Renal Allograft Outcome Research Articles

The role of HLA-DP mismatches and donor specific HLA-DP antibodies in kidney transplantation: a case series

Background: The impact of HLA-DP mismatches on renal allograft outcome is still poorly understood and is suggested to be less than that of the other HLA loci. The common association of HLA-DP donor-specific antibodies (DSA) with other DSA obviates the evaluation of the actual effect of HLA-DP DSA.Methods: From a large multicenter data collection, we retrospectively evaluated the significance of HLA-DP DSA on transplant outcome and the immunogenicity of HLA-DP eplet mismatches with respect to the induction of HLA-DP DSA. Furthermore, we evaluated the association between the MFI of HLA-DP antibodies detected in Luminex assays and the outcome of flowcytometric/complement-dependent cytotoxicity (CDC) crossmatches.Results: In patients with isolated pretransplant HLA-DP antibodies (N = 13), 6 experienced antibody-mediated rejection (AMR) and 3 patients lost their graft. In HLAMatchmaker analysis of HLA-DP mismatches (N = 72), HLA-DP DSA developed after cessation of immunosuppression in all cases with 84DEAV (N = 14), in 86% of cases with 85GPM (N = 6/7), in 50% of cases with 56E (N = 6/12) and in 40% of cases with 56A mismatch (N = 2/5). Correlation analysis between isolated HLA-DP DSA MFI and crossmatches (N = 90) showed negative crossmatch results with HLA-DP DSA MFI <2000 (N = 14). Below an MFI of 10,000 CDC crossmatches were also negative (N = 33). Above these MFI values both positive (N = 35) and negative (N = 16) crossmatch results were generated.Conclusions: Isolated HLA-DP DSA are rare, yet constitute a significant risk for AMR. We identified high-risk eplet mismatches that can lead to HLA-DP DSA formation. We therefore recommend HLA-DP typing to perform HLA-DP DSA analysis before transplantation. HLA-DP DSA with high MFI were not always correlated with positive crossmatch results.

Post Renal Transplant Collapsing Glomerulopathy is Associated with Poor Outcomes.

Introduction:Collapsing glomerulopathy (CG) is a distinct morphologic pattern of proliferative renal parenchymal injury. It differ from focal segmental glomerulosclerosis (FSGS) by clinicopathologic pattern and its adverse outcome. The clinical significance of CG in renal allograft biopsies is not yet clear due to scant data and less occurrence of CG in renal transplant recipients. We conducted this single-center retrospective study to evaluate the prevalence, clinicopathological features, and outcome of post renal transplant CG.Subjects and Methods:We studied 127 renal allograft biopsies performed over a period of 45 months (Jan 2015–Oct 2018). A diagnosis of CG was made if at least one glomerulus demonstrated global or segmental collapse of the glomerular capillary walls, associated marked hyperplasia, and hypertrophy of the overlying visceral epithelial cells. We analyzed clinical, biochemical, and pathological characteristics and its impact on renal allograft outcome. Statistical analysis was performed and continuous variables were expressed as means ± standard deviation (SD) or medians (interquartile range and noncontinuous data were expressed in percentage and numerical values.Results:The prevalence of CG was 5.3% (7/127) of allograft biopsies. Out of the seven patients, six patients had undergone live donor transplant and one patient had undergone deceased donor renal transplant. The native kidney disease was unknown in these patients except one (IgA nephropathy). The median duration of diagnosis for CG was 17 months after transplantation (range 5–132months). Presenting symptoms were pedal edema and hypertension in 71.4% (5) patients each. All patients had proteinuria of more than 1 gm and renal allograft dysfunction and median serum creatinine of 3.05 mg/dl (1.5–4.8 mg/dl). All patients received standard triple immunosuppression. Over a period of 2–20 months, 57.14% (4) patients developed a graft failure and 43% (3) of the other patients had functioning grafts with serum creatinine of 1.5–4.2 mg/dl.Conclusions:CG presents with moderate to severe proteinuria and may lead to rapid graft dysfunction and subsequent graft failure in most of the patients.

Acceptable Donor-Specific Antibody Levels Before and After Desensitization Therapy in Living Donor Kidney Transplantation.

Plasmapheresis (PP) is commonly used for desensitization in highly sensitized patients with donor-specific antibodies (DSA) in living donor kidney transplantation. We analyzed the impact of DSA levels before and after desensitization on renal allograft outcome. Twenty-three patients who underwent desensitization with PP, intravenous immunoglobulin (IVIG), and rituximab before kidney transplantation in Seoul National University Hospital from August 2006 to August 2016 were enrolled. The association of median fluorescent intensity (MFI) value of DSA with graft outcome was analyzed. The frequency of positive HLA class II DSA after desensitization was lower in patients without antibody-mediated rejection (AMR) compared to those with AMR (p = 0.006). The cutoff value of MFI sum of HLA class II DSA after desensitization for predicting AMR was 2,122 with 63% sensitivity and 94% specificity. The frequency of moderate HLA class II DSA (MFI 5,000 - 10,000) after desensitization was significantly higher in patients with graft loss compared to those without graft loss (p = 0.02). Weak HLA class II DSA after desensitization including PP, IVIG, and rituximab was related to AMR and moderate levels of HLA class II DSA after desensitization was related to graft loss in living donor kidney transplantation.

Comparing the effect of induction therapy with or without antithymocyte globulin on renal allograft outcomes in live-donor kidney transplant recipients

Background: This study aimed to investigate the effectiveness of antithymocyte globulin (ATG) in low-risk live-donor kidney transplant recipients (LDKTRs). Methods: In this cohort study, 114 LDKTRs were analyzed in 2 groups of ATG induction therapy (n=77) and control (n=37). In this study, 500 mg pulse therapy with methylprednisolone was provided for both groups for 3 days. In addition, one mg/kg of daily ATG was prescribed for 4 days in ATG induction group. Serum creatinine (Cr) was measured at 3, 7, 30, 90, and 180 days after surgery and discharge day. Acute rejection (AR) was confirmed based on biopsy or rise in serum Cr by three-tenths from baseline if other causes had been ruled out. Survival analysis was used by Stata14 and p < 0.05 was considered significant. Results: Cr changes were not significantly different between ATG induction therapy and control group in all follow-up periods (2.26 and 1.07 in ATG vs 2.26 and 1.03 in control group from the third day; (p=0.999) to the sixth month (p=0.735)). There was no significant difference between the 2 study groups in AR incidence (11.7% in ATG vs 10.8% in control group, P = 0.890) and its time (9.6 in ATG vs 9.8 in control group, p=0.695). Recipients factors were baseline Cr >10 mg/dL (p=0.055), blood group AB (p=0.007), no postoperative pulse therapy with methylprednisolone (PM) (p=0.005); and donors’ factors were age ≤ 30 years (p=0.022) and blood group AB (p=0.006). Also, based on the log rank analysis, recipient-donor weight difference of 0 to 5 kg (p=0.047) had a significant association with earlier AR. Exploring these effects simultaneously by Cox regression analysis showed only significant results for recipients' baseline Cr (p=0.040) and postoperative therapy with PM (p=0.014). Conclusion: Both strategies of induction therapy had the same good results based on Cr decrease. Recipients' baseline Cr and postoperative therapy with PM were the predictors of survival time of the kidney (AR).

Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model.

Introduction: The majority of kidneys used for transplantation are retrieved from brain-dead organ donors. In brain death, the irreversible loss of brain functions results in hemodynamic instability, hormonal changes and immunological activation. Recently, brain death has been shown to cause activation of the complement system, which is adversely associated with renal allograft outcome in recipients. Modulation of the complement system in the brain-dead donor might be a promising strategy to improve organ quality before transplantation. This study investigated the effect of an inhibitory antibody against complement factor B on brain death-induced renal inflammation and injury.Method: Brain death was induced in male Fischer rats by inflating a balloon catheter in the epidural space. Anti-factor B (anti-FB) or saline was administered intravenously 20 min before the induction of brain death (n = 8/group). Sham-operated rats served as controls (n = 4). After 4 h of brain death, renal function, renal injury, and inflammation were assessed.Results: Pretreatment with anti-FB resulted in significantly less systemic and local complement activation than in saline-treated rats after brain death. Moreover, anti-FB treatment preserved renal function, reflected by significantly reduced serum creatinine levels compared to saline-treated rats after 4 h of brain death. Furthermore, anti-FB significantly attenuated histological injury, as seen by reduced tubular injury scores, lower renal gene expression levels (>75%) and renal deposition of kidney injury marker-1. In addition, anti-FB treatment significantly prevented renal macrophage influx and reduced systemic IL-6 levels compared to saline-treated rats after brain death. Lastly, renal gene expression of IL-6, MCP-1, and VCAM-1 were significantly reduced in rats treated with anti-FB.Conclusion: This study shows that donor pretreatment with anti-FB preserved renal function, reduced renal damage and inflammation prior to transplantation. Therefore, inhibition of factor B in organ donors might be a promising strategy to reduce brain death-induced renal injury and inflammation.

Comparing the effect of induction therapy with or without antithymocyte globulin on renal allograft outcomes in live-donor kidney transplant recipients

Background: This study aimed to investigate the effectiveness of antithymocyte globulin (ATG) in low-risk live-donor kidney transplant recipients (LDKTRs). Methods: In this cohort study, 114 LDKTRs were analyzed in 2 groups of ATG induction therapy (n=77) and control (n=37). In this study, 500 mg pulse therapy with methylprednisolone was provided for both groups for 3 days. In addition, one mg/kg of daily ATG was prescribed for 4 days in ATG induction group. Serum creatinine (Cr) was measured at 3, 7, 30, 90, and 180 days after surgery and discharge day. Acute rejection (AR) was confirmed based on biopsy or rise in serum Cr by three-tenths from baseline if other causes had been ruled out. Survival analysis was used by Stata14 and p < 0.05 was considered significant. Results: Cr changes were not significantly different between ATG induction therapy and control group in all follow-up periods (2.26 and 1.07 in ATG vs 2.26 and 1.03 in control group from the third day; (p=0.999) to the sixth month (p=0.735)). There was no significant difference between the 2 study groups in AR incidence (11.7% in ATG vs 10.8% in control group, P = 0.890) and its time (9.6 in ATG vs 9.8 in control group, p=0.695). Recipients factors were baseline Cr >10 mg/dL (p=0.055), blood group AB (p=0.007), no postoperative pulse therapy with methylprednisolone (PM) (p=0.005); and donors' factors were age ≤ 30 years (p=0.022) and blood group AB (p=0.006). Also, based on the log rank analysis, recipient-donor weight difference of 0 to 5 kg (p=0.047) had a significant association with earlier AR. Exploring these effects simultaneously by Cox regression analysis showed only significant results for recipients' baseline Cr (p=0.040) and postoperative therapy with PM (p=0.014). Conclusion: Both strategies of induction therapy had the same good results based on Cr decrease. Recipients' baseline Cr and postoperative therapy with PM were the predictors of survival time of the kidney (AR).

Multiparametric magnetic resonance imaging shows promising results to assess renal transplant dysfunction with fibrosis

Here we assessed the diagnostic value of a quantitative multiparametric magnetic resonance imaging (mpMRI) protocol for evaluation of renal allograft dysfunction with fibrosis. Twenty-seven renal transplant patients, including 15 with stable functional allografts (eGFR mean 71.5 ml/min/1.73m2), and 12 with chronic dysfunction/established fibrosis (eGFR mean 30.1 ml/min/1.73m2), were enrolled in this prospective single-center study. Sixteen of the patients had renal biopsy (mean 150 days) before the MRI. All patients underwent mpMRI at 1.5T including intravoxel-incoherent motion diffusion-weighted imaging, diffusion tensor imaging, blood oxygen level dependent (BOLD R2*) and T1 quantification. True diffusion D, pseudodiffusion D*, perfusion fraction PF, apparent diffusion coefficient (ADC), fractional anisotropy (FA), R2* and T1 were calculated for cortex and medulla. ΔT1 was calculated as (100x(T1 Cortex-T1 Medulla)/T1 Cortex). Test-retest repeatability and inter-observer reproducibility were assessed in four and ten patients, respectively. mpMRI parameters had substantial test-retest and interobserver repeatability (coefficient of variation under 15%), except for medullary PF and D* (coefficient of variation over 25%). Cortical ADC, D, medullary ADC and ΔT1 were all significantly decreased, while cortical T1 was significantly elevated in fibrotic allografts. Cortical T1 showed positive correlation to the Banff fibrosis and tubular atrophy scores. The combination of ΔT1 and cortical ADC had excellent cross-validated diagnostic performance for detection of chronic dysfunction with fibrosis. Cortical ADC and T1 had good performance for predicting eGFR decline at 18 months (4 or more ml/min/1.73m2/year). Thus, the combination of cortical ADC and T1 measurements shows promising results for the non-invasive assessment of renal allograft histology and outcomes.

The temporal and long-term impact of donor body mass index on recipient outcomes after kidney transplantation - a retrospective study.

The impact of increasing body mass index (BMI) on development and progression of chronic kidney disease is established. Even implantation kidney biopsies from obese living donors demonstrate subtle histologic changes despite normal function. We hypothesized that kidneys from obese living (LD) and deceased donors (DD) would have inferior long-term allograft outcomes. In a study utilizing US transplant registry, we studied adult kidney transplant recipients from 2000 to 2014. Donors were categorized as BMI <20 (underweight), 20-25 (normal), 25-30 (overweight), 30-35 (mildly obese), and >35kg/m2 (very obese). Our outcome of interest was death censored graft failure (DCGF). Cox proportional hazards model were fitted separately for recipients of DD and LD kidneys, and adjusted for donor, recipient, and transplant characteristics, including donor and recipient size mismatch ratio. Among 118734 DD and 84377 LD transplants recipients, we observed a significant and graded increase in DCGF risk among the overweight (LD:HR=1.06, DD:HR=1.04), mildly obese (LD:HR=1.16, DD:HR=1.10), and very obese (LD:HR=1.22, DD:HR=1.22) compared to normal BMI (P<0.05). The graded effect of donor BMI on outcomes begins early and persists throughout the post-transplant period. Donor obesity status is an independent risk factor for inferior long-term renal allograft outcome despite adjusting for donor and recipient size mismatch and other donor, recipient, and transplant factors.

Doação de Rins Após Paragem Cardiocirculatória: O Papel da Oxigenação por Membrana Extracorporal

Introdução: A doença renal crónica é uma patologia prevalente, sendo significativo o número de doentes em estádio terminal cujas alternativas se resumem à terapêutica de substituição da função renal e ao transplante, sendo o último associado a maior qualidade de vida e a menor mortalidade. A procura crescente de rins para transplante tem aumentado o desfasamento relativamente aos rins disponíveis. Esse desfasamento impulsionou a pesquisa e desenvolvimento de alternativas aos dadores cadáver em morte cerebral, sendo os dadores após paragem cardiocirculatória uma alternativa viável. Estes obrigam a técnicas de preservação de órgão distintas, de forma a poder oferecer resultados funcionais sobreponíveis. O objetivo deste artigo foi rever a evidência recente sobre o papel da utilização da oxigenação por membrana extracorporal como técnica de preservação, na colheita de rins de dadores após paragem cardiocirculatória.&#x0D; Material e Métodos: Foi efectuada uma pesquisa na base PubMed/MEDLINE, utilizando as expressões: “kidney transplantation”; “non-heart-beating donor”; “donation after cardiac death”; “extracorporeal membrane oxygenation”; “abdominal normothermic perfusion”. Com os artigos selecionados, realizou- se uma revisão não sistemática, sumarizando a evidência recente sobre a utilização da oxigenação por membrana extracorporal na colheita de rins de dadores após paragem cardiocirculatória.&#x0D; Resultados: Verificou-se que os estudos sugerem com unanimidade que a oxigenação por membrana extracorporal é superior às outras técnicas de preservação utilizadas em dadores após paragem cardiocirculatória, uma vez que está associada a melhores resultados a curto prazo do aloenxerto renal. Relativamente aos dadores convencionais, em morte cerebral, a técnica permite resultado semelhantes, quando comparada com os dadores de morte cerebral de critérios expandidos.&#x0D; Discussão: A preservação de órgãos através da oxigenação por membrana extracorporal nos dadores após paragem cardiocirculatória permite resultados funcionais favoráveis e, por esse motivo, poderá contribuir para o aumento do pool de dadores. As dificuldades logísticas associadas à implementação da técnica restringem a sua utilização.&#x0D; Conclusão: A longo prazo, deverão ser criadas condições para a implementação em mais centros da oxigenação por membrana extracorporal nos dadores após paragem cardiocirculatória, aumentando o pool de rins disponíveis para transplante.

CXCR5+PD1+ICOS+ Circulating T Follicular Helpers Are Associated With de novo Donor-Specific Antibodies After Renal Transplantation.

Donor-specific anti-HLA antibodies (DSAs) are a major risk factor associated with renal allograft outcomes. As a trigger of B cell antibody production, T follicular helper cells (Tfhs) promote DSA appearance. Herein, we evaluated whether circulating Tfhs (cTfhs) are associated with the genesis of antibody-mediated rejection. We measured cTfh levels on the day of transplantation and 1 year after transplantation in blood from a prospective cohort of 237 renal transplantation patients without DSA during the first year post-transplantation. Total cTfhs were characterized as CD4+CD45RA−CXCR5+, and the three following subsets of activated cTfh were analyzed: CXCR5+PD1+, CXCR5+PD1+ICOS+, an CXCR5+PD1+CXCR3−. Immunizing events (previous blood transfusion and/or pregnancy) and the presence of class II anti-HLA antibodies were associated with increased frequencies of activated CXCR5+PD1+, CXCR5+PD1+ICOS+, and CXCR5+PD1+CXCR3− cTfh subsets. In addition, ATG-depleting induction and calcineurin inhibitor treatments were associated with a relative increase of activated cTfh subsets frequencies at 1 year post-transplantation. In multivariate survival analysis, we reported that a decrease in activated CXCR5+PD1+ICOS+ at 1 year after transplantation in the blood of DSA-free patients was significantly associated with the risk of developing de novo DSA after the first year (p = 0.018, HR = 0.39), independently of HLA mismatches (p = 0.003, HR = 3.79). These results highlight the importance of monitoring activated Tfhs in patients early after transplantation and show that current treatments cannot provide early, efficient prevention of Tfh activation and migration. These findings indicate the need to develop innovative treatments to specifically target Tfhs to prevent DSA appearance in renal transplantation.

Abstract 003: Early and Late Post-Kidney Transplant Hypertension and Late Renal Allograft Outcome

Background: Association between pattern of blood pressure (BP) change at different period after kidney transplantation (KTx) and renal allograft function is unclear. We examine the association between changes in BP patterns and long-term allograft function. Methods: Kidney transplant recipients were stratified into 4 groups based on presence (+) or absence (-) of systolic hypertension (SHTN; SBP ≥130 mmHg) both at 1 and 6 mo post-KTx (Gr1 (-,-), Gr2 (-,+), Gr3 (+,-), Gr4 (+,+)). Declined allograft function defined by a decrease in eGFR from baseline eGFR at 1-mo post-KTx during 24 mo of follow-up among 4 different groups is examined by multivariable Cox regression analysis. Results: Of all 70 patients, mean±SD age was 52.7±12 yr and 41% was female. Mean SBP at 1- and 6-mo post-KTx were 130.9±18.3 and 136.2±18.2 mmHg, respectively. Baseline mean eGFR at 1-mo post-KTx was 50.86±18.89 ml/min/1.73 m 2 and were not different among all 4 groups. Among 70 patients, 57 patients (81%) had a decrease in eGFR between 1 and 24 mo post-KTx with a median time to outcome of 6.8 mo (IQR 2.8-19.6) and the incidence rate of 0.075 person-mo. The number of patients (% in each group) with declined eGFR in Gr1, 2, 3 and 4 were 15 (88%), 17 (89%), 7 (78%), and 18 (72%) patients, respectively (x 2 2.8830, p 0.410). Compared to Gr1, Gr2 had higher, but Gr 3 and 4 had lower the risk of declining eGFR but no statistical significance (HR(95% CI): Gr2 1.20 (0.60-2.40); Gr3 0.79 (0.32-1.95); Gr4 0.78 (0.39-1.55)). After adjusted for age, gender, race, types of induction immunosuppression, types of KTx, SBP, DBP, and BMI at the time of KTx, Gr3 became higher risk; otherwise, the direction of the association remains the same for Gr2 and Gr4. Conclusion: Changes in SBP from either normotension to HTN or vice versa between 1 and 6 mo post-KTx appears to be associated with poorer allograft function within 24 mo post-KTx; whereas, maintaining SBP pattern both normotension or HTN from 1 to 6 mo post-KTx may be protective for a decline in allograft function. Very early BP levels during 1 mo post-KTx may be the suitable target SBP for kidney transplant recipients and too liberal or tight BP control in normotensive or hypertensive patients after 1 mo post-KTx may associated with greater risk for worsening long-term allograft outcomes.

Impact of Adopting Routine Luminex-Based Pretransplant Assessment of HLA Antibodies on Clinical Practice and Outcomes in Kidney Transplantation

BackgroundAccumulating evidence suggests that detection of human leukocyte antigen (HLA) antibodies by solid phase Luminex assays predicts renal allograft outcomes. However, several controversies exist regarding the interpretation, reproducibility, impact and financial feasibility of global utilization of this assay in pretransplant assessment. MethodsWe studied short-term patient-centered outcomes, medical standards of care, and financial plausibility of using Luminex-based screening for HLA antibodies in renal allograft recipients compared to outcomes in nontested patients. ResultsWe included 1808 patients assessed for transplantation from 2011 to 2018. Luminex-tested patients had lower rates of rejection in the first post-transplant week (OR 0.36, P < .001) and lower odds of antibody-mediated rejection in the first 6 months (OR 0.4, P = .004). Forty-four patients with preformed, donor-specific antibodies were transplanted, and everolimus was introduced into our protocols for low-risk patients based on risk stratification by Luminex results. The number of tests needed to be performed to prevent 1 episode of antibody-mediated rejection in the first 6 months was 28 (P = .004), which was financially plausible. ConclusionsRoutine pre-transplant assessment of HLA antibodies using Luminex assays may allow for better patient-centered, short-term graft outcomes and objective tailoring of immunosuppression at a financially plausible, cost-effective rate.

SUN-120 POST-TRANSPLANT ARSENIC AND THE RISK OF DEATH-CENSORED GRAFT FAILURE IN RENAL TRANSPLANT RECIPIENTS

Arsenic exposure leads to nephrotoxicity, renal fibrosis, and progressive decline in renal function. To date, however, no study has been devoted to evaluate the association between arsenic exposure and renal allograft failure. We investigated the prospective association between circulating arsenic and risk of graft failure in a large cohort of renal transplant recipients (RTRs) with long-term follow-up. Blood arsenic concentrations were measured in an extensively phenotyped cohort of RTRs. Dietary intake was assessed using a validated 177-item food Food Frequency Questionnaire. Backward linear regression analyses were performed to identify determinants of circulating arsenic concentrations. Associations of circulating arsenic concentrations with incident death-censored graft failure were assessed using Cox-proportional hazards regressions analyses. We included 665 RTRs (53 ± 13 years-old, 58% men). The median (interquartile range) arsenic concentration was 1.26 (1.04 - 2.04) ng/mL. Backward linear regression analyses showed that fish consumption and estimated Glomerular Filtration Rate (eGFR) were the major determinants of circulating arsenic concentrations (std. β = 0.22; P-value = 0.001; and, std. β = ─0.19; P-value = 0.003, respectively). At 5 years of follow-up, 72 (11%) patients had developed graft failure. In multivariable Cox regression analyses, circulating arsenic was positively associated with risk of death-censored graft failure (hazard ratio, 1.59; 95% confidence interval, 1.10 to 2.30 per 1 ng/mL higher circulating arsenic concentration), independent of several potential confounders including transplant- and graft failure-related risk factors. Similar findings were found at 4 and 3 years of follow-up (respectively, hazard ratio, 1.75; 95% confidence interval, 1.15 to 2.66; and, hazard ratio, 1.64; 95% confidence interval, 1.02 to 2.64, per 1 ng/mL higher circulating arsenic concentration). Table 1Prospective analyses of the association of circulating arsenic with death-censored graft failure in 665 RTRs at 5-, 4-, and 3-years of follow-upCirculating arsenic, ng/mL3-yrs of follow-up4-yrs of follow-up5-yrs of follow-upHR95%CIHR95%CIHR95%CIEvents, n455672Model 11.481.00─2.171.471.04─2.091.471.08─2.01Model 21.851.22─2.811.891.30─2.761.791.28─2.51Model 31.761.14─2.711.721.16─2.561.771.24─2.53Model 41.641.02─2.641.751.15─2.661.591.10─2.30 Open table in a new tab Model 1: crude. Model 2: adjusted for fish intake. Model 3: model 2 + adjustment for donor age, recipient age, donor type, time since transplantation and baseline, immunosuppressive therapy. Model 4: model 2 + adjustment for eGFR, systolic blood pressure, total cholesterol and triglycerides concentration, history of diabetes, homocysteine, and hs-CRP. The association of post-transplant arsenic exposure with renal allograft outcomes has long been overlooked in clinical research. These data show for the first time that relatively higher post-transplant circulating arsenic concentrations are independently associated with higher long-term risk of graft failure in RTRs.

2013 Banff Criteria for Acute Antibody-Mediated Rejection Are Superior to 2007 Banff Criteria in the Diagnosis and Assessment of Renal Allograft Outcomes

BackgroundThe 2013 Banff meeting updated the requirements for the diagnosis of acute/active antibody-mediated rejection (AAMR) in kidney allografts. There has been speculation that the changes lower the threshold for diagnosing AAMR, and may lead to possible unnecessary and expensive treatment. MethodsWe compared the 2013 Banff classification for AAMR to the previous 2007 Banff to determine if there was an increase in the number of patients receiving a diagnosis of AAMR and if the diagnosis affected allograft survival and post-biopsy 3-month and 6-month creatinine and eGFR values. ResultsA total of 212 renal allograft biopsies were compared to both 2007 and 2013 Banff classification requirements for AAMR. Ten patients (11 biopsies) met the 2007 criteria. An additional 15 patients (20 biopsies) met the 2013 criteria. These 2 groups showed no statistically significant demographic differences. By applying the 2013 Banff classification, we observed a 2.5-fold increase in the number of AAMR cases. One-year post-transplant allograft survival was higher in the 2013 group (.85 vs .55) and the 3-month and 6-month post-biopsy creatinine values were significantly lower for the 2013 group (1.6 ± .6 vs 3.3 ± 2.2, P value .01, and 1.7 ± .6 vs 3.4 ± 2.8, P value .03). The 3-month and 6-month eGFR values were higher in the 2013 group, although not statistically significant. ConclusionsThese results suggest that use of Banff 2013 criteria in place of Banff 2007 may result in diagnosing milder and earlier cases of AAMR with the possibility of initiating earlier treatment and improving graft outcomes.

BK virus histopathologic disease severity does not predict allograft outcome in renal transplant recipients

AimsBK polyomavirus nephropathy (BKPyVN) is an important cause of allograft failure after renal transplantation. Despite early screening for the virus, allograft loss from BKPyVN is still experienced in up to 14% of all renal transplant recipients. The aim of this study was to investigate the association between BKPyVN histopathologic disease severity and allograft outcome at our center. MethodsKidney transplant recipients who had undergone transplantation between 2002 and 2014 with biopsy proven BKPyVN were eligible for this retrospective study. Each biopsy was re-evaluated by a single pathologist blinded to the clinical data and scored according to the Banff criteria for rejection and BKPyVN. Serum creatinine and BK viral load at the time of biopsy diagnosis as well as allograft outcomes to include allograft survival and serum BK viremia resolution were collected for each recipient to determine if BK virus histopathologic disease severity could predict allograft outcome. ResultsTwenty cases of BKPyVN were identified from 1031 total renal transplants performed. There was no statistical association between allograft loss and BKPyVN histopathology (p = 0.49). There was also no statistical association between BKPyVN histopathology and BK viral load at the time of biopsy diagnosis (p = 0.38) or serum BK viremia resolution (p = 0.16). ConclusionsBKPyVN histopathology does not appear to be useful in predicting renal allograft outcome in those recipients diagnosed with BKPyVN which is in contrast to some previously published data.

Early and Late Post-Kidney Transplant Weight Changes and Renal Allograft Outcome (P21-036-19)

ObjectivesPost-Transplant weight gain is associated with poor renal allograft function. Association between pattern of weight gain at different period after kidney transplantation (KTx) especially during late transplantation and renal allograft function is unclear. We aim to address to potential effect of weight changes on renal allograft function. MethodsSeventy kidney transplant recipients from a single center were stratified into 4 groups based on weight gain (+) and/or weight loss (−) compared to weight at the time of KTx both at 1 and 6 months post-KTx (Gr1 (−, −), Gr2 (−, +), Gr3 (+, −), Gr4 (+, +)). Decline in renal allograft function defined by dropped in eGFR from baseline eGFR at 1-month post-KTx during 24 months of follow-up in different 4 groups is examined by multivariable Cox proportional hazard regression analysis. ResultsMean ± SD age was 52.66 ± 11.97 years and 59% was male. Mean ± SD body mass index (BMI) at the time of KTx was 27.64 ± 5.64 kg/m2. Distribution of patients in 4 groups of Gr1, 2, 3, and 4 were 34, 36, 10, and 20%, respectively and mean BMI of all 4 groups at the time of KTx were not statistically significant (p 0.0981). Mean weight changes among 4 groups based on weight change both at 1- and 6-month post-KTx were summarized in the Table 1. Baseline renal allograft function with a mean eGFR of 50.86 ± 18.90 ml/min/1.73 m2 were not different among all 4 groups (Table 1). Among 70 patients, 43 patients (61%) had a decline in eGFR between 1 and 24 months post-KTx and contributed to the incidence rate of 0.056 person-months. The number of patients with dropped eGFR in Gr1, 2, 3 and 4 were 14 (58%), 14 (56%), 4 (57%), and 11 (79%) patients, respectively. Compared to Gr1, Gr2 had lower, but Gr 3 and 4 had higher the risk for declining eGFR but no statistical significance (HR(95% CI): 0.84 (0.40–1.76); 1.18 (0.39–3.60); 1.31 (0.60–2.90)). After adjusted for age, gender, race, types of KTx, systolic and diastolic blood pressure and BMI at the time of KTx, the association remains the same. (HR(95% CI): 0.78 (0.34–1.81); 1.66 (0.46–6.04); 1.32 (0.53–3.34)). ConclusionsWeight loss at very early (1 month) post-KTx appears protective for a decline in renal allograft function during 24 months post-KTx; whereas, weight gain at later time post-KTx (6 months) after initial early weight loss was even associated with better renal allograft outcomes. Factors associated with early post-KTx weight gain may contribute to pathophysiology of poorer renal allograft function. Funding SourcesNone. Supporting Tables, Images and/or Graphs▪

Clinical Significance of Renal Allograft Protocol Biopsies: A Single Tertiary Center Experience in Malaysia.

Background The role of protocol renal allograft biopsy in kidney transplantation is controversial due to the concern with procedural-related complications; however, its role is slowly evolving. Recent evidence suggests that protocol biopsy is useful in detecting subclinical renal pathology. Early recognition and treatment of renal pathologies can improve long-term outcomes of renal allografts. Methodology A total of 362 renal allograft protocol biopsies were performed in adult recipients of kidney transplantation between 2012 and 2017. After excluding those with poor quality or those performed with a baseline serum creatinine level >200 umol/L, we analyzed 334 (92.3%) biopsies. Histology reports were reviewed and categorized into histoimmunological and nonimmunological changes. The immunological changes were subcategorized into the following: (1) no acute rejection (NR), (2) borderline changes (BC), and (3) subclinical rejection (SCR). Nonimmunological changes were subcategorized into the following: (1) chronicity including interstitial fibrosis/tubular atrophy (IFTA), chronic T-cell-mediated rejection (TCMR), unspecified chronic lesions, and arterionephrosclerosis, (2) de novo glomerulopathy/recurrence of primary disease (RP), and (3) other clinically unsuspected lesions (acute pyelonephritis, calcineurin inhibitors toxicity, postinfective glomerulonephritis, and BK virus nephropathy). Risk factors associated with SCR were assessed. Results For the histoimmunological changes, 161 (48.2%) showed NR, 145 (43.4%) were BC, and 28 (8.4%) were SCR. These clinical events were more pronounced for the first 5 years; our data showed BC accounted for 59 (36.4%), 64 (54.2%), and 22 (40.7%) biopsies within <1 year, 1-5 years, and > 5 years, respectively (p = 0.011). Meanwhile, the incidence for SCR was 6 (3.7%) biopsies in <1 year, 18 (15.3%) in 1-5 years, and 4 (7.4%) in >5 years after transplantation (p=0.003). For the nonimmunological changes, chronicity, de novo glomerulopathy/RP, and other clinically unsuspected lesions were seen in 40 (12%), 10 (3%), and 12 (3.6%) biopsies, respectively. Living-related donor recipients were associated with decreased SCR (p=0.007). Conclusions Despite having a stable renal function, our transplant recipients had a significant number of subclinical rejection on renal allograft biopsies.

Pathogenesis and treatment of electrolyte problems post transplant.

Electrolyte abnormalities posttransplant are common occurrences that can have significant short-term and long-term effects on graft outcome and patient quality of life. Understanding the pathophysiology of these electrolyte derangements can help guide management to optimize bone health and minimize cardiovascular disease. This review explores the pathogenesis of the most common postrenal transplant electrolytes abnormalities as well as current treatment options. Clarifications of the role of FGF-23 has improved our understanding of posttransplant bone disease in addition to the known roles of hyperparathyroidism and vitamin D. The mechanisms of renal electrolyte wasting by immunosuppressive agents give insight into potential treatment options for hyperkalemia and hypomagnesemia. Understanding the pathogenesis of the common electrolyte abnormalities found post renal transplant may lead to targeted treatment options that in turn may improve transplant complications. Further studies are required to evaluate the effects on long-term outcomes of renal allografts.

Post-transplant donor specific antibody is associated with poor kidney transplant outcomes only when combined with both T-cell–mediated rejection and non-adherence

Post-transplant donor specific antibody (DSA) is associated with poor renal allograft outcomes. However, variable timing of DSA assessment and inclusion of patients who undergo desensitization treatments have hindered our understanding of its consequences and limited its predictive value. Here we prospectively studied non-desensitized patients to determine factors associated with poor four-year outcomes in patients who developed post-transplant DSA. Using serial monitoring, 67 of 294 patients were found to develop DSA by one year. Compared to patients who do not develop DSA, those with DSA exhibit an increased incidence of both clinical and subclinical T-cell-mediated rejection (TCMR). The combination of TCMR plus DSA led to an almost three-fold increase in graft loss compared to either DSA or TCMR alone. Moreover, DSA was associated with higher Banff grade TCMR and chronic changes at one year. Antibody-mediated rejection was uncommon and always associated with TCMR. Amongst factors independently associated with DSA plus TCMR; non-adherence is potentially modifiable. Non-adherence, measured as intra-patient variability of calcineurin trough levels during the first post-transplant year, further risk-stratified patients with DSA plus TCMR such that about 75% of these patients had impending graft loss by four years, whereas adherent patients with DSA plus TCMR had outcomes comparable to other patient groups. Thus, early post-transplant DSA, especially in non-adherent patients, is associated with increased incidence of TCMR and represents a high-risk group of patients who might benefit from targeted therapeutic interventions.

Cytokine Profiles Associated With Angiotensin II Type 1 Receptor Antibodies

IntroductionAngiotensin II type 1 receptor antibody (AT1R-Ab), is a non–human leukocyte antigen (HLA) antibody implicated in poor renal allograft outcomes, although its actions may be mediated through a different pathway than HLA donor-specific antibodies (DSAs). Our aim was to examine serum cytokine profiles associated with AT1R-Ab and distinguish them from those associated with HLA DSA in serially collected blood samples from a cohort of pediatric renal transplant recipients.MethodsBlood samples from 65 pediatric renal transplant recipients drawn during the first 3 months posttransplant, at 6, 12, and 24 months posttransplant, and during suspected episodes of kidney transplant rejection were tested for AT1R-Ab, HLA DSA, and a panel of 6 cytokines (tumor necrosis factor [TNF]-α, interferon [IFN]-γ, interleukin [IL]-8, IL-1β, IL-6, and IL-17). Associations between antibodies and cytokines were evaluated.ResultsAT1R-Ab, but not HLA DSA, was associated with elevations in TNF-α, IFN-γ, IL-8, IL-1β, IL-6, and IL-17. This relationship remained significant even after controlling for relevant clinical factors and was consistent across all time points. In contrast to HLA DSA, AT1R-Ab was associated with elevations in vascular inflammatory cytokines in the first 2 years posttransplant.ConclusionsThis profile of vascular cytokines may be informative for clinical monitoring and designing future studies to delineate the distinct pathophysiology of AT1R-Ab–mediated allograft injury in kidney transplantation.