5-Year outcomes of the prospective and randomized CISTCERT study comparing steroid withdrawal to replacement of cyclosporine with everolimus in de novo kidney transplant patients.

Withdrawal of either steroids or calcineurin inhibitors are two strategies to reduce treatment-related side effects and improve long-term outcomes of kidney transplantation. The CISTCERT study compared the efficacy and safety of these two strategies. In this multicenter, randomized controlled trial, 151 incident kidney transplant recipients received cyclosporine (CsA), mycophenolic acid (MPA), and steroids during three months, followed by either steroid withdrawal (CsA/MPA) or replacement of cyclosporine with everolimus (EVL) (EVL/MPA/steroids). 5-year patient survival (89% vs. 86%; P = NS) and death-censored graft survival (95% vs. 96%; P = NS) were comparable in the CsA/MPA and EVL/MPA/steroids arm, respectively. 51 CrEDTA clearance was comparable in the intention-to-treat analysis, but in the on-treatment population, the EVL/MPA/steroids arm exhibited a superior 51 CrEDTA clearance at 1 and 5 years after transplantation (61.6 vs. 52.4, P = 0.05 and 59.1 vs. 46.2ml/min/1.73 m2 , P = 0.042). Numerically more and more severe rejections were observed in the EVL/MPA/steroids arm, which also experienced a higher incidence of posttransplant diabetes (26% vs. 6%, P = 0.0016) and infections. No significant differences were observed in cardiovascular outcomes and malignancy. Both regimens provide an excellent long-term patient survival and graft survival. Regarding graft function, EVL/MPA/steroids is an attractive strategy for patients with good tolerability who remain free of rejection. (ClinicalTrials.gov number: NCT00903188; EudraCT Number 2007-005844-26).

The use of plasma donor-derived, cell-free DNA to monitor acute rejection after kidney transplantation.

BACKGROUND: After transplantation, cell-free deoxyribonucleic acid (DNA) derived from the donor organ (ddcfDNA) can be detected in the recipient's circulation. We aimed to investigate the role of plasma ddcfDNA as biomarker for acute kidney rejection. METHODS: From 107 kidney transplant recipients, plasma samples were collected longitudinally after transplantation (Day 1 to 3 months) within a multicentre set-up. Cell-free DNA from the donor was quantified in plasma as a fraction of the total cell-free DNA by next generation sequencing using a targeted, multiplex polymerase chain reaction-based method for the analysis of single nucleotide polymorphisms. RESULTS: Increases of the ddcfDNA% above a threshold value of 0.88% were significantly associated with the occurrence of episodes of acute rejection (P = 0.017), acute tubular necrosis (P = 0.011) and acute pyelonephritis (P = 0.032). A receiver operating characteristic curve analysis revealed an equal area under the curve of the ddcfDNA% and serum creatinine of 0.64 for the diagnosis of acute rejection. CONCLUSIONS: Although increases in plasma ddcfDNA% are associated with graft injury, plasma ddcfDNA does not outperform the diagnostic capacity of the serum creatinine in the diagnosis of acute rejection.

Does Kidney Donor Risk Index implementation lead to the transplantation of more and higher-quality donor kidneys?

BACKGROUND: The Kidney Donor Risk Index (KDRI) is a quantitative evaluation of the quality of donor organs and is implemented in the US allocation system. This single-centre study investigates whether the implementation of the KDRI in our decision-making process to accept or decline an offered deceased donor kidney, increases our acceptance rate. METHODS: From April 2015 until December 2016, we prospectively calculated the KDRI for all deceased donor kidney offers allocated by Eurotransplant to our centre. The number of the transplanted versus declined kidney offers during the study period were compared to a historical set of donor kidney offers. RESULTS: After implementation of the KDRI, 26.1% (75/288) of all offered donor kidneys were transplanted, compared with 20.7% (136/657) in the previous period (P < 0.001). The median KDRI of all transplanted donor kidneys during the second period was 0.97 [Kidney Donor Profile Index (KDPI) 47%], a value significantly higher than the median KDRI of 0.85 (KDPI 34%) during the first period (P = 0.047). A total of 68% of patients for whom a first-offered donor kidney was declined during this period were transplanted after a median waiting time of 386 days, mostly with a lower KDRI donor kidney. CONCLUSIONS: Implementing the KDRI in our decision-making process increased the transplantation rate by 26%. The KDRI can be a supportive tool when considering whether to accept or decline a deceased donor kidney offer. More data are needed to validate this score in other European centres.

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.

Magnesium loss in cyclosporine-treated patients is related to renal epidermal growth factor downregulation.

BACKGROUND: Cyclosporine (CsA) treatment is associated with hypomagnesaemia due to a renal Mg(2+) leak. In animal studies a role for the Mg(2+) channel TRPM6 localized in the distal convoluted tubule and stimulated by epidermal growth factor (EGF) is suggested. We hypothesize that CsA-induced hypomagnesaemia is due to a renal magnesium leak, also in patients, resulting from a downregulation of the renal EGF production, thereby inhibiting the activation of TRPM6. METHODS: Renal transplant patients treated with CsA (n = 55) and 35 chronic kidney disease (CKD) patients were included. At three time points, with an interval of at least 1 month, blood and urine samples were taken to determine creatinine, Mg(2+), sodium and EGF. RESULTS: Serum Mg(2+) was significantly lower in the CsA group versus the CKD group with significantly more CsA-treated patients developing hypomagnesaemia. Although the fractional excretion (FE) Mg(2+) did not differ significantly between the two groups, subanalysis of the patients with hypomagnesaemia showed a significantly higher FE Mg(2+) in CsA-treated patients compared with CKD patients (P = 0.05). The urinary EGF excretion was significantly decreased in the CsA group and was a predictor of the FE Mg(2+) in the two groups. Serum sodium was significantly decreased in the CsA group simultaneously with an increased FE Na(+). CONCLUSIONS: In CsA-treated patients, the association of a low urinary EGF excretion and a decreased renal Mg(2+) reabsorption is in accordance with in vitro and animal studies. In the whole study population, log urinary EGF excretion is an independent predictor of the FE Mg(2+), supporting the role of EGF in magnesium reabsorption.

Kidney donation after circulatory death in a country with a high number of brain dead donors: 10-year experience in Belgium.

Worldwide shortage of standard brain dead donors (DBD) has revived the use of kidneys donated after circulatory death (DCD). We reviewed the Belgian DCD kidney transplant (KT) experience since its reintroduction in 2000. Risk factors for delayed graft function (DGF) were identified using multivariate analysis. Five-year patient/graft survival was assessed using Kaplan-Meier curves. The evolution of the kidney donor type and the impact of DCDs on the total KT activity in Belgium were compared with the Netherlands. Between 2000 and 2009, 287 DCD KT were performed. Primary nonfunction occurred in 1% and DGF in 31%. Five-year patient and death-censored graft survival were 93% and 95%, respectively. In multivariate analysis, cold storage (versus machine perfusion), cold ischemic time, and histidine-tryptophan-ketoglutarate solution were independent risk factors for the development of DGF. Despite an increased number of DCD donations and transplantations, the total number of deceased KT did not increase significantly. This could suggest a shift from DBDs to DCDs. To increase KT activity, Belgium should further expand controlled DCD programs while simultaneously improve the identification of all potential DBDs and avoid their referral for donation as DCDs before brain death occurs. Furthermore, living donation remains underused.

Variability in the incidence of renal replacement therapy over time in Western industrialized countries: A retrospective registry analysis.

INTRODUCTION: A growing number of patients started renal replacement therapy (RRT) in Western industrialized countries between 1980 an early 2000s. Thereafter reports from national and international registries suggest a trend towards stabilization and sometimes a decrease in the incidence rate. AIM: To investigate the differences in overall and age-specific incidence rates between industrialized countries from 1998 until 2013. Secondly, to investigate changes in incidence rates over time and their association with specific age categories. METHOD: We extracted the unadjusted overall incidence of RRT and age-specific incidence rates from renal registry reports in Europe, the United States, Canada, Australia and New Zealand. Time trends in the incidence rate by country and age categories were analyzed by Joinpoint regression analysis. RESULTS: The incidence rate in 2013 ranged from 89 per million population (pmp) in Finland to 363 pmp in the US. Incidence rates in the lower age categories (20-64 year) were similar between countries and remained stable over time. Higher incidence countries were characterized by higher numbers of patients in both the 65-74 and ≥75 year categories starting RRT. Joinpoint analysis confirmed that most countries had significant reductions in the incidence rate at the end of the study period. These reductions were explained by lower numbers of older patients starting RRT and were observed also in countries with lower overall incidence rates. CONCLUSION: This study confirmed different incidence rates of RRT between industrialized countries worldwide. Countries with the highest overall incidence rates also had the highest incidence rates in the oldest age categories. Since the early 2000's the number of older patients starting RRT is either stabilizing or even decreasing in most countries. This reduction is universal and is also observed in countries with previously low incidence rates.

Vasculopathy in the kidney allograft at time of transplantation: impact on later function of the graft.

BACKGROUND: Older and marginal donors, increasingly used to overcome organ shortness, often have a cerebrovascular accident as cause of death and could have vascular lesions in their kidneys. METHODS: In this literature study, we evaluated the predictive value of vasculopathy in the renal allograft at the time of transplantation, on the subsequent graft function. RESULTS: Short-term graft survival rates do not seem to be diminished by suboptimal donor histology. When vasculopathy is clearly present at the time of transplantation, impaired kidney function is showed at 1-week posttransplantation, at hospital discharge, or at 3 months and an increased frequency of delayed graft function. The long-term graft survival rate, in the studies of Pokorna and Taub, was significantly lower in the group with arteriolosclerosis. Wang et al. concluded in their study that arterial fibrous intimal thickening is the single most important histological predictor of both graft loss and delayed graft function. However, Minakawa et al. observed no significant correlation between 1 or 2-year graft survival and vasculopathy score. Severe vascular lesions in the donor kidney do affect the level of kidney function in the later posttransplant period as described in different studies (follow-up till 7 years posttransplantation). CONCLUSIONS: Data obtained from the studies of donor biopsies sustain the notion that vasculopathy is a major determinant of the short-term and the long-term outcome of the kidney allograft.

Chronic allograft nephropathy: what have we learned from protocol biopsies?

Chronic allograft nephropathy, characterized by interstitial fibrosis and tubular atrophy, is still a major cause of graft loss after kidney transplantation. The complex pathophysiology of chronic allograft nephropathy is still poorly understood, and could be clarified by a more systematic performance of implantation and protocol biopsies of the renal allograft. This review highlights the contribution of implantation and protocol biopsies to our current knowledge of the complex interaction of multiple processes, ultimately leading to the development of interstitial fibrosis and tubular atrophy in the transplanted kidney. In addition, the safety and the limitations of protocol biopsies are discussed, as well as potential future directions for clinical practice and clinical research.

Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. METHODS: The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (deltaVvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of deltaVvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. RESULTS: A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The deltaVvintima/artery was not different between treatment and placebo groups (6.9+/-8.2% vs. 6.9+/-7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (kappa 0.86 vs. 0.33). CONCLUSIONS: In summary, there were no differences in deltaVvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

The clinical significance of epitope mismatch load in kidney transplantation: A multicentre study.

Since the advent of kidney transplantation a key strategy for maximising graft survival by avoiding allorecognition has been to minimise HLA mismatching between donor and recipient. As HLA antibodies are now recognised as being specific for epitopes and donor-recipient HLA mismatch at the amino acid level can now be determined, HLA epitope mismatch load could be a better predictor for dnDSA development than classical HLA antigen mismatch calculation. This hypothesis has been investigated by other studies and the aim of our multicentre study was to confirm this observation in our population. Two algorithms, HLAMatchmaker and PIRCHE-II, were used to determine the HLA epitope mismatch load between donor and recipient. We have shown a significant association between the number of HLA epitope mismatches and the development of dnDSA and we have confirmed the earlier observations.

Plasma donor-derived cell-free DNA kinetics after kidney transplantation using a single tube multiplex PCR assay.

BACKGROUND: After transplantation, cell-free DNA derived from the donor organ (ddcfDNA) can be detected in the recipient's circulation. We aimed to quantify ddcfDNA levels in plasma of kidney transplant recipients thereby investigating the kinetics of this biomarker after transplantation and determining biological variables that influence ddcfDNA kinetics in stable and non-stable patients. MATERIALS AND METHODS: From 107 kidney transplant recipients, plasma samples were collected longitudinally after transplantation (day 1-3 months) within a multicenter set-up. Cell-free DNA from the donor was quantified in plasma as a fraction of the total cell-free DNA by next generation sequencing using a targeted, multiplex PCR-based method for the analysis of single nucleotide polymorphisms. A subgroup of stable renal transplant recipients was identified to determine a ddcfDNA threshold value. RESULTS: In stable transplant recipients, plasma ddcfDNA% decreased to a mean (SD) ddcfDNA% of 0.46% (± 0.21%) which was reached 9.85 (± 5.6) days after transplantation. A ddcfDNA threshold value of 0.88% (mean + 2SD) was determined in kidney transplant recipients. Recipients that did not reach this threshold ddcfDNA value within 10 days after transplantation showed a higher ddcfDNA% on the first day after transplantation and demonstrated a higher individual baseline ddcfDNA%. CONCLUSION: In conclusion, plasma ddcfDNA fractions decreased exponentially within 10 days after transplantation to a ddcfDNA threshold value of 0.88% or less. To investigate the role of ddcfDNA for rejection monitoring of the graft, future research is needed to determine causes of ddcfDNA% increases above this threshold value.

Prediction of delayed graft function using different scoring algorithms: A single-center experience.

AIM: To compare the performance of 3 published delayed graft function (DGF) calculators that compute the theoretical risk of DGF for each patient. METHODS: This single-center, retrospective study included 247 consecutive kidney transplants from a deceased donor. These kidney transplantations were performed at our institution between January 2003 and December 2012. We compared the occurrence of observed DGF in our cohort with the predicted DGF according to three different published calculators. The accuracy of the calculators was evaluated by means of the c-index (receiver operating characteristic curve). RESULTS: DGF occurred in 15.3% of the transplants under study. The c index of the Irish calculator provided an area under the curve (AUC) of 0.69 indicating an acceptable level of prediction, in contrast to the poor performance of the Jeldres nomogram (AUC = 0.54) and the Chapal nomogram (AUC = 0.51). With the Irish algorithm the predicted DGF risk and the observed DGF probabilities were close. The mean calculated DGF risk was significantly different between DGF-positive and DGF-negative subjects (P < 0.0001). However, at the level of the individual patient the calculated risk of DGF overlapped very widely with ranges from 10% to 51% for recipients with DGF and from 4% to 56% for those without DGF. The sensitivity, specificity and positive predictive value of a calculated DGF risk ≥ 30% with the Irish nomogram were 32%, 91% and 38%. CONCLUSION: Predictive models for DGF after kidney transplantation are performant in the population in which they were derived, but less so in external validations.

Epitope analysis of DQ6-reactive antibodies in sera from a DQ6-positive transplant candidate sensitized during pregnancy.

This case report describes DQ6-reactive serum antibody reactivity in a patient who types as DQ6. DNA typing showed DQB1*06:09 on the antibody producer and serum reactivity with DQB1*06:01, *06:02 and *06:03 but not with *06:04 and *06:09. HLAMatchmaker serum analysis showed antibody reactivity with a new antibody-verified 85VA eplet on DQB but additional reactivity with DQB1*02:01 could not be readily interpreted. After applying the nonself-self algorithm of HLA immunogenicity we have identified a new DQB epitope structurally described as 140A2+130R+135D and shared by DQB1*02:01 and DQB1*05:01 and DQB1*06:02 of the immunizer.

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial.

BACKGROUND: Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS: The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS: 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION: In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

Conversion from cyclosporine to sirolimus in stable renal transplant recipients.

BACKGROUND: Conversion from cyclosporine (CsA) to sirolimus (SRL) has mainly been done in clinical conditions warranting calcineurin inhibitor discontinuation. Little is known about the clinical outcome of conversion in renal transplant recipients without transplant dysfunction. METHODS: This prospective, open-label, multicentric pilot study evaluates the safety and efficacy of converting patients with stable renal function from CsA to SRL. RESULTS: Forty stable patients on CsA, mycophenolate mofetil (MMF) (1.5 g/day), and steroids (ST) were converted at 7.6+/-1.4 months after renal transplantation. At 1 year, graft and patient survival was 100% and the incidence of acute rejection 5%. Calculated glomerular filtration rate (GFR) increased from 54+/-18 to 66+/-16 ml/min (P<0.0001). Blood pressure remained unchanged. A gradual increase in the incidence and severity of proteinuria was observed from month 6 onwards with de novo proteinuria in 30% of the patients at 1 year. Protein excretion was below 1 g/day in 12.5%, between 1 and 3 g/day in 17.5% and above 3 g/day in 7.5% of the proteinuric cohort (P=0.0043, compared to baseline). No predictors could be identified for the development of proteinuria. All patients had a reduction in protein excretion following renin-angiotensin blockade and were continued on SRL. CONCLUSION: Conversion of stable renal transplant recipients from a CsA-MMF-ST to a SRL-MMF-ST regimen is safe and results in improved renal function but is associated with the development of proteinuria in 30% of the patients requiring renin-angiotensin blockade.

Do elderly recipients really benefit from kidney transplantation?

Data from the nineties showed that even older individuals had a survival advantage with kidney transplantation compared to dialysis. Consequently, we are increasingly wait-listing high-risk patients in terms of age and co-morbidities. However, times are changing. Due to severe organ shortage we now use more often expanded criteria donor kidneys with less favorable outcomes, while at the same time survival on dialysis is improving. The question therefore rises again if elderly patients really benefit from transplantation nowadays. At least for the U.S., recent data still suggest an overall survival benefit with transplantation in older recipients but the risks vary greatly with the health status of the recipient and with the type of donor. Especially for transplant centers outside of the U.S., recent large studies are lacking. Because of continuing changes in both donor and recipient characteristics as well as dialysis outcomes, a permanent area-specific reassessment of data is needed. In this review we describe the important evolutions in transplant and dialysis care over the last 20 years and provide an overview on recent data comparing survival on dialysis versus transplantation in the elderly.

Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates.

BACKGROUND: Clinical trials in renal transplantation must use surrogate markers of long-term graft survival if conclusions are to be drawn at acceptable speed and cost. Morphologic changes in transplant biopsies provide the earliest available evidence of damage, and "protocol" biopsies from stable grafts can be used to reduce the number of patients needed in clinical trials. This approach has been inhibited by concerns over safety, but the risk of biopsy of a stable kidney, with no active inflammation or acute functional impairment, has never been formally estimated. METHODS: In accordance with a predefined set of questions, a retrospective audit of a sequential series of protocol biopsies was performed in four major transplant centers. RESULTS: A total of 2,127 biopsy events were assessed for major complications, and 1,486 were assessed for minor ones. There were no deaths. One graft was lost, under circumstances indicating that the loss should have been prevented. Three episodes of hemorrhage required direct intervention. Three further patients required transfusion. There were two episodes of peritonitis, but one was arguably an unrelated event. All serious complications presented within 4 hr of biopsy. CONCLUSIONS: The incidence of clinically significant complications after protocol biopsy of a stable renal transplant is low. Direct benefits to the patients concerned (irrespective of the benefit that may accrue in clinical trials) were not formally assessed but seem likely to outweigh the risk of the procedure. We believe that it is ethically justifiable to ask renal transplant recipients to undergo protocol biopsies in clinical trials and routine care.