Function In Kidney Transplant Recipients Research Articles

Preservation of kidney function in kidney transplant recipients by alkali therapy (Preserve-Transplant Study): rationale and study protocol

BackgroundGraft survival after kidney transplantation has significantly improved within the last decades but there is a substantial number of patients with declining transplant function and graft loss. Over the past years several studies have shown that metabolic acidosis plays an important role in the progression of Chronic Kidney Disease (CKD) and that alkalinizing therapies significantly delayed progression of CKD. Importantly, metabolic acidosis is highly prevalent in renal transplant patients and a recent retrospective study has shown that metabolic acidosis is associated with increased risk of graft loss and patient death in kidney transplant recipients. However, no prospective trial has been initiated yet to test the role of alkali treatment on renal allograft function.MethodsThe Preserve-Transplant Study is an investigator-initiated, prospective, patient-blinded, multi-center, randomized, controlled phase-IV trial with two parallel-groups comparing sodium bicarbonate to placebo. The primary objective is to test if alkali treatment will preserve kidney graft function and diminish the progression of CKD in renal transplant patients by assesing the change in eGFR over 2 years from baseline. Additionally we want to investigate the underlying pathomechanisms of nephrotoxicity of metabolic acidosis.DiscussionThis study has the potential to provide evidence that alkali treatment may slow or reduce the progression towards graft failure and significantly decrease the rate of end stage renal disease (ESRD), thus prolonging long-term graft survival. The implementation of alkali therapy into the drug regimen of kidney transplant recipients would have a favorable risk-benefit ratio since alkali supplements are routinely used in CKD patients and represent a well-tolerated, safe and cost-effective treatment.Trial registrationClinicalTrials.gov NCT03102996. Trial registration was completed on April 6, 2017.

CYP3A5 and ABCB1 polymorphisms in living donors do not impact clinical outcome after kidney transplantation.

To investigate the association between donor CYP3A5 and ABCB1polymorphisms and tacrolimus (Tac)-induced nephrotoxicity and renal function in kidney transplant recipients. The CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms were determined in 237 recipients and donors. There was no significant association between Tac-related nephrotoxicity and donor CYP3A5 and ABCB1 genotype. The donor ABCB1 3435C>T polymorphism was associated with estimated glomerular filtration rate on day 7 and month 1. The combined donor-recipient ABCB1 genotype (3435C>T polymorphism) was significantly related with estimated glomerular filtration rate on day 3 and 7 in univariate analysis. However, these differences were no longer statistically significant in multivariate analysis. A genetic analysis of ABCB1 and CYP3A5 of kidney transplant donors is not helpful to improve renal transplant outcomes.

Influence of CYP3A5 genetic differences in tacrolimus on quantitative interstitial fibrosis and long-term graft function in kidney transplant recipients

The impact of CYP3A5 polymorphisms on clinical outcomes is controversial. The present study investigated the impact of CYP3A5 genetic differences on the development of interstitial fibrosis (IF) from 0 h to 1 year post-transplantation in biopsy sections from 96 living kidney recipients under the same target trough regimen of tacrolimus. The relationships between CYP3A5 polymorphisms and long-term graft function and death-censored graft survival were also examined. A quantitative analysis of IF was performed using computer-assisted imaging on virtual slides. Percent IF (%IF) in the cortical region at 0 h was defined as the baseline, and increases in the ratio of %IF 1 year post-transplantation were calculated. The relationships between CYP3A5 genetic differences and the development of IF, the incidence of clinical events, and the long-term function and death-censored survival of grafts were assessed. The mean increase in the ratio of %IF from 0 h to 1 year was 1.38 ± 0.74-fold. Despite therapeutic drug monitoring (TDM), trough levels of tacrolimus were lower in carriers with the CYP3A5*1 allele (expressers) than in those with the CTP3A5*3/*3 genotype (non-expressers) throughout the 1-year post-transplantation period. However, CYP3A5 genetic differences were not associated with the development of IF, any clinical events, or the long-term function and survival of grafts. The clinical impact of CYP3A5 genetic differences may be small under the current immunosuppressive regimen consisting of mycophenolate mofetil, steroids, basiliximab, and lower target trough levels of tacrolimus with suitable TDM in a low immunological risk population.

Survival and Evolution of Renal Function in Kidney Transplant Recipients From Type II Asystolic Donations: A Single-center Experience

BackgroundIn recent years, stagnation in the number of kidneys from after brain-dead donors (DBD) has stimulated the use of non–heart beating donors (NHBDs). Herein we present our 5-year experience with type II Maastricht NHBDs in renal transplantation. MethodsAll patients (n = 50) in this study received type II Maastricht NHBD kidneys (March 2012 to February 2017), with a median follow-up of 33 months. ResultsMean donor age was 39 ± 12 years, mean creatinine 1.24 ± 0.2 mg/dL, and the most frequently observed blood group (donors and recipients) was type A (64%). Recipients were slightly younger (51 ± 11 years old), with mean time on dialysis of 30 ± 24 months. Almost all were primary transplants. Pre-transplant panel-reactive antibodies (PRA) were <25%; initial immunosuppression was thymoglobulin, corticosteroids, mycophenolate mofetil, and delayed introduction of tacrolimus. Six percent were nonfunctioning kidneys; 79.6% presented with delayed renal function (mean duration 14 ± 9 days). Acute rejection was seen in 6% of patients. Mean creatinine at month 3 was 1.7 ± 0.8 mg/dL, and 1.5 ± 0.8 mg/dL in the first year. The last available mean creatinine was 1.54 ± 0.7 mg/dL. Proteinuria in the third month, first year, and third year was 0.70, 0.41, and 0.26 g/d, respectively. Recipient survival at the first, third, and fifth year was 100%, 100%, and 86%, and when graft-censored for death was 94%, 91%, and 91%, respectively. The incidence of acute rejection during first year was 6%, and 2% in the second year. Exitus incidence was 4% and cytomegalovirus infection was 21.3%. BK viremia between 1000 and 10,000 copies/mL was seen in 4.3%, and reached >10,000 copies/mL in 2.1%. ConclusionsType II NHBD has shown limited frequency of nonfunctioning kidney and high functional delay. The results in survival and renal function are very acceptable, comparable with levels seen in donation after brain death.

FGF23, NGAL, and Endostatin: the Predictors of Allograft Function in Renal Transplant Recipients.

Increased circulating levels of fibroblast growth factor 23, neutrophil gelatinase-associated lipocalin, and endostatin are independent risk factors for cardiovascular disease. Here, we evaluated correlations among these parameters and graft dysfunction and their relation with arterial stiffness. This prospective study included 73 maintenance kidney transplant patients with stable allograft function who had received the transplant at least 36 months previously. We calculated the estimated glomerular filtration rate (eGFR). Pulsewave velocity was determined. Serum levels of fibroblast growth factor 23, neutrophil gelatinaseassociated lipocalin, and endostatin were measured by enzyme-linked immunosorbent assay. Demographic characteristics and pulse-wave velocity values were similar in groups 1 and 2 (GFR < 60 and > 60 mL/min, respectively). Mean levels of fibroblast growth factor 23 (P = .036), neutrophil gelatinaseassociated lipocalin (P = .018), and endostatin were significantly higher in group 1. Fibroblast growth factor 23 was negatively correlated with eGFR (r = -0.267, P = .023) and positively correlated with neutrophil gelatinase-associated lipocalin (r = 0.258, P = .036) and endostatin (r = 0.321, P = .006). Serum endostatin levels were positively correlated with pulse-wave velocity (r = 0.276, P = .019). In linear regression analysis, eGFR was detected as the unique predictor of neutrophil gelatinase-associated lipocalin (P = .001). In addition, each 1 mL/min decrease in eGFR resulted in a 0.281 pg/mL increase in fibroblast growth factor 23 (P = .023) and a 0.04 ng/mL increase in neutrophil gelatinase-associated lipocalin (P = .007); each 1 cm/s increase in pulse-wave velocity resulted in a 3648.7 U/L increase of endostatin (P = .019). All 3 parameters were associated with loss of graft function in kidney transplant recipients. Moreover, endostatin can be used as an independent predictor for cardiovascular morbidity in this population.

Anticardiolipin antibodies and 12-month graft function in kidney transplant recipients: a prognosis cohort survey.

In kidney transplant recipients, anticardiolipin (ACL) antibodies without antiphospholipid syndrome (APS) are found in up to 38% of patients and could be associated with thrombotic events (TEs). However, the prognostic role of ACL regarding kidney transplant and patients outcomes have still not been well defined. We conducted an observational, monocentric, retrospective cohort study including 446 kidney transplant recipients and standardized follow-up: 36-month allograft and patient survival, 12-month estimated glomerular filtration rate (eGFR) and 3- and 12-month screening biopsies. ACL tests were run on 247 patients, 101 were positive (ACL+ group, 41%) and 146 were negative (ACL- group, 59%). Allografts and patient survival within 36 months as TE were similar between both groups [hazard ratio (HR) = 1.18 and HR = 0.98, respectively]. The 12-month eGFR was significantly lower in the ACL+ group [median (95% confidence interval) 48.5 (35.1-60.3) versus 51.9 (39.1-65.0) mL/min/1.73 m2, P= 0.042]. ACL+ was independently associated with eGFR decrease (P = 0.04). In 12-month screening biopsies, tubular atrophy was significantly more severe in the ACL+ group compared with the ACL- group (P = 0.02). ACL without APS before kidney transplantation is an independent risk factor of eGFR decline within the first year post-transplant without over-incidence of TEs. Specific immunosuppressive therapy including mammalian target of rapamycin inhibitors should be discussed in the future.

Comparing the Effect of Immediate versus Delayed Initiation of Tacrolimus on Delayed Graft Function in Kidney Transplant Recipients: A Randomized Open-label Clinical Trial.

Objective:Delayed graft function (DGF) is an early complication after kidney transplantation with negative impact on allograft outcomes. This study assessed the effect of delayed initiation of tacrolimus as a nephrotoxic drug, on DGF occurrence and allograft function.Methods:This randomized, open-label clinical trial was conducted on kidney transplant recipients with the age of at least 14 years who underwent the first kidney transplantation from deceased or living donor. Patients were randomly allocated to immediate (n = 26) or delayed tacrolimus (n = 27) groups. All patients received thymoglobulin as induction therapy and similar maintenance immunosuppression including tacrolimus, mycophenolate, and prednisolone with the difference in the time of initiation of tacrolimus either on the day of transplantation (immediate tacrolimus group) or day 3 after transplant (delayed tacrolimus group).Findings:DGF incidence (46.15% vs. 37.04%; P = 0.501) and duration (9.75 ± 6.41 vs. 8.6 ± 6.16 days; P = 0.675) were not different between the immediate and delayed tacrolimus groups. Estimated creatinine clearance using Cockcroft–Gault equation (63.14 ± 18.81 vs. 58.19 ± 19.42 mL/min in immediate and delayed tacrolimus groups respectively; P = 0.373) and estimated acute rejection-free survival were also comparable between the groups over the 3 months of follow-up. Compared with the immediate group, the delayed tacrolimus group showed higher estimated 3-month grafts' survival (100% vs. 84.27%; P = 0.072).Conclusion:Delayed initiation of tacrolimus after kidney transplantation under the umbrella of thymoglobulin induction did not result in either lower incidence or duration of DGF or improved the level of graft function in kidney transplant recipients but non-statistically significant increased 3-month grafts' survival.

The Lifetime Health Burden of Delayed Graft Function in Kidney Transplant Recipients in the United States.

Background. Although delayed graft function (DGF) is associated with an increased risk of acute rejection and decreased graft survival, there are no estimates of the long-term or lifetime health burden of DGF. Objectives. To estimate the long-term and lifetime health burden of DGF, defined as the need for at least one dialysis session within the first week after transplantation, for a cohort representative of patients who had their first kidney transplant in 2014. Methods. Data from the United States Renal Data System (USRDS; 2001–2014) were used to estimate a semi-Markov parametric multi-state model with three disease states. Maximum length of follow-up was 13.7 years, and a microsimulation model was used to extrapolate results over a lifetime. The impact of DGF was assessed by simulating the model for each patient in the cohort with and without DGF. Results. At the end of 13.7 years of follow-up, DGF reduces the probability of having a functioning graft from 52% to 32%, increases the probability of being on dialysis from 10% to 19%, and increases the probability of death from 38% to 50% relative to transplant recipients who do not experience DGF. A typical transplant recipient with DGF (median age = 53) is observed to lose 0.87 quality-adjusted life-years (QALYs). Extrapolated over a lifetime, the same 53-year-old DGF patient is projected to lose 3.01 (95% confidence interval: 2.33, 3.70) QALYs relative to a transplant recipient with the same characteristics who does not experience DGF. Conclusions. The lifetime health burden of DGF is substantial. Understanding these consequences will help health care providers weigh kidney transplant decisions and inform policies for patients in the context of varying risks of DGF.

Association of Brain-Dead Donors' Terminal Inflammation With Delayed Graft Function in Kidney Transplant Recipients

BackgroundSystemic inflammation affects kidney function in a wide range of diseases. Even in kidney transplant recipients, higher levels of C-reactive protein (CRP) are invariably associated with both worse short- and long-term graft outcomes. However, little is known about systemic inflammation in kidney donors and, notably, brain death causes a strong systemic inflammatory response. ObjectiveTo analyze the role of systemic inflammation of brain-dead donors on short-term kidney graft outcomes (ie, delayed graft function [DGF], defined as the need of dialysis during the first week after transplantation). Materials and methodsRetrospective analysis of clinical and biochemical characteristics of all brain-dead kidney donors generated in the Hospital Clínic of Barcelona in the 2006 to 2015 period (n = 194). Donors who were tested for CRP in the 24 hours before BD declaration were included (n = 97, 50% of initial population). Clinical and biochemical features of their respective recipients (n = 165) were analyzed, comparing recipients who developed DGF (n = 30) with recipients who did not (n = 135). ResultsDonors whose recipients later developed DGF had much higher CRP values (10.58 [5.1-18.21] vs 4.81 [1.42-12.2] mg/dL, P = .025). Other characteristics associated with the development of DGF were renal biopsy score and recipient dialysis vintage (P = .025 and P = .002, respectively). In logistic regression analysis, PCR maintained significance in the non–expanded criteria donor (ECD) group (odds ratio [OR], 1.102; P = .027), but it lost significance in the ECD group (P = .67). ConclusionsTerminal donor CRP was associated with DGF in kidney transplant recipients and proved to be mostly significant in younger donors.

Urinary miR-155-5p and CXCL10 as prognostic and predictive biomarkers of rejection, graft outcome and treatment response in kidney transplantation.

MicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients. Eighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR-155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1st week and the 1st , 2nd , 3rd and 6th months post-transplantation. Eight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve=0.875; P=0.046) and CXCL10 (area under the curve=0.865; P=0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73pgml-1 , with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function. The regular early post-transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers.

Cystatin C–Based Equation for Predicting the Glomerular Filtration Rate in Kidney Transplant Recipients

BackgroundPrecise monitoring of the glomerular filtration rate (GFR) is needed to estimate the allograft function in kidney transplant recipients (KTRs). The GFR is widely estimated with the use of formulas based on serum cystatin C (SCys) and serum creatinine (SCr) levels. We compared the efficacy of SCys-based equations with that of SCr-based equations to predict the allograft function. MethodsWe calculated the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Cr), CKD-EPI creatinine–cystatin C (CKD-EPI Cr/Cys), and CKD-EPI cystatin C (CKD-EP ICys) equations in 70 KTRs. The measured GFR (mGFR) was defined as the GFR estimated by technetium-99m–diethylene triamine pentaacetic acid (99mTc-DTPA) clearance. The accuracy and precision of the equations were compared with the mGFR. The performance characteristics of SCr and SCys were analyzed with the use of receiver operating characteristic (ROC) curves to ascertain the sensitivity and specificity at the cutoff value of <45 mL/min/1.73 m2 DTPA. ResultsOverall, MDRD and CKD-EPICys did not show significant differences from mGFR (P = .05 and P = .077, respectively), whereas CKD-EPI Cr and CKD-EPI Cr/Cys significantly underestimated mGFR (P < .001 and P = .005, respectively). In the subgroup of patients with mGFR <45 mL/min/1.73 m2, CKD-EPI Cys showed little bias (P = .122), whereas MDRD significantly underestimated mGFR (P = .037). The area under the ROC curve for predicting mGFR <45 mL/min/1.73 m2 was 0.80 for SCys, which was better than that for SCr at 0.763. ConclusionsCystatin C–based equations showed better predictive performance of the allograft function than creatinine-based equations for the KTRs, including patients with lower GFR. Cystatin C level might be a good alternate measurement to monitor the allograft function.

Supplementary Administration of Everolimus Reduces Cardiac Systolic Function in Kidney Transplant Recipients

BACKGROUND The effect of everolimus, one of the mammalian targets of rapamycin inhibitors, on cardiac function was evaluated in kidney transplant recipients. MATERIAL AND METHODS Seventy-six participants who underwent kidney transplant between March 2009 and May 2016 were retrospectively reviewed. To standardize everolimus administration, the following criteria were used: (1) the recipient did not have a donor-specific antigen before kidney transplantation; (2) the recipient did not have proteinuria and uncontrollable hyperlipidemia after kidney transplantation; and (3) acute rejection was not observed on protocol biopsy 3 months after kidney transplantation. According to these criteria, everolimus administration for maintenance immunosuppression after kidney transplantation was included. Cardiac function was compared between the treatment group (n=30) and non-treatment group (n=46). RESULTS The mean observation periods of the treatment and non-treatment groups were 41.3±12.6 and 43.9±19.8 months, respectively (p=0.573). The mean ejection fraction and fractional shortening of the treatment and non-treatment groups after kidney transplant were 66.5±7.9% vs. 69.6±5.5% (p=0.024) and 37.1±6.2% vs. 39.3±4.7% (p=0.045), respectively. In the treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation did not differ significantly (p=0.604 and 0.606, respectively). In the non-treatment group, the mean ejection fraction and fractional shortening before and after kidney transplantation differed significantly (p=0.004 and 0.006, respectively). CONCLUSIONS Supplementary administration of everolimus after kidney transplantation can reduce cardiac systolic function.

Late conversion from tacrolimus to a belatacept-based immuno-suppression regime in kidney transplant recipients improves renal function, acid-base derangement and mineral-bone metabolism.

Calcineurin inhibitor (CNI)-induced nephrotoxicity and chronic graft dysfunction with deteriorating glomerular filtration rate (GFR) are common problems of kidney transplant recipients. The aim of this study was to analyze the role of belatacept as a rescue therapy in these patients. In this retrospective, observational study we investigated 20 patients (10 females, 10 males) who were switched from a CNI (tacrolimus) to a belatacept-based immunosuppression because of CNI intolerance or marginal transplant function. Patient follow-up was 12months. Patients were converted to belatacept in mean 28.8months after transplantation. Reasons for conversion were CNI intolerance (14 patients) or marginal transplant function (6 patients). Mean estimated GFR (eGFR) before conversion was 22.2 ± 9.4ml/min at baseline and improved significantly to 28.3 ± 10.1ml/min at 4weeks and to 32.1 ± 12.6ml/min at 12months after conversion. Serum bicarbonate significantly increased from 24.4 ± 3.2mmol/l at baseline to 28.7 ± 2.6mmol/l after 12months. Conversion to belatacept decreased parathyroid hormone and phosphate concentrations significantly, whereas albumin levels significantly increased. In 6 cases an acute rejection preceded clinically relevant CNI toxicity; only two patients suffered from an acute rejection after conversion. Belatacept was well tolerated and there was no increase in infectious or malignant side effects. A late conversion from a tacrolimus-based immunosuppression to belatacept is safe, effective and significantly improves renal function in kidney transplant recipients. Additionally, the conversion to belatacept has a beneficial impact on acid-base balance, mineral-bone and protein metabolism, independently of eGFR.

The effect of parathyroidectomy on graft function in kidney transplant recipients with persistent hypercalcemia

The effect of parathyroidectomy on graft function in kidney transplant recipients with persistent hypercalcemia

Protective Effects of L-Carnitine Against Delayed Graft Function in Kidney Transplant Recipients: A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial

Delayed graft function (DGF) is an early complication after deceased donor kidney transplantation with significant adverse effects on graft outcomes. Ischemia-reperfusion injury during transplantation is a major cause of DGF. Tissue concentrations of carnitine, an antioxidant and regulator of cellular energy supply, decrease in the kidney following ischemia-reperfusion insult. Based on promising animal data, this study evaluated the possible protective effect of L-carnitine against DGF. This study is a pilot, randomized, double-blind, placebo-controlled clinical trial that was conducted on kidney transplantation patients in kidney transplant ward of Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, Tehran, Iran. Patients older than 14years old undergoing their first kidney transplantation from a deceased donor were evaluated for eligibility to take part in this study. Fifty-six patients were randomly assigned to L-carnitine or placebo groups. During this trial, 3g of oral L-carnitine or placebo was administered in 3 divided doses each day for 4 consecutive days starting the day before kidney transplantation (i.e., days -1, 0, 1, and 2). The need for dialysis within the first week after transplantation, serum creatinine and urine output were assessed daily. After hospital discharge, patients were followed for 3months regarding organ function. DGF incidence did not differ between the L-carnitine and placebo groups (18.51% vs. 23.8%, respectively; P=.68). Total allograft failure within 3months after kidney transplantation happened in 6 patients in the placebo and 1 patient in the L-carnitine group (P=.05). This study showed no protective effects of oral L-carnitine supplementation against DGF occurrence recipients; however, 3-month graft loss was lower in the L-carnitine supplemented group.

The influence of living donor SHROOM3 and ABCB1 genetic variants on renal function after kidney transplantation.

A genome-wide association study has identified several gene polymorphisms associated with loss of renal function. The effect of these variants on renal function in kidney transplant recipients receiving immunosuppressive treatment is unknown. A cohort of 189 kidney transplant recipients and their living donors were recruited from West China Hospital of Sichuan University, on whom we assessed the association of five single nucleotide polymorphisms with renal function after kidney transplantation. Glomerular filtration rate estimated by serum creatinine was significantly higher in recipients carrying allograft with the A allele at rs17319721 in SHROOM3 (shroom family member 3) than those in the group with the GG genotype from month 1 to month 6 after transplantation (P=0.020). Covariate adjustment analysis showed that the variant at rs17319721 in SHROOM3 was an independent risk factor for renal dysfunction after the first month after transplantation (P=0.022). The estimated glomerular filtration rate was the lowest in recipients with allograft carrying both the A allele at rs17319721 in SHROOM3 and the CC genotype at rs1045642 in ABCB1 (P<0.05). The genetic variants in SHROOM3 and ABCB1 in donors were associated closely with renal function after kidney transplantation.

The closure of arteriovenous fistula in kidney transplant recipients is associated with an acceleration of kidney function decline.

The creation of arteriovenous fistula (AVF) may retard chronic kidney disease progression in the general population. Conversely, the impact of AVF closure on renal function in kidney transplant recipients (KTRs) remains unknown. From 2007 to 2013, we retrospectively categorized 285 KTRs into three groups: no AVF (Group 0, n = 90), closed AVF (Group 1, n = 114) and left-open AVF (Group 2, n = 81). AVF closure occurred at 653 ± 441 days after kidney transplantation (KTx), with a thrombosis:ligation ratio of 19:95. Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease equation. Linear mixed models calculated the slope and intercept of eGFR decline versus time, starting at 3 months post-KTx, with a median follow-up of 1807 days (95% confidence interval 1665-2028). The eGFR slope was less in Group 1 (-0.081 mL/min/month) compared with Group 0 (-0.183 mL/min/month; P = 0.03) or Group 2 (-0.164 mL/min/month; P = 0.09). Still, the eGFR slope significantly deteriorated after (-0.159 mL/min/month) versus before (0.038 mL/min/month) AVF closure (P = 0.03). Study periods before versus after AVF closure were balanced to a mean of 13.5 and 12.5 months, respectively, with at least 10 observations per patient ( n = 99). In conclusion, a significant acceleration of eGFR decline is observed over the 12 months following the closure of a functioning AVF in KTRs.

Exome Sequencing and Prediction of Long-Term Kidney Allograft Function.

Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.

The Reference Intervals for Serum C‐Terminal Agrin Fragment in Healthy Individuals and as a Biomarker for Renal Function in Kidney Transplant Recipients

C-terminal agrin fragment (CAF) has been shown to be a promising new biomarker for kidney function. The aim of this study was to verify the reference intervals for CAF in Chinese healthy adults and to assess the efficiency of CAF for monitoring renal function after transplantation. Serum samples were collected from 200 healthy adult subjects and 60 living donor kidney recipients before and on day 1, day 2 and at 6 months after transplantation. We measured serum CAF, creatinine, cystatin C and NGAL concentrations at each time. Estimated glomerular filtration rate (eGFR) was evaluated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Reference intervals for CAF were determined at 2.5th and 97.5th percentiles. Serum CAF concentrations were observed to be higher in females of old age groups while no significant differences were discovered in males between age groups. There were significant gender-related differences in CAF in old age groups (50-64 and ≥65 years). Serum CAF correlated positively with serum creatinine, cystatin C and negatively with eGFR on day 1, day 2 and at 6 months after kidney transplantation. CAF and NGAL fell rapidly into the normal range on the second postoperative day, prior to creatinine and cystatin C. This study verified the reference intervals for serum CAF. CAF could be a potential new biomarker for kidney function monitoring.

Anti-LG3 Antibodies Aggravate Renal Ischemia-Reperfusion Injury and Long-Term Renal Allograft Dysfunction.

Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia-reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia-reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes.