 5/6Nx animals. Totally, 1810 unique phosphopeptides corresponding to 550 phosphoproteins were identified. We identified 113 upregulated and 84 downregulated phosphopeptides in 5/6Nx animals relative to sham animals. Salt load induced 78 upregulated and 91 downregulated phosphopeptides in 5/6Nx rats. The differentially expressed phospholproteins are important transporters, structural molecules, and receptors. Protein-protein interaction analysis revealed that the differentially phosphorylated proteins in 5/6Nx group, Polr2a, Srrm1, Gsta2 and Pxn were the most linked. Salt-induced differential phosphoproteins, Myh6, Lmna and Des were the most linked. Altered phosphorylation levels of lamin A and phospholamban were validated. This study will provide new insight into pathogenetic mechanisms of chronic kidney disease and salt sensitivity. PMID:27775022

Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years.

PubMed

Gonwa, Thomas; Johnson, Christopher; Ahsan, Nasimul; Alfrey, Edward J; Halloran, Philip; Stegall, Mark; Hardy, Mark; Metzger, Robert; Shield, Charles; Rocher, Leslie; Scandling, John; Sorensen, John; Mulloy, Laura; Light, Jimmy; Corwin, Claudia; Danovitch, Gabriel; Wachs, Michael; VanVeldhuisen, Paul; Leonhardt, Maryanne; Fitzsimmons, William E

2003-06-27

Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years. The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF. All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

The effect of the use of a TNF-alpha inhibitor in hypothermic machine perfusion on kidney function after transplantation.

PubMed

Diuwe, Piotr; Domagala, Piotr; Durlik, Magdalena; Trzebicki, Janusz; Chmura, Andrzej; Kwiatkowski, Artur

2017-08-01

One of the most important problems in transplantation medicine is the ischemia/reperfusion injury of the organs to be transplanted. The aim of the present study was to assess the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitor etanercept on the machine perfusion hypothermia of renal allograft kidney function and organ perfusion. No statistically significant differences were found in the impact of the applied intervention on kidney machine perfusion during which the average flow and vascular resistance were evaluated. There were no statistically significant differences in the occurrence of delayed graft function (DGF). Fewer events in patients who received a kidney from the etanercept treated Group A compared to the patients who received a kidney from the control Group B were observed when comparing the functional DGF and occurrence of acute rejection episodes, however, there was no statistically significant difference. In summary, no effect of treatment with etanercept an inhibitor of TNF-alpha in a hypothermic machine perfusion on renal allograft renal survival and its perfusion were detected in this study. However, treatment of the isolated organ may be important for the future of transplantation medicine. Copyright © 2017 Elsevier Inc. All rights reserved.

Tanshinol suppresses cardiac allograft rejection in a murine model.

PubMed

Lu, Chuanjian; Zeng, Yu-Qun; Liu, Huazhen; Xie, Qingfeng; Xu, Shengmei; Tu, Kangsheng; Dou, Changwei; Dai, Zhenhua

2017-02-01

Achieving long-term cardiac allograft survival without continuous immunosuppression is highly desired in organ transplantation. Studies have shown that Salvia miltiorrhiza, an herb also known as danshen, improves microcirculation and is highly effective in treating coronary heart disease. Our objective is to determine whether tanshinol, an ingredient of danshen, improves cardiac allograft survival. Fully vascularized heterotopic heart transplantation was performed using BALB/c mice as donors and C57BL/6 mice as recipients, which were then treated with tanshinol and rapamycin. CD4 + FoxP3 + regulatory T cells (Tregs) were quantified by flow analyses, whereas CCL22 was measured by real-time polymerase chain reaction and Western blotting. We found that tanshinol significantly delayed cardiac allograft rejection. It promoted long-term allograft survival induced by rapamycin, a mammalian target-of-rapamycin (mTOR) inhibitor. Tanshinol increased CD4 + FoxP3 + Treg numbers in cardiac allografts, but not spleens and lymph nodes, of recipient mice by enhancing chemokine CCL22 expression in cardiac allografts, especially cardiac dendritic cells. In contrast, rapamycin increased Treg numbers in both lymphoid organs and allografts, suggesting that it generally expands Tregs. Moreover, Tregs induced by rapamycin plus tanshinol were more potent in suppressing T-cell proliferation in vitro than those from untreated recipients. Neutralizing CCL22 hindered CD4 + FoxP3 + Treg migration to cardiac allografts and reversed long-term allograft survival induced by tanshinol plus rapamycin. Tanshinol suppresses cardiac allograft rejection by recruiting CD4 + FoxP3 + Tregs to the graft, whereas rapamycin does so via expanding the Tregs. Thus, tanshinol cooperates with rapamycin to further extend cardiac allograft survival. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Validating Early Post–Transplant Outcomes Reported for Recipients of Deceased Donor Kidney Transplants

PubMed Central

Potluri, Vishnu S.; Hall, Isaac E.; Ficek, Joseph; Doshi, Mona D.; Butrymowicz, Isabel; Weng, Francis L.; Schröppel, Bernd; Thiessen-Philbrook, Heather; Reese, Peter P.

2016-01-01

Background and objectives Data reported to the Organ Procurement and Transplantation Network (OPTN) are used in kidney transplant research, policy development, and assessment of center quality, but the accuracy of early post–transplant outcome measures is unknown. Design, setting, participants, & measurements The Deceased Donor Study (DDS) is a prospective cohort study at five transplant centers. Research coordinators manually abstracted data from electronic records for 557 adults who underwent deceased donor kidney transplantation between April of 2010 and November of 2013. We compared the post-transplant outcomes of delayed graft function (DGF; defined as dialysis in the first post–transplant week), acute rejection, and post–transplant serum creatinine reported to the OPTN with data collected for the DDS. Results Median kidney donor risk index was 1.22 (interquartile range [IQR], 0.97–1.53). Median recipient age was 55 (IQR, 46–63) years old, 63% were men, and 47% were black; 93% had received dialysis before transplant. Using DDS data as the gold standard, we found that pretransplant dialysis was not reported to the OPTN in only 11 (2%) instances. DGF in OPTN data had a sensitivity of 89% (95% confidence interval [95% CI], 84% to 93%) and specificity of 98% (95% CI, 96% to 99%). Surprisingly, the OPTN data accurately identified acute allograft rejection in only 20 of 47 instances (n=488; sensitivity of 43%; 95% CI, 17% to 73%). Across participating centers, sensitivity of acute rejection varied widely from 23% to 100%, whereas specificity was uniformly high (92%–100%). Six-month serum creatinine values in DDS and OPTN data had high concordance (n=490; Lin concordance correlation =0.90; 95% CI, 0.88 to 0.92). Conclusions OPTN outcomes for recipients of deceased donor kidney transplants have high validity for DGF and 6-month allograft function but lack sensitivity in detecting rejection. Future studies using OPTN data may consider focusing on allograft

Use of cultured human epidermal keratinocytes for allografting burns and conditions for temporary banking of the cultured allografts.

PubMed

Bolívar-Flores, J; Poumian, E; Marsch-Moreno, M; Montes de Oca, G; Kuri-Harcuch, W

1990-02-01

Five children who suffered burns clinically regarded as full skin thickness loss were grafted with cultured allogeneic skin from newborn prepuce. The wounds had remained open and infected without healing for about 20 days before the patients were received in the burn unit. To avoid losing surviving deep epidermal cells the wounds were débrided but not deeply excised and, a few days before allografting, they were washed with isodine solution and sterile water, and treated with silvadene cream application. All children received 76 cultured allografts of about 60 cm2 each. After allografting, the wounds were epithelized in 7-10 days and the allogeneic grafted skin began desquamation suggesting that the allograft did not 'take' permanently but was replaced by the newly formed skin. On the other hand, since allografting is an adequate therapy to provide early temporary coverage in extensively burned patients, we developed conditions for banking cultured skin to make it available for immediate use. The conditions described allow banking of the cultured grafts for 15-20 days with retention of clonal growth ability similar to that of unstored epithelia. The results show that cultured epidermal cells obtained from human newborn foreskin, when used as allografts for coverage of full skin or deep partial skin thickness burns, allow rapid epithelization of the burn wounds.

As in Real Estate, Location Is What Matters: A Case Report of Transplant Ureteral Obstruction Due to an Inguinal Hernia.

PubMed

Bugeja, Ann; Clark, Edward G; Sood, Manish M; Ali, Sohrab N

2018-01-01

Kidney allograft dysfunction is common and often reversible but can lead to allograft loss if not promptly evaluated. Transplant ureteral obstruction in an inguinal hernia is a rare cause of allograft dysfunction, but early recognition may prevent allograft loss. We present a case of a man with acute kidney allograft dysfunction who received a deceased donor kidney transplant 6 years earlier for end-stage kidney disease secondary to polycystic kidney disease. Abdominal ultrasounds revealed hydronephrosis without full visualization of the transplant ureter. Abdominal computed tomography revealed moderate hydronephrosis of the transplant kidney due to obstructed herniation of the transplant ureter in a right inguinal hernia. A stent was inserted into the transplant ureter to prevent further allograft dysfunction and facilitate hernia repair. Transplant ureteral obstruction is a rare cause of acute kidney allograft dysfunction, and its detection can be challenging. The recognition of transplant ureteral obstruction is vital to timely management for preventing allograft loss.

Role of humoral immune reactions as target for antirejection therapy in recipients of a spousal-donor kidney graft.

PubMed

Böhmig, G A; Regele, H; Säemann, M D; Exner, M; Druml, W; Kovarik, J; Hörl, W H; Zlabinger, G J; Watschinger, B

2000-04-01

Excellent graft outcome has been reported for spousal-donor kidney transplantation. In husband-to-wife transplantation, however, a tendency toward inferior graft survival has been described for recipients who were previously pregnant. In our series of spousal-kidney transplantations (nine transplantations; three female recipients), actual graft survival is 100% (median observation time, 339 days). Five patients experienced early allograft rejection. In four transplant recipients, rejection was easily reversible by conventional antirejection therapy. In a multiparous recipient, however, mild interstitial allograft rejection associated with early graft dysfunction was resistant to anticellular treatment (antilymphocyte antibody, tacrolimus rescue therapy). The particular finding of polymorphonuclear neutrophils in peritubular capillaries and the finding of diffuse capillary deposits of the complement split product, C4d, in a posttransplantation biopsy specimen suggested a role of antibody-mediated graft injury. Retrospective flow cytometry cross-matching showed the presence of preformed immunoglobulin G (IgG) antibodies to HLA class I antigens that were not detectable by pretransplantation lymphocytotoxic cross-match testing or screening for panel reactive antibodies. After transplantation, however, complement-fixing antibodies, also presumably triggered by reexposure to spousal-donor HLA antigens, could be detected in the patient's serum. These findings suggested antibody-mediated allograft rejection and led to the initiation of immunoadsorption therapy (14 sessions) with staphylococcal protein A. Selective removal of recipient IgG resulted in complete reversal of graft dysfunction. Our findings suggest that in husband-to-wife transplantation, donor-specific antibodies, presumably triggered by previous pregnancies, might occasionally induce sustained allograft dysfunction. Thus, in this particular setting, a detailed immunologic and histopathologic work-up regarding

Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma.

PubMed

Revelo, Monica P; Federspiel, Charles; Helderman, Harold; Fogo, Agnes B

2005-12-01

Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN. All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0-3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR-gamma immunostaining was assessed on a 0-3 scale in glomeruli, vessels and tubules. Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9+/-1.7 years. Average time after transplant at time of biopsy was 60.5+/-4.9 months (range 7-229). Glomerulosclerosis extent in CAN was on average 26.5+/-2.4% compared with 3.6+/-1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0+/-1.2%), whereas transplant controls showed very minimal fibrosis (2

Acellular Nerve Allografts in Peripheral Nerve Regeneration: A Comparative Study

PubMed Central

Moore, Amy M.; MacEwan, Matthew; Santosa, Katherine B.; Chenard, Kristofer E.; Ray, Wilson Z.; Hunter, Daniel A.; Mackinnon, Susan E.; Johnson, Philip J.

2011-01-01

Background Processed nerve allografts offer a promising alternative to nerve autografts in the surgical management of peripheral nerve injuries where short deficits exist. Methods Three established models of acellular nerve allograft (cold-preserved, detergent-processed, and AxoGen® -processed nerve allografts) were compared to nerve isografts and silicone nerve guidance conduits in a 14 mm rat sciatic nerve defect. Results All acellular nerve grafts were superior to silicone nerve conduits in support of nerve regeneration. Detergent-processed allografts were similar to isografts at 6 weeks post-operatively, while AxoGen®-processed and cold-preserved allografts supported significantly fewer regenerating nerve fibers. Measurement of muscle force confirmed that detergent-processed allografts promoted isograft-equivalent levels of motor recovery 16 weeks post-operatively. All acellular allografts promoted greater amounts of motor recovery compared to silicone conduits. Conclusions These findings provide evidence that differential processing for removal of cellular constituents in preparing acellular nerve allografts affects recovery in vivo. PMID:21660979

Radiation sterilization of tissue allografts: A review.

PubMed

Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

2016-04-28

Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts.

Radiation sterilization of tissue allografts: A review

PubMed Central

Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

2016-01-01

Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

Hand transplantation and vascularized composite tissue allografts in orthopaedics and traumatology.

PubMed

Schuind, F

2010-05-01

Composite tissue allograft (CTA) is defined as heterologous transplantation of a complex comprising skin and subcutaneous, neurovascular and mesenchymal tissue. Such techniques allow complex reconstruction using matched tissue, without donor site morbidity. The potential indications in orthopaedics-traumatology could in the future be more frequent than the present indications of heart, lung, liver, kidney and pancreas transplantation. International clinical experience clearly demonstrates the feasibility of CTA, both surgically and immunologically. However, immunosuppression remains indispensable, exposing the patient to risks that are not acceptable for purely functional surgery, except in very particular indications. The main hope for the future lies in induction of graft-specific tolerance. Copyright 2010 Elsevier Masson SAS. All rights reserved.

Urinary Virome Perturbations in Kidney Transplantation.

PubMed

Sigdel, Tara K; Mercer, Neil; Nandoe, Sharvin; Nicora, Carrie D; Burnum-Johnson, Kristin; Qian, Wei-Jun; Sarwal, Minnie M

2018-01-01

The human microbiome is important for health and plays a role in essential metabolic functions and protection from certain pathogens. Conversely, dysbiosis of the microbiome is seen in the context of various diseases. Recent studies have highlighted that a complex microbial community containing hundreds of bacteria colonizes the healthy urinary tract, but little is known about the human urinary viruses in health and disease. To evaluate the human urinary virome in the context of kidney transplantation (tx), variations in the composition of the urinary virome were evaluated in urine samples from normal healthy volunteers as well as patients with kidney disease after they had undergone kidney tx. Liquid chromatography-mass spectrometry/mass spectrometry analysis was undertaken on a selected cohort of 142 kidney tx patients and normal healthy controls, from a larger biobank of 770 kidney biopsy matched urine samples. In addition to analysis of normal healthy control urine, the cohort of kidney tx patients had biopsy confirmed phenotype classification, coincident with the urine sample analyzed, of stable grafts (STA), acute rejection, BK virus nephritis, and chronic allograft nephropathy. We identified 37 unique viruses, 29 of which are being identified for the first time in human urine samples. The composition of the human urinary virome differs in health and kidney injury, and the distribution of viral proteins in the urinary tract may be further impacted by IS exposure, diet and environmental, dietary, or cutaneous exposure to various insecticides and pesticides.

Protective effect of an intrinsic antioxidant, HMH (5-hydroxy-1-methylhydantoin; NZ-419), against cellular damage of kidney tubules.

PubMed

Ienaga, Kazuharu; Park, Chan Hum; Yokozawa, Takako

2013-07-01

HMH (5-hydroxy-1-methylhydantoin; NZ-419) is a mammalian creatinine metabolite and an intrinsic antioxidant. HMH prevents the progression of chronic kidney disease in rats when a sufficient amount is taken orally. We assessed whether intrinsic and higher levels of HMH could protect tubular epithelial cells, LLC-PK(1) cells, against known cellular damage caused by xenobiotics, such as cisplatin and cephaloridine, or by hypoxia/reoxygenation treatment. Both cell damage and peroxidation, monitored as the leakage of lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively, from cells into the media, were inhibited by HMH in a concentration-dependent manner. The minimum effective concentration of HMH (2.5 μM) seemed to be too low for HMH to only be a direct hydroxyl radical scavenger. Additional antioxidant effect(s) inhibiting reactive oxygen species generation and/or modulating signal transduction pathways were suggested. The possibility that intrinsic HMH could be a protectant for the kidney was indicated. At the same time, for sufficient inhibition, higher concentrations than intrinsic HMH concentrations may be necessary. Patterns of efficacies of HMH on LDH and MDA against different kinds of cellular damage were compared with our reported data on those of corresponding, naturally occurring antioxidants. A common and specific inhibitory mechanism as well as common target(s) in kidney injuries were indicated. Copyright © 2012 Elsevier GmbH. All rights reserved.

HILDA/LIF urinary excretion during acute kidney rejection.

PubMed

Taupin, J L; Morel, D; Moreau, J F; Gualde, N; Potaux, L; Bezian, J H

1992-03-01

Recently, a new lymphokine called HILDA (human interleukin for DA cells) has been described and cloned. This cytokine, initially described to be produced by alloreactive T lymphocyte clones grown from a rejected human kidney allograft, is identical to other factors termed D-factor, differentiation-inducing factor, differentiation inhibitory activity, hepatocyte-stimulating factor III, and leukemia inhibitory factor. HILDA/LIF induces various effects on neural, hemopoietic, embryonic cells as well as on bone remodeling and acute phase protein synthesis in hepatocyte. In this study we demonstrate the presence of HILDA/LIF in the urine but not in the serum of kidney graft recipients during acute rejection episodes, whereas this lymphokine was detectable neither in the serum nor in the urine of kidney transplanted patients with stable renal function. These data reinforce the notion of a possible role for this lymphokine in the inflammatory and/or the immune response.

The Spectrum of Renal Allograft Failure

PubMed Central

Chand, Sourabh; Atkinson, David; Collins, Clare; Briggs, David; Ball, Simon; Sharif, Adnan; Skordilis, Kassiani; Vydianath, Bindu; Neil, Desley; Borrows, Richard

2016-01-01

Background Causes of “true” late kidney allograft failure remain unclear as study selection bias and limited follow-up risk incomplete representation of the spectrum. Methods We evaluated all unselected graft failures from 2008–2014 (n = 171; 0–36 years post-transplantation) by contemporary classification of indication biopsies “proximate” to failure, DSA assessment, clinical and biochemical data. Results The spectrum of graft failure changed markedly depending on the timing of allograft failure. Failures within the first year were most commonly attributed to technical failure, acute rejection (with T-cell mediated rejection [TCMR] dominating antibody-mediated rejection [ABMR]). Failures beyond a year were increasingly dominated by ABMR and ‘interstitial fibrosis with tubular atrophy’ without rejection, infection or recurrent disease (“IFTA”). Cases of IFTA associated with inflammation in non-scarred areas (compared with no inflammation or inflammation solely within scarred regions) were more commonly associated with episodes of prior rejection, late rejection and nonadherence, pointing to an alloimmune aetiology. Nonadherence and late rejection were common in ABMR and TCMR, particularly Acute Active ABMR. Acute Active ABMR and nonadherence were associated with younger age, faster functional decline, and less hyalinosis on biopsy. Chronic and Chronic Active ABMR were more commonly associated with Class II DSA. C1q-binding DSA, detected in 33% of ABMR episodes, were associated with shorter time to graft failure. Most non-biopsied patients were DSA-negative (16/21; 76.1%). Finally, twelve losses to recurrent disease were seen (16%). Conclusion This data from an unselected population identifies IFTA alongside ABMR as a very important cause of true late graft failure, with nonadherence-associated TCMR as a phenomenon in some patients. It highlights clinical and immunological characteristics of ABMR subgroups, and should inform clinical practice and

Transcriptome profile analysis reflects rat liver and kidney damage following chronic ultra-low dose Roundup exposure.

PubMed

Mesnage, Robin; Arno, Matthew; Costanzo, Manuela; Malatesta, Manuela; Séralini, Gilles-Eric; Antoniou, Michael N

2015-08-25

Glyphosate-based herbicides (GBH) are the major pesticides used worldwide. Converging evidence suggests that GBH, such as Roundup, pose a particular health risk to liver and kidneys although low environmentally relevant doses have not been examined. To address this issue, a 2-year study in rats administering 0.1 ppb Roundup (50 ng/L glyphosate equivalent) via drinking water (giving a daily intake of 4 ng/kg bw/day of glyphosate) was conducted. A marked increased incidence of anatomorphological and blood/urine biochemical changes was indicative of liver and kidney structure and functional pathology. In order to confirm these findings we have conducted a transcriptome microarray analysis of the liver and kidneys from these same animals. The expression of 4224 and 4447 transcript clusters (a group of probes corresponding to a known or putative gene) were found to be altered respectively in liver and kidney (p < 0.01, q < 0.08). Changes in gene expression varied from -3.5 to 3.7 fold in liver and from -4.3 to 5.3 in kidneys. Among the 1319 transcript clusters whose expression was altered in both tissues, ontological enrichment in 3 functional categories among 868 genes were found. First, genes involved in mRNA splicing and small nucleolar RNA were mostly upregulated, suggesting disruption of normal spliceosome activity. Electron microscopic analysis of hepatocytes confirmed nucleolar structural disruption. Second, genes controlling chromatin structure (especially histone-lysine N-methyltransferases) were mostly upregulated. Third, genes related to respiratory chain complex I and the tricarboxylic acid cycle were mostly downregulated. Pathway analysis suggests a modulation of the mTOR and phosphatidylinositol signalling pathways. Gene disturbances associated with the chronic administration of ultra-low dose Roundup reflect a liver and kidney lipotoxic condition and increased cellular growth that may be linked with regeneration in response to toxic effects causing damage

Graft protective effect and induction of CD4+Foxp3+ cell by Thrombomodulin on allograft arteriosclerosis in mice.

PubMed

Yin, Enzhi; Matsuyama, Shigefumi; Uchiyama, Masateru; Kawai, Kento; Niimi, Masanori

2018-05-21

Thrombomodulin (TM) is a promising therapeutic natural anti-coagulant, which exerts the effects to control disseminated intravascular coagulation. However, little is known whether TM on micro-vessels could play an important role in the regulation of intimal hyperplasia. We investigated the vessel-protective effect of TM in the survival of fully major histocompatibility complex (MHC)-mismatched murine cardiac allograft transplantation. CBA recipients transplanted with a C57BL/6 heart received intraperitoneal administration of normal saline or 0.2, 2.0, and 20.0 μg/day of TM for 7 days (n = 5, 7, 11, and 11, respectively). Immunohistochemical and fluorescent staining studies were performed to determine whether CD4 + Foxp3 + regulatory T cell were generated at 2 and 4 weeks after grafting. Morphometric analysis for neointimal formation in the coronary arteries of the transplanted allograft was conducted at 2 and 4 weeks after grafting. Untreated CBA recipients rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 7 days). CBA recipients exposed with the above doses had significantly prolonged allograft survival (MSTs, 17, 24 and 50 days, respectively). Morphometric assessment showed that intimal hyperplasia was clearly suppressed in the left and right coronary arteries or allografts from TM-exposed recipients 2 and 4 weeks. Immunohistochemical studies at 2 weeks showed more CD4 + Foxp3 + cells and lower myocardial damage in the allografts from TM-exposed recipients. Notably, fluorescent staining studies demonstrated that TM-exposed recipients 4 weeks post-engraftment had strong aggregation of CD4 + Foxp3 + cells in the intima of the coronary arteries of the cardiac allografts. TM may prolong the survival of fully MHC-mismatched cardiac allografts through suppressing intimal hyperplasia and inducing the accumulation of regulatory CD4 + Foxp3 + cells within coronary arteries.

Allograft-prosthesis composites after bone tumor resection at the proximal tibia.

PubMed

Biau, David Jean; Dumaine, Valérie; Babinet, Antoine; Tomeno, Bernard; Anract, Philippe

2007-03-01

The survival of irradiated allograft-prosthesis composites at the proximal tibia is mostly unknown. However, allograft-prosthesis composites have proved beneficial at other reconstruction sites. We presumed allograft-prosthesis composites at the proximal tibia would improve survival and facilitate reattachment of the extensor mechanism compared with that of conventional (megaprostheses) reconstructions. We retrospectively reviewed 26 patients who underwent resection of proximal tibia tumors followed by reconstruction with allo-graft-prosthesis composites. Patients received Guepar massive custom-made fully constrained prostheses. Allografts were sterilized with gamma radiation, and the stems were cemented into the allograft and host bone. The minimum followup was 6 months (median, 128 months; range, 6-195 months). Fourteen patients had one or more components removed. The median allograft-prosthesis composite survival was 102 months (95% confidence interval, 64.2-infinity). Of the 26 allografts, seven fractured, six showed signs of partial resorption, and six had infections develop. Seven allografts showed signs of fusion with the host bone. Six extensor mechanism reconstructions failed. Allograft-prosthesis composites sterilized by gamma radiation yielded poor results for proximal tibial reconstruction as complications and failures were common. We do not recommend irradiated allograft-prosthesis composites for proximal tibia reconstruction.

Clinical Outcomes of Hepatitis C Treatment Before and After Kidney Transplantation and Its Impact on Time to Transplant: A Multi-Center Study.

PubMed

Chascsa, David M; Mousa, Omar Y; Pungpapong, Surakit; Zhang, Nan; Chervenak, Amy; Nidamanuri, Sreecharita; Rodriguez, Eduardo; Franco, Diana; Ryland, Kristen; Keaveny, Andrew P; Huskey, Janna L; Smith, Maxwell; Reddy, Kunam S; Taner, C Burcin; Vargas, Hugo E; Aqel, Bashar A

2018-05-14

Waitlist time for kidney transplantation is long but may be shortened with the utilization of hepatitis C positive allografts. We retrospectively reviewed the course of 36 hepatitis C positive patients awaiting kidney transplantation at two large centers within the same health system, with near-identical care delivery models with the exception of timing of hepatitis C treatment, to determine the impact of timing of hepatitis C treatment on access to transplant, waitlist time and treatment efficacy and tolerability. The majority of patients had hepatitis C genotype 1a or 1b, and all received direct acting antiviral therapy with 100% treatment response. One patient underwent transplantation in the pre-transplant treatment group. The one year transplantation rate was 12.5% versus 67.9% (p=0.0013) in those treated post-transplantation. The median waitlist time in the post-transplant group was 122 (IQR 21.5, 531.0) days, which was significantly shorter than the center's regional and national wait time. Pathologic review revealed no difference in allograft quality. Overall treatment related adverse events were not different between the two groups. A strategy of post-transplant hepatitis C treatment increased access to transplant, and reduced waitlist time. Delaying treatment until after transplant did not appear to adversely impact recipients' kidney allograft or overall survival. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Musculoskeletal allograft risks and recalls in the United States.

PubMed

Mroz, Thomas E; Joyce, Michael J; Steinmetz, Michael P; Lieberman, Isador H; Wang, Jeffrey C

2008-10-01

There have been several improvements to the US tissue banking industry over the past decade. Tissue banks had limited active government regulation until 1993, at which time the US Food and Drug Administration began regulatory oversight because of reports of disease transmission from allograft tissues. Reports in recent years of disease transmission associated with the use of allografts have further raised concerns about the safety of such implants. A retrospective review of allograft recall data was performed to analyze allograft recall by tissue type, reason, and year during the period from January 1994 to June 30, 2007. During the study period, more than 96.5% of all allograft tissues recalled were musculoskeletal. The reasons underlying recent musculoskeletal tissue recalls include insufficient or improper donor evaluation, contamination, recipient infection, and positive serologic tests. Infectious disease transmission following allograft implantation may occur if potential donors are not adequately evaluated or screened serologically during the prerecovery phase and if the implant is not sterilized before implantation.

Recipient body surface area as a predictor of posttransplant renal allograft evolution.

PubMed

Moreso, F; Serón, D; Anunciada, A I; Hueso, M; Ramón, J M; Fulladosa, X; Gil-Vernet, S; Alsina, J; Grinyó, J M

1998-03-15

The aim of the present study was to analyze whether minor differences in recipient body surface area have any predictive value on renal allograft evolution. For this study, we considered 236 pairs of recipients who received a kidney from the same donor at our center between March 1985 and December 1995. Pairs in whom at least one patient presented any of the following events were excluded: graft loss during the first year of follow-up, diabetes mellitus, noncompliance with treatment, chronic pyelonephritis, and recurrent or de novo glomerulonephritis. Recipients of each pair were classified as large or small according to their body surface area (BSA). The percentage difference of BSA in each pair was calculated, and two cohorts of pairs were defined: BSA difference < or = 10% (n=76 pairs) and BSA difference >10% (n=70 pairs). The large recipients of the cohort with a BSA difference >10% showed a higher incidence of posttransplant delayed graft function (22/70 vs. 12/70, P=0.075), hypertension at 1 year of follow-up (51/70 vs. 35/70, P=0.006), and a higher serum creatinine level at 1-year follow-up (173 vs. 142 micromol/L, P=0.003), whereas in the cohort with a BSA difference < or = 10%, posttransplant evolution in large and small recipients was not different. Multivariate analysis showed that recipient BSA was an independent predictor of delayed graft function, posttransplant hypertension, and serum creatinine at 1-year follow-up. Relatively small differences in recipient BSA influence renal allograft evolution. Consequently, our data support that recipient size should be taken into consideration for renal allograft allocation.

Subclinical chronic kidney disease modifies the diagnosis of experimental acute kidney injury.

PubMed

Succar, Lena; Pianta, Timothy J; Davidson, Trent; Pickering, John W; Endre, Zoltán H

2017-09-01

Extensive structural damage within the kidney must be present before serum creatinine increases. However, a subclinical phase of chronic kidney disease (CKD) usually goes undetected. Here we tested whether experimental subclinical CKD would modify functional and damage biomarker profiles of acute kidney injury (AKI). Subclinical CKD was induced in rats by adenine or aristolochic acid models but without increasing serum creatinine. After prolonged recovery (three to six weeks), AKI was induced with a subnephrotoxic dose of cisplatin. Urinary levels of kidney injury molecule-1 (KIM-1), cytochrome C, monocyte chemotactic protein-1 (MCP-1), clusterin, and interleukin-18 increased during CKD induction, without an increase in serum creatinine. After AKI in adenine-induced CKD, serum creatinine increased more rapidly, while increased urinary KIM-1, clusterin, and MCP-1 were delayed and reduced. Increased serum creatinine and biomarker excretion were associated with diffuse tubulointerstitial injury in the outer stripe of outer medulla coupled with over 50% cortical damage. Following AKI in aristolochic acid-induced CKD, increased serum creatinine, urinary KIM-1, clusterin, MCP-1, cytochrome C, and interleukin-18 concentrations and excretion were greater at day 21 than day 42 and inversely correlated with cortical injury. Subclinical CKD modified functional and damage biomarker profiles in diametrically opposite ways. Functional biomarker profiles were more sensitive, while damage biomarker diagnostic thresholds and increases were diminished and delayed. Damage biomarker concentrations and excretion were inversely linked to the extent of prior cortical damage. Thus, thresholds for AKI biomarkers may need to be lower or sampling delayed in the known presence of CKD. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

[A case report of simultaneous liver, pancreas-duodenum, and kidney transplantation in a patient with post-hepatitic cirrhosis combined with uremia and insulin-dependent diabetes related to chronic pancreatitis].

PubMed

Wang, He; Dou, Ke-feng; Yang, Xiao-jian; Qin, Wei-jun; Zhang, Geng; Yu, Lei; Kang, Fu-xia; Chen, Shao-yang; Xiong, Li-ze; Song, Zhen-shun; Liu, Zheng-cai

2006-09-12

To study the effect of triple organ transplantation (liver, kidney, and pancreas) in patient of end-stage liver disease with renal failure and diabetes, and to explore the optimal surgical procedure. Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation was performed on a 43-year-old male patient with exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) who developed hepatic and renal failure. The pancreatic exocrine secretions were drained enterically to the jejunum. Prednisone, tacrolimus, mycophenolate mofetil, and ATG were used as immunosuppression therapy. Good liver and pancreas allograft function recovery was achieved within 7 days after the operation. And the recovery of renal allograft function was delayed. The renal allograft was removed because of break-down of renal blood flow 16 days after the transplantation. A new renal transplantation was performed at the same position. The second kidney graft recovered its normal function 3 days later. Up to the writing of this paper no acute rejection of organs and such complications as pancreatitis, thrombosis, and localized infection occurred. The patient became insulin independent with normal liver and renal function. Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation can be a good method for the patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.

The biophysical characteristics of human composite flexor tendon allograft for upper extremity reconstruction.

PubMed

DeGeorge, Brent R; Rodeheaver, George T; Drake, David B

2014-01-01

Devastating volar hand injuries with significant damage to the skin and soft tissues, pulley structures and fibro-osseous sheath, flexor tendons, and volar plates pose a major problem to the reconstructive hand surgeon. Despite advances in tendon handling, operative technique, and postoperative hand rehabilitation, patients who have undergone flexor tendon reconstruction are often plagued by chronic pain, stiffness, and decreased range of motion with resultant decreased ability to work and poor quality of life. In this article, we expand the technique of human composite flexor tendon allografts (CFTAs), pioneered by Dr E.E. Peacock, Jr, which consist of both the intrasynovial and extrasynovial flexor digitorum superficialis and flexor digitorum profundus tendons and their respective fibro-osseous sheath consisting of the digital pulley structures, periosteum, and volar plates procured from cadaveric donors with the use of modern tissue processing techniques. Human cadaveric CFTAs were procured and divided into 2 groups-unprocessed CFTAs and processed CFTAs, which are cleansed and sterilized to a sterility assurance level of 10(-6). Physical length and width relationships as well as tensile strength and gliding resistance assessments were recorded pre-tissue and post-tissue processing. The histologic properties of the composite allografts were assessed before and after tissue processing. There was no significant difference with respect to physical properties of the composite allografts before or after tissue processing. The processed composite allografts demonstrated equivalent maximum load to failure and elastic modulus compared to unprocessed tendons. The gliding resistance of the composite tendon allografts was not significantly different between the 2 groups. The use of CFTAs addresses the issues of adhesion formation and lack of suitable donor material by providing a source of intrasynovial tendon in its unaltered fibro-osseous sheath without donor morbidity

Recurrent AA Amyloidosis Combined With Chronic Active Antibody-mediated Rejection After Kidney Transplantation.

PubMed

Yeo, Min-Kyung; Ham, Young Rok; Choi, Song-Yi; Lee, Yong-Moon; Park, Moon Hyang; Suh, Kwang-Sun

2017-07-01

Kidney transplantation for amyloidosis remains a contentious issue. Recurrence of amyloidosis is one of the risks of transplantation. Chronic active antibody-mediated rejection is an important cause of chronic allograft dysfunction. A 47-year-old woman underwent kidney transplantation due to renal AA amyloidosis with unknown etiology. Six years posttransplantation, a kidney biopsy showed AA amyloidosis with chronic active antibody-mediated rejection. Donor-specific antibody class II was positive. The patient underwent intravenous plasmapheresis and treatment with rituximab and colchicine. The relationship between recurrence of amyloidosis and rejection was not obvious. Clinical characteristics of kidney transplantation for AA amyloidosis were subjected to literature review and 315 cases were identified. The incidence of amyloidosis recurrence and acute and chronic rejection rates were 15%, 15%, and 8%, respectively. Five-year patient and graft survival rates were 77% and 82%, respectively. Clinical courses of kidney transplantation in AA amyloidosis were, thus, identified.

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

PubMed

LaMattina, John C; Mezrich, Joshua D; Fernandez, Luis A; D'Alessandro, Anthony M; Djamali, Arjang; Musat, Alexandru I; Pirsch, John D; Foley, David P

2013-01-01

The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen. © 2013 John Wiley & Sons A/S.

Oxygen free radical induced damage in kidneys subjected to warm ischemia and reperfusion. Protective effect of superoxide dismutase.

PubMed Central

Baker, G L; Corry, R J; Autor, A P

1985-01-01

Superoxide anion free radical (O2-.) has been implicated in the pathogenesis of tissue injury consequent to ischemia/reperfusion in several different organs, including heart and bowel. Superoxide dismutase (SOD), an enzyme free radical scavenger specific for O2-., has been used successfully to protect these organs from structural damage during reoxygenation of ischemic tissue. It has been suggested that the catalytic action of xanthine oxidase in injured tissue is an important source of O2-. during reoxygenation. In order to evaluate the potential of SOD to protect against kidney damage resulting from transient ischemia followed by reperfusion with oxygenated blood, a model of warm renal ischemia was studied. LBNF1 rats underwent right nephrectomy and occlusion of the left renal artery for 45 minutes. Survival in the group of ischemic untreated rats (N = 30) was 56% at 7 days and serum creatinine was greatly elevated (p less than 0.01) in rats remaining alive over the full 7-day period. In strong contrast to these results, all of the animals treated with SOD before reperfusion (N = 18) were alive after 7 days similar to sham operated control rats (N = 8). Serum creatinine in the SOD treated rats was significantly elevated only to postoperative day 3 and thereafter returned to normal. Rats treated with inactive SOD (N = 4) or SOD before ischemia (N = 4) had decreased survival rates compared to ischemic untreated animals and prolonged elevation of serum creatinine. When the ischemia time was extended to 60 minutes, only 19% of the untreated animals (N = 16) survived at 7 days whereas nearly 60% of the SOD-treated animals survived (N = 19). Serum creatinine was greatly elevated during the full 7-day observation period in all surviving rats in the untreated ischemic group, whereas serum creatinine returned to normal (p less than 0.05) after 4 days in the surviving rats treated with SOD. To test whether the action of xanthine oxidase contributed to the kidney damage

Skin allograft and vascularized composite allograft: potential for long-term efficacy in the context of lymphatic modulation.

PubMed

Rinkinen, Jacob; Selley, Ryan; Agarwal, Shailesh; Loder, Shawn; Levi, Benjamin

2014-01-01

Tissue transplantation restores form and function in burn patients. The treatment of burn injuries is influenced by severity, location, and the percentage of total body surface area. There have been a number of different techniques developed to temporize and repair the destroyed tissue. However, in patients with large wound burden, sufficient donor site tissue may not be available for autograft harvesting. Such extensive burns necessitate other temporary and permanent options for wound coverage such as skin or vascularized composite allografts (VCA). Rejection of these tissues presents an ongoing problem which is currently managed using a host of systemic immunosuppressive medications. This article discusses the mechanism behind the innate and adaptive immune systems rejection of the allografts. By understanding these pathways, various techniques using immunomodulatory protocols have led to increased allograft survival. However, our primary interest lies in the initial recognition of the graft. We tailor this article to have a specific emphasis on lymphatic modulation as a potential adjunctive therapy. Reviews of the studies evaluating the effect of lymph node modulation on graft survival are described with future implications to allograft transplant research.

Mortality after Renal Allograft Failure and Return to Dialysis.

PubMed

Brar, Amarpali; Markell, Mariana; Stefanov, Dimitre G; Timpo, Edem; Jindal, Rahul M; Nee, Robert; Sumrani, Nabil; John, Devon; Tedla, Fasika; Salifu, Moro O

2017-01-01

The outcomes of patients who fail their kidney transplant and return to dialysis (RTD) has not been investigated in a nationally representative sample. We hypothesized that variations in management of transplant chronic kidney disease stage 5 leading to kidney allograft failure (KAF) and RTD, such as access, nutrition, timing of dialysis, and anemia management predict long-term survival. We used an incident cohort of patients from the United States Renal Data System who initiated hemodialysis between January 1, 2003 and December 31, 2008, after KAF. We used Cox regression analysis for statistical associations, with mortality as the primary outcome. We identified 5,077 RTD patients and followed them for a mean of 30.9 ± 22.6 months. Adjusting for all possible confounders at the time of RTD, the adjusted hazards ratio (AHR) for death was increased with lack of arteriovenous fistula at initiation of dialysis (AHR 1.22, 95% CI 1.02-1.46, p = 0.03), albumin <3.5 g/dL (AHR 1.33, 95% CI 1.18-1.49, p = 0.0001), and being underweight (AHR 1.30, 95% CI 1.07-1.58, p = 0.006). Hemoglobin <10 g/dL (AHR 0.96, 95% CI 0.86-1.06, p = 0.46), type of insurance, and zip code-based median household income were not associated with higher mortality. Glomerular filtration rate <10 mL/min/1.73 m2 at time of dialysis initiation (AHR 0.83, 95% CI 0.75-0.93, p = 0.001) was associated with reduction in mortality. Excess mortality risk observed in patients starting dialysis after KAF is multifactorial, including nutritional issues and vascular access. Adequate preparation of patients with failing kidney transplants prior to resuming dialysis may improve outcomes. © 2017 S. Karger AG, Basel.

Incidence and risk factors for development of new-onset diabetes after kidney transplantation.

PubMed

Bee, Yong Mong; Tan, Hong Chang; Tay, Tunn Lin; Kee, Terence Ys; Goh, Su Yen; Kek, Peng Chin

2011-04-01

New-onset diabetes after transplantation (NODAT) is an increasingly recognised metabolic complication of kidney transplantation that is associated with increased morbidity and mortality. This study aimed to determine the incidence of NODAT and identify risk factors for development of NODAT among kidney allograft recipients in a single centre. We retrospectively reviewed all kidney allograft recipients in our centre between 1998 and 2007. NODAT were determined using criteria as per American Diabetes Association guidelines. Logistic regression analyses were performed to identify predictors of NODAT. Among 388 patients included in the analysis, NODAT was reported in 94 patients (24.2%) after a median follow-up time of 52.1 months. The cumulative incidence of NODAT was 15.8%, 22.8% and 24.5% at 1, 3, and 5 years following transplantation. Seven clinical factors were independent predictors of NODAT: older age, HLA B13 and B15 phenotypes, use of sirolimus, acute rejections, higher pre-transplant and post-transplant (day 1) plasma glucose levels. Patients with NODAT had poorer outcomes in both graft and patient survival. Our study demonstrates a significant risk and burden of NODAT in an Asian transplant population. Risk stratification and aggressive monitoring of blood glucose early post-transplantation is necessary to identify high-risk patients so that appropriate tailoring of immunosuppression and early institution of lifestyle modifications can be implemented.

Liver procurement from a brain-dead kidney transplant recipient--a case report.

PubMed

Romatowska, Edyta; Woderska, Aleksandra; Kusza, Krzysztof; Słupski, Maciej; Neumann, Małgorzata

2012-01-01

The shortage of organ donors has led to new strategies to increase the availability of allografts for transplantation, such as organ procurement from brain-dead organ transplant recipients. We present the case of a 26 year-old male brain-dead liver donor who had been a kidney transplant recipient six years previously. The liver donor described in this report, as the first in Poland, has paved a new, although as yet narrow, way in the field of organ donation. This is also the first case described in the medical literature of liver recovery from a brain-dead kidney transplant recipient on an immunosuppressive regimen with three immunosuppressive agents. Although transplant recipients represent an uncommon group of deceased organ donors, it is probable that situations when they may be considered as potential organ donors will occur more often. Therefore, although specific criteria for organ donors exist, each reported potential donor should be considered individually, and brain-dead solid organ recipients should not be excluded a priori as organ donors; both their native and allografted organs may be recovered and successfully transplanted. In this study, we also review the current state of knowledge on the reuse of organs.

The safety of bone allografts used in dentistry: a review.

PubMed

Holtzclaw, Dan; Toscano, Nicholas; Eisenlohr, Lisa; Callan, Don

2008-09-01

Recent media reports concerning "stolen body parts" have shaken the public's trust in the safety of and the use of ethical practices involving human allografts. The authors provide a comprehensive review of the safety aspects of human bone allografts. The authors reviewed U.S. government regulations, industry standards, independent industry association guidelines, company guidelines and scientific articles related to the use of human bone allografts in the practice of dentistry published in the English language. The use of human bone allografts in the practice of dentistry involves the steps of procurement, processing, use and tracking. Rigorous donor screening and aseptic proprietary processing programs have rendered the use of human bone allografts safe and effective as a treatment option. When purchasing human bone allografts for the practice of dentistry, one should choose products accredited by the American Association of Tissue Banks for meeting uniformly high safety and quality control measures. Knowledge of human bone allograft procurement, processing, use and tracking procedures may allow dental clinicians to better educate their patients and address concerns about this valuable treatment option.

Bile duct ligation in developing rats: temporal progression of liver, kidney, and brain damage.

PubMed

Sheen, Jiunn-Ming; Huang, Li-Tung; Hsieh, Chih-Sung; Chen, Chih-Cheng; Wang, Jia-Yi; Tain, You-Lin

2010-08-01

Cholestatic liver disease may result in progressive end-stage liver disease and other extrahepatic complications. We explored the temporal progression of bile duct ligation (BDL)-induced cholestasis in developing rats, focusing on brain cognition and liver and kidney pathology, to elucidate whether these findings were associated with asymmetric dimethylarginine and oxidative stress alterations. Three groups of young male Sprague-Dawley rats were studied: one group underwent laparotomy (sham), another group underwent laparotomy and BDL for 2 weeks (BDL2), and a third group underwent laparotomy and BDL for 4 weeks (BDL4). The effect of BDL on liver was represented by transforming growth factor beta1 levels and histology activity index scores, which were worse in the BDL4 rats than in the BDL2 rats. BDL4 rats also exhibited more severe spatial memory deficits than BDL2 rats. In addition, renal injury was more progressive in BDL4 rats than in BDL2 rats because BDL4 rats displayed higher Cr levels, elevated tubulointerstitial injury scores, neutrophil gelatinase-associated lipocalin, and symmetric dimethylarginine levels. Our findings highlight the fact that young BDL rats exhibit similar trends of progression of liver, kidney, and brain damage. Further studies are needed to better delineate the nature of progression of organ damage in young cholestatic rats. Copyright 2010 Elsevier Inc. All rights reserved.

Utility of HLA Antibody Testing in Kidney Transplantation

PubMed Central

Konvalinka, Ana

2015-01-01

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor–specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes. PMID:25804279

Determination of residual dimethylsulfoxide in cryopreserved cardiovascular allografts.

PubMed

Díaz Rodríguez, R; Van Hoeck, B; De Gelas, S; Blancke, F; Ngakam, R; Bogaerts, K; Jashari, R

2017-06-01

Dimethylsulfoxide (DMSO) is a solvent which protects the structure of allografts during the cryopreservation and thawing process. However, several toxic effects of DMSO in patients after transplantation of cryopreserved allografts have been described. The aim of this study is to determine the residual DMSO in the cardiovascular allografts after thawing and preparation of cryopreserved allografts for clinical application following guidelines of the European Pharmacopoeia for DMSO detection. Four types of EHB allografts (aortic valve-AV, pulmonary valve-PV, descending thoracic aorta-DA, and femoral artery-FA) are cryopreserved using as cryoprotecting solution a 10% of DMSO in medium 199. Sampling is carried out after thawing, after DMSO dilution and after delay of 30 min from final dilution (estimated delay until allograft implantation). After progressive thawing in sterile water bath at 37-42 °C (duration of about 20 min), DMSO dilution is carried out by adding consecutively 33, 66 and 200 mL of saline. Finally, tissues are transferred into 200 mL of a new physiologic solution. Allograft samples are analysed for determination of the residual DSMO concentration using a validated Gas Chromatography analysis. Femoral arteries showed the most important DMSO reduction after the estimated delay: 92.97% of decrease in the cryoprotectant final amount while a final reduction of 72.30, 72.04 and 76.29% in DMSO content for AV, PV and DA, was found, respectively. The residual DMSO in the allografts at the moment of implantation represents a final dose of 1.95, 1.06, 1.74 and 0.26 mg kg -1 in AV, PV, DA and FA, respectively, for men, and 2.43, 1.33, 2.17 and 0.33 mg kg -1 for same tissues for women (average weight of 75 kg in men, and 60 kg in women). These results are seriously below the maximum recommended dose of 1 g DMSO kg -1 (Regan et al. in Transfusion 50:2670-2675, 2010) of weight of the patient guaranteeing the safety and quality of allografts.

Modulatory effect of Mangifera indica against carbon tetrachloride induced kidney damage in rats.

PubMed

Awodele, Olufunsho; Adeneye, Adejuwon Adewale; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

2015-12-01

There is little scientific evidence on the local use of Mangifera indica in kidney diseases. This study investigated the reno-modulatory roles of the aqueous stem bark extract of Mangifera indica (MIASE) against CCl4-induced renal damage. Rats were treated intragastrically with 125, 250 and 500 mg/kg/day MIASE for 7 days before and after the administration of CCl4 (3 ml/kg of 30% CCl4, i.p.). Serum levels of electrolytes (Na+, K+, Cl(-), HCO3(-)), urea and creatinine were determined. Renal tissue reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), superoxide (SOD) activities were also assessed. The histopathological changes in kidneys were determined using standard methods. In CCl4 treated rats the results showed significant (p<0.05) increases in serum Na+, K+, Cl(-), urea and creatinine. CCl4 also caused significant (p<0.05) decreases in renal tissue SOD, CAT and GSH and significant (p<0.05) increases in MDA. The oral MIASE treatment (125-500 mg/kg) was found to significantly (p<0.05) attenuate the increase in serum electrolytes, urea and creatinine. Similarly, MIASE significantly (p<0.05) attenuated the decrease in SOD, CAT and GSH levels and correspondingly attenuated increases in MDA. Mangifera indica may present a great prospect for drug development in the management of kidney disease with lipid peroxidation as its etiology.

Modulatory effect of Mangifera indica against carbon tetrachloride induced kidney damage in rats

PubMed Central

Adeneye, Adejuwon Adewale; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

2015-01-01

There is little scientific evidence on the local use of Mangifera indica in kidney diseases. This study investigated the reno-modulatory roles of the aqueous stem bark extract of Mangifera indica (MIASE) against CCl4-induced renal damage. Rats were treated intragastrically with 125, 250 and 500 mg/kg/day MIASE for 7 days before and after the administration of CCl4 (3 ml/kg of 30% CCl4, i.p.). Serum levels of electrolytes (Na+, K+, Cl−, HCO3−), urea and creatinine were determined. Renal tissue reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), superoxide (SOD) activities were also assessed. The histopathological changes in kidneys were determined using standard methods. In CCl4 treated rats the results showed significant (p<0.05) increases in serum Na+, K+, Cl−, urea and creatinine. CCl4 also caused significant (p<0.05) decreases in renal tissue SOD, CAT and GSH and significant (p<0.05) increases in MDA. The oral MIASE treatment (125-500 mg/kg) was found to significantly (p<0.05) attenuate the increase in serum electrolytes, urea and creatinine. Similarly, MIASE significantly (p<0.05) attenuated the decrease in SOD, CAT and GSH levels and correspondingly attenuated increases in MDA. Mangifera indica may present a great prospect for drug development in the management of kidney disease with lipid peroxidation as its etiology. PMID:27486379

Bilateral native nephrectomy to reduce oxalate stores in children at the time of combined liver-kidney transplantation for primary hyperoxaluria type 1.

PubMed

Lee, Eliza; Ramos-Gonzalez, Gabriel; Rodig, Nancy; Elisofon, Scott; Vakili, Khashayar; Kim, Heung Bae

2018-05-01

Primary hyperoxaluria type-1 (PH-1) is a rare genetic disorder in which normal hepatic metabolism of glyoxylate is disrupted resulting in diffuse oxalate deposition and end-stage renal disease (ESRD). While most centers agree that combined liver-kidney transplant (CLKT) is the appropriate treatment for PH-1, perioperative strategies for minimizing recurrent oxalate-related injury to the transplanted kidney remain unclear. We present our management of children with PH-1 and ESRD on hemodialysis (HD) who underwent CLKT at our institution from 2005 to 2015. On chart review, three patients (2 girls, 1 boy) met study criteria. Two patients received deceased-donor split-liver grafts, while one patient received a whole liver graft. All patients underwent bilateral native nephrectomy at transplant to minimize the total body oxalate load. Median preoperative serum oxalate was 72 μmol/L (range 17.8-100). All patients received HD postoperatively until predialysis serum oxalate levels fell <20 μmol/L. All patients, at a median of 7.5 years of follow-up (range 6.5-8.9), demonstrated stable liver and kidney function. While CLKT remains the definitive treatment for PH-1, bilateral native nephrectomy at the time of transplant reduces postoperative oxalate stores and may mitigate damage to the renal allograft.

Fresh-frozen Complete Extensor Mechanism Allograft versus Autograft Reconstruction in Rabbits

PubMed Central

Chen, Guanyin; Zhang, Hongtao; Ma, Qiong; Zhao, Jian; Zhang, Yinglong; Fan, Qingyu; Ma, Baoan

2016-01-01

Different clinical results have been reported in the repair of extensor mechanism disruption using fresh-frozen complete extensor mechanism (CEM) allograft, creating a need for a better understanding of fresh-frozen CME allograft reconstruction. Here, we perform histological and biomechanical analyses of fresh-frozen CEM allograft or autograft reconstruction in an in vivo rabbit model. Our histological results show complete incorporation of the quadriceps tendon into the host tissues, patellar survival and total integration of the allograft tibia, with relatively fewer osteocytes, into the host tibia. Vascularity and cellularity are reduced and delayed in the allograft but exhibit similar distributions to those in the autograft. The infrapatellar fat pad provides the main blood supply, and the lowest cellularity is observed in the patellar tendon close to the tibia in both the allograft and autograft. The biomechanical properties of the junction of quadriceps tendon and host tissues and those of the allograft patellar tendon are completely and considerably restored, respectively. Therefore, fresh-frozen CEM allograft reconstruction is viable, but the distal patellar tendon and the tibial block may be the weak links of the reconstruction. These findings provide new insight into the use of allograft in repairing disruption of the extensor mechanism. PMID:26911538

Fresh-frozen Complete Extensor Mechanism Allograft versus Autograft Reconstruction in Rabbits.

PubMed

Chen, Guanyin; Zhang, Hongtao; Ma, Qiong; Zhao, Jian; Zhang, Yinglong; Fan, Qingyu; Ma, Baoan

2016-02-25

Different clinical results have been reported in the repair of extensor mechanism disruption using fresh-frozen complete extensor mechanism (CEM) allograft, creating a need for a better understanding of fresh-frozen CME allograft reconstruction. Here, we perform histological and biomechanical analyses of fresh-frozen CEM allograft or autograft reconstruction in an in vivo rabbit model. Our histological results show complete incorporation of the quadriceps tendon into the host tissues, patellar survival and total integration of the allograft tibia, with relatively fewer osteocytes, into the host tibia. Vascularity and cellularity are reduced and delayed in the allograft but exhibit similar distributions to those in the autograft. The infrapatellar fat pad provides the main blood supply, and the lowest cellularity is observed in the patellar tendon close to the tibia in both the allograft and autograft. The biomechanical properties of the junction of quadriceps tendon and host tissues and those of the allograft patellar tendon are completely and considerably restored, respectively. Therefore, fresh-frozen CEM allograft reconstruction is viable, but the distal patellar tendon and the tibial block may be the weak links of the reconstruction. These findings provide new insight into the use of allograft in repairing disruption of the extensor mechanism.

Bone allograft banking in South Australia.

PubMed

Campbell, D G; Oakeshott, R D

1995-12-01

The South Australian Bone Bank had expanded to meet an increased demand for allograft bone. During a 5 year period from 1988 to 1992, 2361 allografts were harvested from 2146 living donors and 30 cadaveric donors. The allografts were screened by contemporary banking techniques which include a social history, donor serum tests for HIV-1, HIV-2, hepatitis B and C, syphilis serology, graft microbiology and histology. Grafts were irradiated with 25 kGy. The majority of grafts were used for arthroplasty or spinal surgery and 99 were used for tumour reconstruction. Of the donated grafts 336 were rejected by the bank. One donor was HIV-positive and two had false positive screens. There were seven donors with positive serology for hepatitis B, eight for hepatitis C and nine for syphilis. Twenty-seven grafts had positive cultures. Bone transplantation is the most frequent non-haematogenous allograft in South Australia and probably nationally. The low incidence of infectious viral disease in the donor population combined with an aggressive discard policy has ensured relative safety of the grafts. The frequency of graft rejection was similar to other bone banks but the incidence of HIV was lower.

Serum creatinine detection by a conducting-polymer-based electrochemical sensor to identify allograft dysfunction.

PubMed

Wei, Fang; Cheng, Scott; Korin, Yael; Reed, Elaine F; Gjertson, David; Ho, Chih-ming; Gritsch, H Albin; Veale, Jeffrey

2012-09-18

Kidney transplant recipients who have abnormally high creatinine levels in their blood often have allograft dysfunction secondary to rejection. Creatinine has become the preferred marker for renal dysfunction and is readily available in hospital clinical settings. We developed a rapid and accurate polymer-based electrochemical point-of-care (POC) assay for creatinine detection from whole blood to identify allograft dysfunction. The creatinine concentrations of 19 blood samples from transplant recipients were measured directly from clinical serum samples by the conducting polymer-based electrochemical (EC) sensor arrays. These measurements were compared to the traditional clinical laboratory assay. The time required for detection was <5 min from sample loading. Sensitivity of the detection was found to be 0.46 mg/dL of creatinine with only 40 μL sample in the creatinine concentration range of 0 mg/dL to 11.33 mg/dL. Signal levels that were detected electrochemically correlated closely with the creatinine blood concentration detected by the UCLA Ronald Reagan Medical Center traditional clinical laboratory assay (correlation coefficient = 0.94). This work is encouraging for the development of a rapid and accurate POC device for measuring creatinine levels in whole blood.

Micro-organisms isolated from cadaveric samples of allograft musculoskeletal tissue.

PubMed

Varettas, Kerry

2013-12-01

Allograft musculoskeletal tissue is commonly used in orthopaedic surgical procedures. Cadaveric donors of musculoskeletal tissue supply multiple allografts such as tendons, ligaments and bone. The microbiology laboratory of the South Eastern Area Laboratory Services (SEALS, Australia) has cultured cadaveric allograft musculoskeletal tissue samples for bacterial and fungal isolates since 2006. This study will retrospectively review the micro-organisms isolated over a 6-year period, 2006-2011. Swab and tissue samples were received for bioburden testing and were inoculated onto agar and/or broth culture media. Growth was obtained from 25.1 % of cadaveric allograft musculoskeletal tissue samples received. The predominant organisms isolated were coagulase-negative staphylococci and coliforms, with the heaviest bioburden recovered from the hemipelvis. The rate of bacterial and fungal isolates from cadaveric allograft musculoskeletal tissue samples is higher than that from living donors. The type of organism isolated may influence the suitability of the allograft for transplant.

Anterior cruciate ligament allograft transplantation in dogs.

PubMed

Vasseur, P B; Stevenson, S; Gregory, C R; Rodrigo, J J; Pauli, S; Heitter, D; Sharkey, N

1991-08-01

The biomechanical and clinical performance of bone-ligament-bone anterior cruciate ligament (ACL) allografts was studied in eight dogs. Allografts were collected from skeletally mature, healthy dogs using aseptic technique, and stored at -70 degrees for three to five weeks before implantation. The allografts were size-matched to the recipient dogs using ACL length and then rigidly fixed in position with interference screws and Kirschner wires. Three dogs regained a normal gait, and their grafts sustained breaking loads that were 25%, 41%, and 59% of controls. Partial or complete graft failure occurred in the other five dogs at some point in the study. Four had intraligamentous rupture and one had an avulsion fracture of the femoral attachment site. Joint-fluid cytology was normal in all eight dogs. Histologic examination showed persistent lymphoplasmacytic infiltrate. Eventually the allograft cores were incorporated in the host bed. Hyperplasia and fibrosis of the synovial membrane were diffuse and persisted as focal accumulations of mononuclear inflammatory cells.

Comparison of the long-term outcomes of kidney transplantation: USA versus Spain

PubMed Central

Ojo, Akinlolu O.; Morales, José María; González-Molina, Miguel; Steffick, Diane E.; Luan, Fu L.; Merion, Robert M.; Ojo, Tammy; Moreso, Francesc; Arias, Manuel; Campistol, Josep María; Hernandez, Domingo; Serón, Daniel

2013-01-01

Background The long-term outcomes of kidney transplantation are suboptimal because many patients lose their allografts or experience premature death. Cross-country comparisons of long-term outcomes of kidney transplantation may provide insight into factors contributing to premature graft failure and death. We evaluated the rates of late graft failure and death among US and Spanish kidney recipients. Methods This is a cohort study of US (n = 9609) and Spanish (n = 3808) patients who received a deceased donor kidney transplant in 1990, 1994, 1998 or 2002 and had a functioning allograft 1 year after transplantation with follow-up through September 2006. Ten-year overall and death-censored graft survival and 10-year overall recipient survival and death with graft function (DWGF) were estimated with multivariate Cox models. Results Among recipients alive with graft function 1 year after transplant, the 10-year graft survival was 71.3% for Spanish and 53.4% for US recipients (P < 0.001). The 10-year, death-censored graft survival was 75.6 and 76.0% for Spanish and US recipients, respectively (P = 0.73). The 10-year recipient survival was 86.2% for Spanish and 67.4% for US recipients (P < 0.001). In recipients with diabetes as the cause of ESRD, the adjusted DWGF rates at 10 years were 23.9 and 53.8 per 1000 person-years for Spanish and US recipients, respectively (P < 0.001). Among recipients whose cause of ESRD was not diabetes mellitus, the adjusted 10-year DWGF rates were 11.0 and 25.4 per 1000 person-years for Spanish and US recipients, respectively. Conclusions US kidney transplant recipients had more than twice the long-term hazard of DWGF compared with Spanish kidney transplant recipients and similar levels of death-censored graft function. Pre-transplant medical care, comorbidities, such as cardiovascular disease, and their management in each country's health system are possible explanations for the differences between the two countries. PMID:22759384

Comparison of the long-term outcomes of kidney transplantation: USA versus Spain.

PubMed

Ojo, Akinlolu O; Morales, José María; González-Molina, Miguel; Steffick, Diane E; Luan, Fu L; Merion, Robert M; Ojo, Tammy; Moreso, Francesc; Arias, Manuel; Campistol, Josep María; Hernandez, Domingo; Serón, Daniel

2013-01-01

The long-term outcomes of kidney transplantation are suboptimal because many patients lose their allografts or experience premature death. Cross-country comparisons of long-term outcomes of kidney transplantation may provide insight into factors contributing to premature graft failure and death. We evaluated the rates of late graft failure and death among US and Spanish kidney recipients. This is a cohort study of US (n = 9609) and Spanish (n = 3808) patients who received a deceased donor kidney transplant in 1990, 1994, 1998 or 2002 and had a functioning allograft 1 year after transplantation with follow-up through September 2006. Ten-year overall and death-censored graft survival and 10-year overall recipient survival and death with graft function (DWGF) were estimated with multivariate Cox models. Among recipients alive with graft function 1 year after transplant, the 10-year graft survival was 71.3% for Spanish and 53.4% for US recipients (P < 0.001). The 10-year, death-censored graft survival was 75.6 and 76.0% for Spanish and US recipients, respectively (P = 0.73). The 10-year recipient survival was 86.2% for Spanish and 67.4% for US recipients (P < 0.001). In recipients with diabetes as the cause of ESRD, the adjusted DWGF rates at 10 years were 23.9 and 53.8 per 1000 person-years for Spanish and US recipients, respectively (P < 0.001). Among recipients whose cause of ESRD was not diabetes mellitus, the adjusted 10-year DWGF rates were 11.0 and 25.4 per 1000 person-years for Spanish and US recipients, respectively. US kidney transplant recipients had more than twice the long-term hazard of DWGF compared with Spanish kidney transplant recipients and similar levels of death-censored graft function. Pre-transplant medical care, comorbidities, such as cardiovascular disease, and their management in each country's health system are possible explanations for the differences between the two countries.

Tendon allograft sterilized by peracetic acid/ethanol combined with gamma irradiation.

PubMed

Zhou, Mo; Zhang, Naili; Liu, Xiaoming; Li, Youchen; Zhang, Yumin; Wang, Xusheng; Li, Baoming; Li, Baoxing

2014-07-01

Research and clinical applications have demonstrated that the effects of tendon allografts are comparable to those of autografts when reconstructing injured tendons or ligaments, but allograft safety remains problematic. Sterilisation could eliminate or decrease the possibility of disease transmission, but current methods seldom achieve satisfactory sterilisation without affecting the mechanical properties of the tendon. Peracetic acid-ethanol in combination with low-dose gamma irradiation (PE-R) would inactivate potential deleterious microorganisms without affecting mechanical and biocompatible properties of tendon allograft. Controlled laboratory design. HIV, PPV, PRV and BVDV inactivation was evaluated. After verifying viral inactivation, the treated tendon allografts were characterised by optical microscopy, scanning electron microscopy and tensile testing, and the cytocompatibility was assessed with an MTT assay and by subcutaneous implantation. Effective and efficient inactivation of HIV, PPV, PRV and BVDV was observed. Histological structure and ultrastructure were unchanged in the treated tendon allograft, which also exhibited comparable biomechanical properties and good biocompatibility. The preliminary results confirmed our hypothesis and demonstrated that the PE-R tendon allograft has significant potential as an alternative to ligament/tendon reconstruction. Tendon allografts have been extensively used in ligament reconstruction and tendon repair. However, current sterilisation methods have various shortcomings, so PE-R has been proposed. This study suggests that PE-R tendon allograft has great potential as an alternative for ligament/tendon reconstruction. Sterilisation has been a great concern for tendon allografts. However, most sterilisation methods cannot inactivate viruses and bacteria without impairing the mechanical properties of the tendon allograft. Peracetic acid/ethanol with gamma irradiation can effectively inactivate viruses and bacteria

Gut Microbiota Dysbiosis and Diarrhea in Kidney Transplant Recipients.

PubMed

Lee, John Richard; Magruder, Matthew; Zhang, Lisa; Westblade, Lars F; Satlin, Michael J; Robertson, Amy; Edusei, Emmanuel; Crawford, Carl; Ling, Lilan; Taur, Ying; Schlueter, Jonas; Lubetzky, Michelle; Dadhania, Darshana; Pamer, Eric; Suthanthiran, Manikkam

2018-06-19

Post-transplant diarrhea is associated with kidney allograft failure and death but its etiology remains unknown in the majority of cases. Because altered gut microbial ecology is a potential basis for diarrhea, we investigated whether post-transplant diarrhea is associated with gut dysbiosis. We enrolled 71 kidney allograft recipients for serial fecal specimen collections in the first 3 months of transplantation and profiled the gut microbiota using 16S rRNA gene V4-V5 deep sequencing. The Shannon diversity index was significantly lower in 28 diarrheal fecal specimens from 25 recipients with post-transplant diarrhea than in 112 fecal specimens from 46 recipients without post-transplant diarrhea. We found lower relative abundance of 13 commensal genera (Benjamini-Hochberg adjusted p value ≤ 0.15) in the diarrheal fecal specimens including the same 4 genera identified in our prior study. The 28 diarrheal fecal specimens were also evaluated by a multiplexed PCR assay for 22 bacterial, viral, and protozoan gastrointestinal pathogens, and 26 specimens were negative for infectious etiologies. Using PICRUSt to predict metagenomic functions, we found diarrheal fecal specimens had a lower abundance of metabolic genes. Our findings suggest that post-transplant diarrhea is not associated with common infectious diarrheal pathogens but with a gut dysbiosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Physical Activity and Kidney Injury in Pediatric and Young Adult Kidney Transplant Recipients.

PubMed

Wolf, Mattie F; George, Roshan P; Warshaw, Barry; Wang, Elizabeth; Greenbaum, Larry A

2016-12-01

To quantify physical activity and grip strength in pediatric kidney transplant recipients and describe attitudes about exercise and exercise counseling given concerns about allograft injury. This was a cross-sectional analysis of 101 kidney transplant recipients (7-21 years old) >6 months post-transplant. Patients completed the Physical Activity Questionnaire (PAQ). Grip strength was measured with a dynamometer. We asked about activity limitations and provider counseling. Univariate analysis and multiple linear regression were used to determine independent predictors of PAQ score and grip strength z score. We enrolled 101 of 122 eligible patients. Median PAQ score was 2.2 (range 0-5) and was lower compared with controls (P < .001). The average grip strength z score was -1.1 and -0.7 in the right and left hand, respectively. Predictors of lower grip strength were younger age (P = .036), non-African American race (P = .029), lower height z score (P = .010), and longer percentage of lifetime with kidney disease (P = .029). Although 49% and 67% limited exercise before and after transplant, respectively, 67% reported increased activity after transplant. By parent report, provider counseling included limiting certain activities (71%) and encouraging regular exercise (45%). Physical activity and grip strength are low after kidney transplant. Patients perceive an emphasis on exercise limitations rather than the benefits of regular exercise. Interventions that encourage physical activity may be beneficial. Copyright © 2016 Elsevier Inc. All rights reserved.

Kidney injury molecule-1 and microalbuminuria levels in Zambian population: biomarkers of kidney injury.

PubMed

Zulu, Mildred; Kaile, Trevor; Kantenga, Timothy; Chileshe, Chisanga; Nkhoma, Panji; Sinkala, Musalula

2016-01-01

Kidney injury affects renal excretion of plasma analytes and metabolic waste products with grave pathologic consequences. Early detection, thus of kidney injury is essential for injury specific intervention that may avert permanent renal damage and delay progression of kidney injury. We aimed to evaluate Kidney Injury Molecule-1 (KIM-1) and Microalbuminuria (MAU), as biomarkers of kidney injury, in comparison with creatinine. We compared the levels of urine MAU, urine KIM-1 and other plasma biochemical tests in specimens from 80 individuals with and without kidney disease. We found no difference in KIM-1 levels between the kidney disease group (2.82± 1.36ng/mL) and controls (3.29 ± 1.14ng/mL), p = 0.122. MAU was higher in participants with kidney disease (130.809± 84.744 µg/mL) than the controls (15.983± 20.442µg/mL), p ?0.001. KIM-1 showed a weak negative correlation with creatinine (r = -0.279, p = 0.09), whereas MAU was positively correlated with creatinine in participants with kidney disease with statistical significance (r = 0.556, p = 0.001). The study demonstrated that in Zambian setting MAU and creatinine are sensitive biomarkers in the diagnosis of kidney damage. We moreover propose further evaluation of KIM-1 as a biomarker of kidney injury.

Kidney injury molecule-1 and microalbuminuria levels in Zambian population: biomarkers of kidney injury

PubMed Central

Zulu, Mildred; Kaile, Trevor; Kantenga, Timothy; Chileshe, Chisanga; Nkhoma, Panji; Sinkala, Musalula

2016-01-01

Introduction Kidney injury affects renal excretion of plasma analytes and metabolic waste products with grave pathologic consequences. Early detection, thus of kidney injury is essential for injury specific intervention that may avert permanent renal damage and delay progression of kidney injury. We aimed to evaluate Kidney Injury Molecule-1 (KIM-1) and Microalbuminuria (MAU), as biomarkers of kidney injury, in comparison with creatinine. Methods We compared the levels of urine MAU, urine KIM-1 and other plasma biochemical tests in specimens from 80 individuals with and without kidney disease. Results We found no difference in KIM-1 levels between the kidney disease group (2.82± 1.36ng/mL) and controls (3.29 ± 1.14ng/mL), p = 0.122. MAU was higher in participants with kidney disease (130.809± 84.744 µg/mL) than the controls (15.983± 20.442µg/mL), p ?0.001. KIM-1 showed a weak negative correlation with creatinine (r = -0.279, p = 0.09), whereas MAU was positively correlated with creatinine in participants with kidney disease with statistical significance (r = 0.556, p = 0.001). Conclusion The study demonstrated that in Zambian setting MAU and creatinine are sensitive biomarkers in the diagnosis of kidney damage. We moreover propose further evaluation of KIM-1 as a biomarker of kidney injury. PMID:27642395

Cadmium, type 2 diabetes, and kidney damage in a cohort of middle-aged women

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barregard, Lars, E-mail: lars.barregard@amm.gu.se; Bergström, Göran, E-mail: goran.bergstrom@wlab.gu.se; Department of Molecular and Clinical Medicine, University of Gothenburg, SE-405 30 Gothenburg

Background: It has been proposed that diabetic patients are more sensitive to the nephrotoxicity of cadmium (Cd) compared to non-diabetics, but few studies have examined this in humans, and results are inconsistent. Aim: To test the hypothesis that women with type 2 diabetes mellitus (DM) or impaired glucose tolerance (IGT) have higher risk of kidney damage from cadmium compared to women with normal glucose tolerance (NGT). Methods: All 64-year-old women in Gothenburg, Sweden, were invited to a screening examination including repeated oral glucose tolerance tests. Random samples of women with DM, IGT, and NGT were recruited for further clinical examinations.more » Serum creatinine was measured and used to calculate estimated glomerular filtration rate (eGFR). Albumin (Alb) and retinol-binding protein (RBP) were analyzed in a 12 h urine sample. Cadmium in blood (B-Cd) and urine (U-Cd) was determined using inductively coupled plasma mass spectrometry. Associations between markers of kidney function (eGFR, Alb, and RBP) and quartiles of B-Cd and U-Cd were evaluated in models, including also blood pressure and smoking habits. Results: The mean B-Cd (n=590) was 0.53 µg/L (median 0.34 µg/L). In multivariable models, a significant interaction was seen between high B-Cd (upper quartile, >0.56 µg/L) and DM (point estimate +0.40 mg Alb/12 h, P=0.04). In stratified analyzes, the effect of high B-Cd on Alb excretion was significant in women with DM (53% higher Alb/12 h, P=0.03), but not in women with IGT or NGT. Models with urinary albumin adjusted for creatinine showed similar results. In women with DM, the multivariable odds ratio (OR) for microalbuminuria (>15 mg/12 h) was increased in the highest quartile of B-Cd vs. B-Cd quartiles 1–3 in women with DM (OR 4.2, 95% confidence interval 1.1–12). No such effect was found in women with IGT or NGT. There were no associations between B-Cd and eGFR or excretion of RBP, and no differences between women with DM, IGT, or

Tuberculosis after kidney transplantation is associated with significantly impaired allograft function.

PubMed

Costa, Silvana Daher; de Sandes-Freitas, Tainá Veras; Jacinto, Camilla Neves; Martiniano, Lorena Vasconcelos Mesquita; Amaral, Yago Sucupira; Paes, Fernando José Villar Nogueira; Sales, Maria Luiza de Mattos Brito Oliveira; Esmeraldo, Ronaldo de Matos; Daher, Elizabeth de Francesco

2017-10-01

This study aimed to evaluate renal function before, during, and after the course of tuberculosis (TB) disease in kidney transplant recipients, and assess the risk factors for non-recovery of baseline renal function. We performed a retrospective, single-center cohort study, including all patients with confirmed or presumed TB diagnosis after kidney transplant (n=34, 2.1%). Renal function was assessed by serum creatinine (Cr) and glomerular filtration rate (GFR) adjusted for deaths and graft losses. A significant increase was seen in serum Cr during TB disease and treatment: 1.5 mg/dL at baseline (Cr base ), 1.7 mg/dL at diagnosis (P<.001 vs. Cr base ), and 2.4 mg/dL during the peak (P<.001 vs. Cr base ). According to acute kidney injury (AKI) Kidney Disease: Improving Global Outcomes (KDIGO) classification, 29 (85%) patients had AKI: 16 stage 1, 2 stage 2, and 11 stage 3. Three months after the end of the TB treatment, five patients (14.7%) had lost their graft and two others (5.9%) had died. The GFR was lower than the baseline (42.4 mL/min vs 51.6 mL/min, P=.007). In the univariate analysis, peak Cr (odds ratio [OR] 1.276, 95% confidence interval [CI] 0.955-1.705, P=.100), AKI KDIGO stages 2 or 3 (OR 4.958, 95% CI 1.062-23.157, P=.042), severe disease (OR 5.700, 95% CI 1.147-28.330, P=.033), and acute rejection (AR) episodes after TB diagnosis (OR 3.937, 95% CI 0.551-28.116, P=.172) were associated with non-recovery of baseline renal function. No variable was identified in the multivariable model. Post-transplantation TB was associated with a high incidence of AKI, and complete recovery of baseline renal function was not achieved after treatment. The severity of TB disease, AKI, and AR episodes that occurred after TB diagnosis are potential causes for this outcome. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Fresh osteochondral allografts-procurement and tissue donation in Europe.

PubMed

Schmidt, S; Schulte, A; Schwarz, S; Hofmann, N; Tietz, S; Boergel, M; Sixt, S U

2017-07-01

Fresh osteochondral allografts are a well-established treatment for large, full-thickness cartilage defects. The clinical outcome for carefully selected patients is very favorable, especially for the young and active and graft survival up to 25 years has been described in the literature. Furthermore, a high patient satisfaction rate has been reported, but the biggest obstacle to overcome is the availability of tissue for transplantation. Large fresh bone allografts for cartilage damage repair only can be harvested from organ donors following organ removal or cadaveric donors, preferably in the setting of an operation room to minimize possible contamination of the tissue. Apart from the logistic challenges this entails, an experienced recovery team is needed. Furthermore, the public as well as medical staff is much less aware of the possibility and requirements of tissue donation than organ donation and families of deceased are rarely approached for bone and cartilage donation. This review aims to highlight the current situation of organ and tissue donation in Europe with special focus on the processing of bones and possible safety and quality concerns. We analyze what may prevent consent and what might be done to improve the situation of tissue donation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study.

PubMed

Schachtner, Thomas; Otto, Natalie M; Reinke, Petra

2018-06-03

Kidney transplant recipients (KTRs) are at increased risk of avascular necrosis (AVN) due to bone disorder, steroid use and common comorbidities. However, knowledge on risk factors and outcomes of AVN among KTRs in the modern era of immunosuppression remains scarce. We analysed 765 KTRs between 2001 and 2013 for AVN. Cases of symptomatic AVN were diagnosed by hip X-ray, radioisotope bone scan or magnetic resonance imaging. We evaluated risk factors and clinical characteristics of AVN. KTRs showed a constant incidence rate of AVN of 4.1% at 10 years after transplantation. The use of cyclosporine compared with tacrolimus was identified as an independent risk factor, with a rate of 8.0% compared with 2.7% at 10 years (P < 0.01). In addition, male gender was independently associated with AVN (P = 0.047). Eighty-three per cent of AVN cases were of the femoral head and treated operatively. None of the operated KTRs experienced complications in the long term. Thirty-three per cent of KTRs had bilateral AVN. Ninety-two per cent of KTRs showed AVN at the allograft side. The decreasing incidence of AVN may be attributed to the replacement of cyclosporine by tacrolimus over the last decade. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney impacting AVN at the allograft side.

Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via PD-L1

PubMed Central

Fiorina, Paolo; Jurewicz, Mollie; Vergani, Andrea; Petrelli, Alessandra; Carvello, Michele; D’Addio, Francesca; Godwin, Jonathan G.; Law, Kenneth; Wu, Erxi; Tian, Ze; Thoma, Gebhard; Kovarik, Jiri; La Rosa, Stefano; Capella, Carlo; Rodig, Scott; Zerwes, Hans-Guenter; Sayegh, Mohamed H.; Abdi, Reza

2012-01-01

Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on HSCs and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of hematopoietic stem cells (HSCs) to the periphery. Due to their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of Rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative co-stimulatory molecule PD-L1, and HSCs extracted from WT mice, but not from PD-L1 KO, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 KO mice failed to prolong islet allograft survival. Targeting the CXCR4-CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1-mediated mechanism. PMID:21131428

Cryopreserved Cadaveric Arterial Allograft for Arterial Reconstruction in Patients with Prosthetic Infection.

PubMed

Lejay, Anne; Delay, Charline; Girsowicz, Elie; Chenesseau, Bettina; Bonnin, Emilie; Ghariani, Mohamed-Zied; Thaveau, Fabien; Georg, Yannick; Geny, Bernard; Chakfe, Nabil

2017-11-01

The aim of this study was to report outcomes of cryopreserved arterial allografts used as a vascular substitute in the setting of prosthetic material infection. A retrospective analysis of prospectively collected data was conducted including all consecutive interventions performed with cryopreserved arterial allografts used for vascular reconstruction in the setting of prosthetic material infection between January 2005 and December 2014. Five year outcomes included allograft related re-interventions, survival, primary patency, and limb salvage rates. Fifty-three procedures were performed using cryopreserved allografts for vascular prosthetic infection: 25 procedures (47%) were performed at aorto-iliac level (Group 1) and 28 procedures (53%) at peripheral level (Group 2). The mean follow-up was 52 months. Five year allograft related re-intervention was 55% in Group 1 (6 allograft ruptures and 5 allograft aneurysm degenerations) and 33% in Group 2 (2 allograft ruptures and 7 allograft aneurysm degenerations). Five year survival was 40% and 68%, primary patency was 89% and 59% and limb salvage was 100% and 89% for Group 1 and 2 respectively. Use of cryopreserved arterial allografts provides acceptable results but is tempered by suboptimal 5 year outcomes with high re-intervention rates. Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Methanol exposure does not produce oxidatively damaged DNA in lung, liver or kidney of adult mice, rabbits or primates

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCallum, Gordon P.; Siu, Michelle; Sweeting, J. Nicole

2011-01-15

In vitro and in vivo genotoxicity tests indicate methanol (MeOH) is not mutagenic, but carcinogenic potential has been claimed in one controversial long-term rodent cancer bioassay that has not been replicated. To determine whether MeOH could indirectly damage DNA via reactive oxygen species (ROS)-mediated mechanisms, we treated male CD-1 mice, New Zealand white rabbits and cynomolgus monkeys with MeOH (2.0 g/kg ip) and 6 h later assessed oxidative damage to DNA, measured as 8-oxo-2'-deoxyguanosine (8-oxodG) by HPLC with electrochemical detection. We found no MeOH-dependent increases in 8-oxodG in lung, liver or kidney of any species. Chronic treatment of CD-1 micemore » with MeOH (2.0 g/kg ip) daily for 15 days also did not increase 8-oxodG levels in these organs. These results were corroborated in DNA repair-deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice, which accumulated 8-oxodG in lung, kidney and liver with age, but exhibited no increase following MeOH, despite a 2-fold increase in renal 8-oxodG in Ogg1 KO mice following treatment with a ROS-initiating positive control, the renal carcinogen potassium bromate (KBrO{sub 3}; 100 mg/kg ip). These observations suggest that MeOH exposure does not promote the accumulation of oxidatively damaged DNA in lung, kidney or liver, and that environmental exposure to MeOH is unlikely to initiate carcinogenesis in these organs by DNA oxidation.« less

Associations between Deceased-Donor Urine MCP-1 and Kidney Transplant Outcomes.

PubMed

Mansour, S G; Puthumana, J; Reese, P P; Hall, I E; Doshi, M D; Weng, F L; Schröppel, B; Thiessen-Philbrook, H; Bimali, M; Parikh, C R

2017-07-01

Existing methods to predict recipient allograft function during deceased-donor kidney procurement are imprecise. Understanding the potential renal reparative role for monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in macrophage recruitment after injury, might help predict allograft outcomes. We conducted a sub-study of the multicenter prospective Deceased Donor Study cohort, which evaluated deceased kidney donors from five organ procurement organizations from May 2010 to December 2013. We measured urine MCP-1 (uMCP-1) concentrations from donor samples collected at nephrectomy to determine associations with donor acute kidney injury (AKI), recipient delayed graft function (DGF), 6-month estimated GFR (eGFR), and graft failure. We also assessed perfusate MCP-1 concentrations from pumped kidneys for associations with DGF and 6-month eGFR. AKI occurred in 111 (9%) donors. Median (interquartile range) uMCP-1 concentration was higher in donors with AKI compared to donors without AKI (1.35 [0.41-3.93] ng/ml vs. 0.32 [0.11-0.80] ng/ml, p<0.001). DGF occurred in 756 (31%) recipients, but uMCP-1 was not independently associated with DGF. Higher donor uMCP-1 concentrations were independently associated with higher 6-month eGFR in those without DGF [0.77 (0.10, 1.45) ml/min/1.73m 2 per doubling of uMCP1]. However, there were no independent associations between uMCP-1 and graft failure over a median follow-up of about 2 years. Lastly, perfusate MCP-1 concentrations significantly increased during pump perfusion but were not associated with DGF or 6-month eGFR. Donor uMCP-1 concentrations were modestly associated with higher recipient 6-month eGFR in those without DGF. However, the results suggest that donor uMCP-1 has minimal clinical utility given no associations with graft failure.

Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction.

PubMed

Xu, Jin; Casas-Ferreira, Ana M; Ma, Yun; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, Maltina; Tena, Maria; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido-Quigley, Cristina

2015-12-04

Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation.

Host-Pathogen Interactions and Chronic Lung Allograft Dysfunction.

PubMed

Belperio, John; Palmer, Scott M; Weigt, S Sam

2017-09-01

Lung transplantation is now considered to be a therapeutic option for patients with advanced-stage lung diseases. Unfortunately, due to post-transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Infections (e.g., bacterial, viral, and fungal) in the immunosuppressed lung transplant recipient are a common cause of mortality post transplant. Infections have more recently been explored as factors contributing to the risk of chronic lung allograft dysfunction (CLAD). Each major class of infection-(1) bacterial (Staphylococcus aureus and Pseudomonas aeruginosa); (2) viral (cytomegalovirus and community-acquired respiratory viruses); and (3) fungal (Aspergillus)-has been associated with the development of CLAD. Mechanistically, the microbe seems to be interacting with the allograft cells, stimulating the induction of chemokines, which recruit recipient leukocytes to the graft. The recipient leukocyte interactions with the microbe further up-regulate chemokines, amplifying the influx of allograft-infiltrating mononuclear cells. These events can promote recipient leukocytes to interact with the allograft, triggering an alloresponse and graft dysfunction. Overall, interactions between the microbe-allograft-host immune system alters chemokine production, which, in part, plays a role in the pathobiology of CLAD and mortality due to CLAD.

Effects of a peracetic acid disinfection protocol on the biocompatibility and biomechanical properties of human patellar tendon allografts.

PubMed

Lomas, R J; Jennings, L M; Fisher, J; Kearney, J N

2004-01-01

Patellar tendon allografts, retrieved from cadaveric human donors, are widely used for replacement of damaged cruciate ligaments. In common with other tissue allografts originating from cadaveric donors, there are concerns regarding the potential for disease transmission from the donor to the recipient. Additionally, retrieval and subsequent processing protocols expose the graft to the risk of environmental contamination. For these reasons, disinfection or sterilisation protocols are necessary for these grafts before they are used clinically. A high-level disinfection protocol, utilising peracetic acid (PAA), has been developed and investigated for its effects on the biocompatibility and biomechanics of the patellar tendon allografts. PAA disinfection did not render the grafts either cytotoxic or liable to provoke an inflammatory response as assessed in vitro . However, the protocol was shown to increase the size of gaps between the tendon fibres in the matrix and render the grafts more susceptible to digestion with collagenase. Biomechanical studies of the tendons showed that PAA treatment had no effect on the ultimate tensile stress or Young's modulus of the tendons, and that ultimate strain was significantly higher in PAA treated tendons.

Nebivolol ameliorated kidney damage in Zucker diabetic fatty rats by regulation of oxidative stress/NO pathway: comparison with captopril.

PubMed

Wang, Yan; An, Wenjing; Zhang, Fei; Niu, Mengzhen; Liu, Yu; Shi, Ruizan

2018-06-23

The aim was to evaluate the effects and mechanisms of nebivolol on renal damage in Zucker diabetic fatty (ZDF) rats, in comparison with those of atenolol and captopril. Animals were divided into: control lean Zucker rats, ZDF rats, ZDF rats orally treated with nebivolol (10 mg/kg), atenolol (100 mg/kg) or captopril (40 mg/kg) for 6 months. Systolic blood pressure (SBP), blood glucose, kidney structure and function, plasma and kidney levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA), and oxidant status were evaluated. Kidney expressions of AMP-activated protein kinase (AMPK), NADPH oxidase (NOX) isoforms 2 and 4 and subunit p22 phox , nitric oxide synthase (NOS) isoforms, eNOS uncoupling, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 were tested. All drugs induced a similar control of SBP. Nebivolol did not affect the increased plasma glucose. Unlike atenolol, nebivolol prevented the decrease in plasma insulin, and, like captopril, it reduced plasma lipid contents. Nebivolol ameliorated, to a greater extent than captopril, damages to renal structure and function, which were associated with an improvement in interlobular artery dysfunction. Nebivolol elevated kidney phosphorylation of AMPK, attenuated NOX4 and p22 phox expression and oxidative stress marker levels. Nebivolol increased plasma and renal NO, enhanced expressions of eNOS, p-eNOS and nNOS, and suppressed eNOS uncoupling and iNOS expression. High ADMA in plasma and kidney were decreased by nebivolol through increasing DDAH2 and decreasing PRMT1. Long-term treatment of nebivolol ameliorated diabetic nephropathy, at least in part, via regulation of renal oxidative stress/NO pathway. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Increasing access to kidney transplantation for sensitized recipient through three-way kidney paired donation with desensitization: The first Indian report

PubMed Central

Kute, Vivek B; Patel, Himanshu V; Shah, Pankaj R; Modi, Pranjal R; Shah, Veena R; Rizvi, Sayyed J; Pal, Bipin C; Modi, Manisha P; Shah, Priya S; Varyani, Umesh T; Wakhare, Pavan S; Shinde, Saiprasad G; Ghodela, Viajay A; Patel, Minaxi H; Trivedi, Varsha B; Trivedi, Hargovind L

2016-01-01

The combination of kidney paired donation (KPD) with desensitization represents a promising method of increasing the rate of living donor kidney transplantation (LDKT) in immunologically challenging patients. Patients who are difficult to match and desensitize due to strong donor specific antibody are may be transplanted by a combination of desensitization and KPD protocol with more immunologically favorable donor. We present our experience of combination of desensitization protocol with three-way KPD which contributed to successful LDKT in highly sensitized end stage renal disease patient. All recipients were discharged with normal and stable allograft function at 24 mo follow up. We believe that this is first report from India where three-way KPD exchange was performed with the combination of KPD and desensitization. The combination of desensitization protocol with KPD improves access and outcomes of LDKT. PMID:27803919

Intraoperative culture positive allograft bone and subsequent postoperative infections: a retrospective review.

PubMed

Sims, Laura; Kulyk, Paul; Woo, Allan

2017-04-01

Obtaining intraoperative cultures of allograft bone just before use in orthopedic procedures is standard practice in many centres; however, the association between positive cultures and subsequent surgical infections is unknown. Our study had 3 goals: to determine the prevalence of positive intraoperative allograft culture and subsequent infection; to determine if, in cases of subsequent infection, organisms isolated at reoperation were the same as those cultured from the allograft at the time of the index procedure; and to assess the costs associated with performing intraoperative allograft cultures. In this retrospective case series, we obtained data on patients receiving allograft bone between 2009 and 2012. Patients receiving allograft with positive cultures were reviewed to identify cases of significant infection. Organisms isolated at reoperation were compared with the allograft culture taken at the time of implantation, and we performed a cost assessment. Of the 996 allograft bone grafts used, 43 (4.3%) had positive intraoperative cultures and significant postoperative infections developed in 2, requiring reoperation. Antibiotics based on culture results were prescribed in 24% of cases. Organisms cultured at the time of reoperation differed from those isolated initially. The cost of performing 996 allograft cultures was $169 320. This series suggests that rates of positive intraoperative bone allograft culture are low, and subsequent infection is rare. In cases of postoperative infection, primary allograft culture and secondary tissue cultures isolated different organisms. Costs associated with performing cultures are high. Eliminating initial culture testing could save $42 500 per year in our health region.

Intraoperative culture positive allograft bone and subsequent postoperative infections: a retrospective review

PubMed Central

Sims, Laura; Kulyk, Paul; Woo, Allan

2017-01-01

Background Obtaining intraoperative cultures of allograft bone just before use in orthopedic procedures is standard practice in many centres; however, the association between positive cultures and subsequent surgical infections is unknown. Our study had 3 goals: to determine the prevalence of positive intraoperative allograft culture and subsequent infection; to determine if, in cases of subsequent infection, organisms isolated at reoperation were the same as those cultured from the allograft at the time of the index procedure; and to assess the costs associated with performing intraoperative allograft cultures. Methods In this retrospective case series, we obtained data on patients receiving allograft bone between 2009 and 2012. Patients receiving allograft with positive cultures were reviewed to identify cases of significant infection. Organisms isolated at reoperation were compared with the allograft culture taken at the time of implantation, and we performed a cost assessment. Results Of the 996 allograft bone grafts used, 43 (4.3%) had positive intraoperative cultures and significant postoperative infections developed in 2, requiring reoperation. Antibiotics based on culture results were prescribed in 24% of cases. Organisms cultured at the time of reoperation differed from those isolated initially. The cost of performing 996 allograft cultures was $169 320. Conclusion This series suggests that rates of positive intraoperative bone allograft culture are low, and subsequent infection is rare. In cases of postoperative infection, primary allograft culture and secondary tissue cultures isolated different organisms. Costs associated with performing cultures are high. Eliminating initial culture testing could save $42 500 per year in our health region. PMID:28234217

Tolerance to Vascularized Composite Allografts in Canine Mixed Hematopoietic Chimeras

PubMed Central

Mathes, David W.; Hwang, Billanna; Graves, Scott S.; Edwards, James; Chang, Jeff; Storer, Barry E.; Butts-Miwongtum, Tiffany; Sale, George E.; Nash, Richard A.; Storb, Rainer.

2012-01-01

Background Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a highly reproducible strategy for the induction of tolerance towards solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of highly antigenic vascularized composite allografts. Methods Stable mixed chimerism was established in dogs given a sublethal dose (1–2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 (range 4-54) months after HCT. Results All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted composite tissue grafts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18–29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared to extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared to normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared to non-draining lymph nodes of vascularized composite allografts. Conclusion These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function towards maintenance of the vascularized composite allograft. PMID:22082819

[Combined heart-kidney transplantation in Mexic].

PubMed

Careaga-Reyna, Guillermo; Zetina-Tun, Hugo Jesús; Lezama-Urtecho, Carlos Alberto; Hernández-Domínguez, José Mariano; Santos-Caballero, Marlene

In our country, heart and kidney transplantation is a novel option for treatment of combined terminal heart and kidney failure. This program began in 2012 for selected patients with documented terminal heart failure and structural kidney damage with renal failure. Description of cases: Between January 1, 2012 and April 30, 2016, we made 92 orthotopic heart transplantations. In five of these cases the heart transplantation was combined with kidney transplantation. There were three male and two female patients with a mean age 25.6 ± 5.2 years (range, 17-29). The patients improved their renal function and the heart transplantation was successful with an improved quality of life. One patient died from abdominal sepsis. The other patients are doing well. The combined heart-kidney transplantation is a safe and efficient procedure for patients with structural kidney and heart damage as a cause of terminal failure.

[Ureterostomy cytomegalovirus infection presenting as stoma ulceration in a kidney allograft receptor: a case report].

PubMed

Rico, J E; Cardona, X; Rodelo, J; Reino, A; Arias, L F; Arbeláez, M

2008-06-01

Cytomegalovirus (CMV) is the most common viral infection affecting transplant patients, but urinary tract involvement has been rare. Only a few cases of symptomatic ureteritis have been reported in renal transplant recipients. In previous reports the presentation of CMV ureteritis is obstructive nephropathy, often in the absence of systemic illness, or rarely it may also mimic allograft rejection with minimal obstructive symptoms. We describe an additional case of CMV ureteritis in a patient with cutaneous ureterostomy. The unusual clinical presentation with urinary infection symptoms and ureterostomy stoma ulceration constitute a very particular presentation. The increasing report cases with CMV ureteritis suggest an increase of this post-transplant complication.

TH1/TH2 cytokines and soluble CD30 levels in kidney allograft patients with donor bone marrow cell infusion.

PubMed

Solgi, G; Amirzagar, A A; Pourmand, G; Mehrsai, A R; Taherimahmoudi, M; Baradaran, N; Nicknam, M H; Ebrahimi Rad, M R; Saraji, A; Asadpoor, A A; Moheiydin, M; Nikbin, B

2009-09-01

We investigated the relevance of donor bone marrow cell infusion (DBMI) and serum levels of interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and soluble CD30 (sCD30) in kidney recipients. We analyzed the allograft outcomes correlated with sCD30, IFN-gamma, and IL-10 levels using pre- and posttransplantation sera from 40 live donor renal transplants (20 patients with DBMI [2.1 x 10(9) +/- 1.3 x 10(9) mononuclear cells/body] and 20 controls). Patients with acute rejection episodes (ARE)-3/20 DBMI and 6/20 controls-showed increased sCD30 and IFN-gamma as well as decreased IL-10 posttransplantation compared with nonrejectors. Significant differences were observed for sCD30 and IFN-gamma levels: 59.54 vs 30.92 ng/mL (P = .02) and 11.91 vs 3.01 pg/mL (P = .01), respectively. Comparison of pre- and posttransplant levels of IFN-gamma, IL-10, and sCD30 in ARE patients showed higher levels in posttransplant sera except for IFN-gamma in controls (6.37 vs 11.93; P = .01). Increased IFN-gamma and IL-10 were correlated with rejection (r = .93; P = .008). sCD30 correlated with serum creatinine among ARE patients in control and DBMI groups (r = .89; P = .019; and r = 1.00; P < .0001, respectively). Higher levels of sCD30, IFN-gamma, and IL-10 posttransplantation in rejecting patients provided evidence for coexistence of cellular and humoral responses in ARE. There appeared to be a down-regulatory effect of infusion on alloresponses.

Complement-binding anti-HLA antibodies are independent predictors of response to treatment in kidney recipients with antibody-mediated rejection.

PubMed

Viglietti, Denis; Bouatou, Yassine; Kheav, Vissal David; Aubert, Olivier; Suberbielle-Boissel, Caroline; Glotz, Denis; Legendre, Christophe; Taupin, Jean-Luc; Zeevi, Adriana; Loupy, Alexandre; Lefaucheur, Carmen

2018-05-22

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies (DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Renal and obstetric outcomes in pregnancy after kidney transplantation: Twelve-year experience in a Singapore transplant center.

PubMed

Kwek, Jia Liang; Tey, Vanessa; Yang, Liying; Kanagalingam, Devendra; Kee, Terence

2015-09-01

Renal and obstetric outcomes in pregnancy after kidney transplantation in Singapore were last studied in 2002. A review of these outcomes in Singapore is now timely following advances in transplant and obstetric medicine. The aim was to evaluate the renal and obstetric outcomes in pregnancy after kidney transplantation in a Singapore tertiary center. Kidney transplant recipients who underwent pregnancy after transplantation at Singapore General Hospital between January 2001 and December 2012 were identified. Data on demographics, comorbidities and clinical outcomes were collected. There were 10 pregnancies identified in nine recipients. The median age of recipient at childbearing was 34.6 years (IQR, 32.8-36.8) and the median interval from transplantation to conception was 69 months (IQR, 38-97). There was no difference between the median pre-pregnancy estimated glomerular filtration rate (eGFR) (47.9 mL/min/1.73 m(2); IQR, 38.4-56.8) and median eGFR at time of last post-partum follow up (43.9 mL/min/1.73 m(2); IQR, 34.5-48.7, P = 0.549). Borderline allograft rejection occurred in one recipient (10.0%) 36 days after birth due to non-adherence to immunosuppressive medication, with subsequent allograft loss 37 months after birth. No mortalities were recorded during the study period. All the 10 pregnancies (100%) ended in singleton live births. Pre-eclampsia occurred in five pregnancies (50.0%), and there were seven (70.0%) preterm deliveries. The median gestational age was 35.4 weeks (IQR, 32.6-38.2) and the median birthweight was 2353 g (IQR, 1811-2648). Post-transplantation pregnancies ended successfully with no significant worsening of allograft function, but they were associated with risks to both recipients and newborns. © 2015 Japan Society of Obstetrics and Gynecology.

Protective Effects of Pinus halepensis L. Essential Oil on Aspirin-induced Acute Liver and Kidney Damage in Female Wistar Albino Rats.

PubMed

Bouzenna, Hafsia; Samout, Noura; Amani, Etaya; Mbarki, Sakhria; Tlili, Zied; Rjeibi, Ilhem; Elfeki, Abdelfattah; Talarmin, Hélène; Hfaiedh, Najla

2016-08-01

Aromatic and medicinal plants are sources of natural antioxidants thanks to their secondary metabolites. Administration of Pinus halepensis L. (Pinaceae family) in previous studies was found to alleviate deleterious effects of aspirin-induced damage on liver and kidney. The present study, carried out on female rats, evaluates the effects of P. halepensis L. essential oil (EOP) on aspirin (A)-induced damage to liver and kidney. The animals used in this study were rats (n=28) divided into 4 groups of 7 each: (1) a control group (C); (2) a group given NaCl for 56 days then treated with (A) (600 mg/kg) for 4 days (A); (3) a group fed with (EOP) for 56 days then (A) for 4 days; and a group fed with only (EOP) for 56 days and given NaCl for 4 days. Estimations of biochemical parameters in blood were determined using kit methods (Spinreact). Lipid peroxidation levels (TBARS), superoxide dismutase (SOD) and catalase (CAT), glutathione peroxidase (GPx) activities were determined. Histopathological study was done by immersing pieces of both organs in a fixative solution followed by paraffin embeddeding and hematoxylin-eosin staining. Under our experimental conditions, Aspirin at dose 600 mg/kg body weight induced an increase of serum biochemical parameters as well as an oxidative stress in both organs. An increase occurred in TBARS by 108% and 55%, a decrease in SOD by 78% and 53%, CAT by 53% and 78%, and GPx by 78% and 51% in liver and kidney, respectively, compared to control. Administration of EOP given to rats enabled correction in these parameters. It could be concluded that the treatment with P. halepensis L. essential oil inhibited aspirin-induced liver and kidney damage.

21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiac allograft gene expression profiling test... Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system. (a) Identification. A cardiac allograft gene expression profiling test system is a device that measures the...

Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts.

PubMed Central

MacMillan-Crow, L A; Crow, J P; Kerby, J D; Beckman, J S; Thompson, J A

1996-01-01

Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 microM) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8876227

Allografts with autogenous platelet-rich plasma for tibial defect reconstruction: a rabbit study.

PubMed

Nather, Aziz; Wong, Keng Lin; David, Vikram; Pereira, Barry P

2012-12-01

To evaluate the effect of autogenous platelet-rich plasma (PRP) for fresh-frozen allografts in tibial defect reconstruction in rabbits. 40 adult New Zealand white rabbits underwent tibial defect reconstruction with autografts (n=12), allografts without PRP (n=12), or allografts with PRP (n=12) and were observed for 12, 16, and 24 weeks (4 for each period). Tibias of the remaining 4 rabbits were used as donor allografts, and the remaining allografts were procured from recipient rabbits. A 1.5- cm cortical segment of the tibia was osteotomised, and then fixed with a 9-hole mini-compression plate and 2 cerclage wires. Allografts were stripped off the periosteum and soft tissues and medullary contents, and then stored in a freezer at -80 ºC. All allografts were deep frozen for at least 4 weeks before transplantation. 7 ml of whole blood was drawn to prepare 1 ml of PRP. The PRP was then mixed with 1.0 ml of human thrombin to form a platelet gel. The PRP gel was then packed into the medullary canal of the allograft and applied on the cortical surface before tibial defect reconstruction. Rabbits were sacrificed at 12, 16, and 24 weeks. The specimens were assessed for bone union at host-graft junctions and for bone resorption, new bone formation, callus encasement, and viable osteocyte counts. There were 4 specimens in each group at each observation period. Osteoid bridging the gap at host-graft junctions was noted in all specimens in the autograft and allograft-with-PRP groups at week 12 and in the allograft-without-PRP group at week 24. Bone union in allografts without PRP was delayed. All indices for biological incorporation (resorption index, new bone formation index, callus encasement index, and viable osteocyte count) were significantly greater in the autograft than allograft-without-PRP groups, except for the resorption index at week 24, whereas the differences were not significant between the autograft and allograft-with-PRP groups. The differences between the 2

Supply of human allograft tissue in Canada.

PubMed

Lakey, Jonathan R T; Mirbolooki, Mohammadreza; Rogers, Christina; Mohr, Jim

2007-01-01

There is relatively little known about the supply for allograft tissues in Canada. The major aim of this study is to quantify the current or "Known Supply" of human allograft tissue (bone, tendons, soft tissue, cardiovascular, ocular and skin) from known tissue banks in Canada, to estimate the "Unknown Supply" of human allograft tissue available to Canadian users from other sources, and to investigate the nature and source of these tissue products. Two surveys were developed; one for tissue banks processing one or more tissue types and the other specific to eye banks. Thirty nine sites were initially identified as potential tissue bank respondent sites. Of the 39 sites, 29 sites indicated that they were interested in participating or would consider completing the survey. A survey package and a self-addressed courier envelope were couriered to each of 29 sites. A three week response time was indicated. The project consultants conducted telephone and email follow-up for incomplete data. Unknown supply was estimated by 5 methods. Twenty-eight of 29 sites (97%) completed and returned surveys. Over the past year, respondents reported a total of 5,691 donors (1,550 living and 4,141 cadaveric donors). Including cancellous ground bone, there were 10,729 tissue products produced by the respondent banks. Of these, 71% were produced by accredited banks and 32% were ocular tissues. Total predicted shortfall of allograft tissues was 31,860-66,481 grafts. Through estimating Current supply, and compiling additional qualitative information, this study has provided a snapshot of the current Canadian supply and shortfall of allograft tissue grafts.

Longitudinal Analysis of Whole Blood Transcriptomes to Explore Molecular Signatures Associated With Acute Renal Allograft Rejection

PubMed Central

Shin, Heesun; Günther, Oliver; Hollander, Zsuzsanna; Wilson-McManus, Janet E.; Ng, Raymond T.; Balshaw, Robert; Keown, Paul A.; McMaster, Robert; McManus, Bruce M.; Isbel, Nicole M.; Knoll, Greg; Tebbutt, Scott J.

2014-01-01

In this study, we explored a time course of peripheral whole blood transcriptomes from kidney transplantation patients who either experienced an acute rejection episode or did not in order to better delineate the immunological and biological processes measureable in blood leukocytes that are associated with acute renal allograft rejection. Using microarrays, we generated gene expression data from 24 acute rejectors and 24 nonrejectors. We filtered the data to obtain the most unambiguous and robustly expressing probe sets and selected a subset of patients with the clearest phenotype. We then performed a data-driven exploratory analysis using data reduction and differential gene expression analysis tools in order to reveal gene expression signatures associated with acute allograft rejection. Using a template-matching algorithm, we then expanded our analysis to include time course data, identifying genes whose expression is modulated leading up to acute rejection. We have identified molecular phenotypes associated with acute renal allograft rejection, including a significantly upregulated signature of neutrophil activation and accumulation following transplant surgery that is common to both acute rejectors and nonrejectors. Our analysis shows that this expression signature appears to stabilize over time in nonrejectors but persists in patients who go on to reject the transplanted organ. In addition, we describe an expression signature characteristic of lymphocyte activity and proliferation. This lymphocyte signature is significantly downregulated in both acute rejectors and nonrejectors following surgery; however, patients who go on to reject the organ show a persistent downregulation of this signature relative to the neutrophil signature. PMID:24526836

[The clinical use of cryopreserved human skin allografts for transplantation].

PubMed

Martínez-Flores, Francisco; Chacón-Gómez, María; Madinaveitia-Villanueva, Juan Antonio; Barrera-Lopez, Araceli; Aguirre-Cruz, Lucinda; Querevalu-Murillo, Walter

2015-01-01

The biological recovery of human skin allografts is the gold standard for preservation in Skin Banks. However, there is no worldwide consensus about specific allocation criteria for preserved human skin allografts with living cells. A report is presented on the results of 5 years of experience of using human skin allografts in burned patient in the Skin and Tissue Bank at the "Instituto Nacional de Rehabilitacion" The human skin allografts were obtained from multi-organ donors. processed and preserved at -80 °C for 12 months. Allocation criteria were performed according to blood type match, clinical history, and burned body surface. Up to now, the Skin and Tissue Bank at 'Instituto Nacional de Rehabilitacion" has processed and recovered 125,000 cm(2) of human skin allografts. It has performed 34 surgical implants on 21 burned patients. The average of burn body surface was 59.2%. More than two-thirds (67.7%) of recipients of skin allografts were matched of the same to type blood of the donor, and 66.6% survived after 126 days hospital stay. It is proposed to consider recipient's blood group as allocation criteria to assign tissue; and use human skin allografts on patiens affected with burns over 30% of body surface (according the "rule of the 9"). Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Newly developed central diabetes insipidus following kidney transplantation: a case report.

PubMed

Kim, K M; Kim, S M; Lee, J; Lee, S Y; Kwon, S K; Kim, H-Y

2013-09-01

Polyuria after kidney transplantation is a common, usually self-limiting disorder. However, persistent polyuria can cause not only patient discomfort, including polyuria and polydipsia, but also volume depletion that can produce allograft dysfunction. Herein, we have report a case of central diabetes insipidus newly diagnosed after kidney transplantation. A 45-year-old woman with end-stage kidney disease underwent deceased donor kidney transplantation. Two months after the transplantation, she was admitted for persistent polyuria, polydipsia, and nocturia with urine output of more than 4 L/d. Urine osmolarity was 100 mOsm/kg, which implied that the polyuria was due to water rather than solute diuresis. A water deprivation test was compatible with central diabetes insipidus; desmopressin treatment resulted in immediate symptomatic relief. Brain magnetic resonance imaging (MRI) demonstrated diffuse thickening of the pituitary stalk, which was considered to be nonspecific finding. MRI 12 months later showed no change in the pituitary stalk, although the patient has been in good health without polyuria or polydipsia on desmopressin treatment. The possibility of central diabetes insipidus should be considered in patients presenting with persistent polyuria after kidney transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

Autograft versus Allograft for Cervical Spinal Fusion: A Systematic Review.

PubMed

Tuchman, Alexander; Brodke, Darrel S; Youssef, Jim A; Meisel, Hans-Jörg; Dettori, Joseph R; Park, Jong-Beom; Yoon, S Tim; Wang, Jeffrey C

2017-02-01

Systematic review. To compare the effectiveness and safety between iliac crest bone graft (ICBG), non-ICBG autologous bone, and allograft in cervical spine fusion. To avoid problems at the donor site, various allograft materials have been used as a substitute for autograft. However, there are still questions as to the comparative effectiveness and safety of cadaver allograft compared with autologous ICBG. A systematic search of multiple major medical reference databases was conducted to identify studies evaluating spinal fusion in patients with cervical degenerative disk disease using ICBG compared with non-ICBG autograft or allograft or non-ICBG autograft compared with allograft in the cervical spine. Radiographic fusion, patient-reported outcomes, and functional outcomes were the primary outcomes of interest. Adverse events were evaluated for safety. The search identified 13 comparative studies that met our inclusion criteria: 2 prospective cohort studies and 11 retrospective cohort studies. Twelve cohort studies compared allograft with ICBG autograft during anterior cervical fusion and demonstrated with a low evidence level of support that there are no differences in fusion percentages, pain scores, or functional results. There was insufficient evidence comparing patients receiving allograft with non-ICBG autograft for fusion, pain, revision, and functional and safety outcomes. No publications directly comparing non-ICBG autograft with ICBG were found. Although the available literature suggests ICBG and allograft may have similar effectiveness in terms of fusion rates, pain scores, and functional outcomes following anterior cervical fusion, there are too many limitations in the available literature to draw any significant conclusions. No individual study provided greater than class III evidence, and when evaluating the overall body of literature, no conclusion had better than low evidence support. A prospective randomized trial with adequate sample size to

Fresh Osteochondral Allograft Versus Autograft: Twelve-Month Results in Isolated Canine Knee Defects.

PubMed

McCarty, Eric C; Fader, Ryan R; Mitchell, Justin J; Glenn, R Edward; Potter, Hollis G; Spindler, Kurt P

2016-09-01

Osteochondral autografts and allografts have been widely used in the treatment of isolated grade 4 articular cartilage lesions of the knee. However, there is a paucity of literature regarding the basic science investigating the direct comparison between fresh osteochondral allografts to autografts. At 12 months, fresh osteochondral allografts are equal to autografts with respect to function, bony incorporation into host bone, and chondrocyte viability. Controlled laboratory study. Eight adult mongrel dogs underwent bilateral hindlimb osteochondral graft implantation in the knee after creation of an acute Outerbridge grade 4 cartilage defect. One hindlimb of each dog knee received an autograft, and the contralateral knee received an allograft. All dogs were sacrificed at 12 months. Graft analysis included gross examination, radiographs, magnetic resonance imaging (MRI), biomechanical testing, and histology. MRI demonstrated excellent bony incorporation of both autografts and allografts, except for 1 allograft that revealed partial incorporation. Histologic examination of cartilage showed intact hyaline appearance for both autografts and allografts, with fibrocartilage at the host-graft interface of both. Biomechanical testing demonstrated no significant difference between allografts and autografts (P = .76). Furthermore, no significant difference was observed between allografts and the native cartilage with biomechanical testing (P = .84). After 12 months from time of implantation, fresh osteochondral allograft tissue and autograft tissue in this study were not statistically different with respect to biomechanical properties, gross morphology, bony incorporation, or overall histologic characteristics. When compared with the previously reported 6-month incorporation rates, there was improved allograft and autograft incorporation at 12 months. With no significant differences in gross examination, radiographs, MRI, biomechanical testing, or histology in the canine

Genetic polymorphisms of Interleukin-18 are not associated with allograft function in kidney transplant recipients.

PubMed

do Nascimento, Wenna Gleyce Araújo; Cilião, Daiani Alves; Genre, Julieta; Gondim, Dikson Dibe; Alves, Renata Gomes; Hassan, Neife Deghaide; Lima, Francisco Pignataro; Pereira, Maurício Galvão; Donadi, Eduardo Antônio; de Oliveira Crispim, Janaina Cristiana

2014-06-01

Interleukin 18 (IL-18) is a proinflammatory cytokine that plays a role in host defense by upregulating both innate and acquired immune responses. Analysis of IL18 polymorphisms may be clinically important since their roles have been recognized in a variety of inflammatory and autoimmune disorders. However, the role of this cytokine polymorphisms in kidney transplant still remains unclear. In this study, we evaluated the associations between IL18 polymorphisms and graft function assessed by creatinine clearance in kidney transplant recipients. A total of 82 kidney transplant recipients and 183 healthy controls were enrolled, and frequencies of alleles, genotypes and haplotypes for IL18 polymorphisms were determined and compared with creatinine clearance. The -607C/A (rs1946518) and -137C/G (rs187238) variant alleles in the IL18 gene were determined by polymerase chain reaction. In our study, no significant association was found between the IL18 variants and creatinine clearance (p > 0.05). Nonetheless, polymorphism analysis revealed an increase in the frequency of the IL18 major haplotype -607C/-137G in kidney transplant patients (odds ratio 2.57, 95% confidence interval 1.45-4.55, p = 0.0014). Finally, we found that IL18 polymorphisms did not influence the renal function and that IL18 haplotype -607C/-137G seems to be associated with kidney transplant recipients.

Genetic polymorphisms of Interleukin-18 are not associated with allograft function in kidney transplant recipients

PubMed Central

do Nascimento, Wenna Gleyce Araújo; Cilião, Daiani Alves; Genre, Julieta; Gondim, Dikson Dibe; Alves, Renata Gomes; Hassan, Neife Deghaide; Lima, Francisco Pignataro; Pereira, Maurício Galvão; Donadi, Eduardo Antônio; de Oliveira Crispim, Janaina Cristiana

2014-01-01

Interleukin 18 (IL-18) is a proinflammatory cytokine that plays a role in host defense by upregulating both innate and acquired immune responses. Analysis of IL18 polymorphisms may be clinically important since their roles have been recognized in a variety of inflammatory and autoimmune disorders. However, the role of this cytokine polymorphisms in kidney transplant still remains unclear. In this study, we evaluated the associations between IL18 polymorphisms and graft function assessed by creatinine clearance in kidney transplant recipients. A total of 82 kidney transplant recipients and 183 healthy controls were enrolled, and frequencies of alleles, genotypes and haplotypes for IL18 polymorphisms were determined and compared with creatinine clearance. The -607C/A (rs1946518) and -137C/G (rs187238) variant alleles in the IL18 gene were determined by polymerase chain reaction. In our study, no significant association was found between the IL18 variants and creatinine clearance (p > 0.05). Nonetheless, polymorphism analysis revealed an increase in the frequency of the IL18 major haplotype -607C/-137G in kidney transplant patients (odds ratio 2.57, 95% confidence interval 1.45–4.55, p = 0.0014). Finally, we found that IL18 polymorphisms did not influence the renal function and that IL18 haplotype -607C/-137G seems to be associated with kidney transplant recipients. PMID:25071398

rs3212227 SNP in the IL12B Gene Prevents Delayed Graft Function after Kidney Transplantation.

PubMed

Perovic, Vladimir; Markovic, Milos; Kravljaca, Milica; Milosevic, Emina; Djoric, Milica; Pravica, Vera; Naumovic, Radomir

2018-05-10

Transplantation is the best treatment option for end stage kidney disease. The most common early complications in post-transplant period are acute rejection (AR) of the graft and delayed graft function (DGF). The underlying mechanisms in these events are heterogeneous and at least in part involve cytokine genes which regulate immune response to allograft. We have investigated whether functional single nucleotide polymorphisms (SNP) in the genes encoding IFN-γ (IFNG), TNF (TNFA), IL-10 (IL10) and p40 subunit of IL-12/IL-23 (IL12B) could predict risk of AR and DGF in kidney allograft recipients. Our study involved 152 kidney transplant recipients on standard immunosuppressive regimen which included calcineurin inhibitors, mycophenolic acid derivatives and corticosteroids. Genotyping of IFNG, TNFA, IL10 and IL12B was performed using commercial TaqMan assays. We found association between the carriers of AA genotype of IL12B +1188A/C polymorphism (rs3212227) and a lower rate of DGF (p = 0.037, OR = 0.45, 95% CI = 0.21-0.96), implying protective role of A allele in the pathogenesis of DGF in kidney transplant recipients, whereas no such association was observed with AR. None of the analyzed SNPs in TNFA (-308G/A), IFNG (+874T/A), IL10 (-1082G/A, -819T/C, -592C/A) were associated with AR or DGF in our patients. Our study shows a preliminary evidence that the AA genotype of rs3212227 SNP in the IL12B gene might be associated with a lower risk for DGF after kidney transplantation. In the future, additional well-designed large studies are required for the validation of our results. Copyright © 2018 IMSS. Published by Elsevier Inc. All rights reserved.

Effects of molybdenum and cadmium on the oxidative damage and kidney apoptosis in Duck.

PubMed

Shi, Lele; Cao, Huabin; Luo, Junrong; Liu, Ping; Wang, Tiancheng; Hu, Guoliang; Zhang, Caiying

2017-11-01

Molybdenum (Mo) is an essential element for human beings and animals; however, high dietary intake of Mo can lead to adverse reactions. Cadmium (Cd) is one of the major transitional metals which has toxic effects in animals. To investigate the co-induced toxic effects of Mo and Cd on oxidative damage and kidney apoptosis in duck, 120 ducks were randomly divided into control group and 5 treatment groups which were treated with a commercial diet containing different dosages of Mo and Cd. Kidney samples were collected on the 60th and 120th days to determine the mRNA expression levels of ceruloplasmin (CP), metallothionein (MT), Bak-1, and Caspase-3 by quantitative RT-PCR. Additionally, we also determined the antioxidant activity indexes and contents of Mo, Cd, copper (Cu), iron (Fe), zinc (Zn), and selenium (Se) in serum. Meanwhile, ultrastructural changes of the kidney were observed. The results showed that glutathione reductase (GR) activity and CP level in serum were decreased in combination groups. In addition, the antioxidant indexes were decreased in co-treated groups compared with single treated groups. The mRNA expression levels of Bak-1 and Caspase-3 increased in co-treated groups. The mRNA expression level of CP in high-dose combination group was downregulated, while the mRNA expression of MT was upregulated except for low-dose Mo group. Additionally, in the later period the content of Cu in serum decreased in joint groups while the contents of Mo and Cd increased. In addition, ultrastructural changes showed mitochondrial crest fracture, swelling, deformed nuclei, and karyopyknosis in co-treated groups. Taken together, it was suggested that dietary Mo and Cd might lead to oxidative stress, kidney apoptosis and disturb homeostasis of trace elements in duck, and it showed a possible synergistic relationship between the two elements. Copyright © 2017 Elsevier Inc. All rights reserved.

The protective effect of Malva sylvestris on rat kidney damaged by vanadium

PubMed Central

2011-01-01

Background The protective effect of the common mallow (Malva sylvestris) decoction on renal damages in rats induced by ammonium metavanadate poisoning was evaluated. On the one hand, vanadium toxicity is associated to the production of reactive oxygen species, causing a lipid peroxidation and an alteration in the enzymatic antioxidant defence. On the other hand, many medicinal plants are known to possess antioxidant and radical scavenging properties, thanks to the presence of flavonoids. These properties were confirmed in Malva sylvestris by two separate methods; namely, the Diphenyl-2-picrylhydrazyl assay and the Nitroblue Tetrazolium reduction assay. Results In 80 rats exposed to ammonium metavanadate (0.24 mmol/kg body weight in drinking water) for 90 days, lipid peroxidation levels and superoxide dismutase, catalase and glutathione peroxidase activities were measured in kidney. A significant increase in the formation of free radicals and antioxidant enzyme activities was noticed. In addition, a histological examination of kidney revealed a structural deterioration of the renal cortical capsules and a shrinking of the Bowman space. In animals intoxicated by metavanadate but also given a Malva sylvestris decoction (0.2 g dry mallow/kg body weight), no such pathologic features were observed: lipid peroxidation levels, antioxidant enzyme activities and histological features appeared normal as compared to control rats. Conclusion Malva sylvestris is proved to have a high antioxidative potential thanks to its richness in phenolic compounds. PMID:21513564

Allograft update: the current status of tissue regulation, procurement, processing, and sterilization.

PubMed

McAllister, David R; Joyce, Michael J; Mann, Barton J; Vangsness, C Thomas

2007-12-01

Allografts are commonly used during sports medicine surgical procedures in the United States, and their frequency of use is increasing. Based on surgeon reports, it is estimated that more than 60 000 allografts were used in knee surgeries by members of the American Orthopaedic Society for Sports Medicine in 2005. In the United States, there are governmental agencies and other regulatory bodies involved in the oversight of tissue banks. In 2005, the Food and Drug Administration finalized its requirements for current good tissue practice and has mandated new rules regarding the "manufacture" of allogenic tissue. In response to well-publicized infections associated with the implantation of allograft tissue, some tissue banks have developed methods to sterilize allograft tissue. Although many surgeons have significant concerns about the safety of allografts, the majority believe that sterilized allografts are safe but that the sterilization process negatively affects tissue biology and biomechanics. However, most know very little about the principles of sterilization and the proprietary processes currently used in tissue banking. This article will review the current status of allograft tissue regulation, procurement, processing, and sterilization in the United States.

Bone allografting in children

NASA Astrophysics Data System (ADS)

Sadovoy, M. A.; Kirilova, I. A.; Podorognaya, V. T.; Matsuk, S. A.; Novoselov, V. P.; Moskalev, A. V.; Bondarenko, A. V.; Afanasev, L. M.; Gubina, E. V.

2017-09-01

A total of 522 patients with benign and intermediate bone tumors of various locations, aged 1 to 15 years, were operated in the period from 1996 to 2016. To diagnose skeleton tumors, we used clinical observation, X-ray, and, if indicated, tomography and tumor site biopsy. In the extensive bone resection, we performed bone reconstruction with the replacement of a defect with an allograft (bone strips, deproteinized and spongy grafts), sometimes in the combination with bone autografting. After segmental resection, the defects were filled with bone strips in the form of matchstick grafts; the allografts were received from the Laboratory for Tissue Preparation and Preservation of the Novosibirsk Research Institute of Traumatology and Orthopedics. According to the X-ray data, a complete reorganization of bone grafts occurred within 1.5 to 3 years. The long-term result was assessed as good.

VASCULARIZED COMPOSITE ALLOGRAFT TRANSPLANT SURVIVAL IN MINIATURE SWINE: IS MHC TOLERANCE SUFFICIENT FOR ACCEPTANCE OF EPIDERMIS?

PubMed Central

Cetrulo, Curtis L.; Torabi, Radbeh; Scalea, Joseph R.; Shimizu, Akira; Leto Barone, Angelo A.; Gillon, Brad C.; Tasaki, Masayuki; Leonard, David A.; Cormack, Taylor A.; Villani, Vincenzo; Randolph, Mark A.; Sachs, David H.; Yamada, Kazuhiko

2014-01-01

Background We have previously reported that MGH miniature swine which had accepted class-I mismatched kidneys long-term (LT) following 12 days of high dose Cyclosporine (CyA), uniformly accepted donor-MHC matched kidneys without immunosuppression but rejected donor-MHC matched split-thickness skin grafts (STSG) by day 25, without changes in renal graft function or anti-donor in vitro responses. We have now tested whether this “split tolerance” would also be observed for the primarily-vascularized skin of vascularized composite allografts (VCAs). Methods Group 1 animals (n=3) received donor-MHC matched VCAs <70 days following primary kidney transplant (KTx). Group 2 animals (n=3) received a second donor-matched t KTx followed by a donor-matched VCA >200 days after primary KTx. Results Animals in Group 1 lost the epidermis on days 28, 30, and 40, with all other components of the VCAs remaining viable. Histology showed cellular infiltration localized to dermal-epidermal junction. One of 3 recipients of VCAs including epidermis in Group 2 accepted all components of the VCAs (>200 days). The other two recipients lost only the epidermis at day 45 and 85, with survival of the remainder of the VCA long-term. Conclusions All tissues of a VCA are accepted long-term on animals tolerant of class-I mismatched kidneys, with the exception of epidermis, the survival of which is markedly prolonged compared to STSG, but not indefinite. Exposure of tolerant animals to second donor-matched kidneys prior to VCA increases the longevity of the VCA epidermis, suggesting an increase in the immunomodulatory mechanisms associated with tolerance of the kidney. PMID:24056624

History of osteochondral allograft transplantation.

PubMed

Nikolaou, V S; Giannoudis, P V

2017-07-01

Osteochondral defects or injuries represent the most challenging entities to treat, especially when occur to young and active patients. For centuries, it has been recognized that such defects are almost impossible to treat. However, surgeons have never stopped the effort to develop reliable methods to restore articular cartilage and salvage the endangered joint function. Osteochondral allograft transplantation in human was first introduced by Eric Lexer in 1908. Since that era, several pioneers have been worked in the field of osteochondral allotransplantation, presenting and developing the basic research, the methodology and the surgical techniques. Herein we present in brief, the history and the early clinical results of osteochondral allograft transplantation in human. Copyright © 2017 Elsevier Ltd. All rights reserved.

[The role of percutaneous renal biopsy in kidney transplant].

PubMed

Manfro, R C; Lee, J Y; Lewgoy, J; Edelweiss, M I; Gonçalves, L F; Prompt, C A

1994-01-01

Percutaneous renal biopsy (PRB) is an useful tool for diagnostic and therapeutic orientation in renal transplantation. PURPOSE--To evaluate the current role of PRB in post-transplant acute renal dysfunction (ARD) of renal allografts. METHODS--Sixty-five renal transplant patients were submitted to 95 valid renal biopsies with no major complications. RESULTS--There was disagreement between the clinical and the pathological diagnosis in 28 occasions (29.5%). In 36 cases (37.9%) the results of the pathological examination led to a modification in patient's management. These modifications were most commonly the avoidance or witholding of a steroid pulse (8 cases); nephrectomy of the renal allograft (8 cases); witholding or decrease of cyclosporine dosage (6 cases); giving a steroid pulse (5 cases) and giving antibiotics to treat acute pyelonephritis in 4 cases. The use of kidneys from cadaveric donors was significantly associated with an increased number of biopsies (p < 0.05). CONCLUSION--These results demonstrate that even though several less invasive procedures are currently employed, renal biopsy is still an indispensable method to the management of ARD in renal transplant patients.

Severe adult burn survivors. What information about skin allografts?

PubMed Central

Gaucher, Sonia; Duchange, Nathalie; Jarraya, Mohamed; Magne, Jocelyne; Rochet, Jean-Michel; Stéphanazzi, Jean; Hervé, Christian; Moutel, Grégoire

2013-01-01

Background and objective During the acute phase of a severe burn, surgery is an emergency. In this situation, human skin allografts constitute an effective temporary skin substitute. However, information about the use of human tissue can not be given to the patients because most of the allografted patients are unconscious due to their injury. Objective This study explored the restitution of information on skin donation to patients who have been skin allografted and who have survived their injury. Method A qualitative study was conducted due to the limited number of patients in ability to be interviewed according to our medical and psychological criteria. Results and discussion Twelve patients who had been treated between 2002 and 2008 were interviewed. Our results show that 10 of them ignored that they had received skin allografts. One of the two patients who knew that they had received allografts knew that skin had been harvested from deceased donor. All patients expressed that there is no information that should not be delivered. They also expressed their relief to have had the opportunity to discuss their case and at being informed during their interview. Their own experience impacted their view in favor of organ and tissue donation. PMID:23229877

Inability to determine tissue health is main indication of allograft use in intermediate extent burns.

PubMed

Fletcher, John L; Cancio, Leopoldo C; Sinha, Indranil; Leung, Kai P; Renz, Evan M; Chan, Rodney K

2015-12-01

Cutaneous allograft is commonly used in the early coverage of excised burns when autograft is unavailable. However, allograft is also applied in intermediate-extent burns (25-50%), during cases in which it is possible to autograft. In this population, there is a paucity of data on the indications for allograft use. This study explores the indications for allograft usage in moderate size burns. Under an IRB-approved protocol, patients admitted to our burn unit between March 2003 and December 2010 were identified through a review of the burn registry. Data on allograft use, total burn surface area, operation performed, operative intent, number of operations, intensive care unit length of stay, and overall length of stay were collected and analyzed. Data are presented as means±standard deviations, except where noted. In the study period, 146 patients received allograft during their acute hospitalization. Twenty-five percent of allograft recipients sustained intermediate-extent burns. Patients with intermediate-extent burns received allograft later in their hospitalization than those with large-extent (50-75% TBSA) burns (6.8 days vs. 3.4 days, p=0.01). Allografted patients with intermediate-extent burns underwent more operations (10.8 vs. 6.1, p=0.002) and had longer hospitalizations (78.3 days vs. 40.9 days, p<0.001) than non-allografted patients, when controlled for TBSA. Clinical rationale for placement of allograft in this population included autograft failure, uncertain depth of excision, lack of autograft donor site, and wound complexity. When uncertain depth of excision was the indication, allograft was universally applied onto the face. In half of allografted intermediate-extent burn patients the inability to identify a viable recipient bed was the ultimate reason for allograft use. Unlike large body surface area burns, allograft skin use in intermediate-extent injury occurs later in the hospitalization and is driven by the inability to determine wound bed

Autograft versus nonirradiated allograft tissue for anterior cruciate ligament reconstruction: a systematic review.

PubMed

Mariscalco, Michael W; Magnussen, Robert A; Mehta, Divyesh; Hewett, Timothy E; Flanigan, David C; Kaeding, Christopher C

2014-02-01

An autograft has traditionally been the gold standard for anterior cruciate ligament reconstruction (ACLR), but the use of allograft tissue has increased in recent years. While numerous studies have demonstrated that irradiated allografts are associated with increased failure rates, some report excellent results after ACLR with nonirradiated allografts. The purpose of this systematic review was to determine whether the use of nonirradiated allograft tissue is associated with poorer outcomes when compared with autografts. Patients undergoing ACLR with autografts versus nonirradiated allografts will demonstrate no significant differences in graft failure risk, laxity on postoperative physical examination, or differences in patient-oriented outcome scores. Systematic review. A systematic review was performed to identify prospective or retrospective comparative studies (evidence level 1, 2, or 3) of autografts versus nonirradiated allografts for ACLR. Outcome data included graft failure based on clinical findings and instrumented laxity, postoperative laxity on physical examination, and patient-reported outcome scores. Studies were excluded if they did not specify whether the allograft had been irradiated. Quality assessment and data extraction were performed by 2 examiners. Nine studies comparing autografts and nonirradiated allografts were included. Six of the 9 studies compared bone-patellar tendon-bone (BPTB) autografts with BPTB allografts. Two studies compared hamstring tendon autografts to hamstring tendon allografts, and 1 study compared hamstring tendon autografts to tibialis anterior allografts. The mean patient age in 7 of 9 studies ranged from 24.5 to 32 years, with 1 study including only patients older than 40 years and another not reporting patient age. The mean follow-up duration was 24 to 94 months. Six of 9 studies reported clinical graft failure rates, 8 of 9 reported postoperative instrumented laxity measurements, 7 of 9 reported postoperative

Antibody-Mediated Rejection of Single Class I MHC-Disparate Cardiac Allografts

PubMed Central

Hattori, Yusuke; Bucy, R. Pat; Kubota, Yoshinobu; Baldwin, William M.; Fairchild, Robert L.

2012-01-01

Murine CCR5−/− recipients produce high titers of antibody to complete MHC-mismatched heart and renal allografts. To study mechanisms of class I MHC antibody-mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild-type C57BL/6 (H-2b) and B6.CCR5−/− recipients. Donor-specific antibody titers in CCR5−/− recipients were 30-fold higher than in wild-type recipients. B6.Kd allografts survived longer than 60 days in wild-type recipients whereas CCR5−/− recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils, and macrophages and C4d deposition in the graft capillaries. B6.Kd allografts were rejected by CD8−/−/CCR5−/−, but not μMT−/−/CCR5−/−, recipients indicating the need for antibody but not CD8 T cells. Grafts retrieved at day 10 from CCR5−/− and CD8−/−/CCR5−/− recipients and from RAG-1−/− allograft recipients injected with anti-Kd antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of anti-donor class I MHC antibody can mediate allograft rejection, that donor-reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity. PMID:22578247

Induction of allograft tolerance through costimulatory blockade: first selection of drugs in vitro.

PubMed

Vierboom, Michel P M; Ossevoort, Miriam; Sick, Ella A; Haanstra, Krista; Jonker, Margreet

2003-01-01

The development of an in vitro assay predicting the chances of graft survival after treatment with immunoregulatory agents is a major topic in transplantation. Antibodies (Abs) interfering in the costimulatory pathway are promising candidates for the induction of tolerance. To evaluate these antibodies for clinical use studies non-human primates are the only feasible option due to species specificity of the antibodies. Peripheral blood mononuclear cells, isolated from a large panel of rhesus monkeys, were used in a unidirectional mixed lymphocyte reaction to evaluate the ability of antibodies blocking the costimulatory pathway, to affect both primary and secondary proliferative and cytolytic allospecific immune responses in vitro. These blocking antibodies were also used in protocols prolonging allograft survival in a life-supporting kidney allotransplant model in rhesus macaques. The ultimate aim is to establish a correlation between parameters obtained in vitro and the success of transplantation in vivo. The combination of anti-CD80 and anti-CD86 resulted in a complete abrogation of the primary alloresponse as measured in a proliferation assay. Adding anti-CD40 significantly reduced this inhibitory effect although the in vivo effects of this antibody have been shown to be beneficial. The secondary response was most prominently inhibited by the combination of anti-CD80/86. Paradoxically, anti-CD40 alone markedly inhibited the secondary proliferative response, but did not add to the inhibitory effect of the combination of anti-CD80/86. The cytolytic response was inhibited maximally only when CsA was added to the combination of anti-CD80/86. Treatment with monoclonal antibodies alone without immunosuppressive drugs was sufficient to maintain graft survival during the time of treatment in most animals. However, rejection was initiated as soon as the treatment ceased and no tolerance, resulting in long-term graft and patient survival, was established. The complete

Kidney transplantation from a mother with unrecognized Fabry disease to her son with low α-galactosidase A activity: A 14-year follow-up without enzyme replacement therapy.

PubMed

Odani, Keiko; Okumi, Masayoshi; Honda, Kazuho; Ishida, Hideki; Tanabe, Kazunari

2016-07-01

We report a case of kidney transplantation from mother to son, both of whom were likely to have had an unrecognized renal variant phenotype of Fabry disease. The patient was a 54-year-old man, with an unknown primary cause of end stage renal disease. He had no notable past medical history, other than end stage renal disease. He underwent living-related kidney transplantation from his mother at age 40 years. Foam cells in the glomeruli were identified on histology assessment of a 0-hour allograft biopsy, with zebra bodies identified in the glomerular visceral epithelial cells by electron microscopy. These findings were indicative of Fabry disease in the donated kidney. As a definitive diagnosis of Fabry's disease could not be confirmed, enzyme replacement therapy was not initiated. Thirteen years after kidney transplantation, the patient underwent left nephrectomy for a left renal tumour, with pathological findings of clear cell carcinoma, foam cells and zebra bodies in the native kidney. Detailed examinations identified low α-galactosidase A activity and mutation of the α-Gal A gene, confirming a diagnosis of a renal variant phenotype of Fabry disease. Histology of several allograft biopsies performed over the 14 years from the time of kidney transplantation revealed only moderate interstitial fibrosis and tubular atrophy, with no evidence of disease progression on electron microscopy, despite the presence of zebra bodies in the glomerular visceral epithelial cells. © 2016 Asian Pacific Society of Nephrology.

Renal transplantation induces mitochondrial uncoupling, increased kidney oxygen consumption, and decreased kidney oxygen tension.

PubMed

Papazova, Diana A; Friederich-Persson, Malou; Joles, Jaap A; Verhaar, Marianne C

2015-01-01

Hypoxia is an acknowledged pathway to renal injury and ischemia-reperfusion (I/R) and is known to reduce renal oxygen tension (Po2). We hypothesized that renal I/R increases oxidative damage and induces mitochondrial uncoupling, resulting in increased oxygen consumption and hence kidney hypoxia. Lewis rats underwent syngenic renal transplantation (TX) and contralateral nephrectomy. Controls were uninephrectomized (1K-CON) or left untreated (2K-CON). After 7 days, urinary excretion of protein and thiobarbituric acid-reactive substances were measured, and after 14 days glomerular filtration rate (GFR), renal blood flow, whole kidney Qo2, cortical Po2, kidney cortex mitochondrial uncoupling, renal oxidative damage, and tubulointerstitial injury were assessed. TX, compared with 1K-CON, resulted in mitochondrial uncoupling mediated via uncoupling protein-2 (16 ± 3.3 vs. 0.9 ± 0.4 pmol O2 · s(-1)· mg protein(-1), P < 0.05) and increased whole kidney Qo2 (55 ± 16 vs. 33 ± 10 μmol O2/min, P < 0.05). Corticomedullary Po2 was lower in TX compared with 1K-CON (30 ± 13 vs. 47 ± 4 μM, P < 0.05) whereas no significant difference was observed between 2K-CON and 1K-CON rats. Proteinuria, oxidative damage, and the tubulointerstitial injury score were not significantly different in 1K-CON and TX. Treatment of donors for 5 days with mito-TEMPO reduced mitochondrial uncoupling but did not affect renal hemodynamics, Qo2, Po2, or injury. Collectively, our results demonstrate increased mitochondrial uncoupling as an early event after experimental renal transplantation associated with increased oxygen consumption and kidney hypoxia in the absence of increases in markers of damage. Copyright © 2015 the American Physiological Society.

Hyperhomocysteinemia and protein damage in chronic renal failure and kidney transplant pediatric patients--Italian initiative on uremic hyperhomocysteinemia (IIUH).

PubMed

Perna, Alessandra F; Ingrosso, Diego; Molino, Daniela; Galletti, Patrizia; Montini, Giovanni; Zacchello, Graziella; Bellantuono, Rosa; Caringella, Angela; Fede, Carmelo; Chimenz, Roberto; De Santo, Natale G

2003-01-01

Plasma homocysteine, a new cardiovascular risk factor in both children and adults, is higher in chronic renal failure or kidney transplant patients. This alteration has been linked, in chronic renal failure, to plasma protein damage, represented by increased L-isoaspartyl residues. We measured plasma homocysteine levels and plasma protein damage in pediatric patients from four different Italian regions with conservatively treated renal failure; hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), or transplants, to establish the presence of protein damage and the relative role of hyperhomocysteinemia. High performance liquid chromatography (HPLC) separation measured total plasma homocysteine levels, using precolumn derivatization with ammonium 7-fluorobenzo-2-oxa-1, 3-diazole-4-sulphonate (SBD-F). Plasma protein L-isoaspartyl residues were quantitated using human recombinant protein carboxyl methyl transferase (PCMT). In all patient groups, homocysteine levels were significantly higher with respect to the control (Control: 6.87 +/- 0.73 microM) conservatively treated, 14.19 +/- 1.73 microM; hemodialysis, 27.03 +/- 4.32 microM; CAPD, 22.38 +/- 3.73 microM; transplanted, 20.22 +/- 2.27 microM, p < 0.001 vs. control]. Plasma protein damage was significantly higher in conservatively treated, hemodialysis (HD) and CAPD patients, while in transplant patients it was no different from the control. We concluded that in pediatric patients of different Italian geographical origin, plasma homocysteine levels were significantly higher in all groups with respect to healthy children; therefore contributing to the elevated cardiovascular risk present in these patients. Plasma protein L-isoaspartyl content was higher in renal failure patients, but kidney transplant patients had normal levels, indicating that this kind of protein damage relates more to the toxic action of uremic retention solutes, than to plasma homocysteine levels.

Selenium deficiency induced damages and altered expressions of metalloproteinases and their inhibitors (MMP1/3, TIMP1/3) in the kidneys of growing rats.

PubMed

Han, Jing; Liang, Hua; Yi, Jianhua; Tan, Wuhong; He, Shulan; Wu, Xiaofang; Shi, Xiaowei; Ma, Jing; Guo, Xiong

2016-03-01

Selenium is an essential trace element for the maintenance of structures and functions of kidney. To evaluate the effects of low selenium on the kidneys of growing rats, newborn rats were fed with selenium deficient and normal diets respectively for 109 days. As a result, rats fed with low selenium diets resulted in a decline in the body weight and the concentration of selenium in the kidney, especially the male rats from the low selenium groups. Moreover, the ultrastructure of glomerulus and tubules were damaged in low selenium group: the glomeruli were observed with hyperplasia of mesangial cells, fusion of podocyte foot processes and thickening of basement membrane; and the tubules were observed with vacuolar degenerated epithelial cells, increased edema fluid or protein solution between cells, microvilli edema, increased cell gaps and decreased cell links. Furthermore, the pathological changes in selenium deficient group included the increase of fibers around renal hilum aorta and in the renal collecting duct, and shed of cells in the proximal convoluted tubules. In addition, up-regulated expressions of matrix metalloproteinases (MMP1/3) and down-regulated expressions of their inhibitors (TIMP1/3) at the mRNA and protein levels were also appeared to be relevant to low selenium. The results suggested that low selenium in diet may cause low selenium concentration in the kidney of growing rat and lead to damages of the ultrastructure and extracellular matrix (ECM) of kidney. Copyright © 2015 Elsevier GmbH. All rights reserved.

Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation

PubMed Central

Dedeoglu, Burç; Meijers, Ruud W. J.; Klepper, Mariska; Hesselink, Dennis A.; Baan, Carla C.; Litjens, Nicolle H. R.; Betjes, Michiel G. H.

2016-01-01

Background End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR). Methods 222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31+ naive T cells were determined as T-cell ageing parameters. Results Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4+CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8+CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4+CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001). Conclusion Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR. PMID:26950734

Estimating the usage of allograft in the treatment of major burns.

PubMed

Horner, C W M; Atkins, J; Simpson, L; Philp, B; Shelley, O; Dziewulski, P

2011-06-01

To assess the amount of allograft used in the past treatment of major burns and calculate a figure to guide estimation of the quantity of allograft required to treat future patients and aid resource planning. A retrospective observational study. Records of 143 patients treated with major burns at a regional centre, from January 2004 to November 2008 were accessed with biometric data and quantity of allograft used being recorded. This data was used to calculate an allograft index (cm² allograft used/burn surface area (cm²)) (AI) for each patient. 112 of the 143 patients had complete sets of data, of the 112, 89 patients survived the initial stay in hospital. For all data average AI=1.077 ± 0.090. AI varied according to burn % area with burns < 40% requiring 0.490 cm² allo/cm²burn, increasing in a logarithmic fashion (R²=0.995) for burn areas > 40%. The ability to estimate deceased donor skin requirements based on % body surface area affected is important in the care planning for patients with major burns. Our findings of 0.5 cm² allograft/cm² burn for injuries less than 40% TBSA, increasing to 1.82 cm² allograft/cm² burn for injuries up to 80% TBSA can be used for planning purposes for individual services and for burn disaster planning. Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.

Combining Functional and Tubular Damage Biomarkers Improves Diagnostic Precision for Acute Kidney Injury After Cardiac Surgery

PubMed Central

Basu, Rajit K.; Wong, Hector R.; Krawczeski, Catherine D.; Wheeler, Derek S.; Manning, Peter B.; Chawla, Lakhmir S.; Devarajan, Prasad; Goldstein, Stuart L.

2015-01-01

BACKGROUND Increases in serum creatinine (ΔSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication. OBJECTIVES This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI. METHODS Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (>100% ΔSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline ≤48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to ΔSCr increases of ≤50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values. RESULTS Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than ΔSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL−/pCysC+ composite was superior to ΔSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than ΔSCr strata. CONCLUSIONS Composites of functional and tubular damage biomarkers are superior to ΔSCr for predicting discrete characteristics of AKI. PMID:25541128

Automatic allograft bone selection through band registration and its application to distal femur.

PubMed

Zhang, Yu; Qiu, Lei; Li, Fengzan; Zhang, Qing; Zhang, Li; Niu, Xiaohui

2017-09-01

Clinical reports suggest that large bone defects could be effectively restored by allograft bone transplantation, where allograft bone selection acts an important role. Besides, there is a huge demand for developing the automatic allograft bone selection methods, as the automatic methods could greatly improve the management efficiency of the large bone banks. Although several automatic methods have been presented to select the most suitable allograft bone from the massive allograft bone bank, these methods still suffer from inaccuracy. In this paper, we propose an effective allograft bone selection method without using the contralateral bones. Firstly, the allograft bone is globally aligned to the recipient bone by surface registration. Then, the global alignment is further refined through band registration. The band, defined as the recipient points within the lifted and lowered cutting planes, could involve more local structure of the defected segment. Therefore, our method could achieve robust alignment and high registration accuracy of the allograft and recipient. Moreover, the existing contour method and surface method could be unified into one framework under our method by adjusting the lift and lower distances of the cutting planes. Finally, our method has been validated on the database of distal femurs. The experimental results indicate that our method outperforms the surface method and contour method.

Arthroscopic single-bundle anterior cruciate ligament reconstruction with six-strand hamstring tendon allograft versus bone-patellar tendon-bone allograft.

PubMed

Dai, Chengliang; Wang, Fei; Wang, Xiaomeng; Wang, Ruipeng; Wang, Shengjie; Tang, Shiyu

2016-09-01

The aim of this study was to compare the clinical outcomes of arthroscopic single-bundle anterior cruciate ligament (ACL) reconstruction with six-strand hamstring tendon (HT) allograft versus bone-patellar tendon-bone (BPTB) allograft. The prospective randomized controlled trial was included 129 patients. Sixty-nine patients received reconstruction with six-strand HT allografts (HT group), whereas 60 patients with BPTB allografts (BPTB group). Outcome assessment included re-rupture findings, International Knee Documentation Committee (IKDC) scores, Lysholm scores, KT-1000 arthrometer, Lachman test, pivot-shift test, range of motion (ROM) and single-leg hop test. At a mean follow-up of 52 months, 113 patients (HT group, 61 patients; BPTB group, 52 patients) completed a minimum 4-year follow-up. Four patients in HT group and six in BPTB group experienced ACL re-rupture (6.2 vs. 10.3 %) and received revision surgery. Significant between-group differences were observed in KT-1000 outcomes and pivot-shift test 1 (1.2 ± 1.5 vs. 1.8 ± 1.3, p = 0.025; positive rate 6.5 vs. 18.9 %, p = 0.036), 2 (1.1 ± 1.4 vs. 1.6 ± 1.2, p = 0.044; 8.1 vs. 20.7 %, p = 0.039), 4 (1.1 ± 1.5 vs. 1.7 ± 1.4, p = 0.031; 9.7 vs. 25 %, p = 0.012) years postoperatively. The outcomes between the two groups were comparable in terms of IKDC scores, Lysholm scores, Lachman test, ROM and single-leg hop test. Six-strand HT allograft achieved superior anteroposterior and rotational stability after single-bundle ACL reconstruction. It is a reasonable graft substitute for ACL reconstruction. II.

Tenofovir-induced kidney injury.

PubMed

Gitman, Michael D; Hirschwerk, David; Baskin, Cindy H; Singhal, Pravin C

2007-03-01

Tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor with activity against both HIV and the hepatitis B virus. It has had minimal nephrotoxic effects in early clinical trials, but as clinical use has widened, case reports describing tenofovir-induced renal tubular damage, Fanconi's syndrome and diabetes insipidus have been described. The authors review the pharmacokinetics, mechanism of action and clinical uses of tenofovir disoproxil fumarate. The large clinical trials, as well as the case reports of tenofovir-induced kidney injury, are also reviewed. The potential mechanism of renal damage is discussed and recommendations for evaluation and treatment of tenofovir-induced kidney injury are given.

IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES IN THE KIDNEYS OF GROWTH HORMONE TRANSGENIC MICE

PubMed Central

Coschigano, K.T.; Wetzel, A.N.; Obichere, N.; Sharma, A.; Lee, S.; Rasch, R.; Guigneaux, M.M.; Flyvbjerg, A.; Wood, T.G.; Kopchick, J.J.

2010-01-01

Objective Bovine growth hormone (bGH) transgenic mice develop severe kidney damage. This damage may be due, at least in part, to changes in gene expression. Identification of genes with altered expression in the bGH kidney may identify mechanisms leading to damage in this system that may also be relevant to other models of kidney damage. Design cDNA subtraction libraries, northern blot analyses, microarray analyses and real-time reverse transcription polymerase chain reaction (RT/PCR) assays were used to identify and verify specific genes exhibiting differential RNA expression between kidneys of bGH mice and their non-transgenic (NT) littermates. Results Immunoglobulins were the vast majority of genes identified by the cDNA subtractions and the microarray analyses as being up-regulated in bGH. Several glycoprotein genes and inflammation-related genes also showed increased RNA expression in the bGH kidney. In contrast, only a few genes were identified as being significantly down-regulated in the bGH kidney. The most notable decrease in RNA expression was for the gene encoding kidney androgen-regulated protein. Conclusions A number of genes were identified as being differentially expressed in the bGH kidney. Inclusion of two groups, immunoglobulins and inflammation-related genes, suggests a role of the immune system in bGH kidney damage. PMID:20655258

Kidney Disease and the Nexus of Chronic Kidney Disease and Acute Kidney Injury: The Role of Novel Biomarkers as Early and Accurate Diagnostics.

PubMed

Yerramilli, Murthy; Farace, Giosi; Quinn, John; Yerramilli, Maha

2016-11-01

Chronic kidney disease (CKD) and acute kidney injury (AKI) are interconnected and the presence of one is a risk for the other. CKD is an important predictor of AKI after exposure to nephrotoxic drugs or major surgery, whereas persistent or repetitive injury could result in the progression of CKD. This brings new perspectives to the diagnosis and monitoring of kidney diseases highlighting the need for a panel of kidney-specific biomarkers that reflect functional as well as structural damage and recovery, predict potential risk and provide prognosis. This article discusses the kidney-specific biomarkers, symmetric dimethylarginine (SDMA), clusterin, cystatin B, and inosine. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessment of nerve regeneration across nerve allografts treated with tacrolimus.

PubMed

Haisheng, Han; Songjie, Zuo; Xin, Li

2008-01-01

Although regeneration of nerve allotransplant is a major concern in the clinic, there have been few papers quantitatively assessing functional recovery of animals' nerve allografts in the long term. In this study, functional recovery, histopathological study, and immunohistochemistry changes of rat nerve allograft with FK506 were investigated up to 12 weeks without slaughtering. C57 and SD rats were used for transplantation. The donor's nerve was sliced and transplanted into the recipient. The sciatic nerve was epineurally sutured with 10-0 nylon. In total, 30 models of transplantation were performed and divided into 3 groups that were either treated with FK506 or not. Functional recovery of the grafted nerve was serially assessed by the pin click test, walking track analysis and electrophysiological evaluations. A histopathological study and immunohistochemistry study were done in the all of the models. Nerve allografts treated with FK506 have no immune rejection through 12 weeks. Sensibility had similarly improved in both isografts and allografts. There has been no difference in each graft. Walk track analysis demonstrates significant recovery of motor function of the nerve graft. No histological results of difference were found up to 12 weeks in each graft. In the rodent nerve graft model, FK506 prevented nerve allograft rejection across a major histocompatibility barrier. Sensory recovery seems to be superior to motor function. Nerve isograft and allograft treated with FK506 have no significant difference in function recovery, histopathological result, and immunohistochemistry changes.

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

PubMed Central

Krupnick, Alexander Sasha; Lin, Xue; Li, Wenjun; Higashikubo, Ryuiji; Zinselmeyer, Bernd H.; Hartzler, Hollyce; Toth, Kelsey; Ritter, Jon H.; Berezin, Mikhail Y.; Wang, Steven T.; Miller, Mark J.; Gelman, Andrew E.; Kreisel, Daniel

2014-01-01

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8+ T cells (CD44hiCD62LhiCCR7+). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8+ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8+ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung. PMID:24569377

Allograft reconstruction after resection of malignant tumors of the scapula.

PubMed

Mnaymneh, Walid A; Temple, H Thomas; Malinin, Theodore I

2002-12-01

The oncologic and functional outcomes of six patients who had scapular allograft reconstruction after scapulectomy for malignant tumors were reviewed. Five patients had Stage IIB and one patient had Stage IB tumors. Total scapulectomy was done in five patients, and partial scapulectomy (glenoid and neck) was done in one patient. Frozen glycerolized scapular allografts were implanted and fixed with plates and screws. The scapular muscles were reattached to the allograft. Tendon reconstruction to replace the excised muscles was done in two patients. The patients were followed up for an average of 3.8 years (range, 2-6 years). Cosmesis, elbow, and hand function were good in all patients. There were no infections, nonunions, or shoulder dislocations. One patient fractured the body of the allograft after a fall. One patient had local recurrence and had scapulectomy 5 years postoperatively. Two patients died 3 and 5 years postoperatively with lung metastases but with functioning grafts. The mean functional result using the Musculoskeletal Tumor Society functional score was 82 (range, 77-87). In this series, scapular allograft reconstruction restored cosmesis, shoulder stability, and function. Preservation or reconstruction of rotator cuff muscles is recommended.

Imaging mouse lung allograft rejection with 1H MRI

PubMed Central

Guo, Jinbang; Huang, Howard J.; Wang, Xingan; Wang, Wei; Ellison, Henry; Thomen, Robert P.; Gelman, Andrew E.; Woods, Jason C.

2014-01-01

Purpose To demonstrate that longitudinal, non-invasive monitoring via MRI can characterize acute cellular rejection (ACR) in mouse orthotopic lung allografts. Methods Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig vs anti-CD4/anti-CD8 treated groups. A two-dimensional multi-slice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at post-operative days 3, 7 and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. Results Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 post transplantation (0.046→0.789, P < 0.05), despite large inter-mouse variations; this was consistent with histopathologic evidence of rejection. Compliance of the control-Ig allograft decreased significantly over time (0.013→0.003, P < 0.05), but remained constant in mice treated with anti-CD4/anti-CD8 antibodies. Conclusion Lung allograft rejection in individual mice can be monitored by lung parenchymal signal changes and by lung compliance through MRI. Longitudinal imaging can help us better understand the time course of individual lung allograft rejection and response to treatment. PMID:24954886

Imaging mouse lung allograft rejection with (1)H MRI.

PubMed

Guo, Jinbang; Huang, Howard J; Wang, Xingan; Wang, Wei; Ellison, Henry; Thomen, Robert P; Gelman, Andrew E; Woods, Jason C

2015-05-01

To demonstrate that longitudinal, noninvasive monitoring via MRI can characterize acute cellular rejection in mouse orthotopic lung allografts. Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig versus anti-CD4/anti-CD8 treated groups. A two-dimensional multislice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at postoperative days 3, 7, and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 posttransplantation (0.046→0.789; P < 0.05), despite large intermouse variations; this was consistent with histopathologic evidence of rejection. Compliance of the control-Ig allograft decreased significantly over time (0.013→0.003; P < 0.05), but remained constant in mice treated with anti-CD4/anti-CD8 antibodies. Lung allograft rejection in individual mice can be monitored by lung parenchymal signal changes and by lung compliance through MRI. Longitudinal imaging can help us better understand the time course of individual lung allograft rejection and response to treatment. © 2014 Wiley Periodicals, Inc.

Endogenous Memory CD8 T Cells Directly Mediate Cardiac Allograft Rejection

PubMed Central

Su, C. A.; Iida, S.; Abe, T.; Fairchild, R. L.

2014-01-01

Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pre-transplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen, or adoptive transfer of donor-antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor-reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming. PMID:24502272

Involvement of dendritic cells in allograft rejection new implications of dendritic cell-endothelial cell interactions.

PubMed

Schlichting, C L; Schareck, W D; Kofler, S; Weis, M

2007-04-01

For almost half a century immunologists have tried to tear down the MHC barrier, which separates two unrelated individuals during transplantation. Latest experimental data suggest that a breakthrough in vitro is imminent. Dendritic cells (DCs), which activate naïve allo-reactive T-cells (TCs), play a central role in the establishment of allo-antigen-specific immunity. Allograft solid organ rejection is initiated at the foreign endothelial cell (EC) layer, which forms an immunogenic barrier for migrating DCs. Thus, DC/EC interactions might play a crucial role in antigen-specific allograft rejection. Organ rejection is mediated by host allo-reactive TCs, which are activated by donor DCs (direct activation) or host DCs (indirect activation). Direct allo-antigen presentation by regulatory dendritic cells (DCreg) can play an instructive role towards tolerance induction. Several groups established that, DCregs, if transplanted beforehand, enter host thymus, spleen, or bone marrow where they might eventually establish allo-antigen-specific tolerance. A fundamental aspect of DC function is migration throughout the entire organism. After solid organ transplantation, host DCs bind to ECs, invade allograft tissues, and finally transmigrate into lymphoid vessels and secondary lymphoid organs, where they present allo-antigens to naïve host TCs. Recent data suggest that in vitro manipulated DCregs may mediate allo-transplantation tolerance induction. However, the fundamental mechanisms on how such DCregs cause host TCs in the periphery towards tolerance remain unclear. One very promising experimental concept is the simultaneous manipulation of DC direct and indirect TC activation/suppression, towards donor antigen-specific allo-transplantation tolerance. The allo-antigen-specific long-term tolerance induction mediated by DCreg pre-transplantation (with simultaneous short-term immunosuppression) has become reproducible in the laboratory animal setting. Despite the shortcomings

Acute allograft failure in thoracic organ transplantation.

PubMed

Jahania, M S; Mullett, T W; Sanchez, J A; Narayan, P; Lasley, R D; Mentzer, R M

2000-01-01

Thoracic organ transplantation is an effective form of treatment for end-stage heart and lung disease. Despite major advances in the field, transplant patients remain at risk for acute allograft dysfunction, a major cause of early and late mortality. The most common causes of allograft failure include primary graft failure secondary to inadequate heart and lung preservation during cold storage, cellular rejection, and various donor-recipient-related factors. During cold storage and early reperfusion, heart and lung allografts are vulnerable to intracellular calcium overload, acidosis, cell swelling, injury mediated by reactive oxygen species, and the inflammatory response. Brain death itself is associated with a reduction in myocardial contractility, and recipient-related factors such as preexisting pulmonary hypertension can lead to acute right heart failure and the pulmonary reimplantation response. The development of new methods to prevent or treat these various causes of acute graft failure could lead to a marked improvement in short- and long-term survival of patients undergoing thoracic organ transplantation.

Is Kidney Transplantation a Better State of CKD? Impact on Diagnosis and Management.

PubMed

Parajuli, Sandesh; Clark, Dana F; Djamali, Arjang

2016-09-01

Patients with CKD are at increased risk for cardiovascular events, hospitalizations, and mortality. Kidney transplantation (KTx) is the preferred treatment for end-stage kidney disease. Although comorbidities including anemia and bone and mineral disease improve or are even halted after KTx, kidney transplant recipients carry higher cardiovascular mortality risk than the general population, as well as an increased risk of infections, malignancies, fractures, and obesity. When comparing CKD with CKD after transplantation (CKD-T), the rate of decline of estimated glomerular filtration rate (eGFR) is significantly lower in CKD-T. Higher rate of decline of eGFR has been associated with increased risk of mortality. However, due to the significant increased risk of mortality due to cardiovascular events, infections, and malignancies, many kidney transplant recipients may not benefit of decline in the rate of eGFR. Patients with CKD-T are a unique subset of patients with multiple traditional and transplant-specific risk factors. Proper management and appropriate preventive health measures may improve long-term patient and allograft survival in patients with CKD-T. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Cost effectiveness of meniscal allograft for torn discoid lateral meniscus in young women.

PubMed

Ramme, Austin J; Strauss, Eric J; Jazrawi, Laith; Gold, Heather T

2016-09-01

A discoid meniscus is more prone to tears than a normal meniscus. Patients with a torn discoid lateral meniscus are at increased risk for early onset osteoarthritis requiring total knee arthroplasty (TKA). Optimal management for this condition is controversial given the up-front cost difference between the two treatment options: the more expensive meniscal allograft transplantation compared with standard partial meniscectomy. We hypothesize that meniscal allograft transplantation following excision of a torn discoid lateral meniscus is more cost-effective compared with partial meniscectomy alone because allografts will extend the time to TKA. A decision analytic Markov model was created to compare the cost effectiveness of two treatments for symptomatic, torn discoid lateral meniscus: meniscal allograft and partial meniscectomy. Probability estimates and event rates were derived from the scientific literature, and costs and benefits were discounted by 3%. One-way sensitivity analyses were performed to test model robustness. Over 25 years, the partial meniscectomy strategy cost $10,430, whereas meniscal allograft cost on average $4040 more, at $14,470. Partial meniscectomy postponed TKA an average of 12.5 years, compared with 17.30 years for meniscal allograft, an increase of 4.8 years. Allograft cost $842 per-year-gained in time to TKA. Meniscal allografts have been shown to reduce pain and improve function in patients with discoid lateral meniscus tears. Though more costly, meniscal allografts may be more effective than partial meniscectomy in delaying TKA in this model. Additional future long term clinical studies will provide more insight into optimal surgical options.

Osteoinductive effect of bone bank allografts on human osteoblasts in culture.

PubMed

de la Piedra, Concepción; Vicario, Carlos; de Acuña, Lucrecia Rodríguez; García-Moreno, Carmen; Traba, Maria Luisa; Arlandis, Santiago; Marco, Fernando; López-Durán, Luis

2008-02-01

Incorporation of a human bone allograft requires osteoclast activity and growth of recipient osteoblasts. The aim of this work was to study the effects produced by autoclavated and -80 degrees C frozen bone allografts on osteoblast proliferation and synthesis of interleukin 6 (IL6), activator of bone resorption, aminoterminal propeptide of procollagen I (PINP), marker of bone matrix formation, and osteoprotegerin (OPG), inhibitor of osteoclast activity and differentiation. Allografts were obtained from human femoral heads. Human osteoblasts were cultured in the presence (problem group) or in the absence (control group) of allografts during 15 days. Allografts produced a decrease in osteoblast proliferation in the first week of the experiment, and an increase in IL6 mRNA, both at 3 h and 2 days, and an increase in the IL6 released to the culture medium the second day of the experiment. We found a decrease in OPG released to the culture on the 2nd and fourth days. These results suggest an increase in bone resorption and a decrease in bone formation in the first week of the experiment. In the second week, allografts produced an increase in osteoblast proliferation and PINP release to the culture medium, indicating an increase in bone formation; an increase in OPG released to the culture medium, which would indicate a decrease in bone resorption; and a decrease in IL6, indicating a decrease in bone resorption stimulation. These results demonstrate that autoclavated and -80 degrees C frozen bone allografts produce in bone environment changes that regulate their own incorporation to the recipient bone.

Acoustic radiation force impulse (ARFI) elastography for detection of renal damage in children.

PubMed

Göya, Cemil; Hamidi, Cihad; Ece, Aydın; Okur, Mehmet Hanifi; Taşdemir, Bekir; Çetinçakmak, Mehmet Güli; Hattapoğlu, Salih; Teke, Memik; Şahin, Cahit

2015-01-01

Acoustic radiation force impulse (ARFI) imaging is a promising method for noninvasive evaluation of the renal parenchyma. To investigate the contribution of ARFI quantitative US elastography for the detection of renal damage in kidneys with and without vesicoureteral reflux (VUR). One hundred seventy-six kidneys of 88 children (46 male, 42 female) who had been referred for voiding cystourethrography and 20 healthy controls were prospectively investigated. Patients were assessed according to severity of renal damage on dimercaptosuccinic acid (DMSA) scintigraphy. Ninety-eight age- and gender-matched healthy children constituted the control group. Quantitative shear wave velocity (SWV) measurements were performed in the upper and lower poles and in the interpolar region of each kidney. DMSA scintigraphy was performed in 62 children (124 kidneys). Comparisons of SWV values of kidneys with and without renal damage and/or VUR were done. Significantly higher SWV values were found in non-damaged kidneys. Severely damaged kidneys had the lowest SWV values (P < 0.001). High-grade (grade V-IV) refluxing kidneys had the lowest SWV values, while non-refluxing kidneys had the highest values (P < 0.05). Significant negative correlations were found between the mean quantitative US elastography values and DMSA scarring score (r = -0.788, P < 0.001) and VUR grade (r = -0.634, P < 0.001). SWV values of the control kidneys were significantly higher than those of damaged kidneys (P < 0.05). Our findings suggest decreasing SWV of renal units with increasing grades of vesicoureteric reflux, increasing DMSA-assessed renal damage and decreasing DMSA-assessed differential function.