Lower Graft Function Research Articles

#2462 Impact of tacrolimus peak concentration on kidney graft outcomes

Abstract Background and Aims Low tacrolimus (Tac) trough concentration-to-dose ratio (C0/D ratio) identifies kidney transplant patients with high level of Tac metabolization and has been shown to be associated with lower graft function and survival. Why fast metabolizers experience poorer outcomes is however unclear. We hypothesized that fast metabolization is associated with higher maximal Tac blood concentration (Cmax) and that Tac Cmax has a detrimental effect by itself. Method We retrospectively selected consecutive kidney transplant patients who (I) were treated by Tac (irrespective of the pharmaceutical formulation), (ii) had systematic abbreviated pharmacokinetic tac evaluation at 3- and 12-months’ post-transplant, and (iii) had a minimal follow-up of 5 years. Fast metabolizers were defined by a C0/D ratio <1.05. Cmax was defined by the higher value of Tac concentration observed at 30, 90 or 180 minutes after Tac morning ingestion and was indexed to C0 in order to exclusively focus on patients with no obvious Tac overexposure. Association between Tac Cmax/C0 with traditional transplant outcomes was analysed by univariate and multivariate cox model and logrank test when appropriate. Results 436 patients transplanted from 2008 to 2016 (64% of male, mean age of 55 ± 13 y) with a median follow-up of 8 years (Q1: 6; Q3: 11) were analysed. Fast metabolizers had lower C0 while receiving higher dose of Tac and displayed significantly higher median Cmax (20 vs 17 μg/l, p < 0.001). Median Cmax/C0 was 3 and 2 in fast and non-fast metabolizers, respectively (p < 0.001). At 15 years’ post-transplant, death-censored graft survival was 13% lower for patients with the highest Cmax/C0 values (p = 0.04). In multivariate cox analysis, higher Cmax/C0 was independently associated with death-censored graft survival (HR = 1.30 (1.03;1.64), p = 0.026). Conclusion Our data support the hypotheses 1—that fast metabolizers exhibit higher Tac Cmax even in situations where Tac C0 are not elevated and 2—that exposure to high Cmax is a potential mechanism underlying their poorer outcome. Tac formulations prone to mitigate pharmacokinetic peak could thus be particularly beneficial to fast metabolizers and should be thoroughly evaluated in this indication.

Serum uric acid concentration is associated with lower glomerular filtration rate in children undergoing kidney transplantation.

The relationship between serum concentration of uric acid (UA) and chronic kidney disease is complex due to many confounding variables. There is currently debate over whether hyperuricemia acts as a marker of kidney disease or as an independent risk factor. To test the impact of serum UA concentration on the estimated glomerular filtration rate (GFR) of children undergoing kidney transplantation. Prospective longitudinal study of children and adolescents after kidney transplantation. We analyzed clinical, anthropometric, and laboratory data at pre-transplant and 1, 3, and 6 months after transplant. We developed models of repeated measures analysis, using the generalized estimating equations technique for the outcome evolution of the estimated GFR at 1, 3 and 6 months. High serum UA concentration at 1 and 3 months was modeled as the main exposure variable. We included 103 transplant patients. In a model adjusted for time, recipient sex and age, the occurrence of acute rejection episodes, and the estimated glomerular filtration at baseline, the trajectory of GFR exhibited an inverse relationship with UA (β = -7.1, 95% CI: -11.5 to -2.6, p < .01). Serum UA increase was associated with lower graft function over time.

The Association Between Kidney Donor Profile Index and 1-y Graft Function.

This single-center, retrospective cohort study analyzed data from 3059 consecutive deceased donor kidney transplant recipients with a 1-y follow-up from January 2013 to December 2017. The aim was to determine the association between the KDPI strata (0%-35%, 36%-50%, 51%-85%, 86%-100%) and 1-y eGFR estimated by the CKD-EPI equation. The incidence of delayed graft function (50.6% versus 59.3% versus 62.7% versus 62.0%; P < 0.001) and cytomegalovirus infection (36.7% versus 36.6% versus 43.3% versus 57.8%; P < 0.001) increased with increasing KDPI strata but not biopsy-proven acute rejection (9.1% versus 9.8% versus 8.4% versus 9.1%; P = 0.736). The median 1-y eGFR decreased with increasing KDPI strata (64.8 versus 53.5 versus 46.9 versus 39.1 mL/min/1.73 m2; P < 0.001). In the Cox regression, the higher the KDPI was, the lower the probability of a lower 1-y eGFR was. Assuming the 0%-35% strata as the reference, the likelihood of eGFR <50 mL/min/1.73 m2 was increased by 76.6% (hazard ratio [HR] = 1.767, 95% confidence interval [CI] = 1.406-2.220), 2.24- and 2.87-fold higher for KDPI higher >35%-50% (HR = 2.239, 95% CI = 1.862-2.691), and >51%-85% (HR = 2.871, 95% CI = 2.361-3.491), respectively. Other variables associated with a lower graft function were donor sex (HR male versus female = 0.896, 95% CI = 0.813-0.989) and cold ischemia time (HR for each hour = 1.011, 95% CI = 1.004-1.019). This association was sustained after the Poisson mediation analysis, including delayed graft function, cytomegalovirus, and acute rejection as mediators. In this cohort of deceased donor kidney recipients, KDPI, and cold ischemia time were the major independent risk factors associated with lower 1-y kidney function.

De novo Donor-specific Anti-human Leukocyte Antigen Antibody and Its Outcome in Pediatric Renal Transplant Recipients: A Single-center Experience in India

Development of de novo donor-specific anti-HLA antibody (dnDSA) is associated with poor graft survival in adults. However, there is a paucity of data about its prevalence and outcome in Indian children. We retrospectively assessed the proportion and spectrum of dnDSA and its outcome on antibody-mediated rejection (ABMR) and graft function. Children ≤18 years who were transplanted between November 2016 and October 2019 were included in this study. Pretransplant donor-specific antibody (DSA) was screened by complement-dependent cytotoxicity, flow cytometry crossmatch, and single antigen bead (SAB) class I and II by Luminex platform. Either antithymocyte globulin or basiliximab was used as induction. Tacrolimus, mycophenolate, and prednisolone were used for the maintenance of immunosuppression. SAB screening was done at 1, 3, 6 months, and yearly in seven children and at the time of acute graft dysfunction in eight. Mean fluorescence intensity ≥1000 was considered positive. Protocol biopsies were done at 3, 6, and 12 months and annually thereafter in seven children. Fifteen children, all males with a median age (interquartile range) of 13 years (11; 15.5) were analyzed. Only one child had pretransplant DSA who developed dnDSA posttransplant. Overall, 8 (53%) developed dnDSA over a median follow-up of 18 months. Seven (87%) had Class II, one Class I and 3 (37%) both Class I and II. Six had dQ and two had DR. All children with dnDSA had ABMR, of these two had subclinical rejection. DSAs persisted despite treatment, though graft function improved. Children with DSA and ABMR had lower graft function than those without DSA. The proportion of dnDSA was high in our study, majority against DQ. The detection of dnDSA prompted early diagnosis and treatment of ABMR.

Mesangiolysis in Pathological Chronic Active Antibody-Mediated Rejection in Kidney Transplant Biopsies

Introduction: This study aimed to determine if immune or nonimmune and acute or chronic lesions associated with mesangiolysis (MGLS) occurred in biopsy-proven pathological chronic active antibody-mediated rejection (P-CAABMR) in kidney transplant biopsies. Methods: We evaluated MGLS in 41 patients with biopsy findings of P-CAABMR from January 2016 to December 2019. Histological scoring was evaluated by Banff classification. Multivariate logistic regression analysis was performed using a forward selection method. Results: Fifteen of the 41 P-CAABMR biopsies (36.6%) cases showed MGLS. The estimated glomerular filtration rate (eGFR) was significantly lower in the MGLS-positive compared with the MGLS-negative group, and proteinuria was significantly higher in the MGLS-positive compared with the MGLS-negative group. In the clinical model, multivariate analysis was performed using covariates of eGFR and duration after transplantation significantly correlated with MGLS by simple analysis, in addition to type of calcineurin inhibitor use (tacrolimus or cyclosporine), donor-specific antibodies, diabetes, and hypertension grade defined by use of antihypertensive therapy or/and blood pressure level. Only hypertension grade was significantly correlated with MGLS. In the pathological model, multivariate analysis was performed using the presence of FSGS and the aah and cg scores significantly correlated with MGLS by simple analysis, in addition to g and ptc scores. The cg score was significantly correlated with hypertension grade, duration after transplantation, g, ah, and aah. Conclusion: Lower graft function and higher proteinuria was observed in MGLS of P-CAABMR. The Banff cg score was independently related to MGLS in multivariate analysis. Sustained glomerulitis, calcineurin inhibitor nephrotoxicity, and hypertension may cause Banff cg lesions, leading to MGLS in P-CAABMR.

HLA-DPB1 molecular mismatches are risk factors for acute rejection and low 5-year graft function in first kidney transplants.

The study aimed to investigate the impact of HLA-DPB1 allelic and molecular mismatches on the occurrence of acute rejection (AR) and low 5-year graft function (5Y-GF) in first kidney transplant (KT) recipients. This is a single center retrospective study of 130 deceased donor KT recipients transplanted between 2014 and 2016. HLA-DPB1 allelic MM and the following molecular MM (mMM) were analyzed: expression MM with the high expression G allele in the donor; T cell epitope MM (TCE MM); epitope MM (EMM), considering all six hypervariable regions (EMM-ABCDEF HVR), or only ABEF regions (EMM-ABEF HVR); eplet MM (EpMM); antibody-verified eplet MM (AbVer EpMM); and solvent accessible amino acid MM (SAMM). There was no association of allelic MM with AR or 5Y-GF. The variables independently associated (Cox regression analyses) with AR were high donor final creatinine, nonpermissive TCE MM, ABCDEF EMM load ≥6, EpMM load ≥6; SAMM load ≥5, and AbVer EpMM load ≥3. No association between any HLA-DPB1 mMM and 5Y-GF was observed when all 130 transplant recipients were considered. However, when transplants from expanded criteria donors were excluded, independent associations were detected (logistic regression analyses) with AbVerEpMM load ≥2, SAMM load ≥7, cerebro-vascular death, donor age, and AR. To our knowledge, this is the first study that shows that some HLA-DPB1 mMM are associated with AR and low 5Y-GF in a population of exclusively first kidney transplant recipients.

Risk factors for 1-year low graft function after deceased donor kidney transplantation

Risk factors for 1-year low graft function after deceased donor kidney transplantation

316.11: HLA-DPB1 Molecular Mismatches Are Associated With Acute Rejection and Long-term Graft Function in First Kidney Transplants

Introduction: It is generally accepted that HLA-DP mismatches (MM) do not impact the survival of first transplants but that they may exert a deleterious effect in retransplants. This study aimed to investigate the impact of HLA-DPB1 allele and molecular MM (mMM) on the occurrence of acute rejection (AR) and low 5-year graft function (5-yGF) in first kidney transplants (KT). Method: HLA-DPB1 allele and mMM were determined in 130 first KT from deceased donors, performed between 2014 and 2016. The following mMM models were investigated: expression MM, with the high expression G allele in the donor, T cell epitope (TCE) MM, classified as permissive and nonpermissive MM, epitope MM (EMM), considering all six HLA-DPB1 hypervariable regions (EMM-ABCDEF HVR) or only ABEF regions (EMM-ABEF HVR), Eplet MM (EpMM), considering all or only antibody-verified (AbVer) eplets, and solvent accessible amino acid MM (SAMM). EMM, EpletMM and SAMM loads were categorized using thresholds determined by ROC analysis for each outcome. The outcomes were AR and 5-yGF (estimated by CKD-EPI). Logistic and Cox regressions were used to investigate variables associated with 5-yGF and AR, respectively. Results: 119 (91.5%) KT were performed with one or two HLA-DPB1 allele MM. The overall incidence of AR was 17.7% and the median 5-yGF was 40.3 (27.0 - 51.7) mL/min/1.73m2. No association between HLA-DPB1 allele MM and 5-yGF or rejection was observed. Considering only recipients of standard criteria donor, five logistic models for 5-yGF were built including variables that reached a p-value <0.10 in the univariable analysis (age and donor sex, cause of brain death, ABDR MM and AR) and the mMM (TCE, SAMM, all and AbVer EpMM, EMM-ABCDEF and ABEF HVR). In the model 2, variables associated with 5-yGF≤ 40 were donor age (OR=1.08; CI95%=1.02-1.14; p=0.005) and SAMM≥7 (OR=4.40; CI95%=1.56-12.36, p<0.005), while in the model 4, donor age (OR= 1.09; CI95%=1.03-1.15; p=0.003) and EpMM(AbVer≥2 (OR=3.39; CI95%=1.2-9.45, p=0.02) were associated with low GF. The AUC-ROC for predicting 5-yGF was 0.83 (0.75-0.92) for the model 2, and 0.68 (0.57-0.79) for the model 4. Lastly, for the outcome AR in all recipients, beyond the final donor creatinine, the following mMM models were statistically significant: TCE (HR=3.01; CI95%=1.33-6.84; p=0.008), SAMM≥5 (HR=2.69; CI95%=1.10-6.56; p=0.03), AbVerEpMM ≥3 (HR=3.38; 95%CI=1.32-8.70; p=0.01), and EMM-ABCDEF HVR ≥ 6 (HR=5.08; 95%CI=2.19-11.82; p<0.001). Conclusion: To the best of our knowledge, this is the first study that shows that some mMM, in contrast to classical allele HLA-DPB1 MM, are associated with acute rejection and long-term graft function in a population of exclusively first kidney transplants.

MO974: Post-Transplant Glomerulonephritis: A Comparative Cohort Study

Abstract BACKGROUND AND AIMS Post-transplant glomerulonephritis (GMNPTR) is considered the third cause of graft loss. This entity is associated with worse outcomes when compared with the rest of the transplanted population; however, it is little explored whether this risk is maintained despite comparing it with a similar immunological risk. METHOD Retrospective cohort study of 12-year kidney transplant recipients (KT) with active follow-up and biopsy-proven diagnosis of GMNPTR. The objectives were to describe the incidence of GMNPTR, describe the frequency of histological diagnoses, and perform a comparative analysis of outcomes with 1: 1 matched controls by: gender, age ± 3 years, shared haplotypes, and year of RT ± 3 years. Kaplan–Meier was used for the analysis of time-dependent variables and Mann–Whitney U was used for comparison of graft function. RESULTS In the study period, 632 TR were performed, 54 cases of GMNPTR were found for an incidence of 8.5%. Of these 44 (81.5%) correspond to primary nephropathies, the most frequent being the mesangioproliferative pattern (n = 14, 25.9%), IgA nephropathy (n = 10, 18.5%), focal and segmental glomerulosclerosis (n = 7,12.9%); 10 cases of secondary GMNPTR were reported, of which the most frequent were: diabetic nephropathy and lupus nephritis, in 9.3% and 7.4% respectively. Of the total cases, 4 (7.4%) correspond to true recurrence, 4 (7.4%) to de novo disease and 46 (85%) to graft glomerulonephritis with unknown primary disease. The median time for the diagnosis of GMNPTR was 10 months (IQR: 3–14), the eGFR by CKD-EPI was 67.4 (± 21.2) mL/min/1.73 m2 and proteinuria 231 mg/24 h (IQR: 100–600 mg/day). Fifty-four controls were selected with the previously described matching criteria: age at the time of RT was 38.6 (± 12) years, female gender was 57.4% and the median time on dialysis was 45 months (IQR: 35–61), similar between both groups. The haplotypes shared with the donor were: 0 (n = 33, 61%), 1 (n = 13, 24%), 2 (n = 8, 15%) and 0 (n = 32, 59%), 1 (n = 14, 26%), 2 (n = 8, 15%) for cases and controls, respectively, P = NS. Renal transplantation from a deceased donor was 41% for both groups; the median follow-up for the cases was 43 months (IQR: 24–90) and for the controls 53.5 (IQR: 33–85), P = 0.5. An overall incidence of rejection of 31.8% was observed at a median of 140 months (95% CI: 28–252), log-rank P = 0.27, it was striking that the median time for the appearance of cellular rejection showed a tendency to be higher in the cases of GMNPTR (168 versus 123 months), log-rank P = 0.08; the overall incidence of graft loss was 7.5% at a median follow-up of 149 months (95% CI: 130.5–168.3) log-rank P = 0.91. Finally, when comparing eGFR by CKD-EPI in the last follow-up, no difference was observed (eGFR 64.6 ± 26 versus 60.9 ± 27 mL/min/1.73 m2 P = 0.4). CONCLUSION In this study the incidence of GMNPTR is similar to that reported in other cohorts, the most frequent were the primary ones and those with a mesangioproliferative pattern; After adjusting for immune risk factors, GMNPTR did not affect survival compared to a homogeneous immune risk population. On the contrary, and as is well known, the presence of rejection was associated with lower graft function. Maintenance with triple therapy could modulate the severity of GMNPTR, and therefore we see histological diagnoses of little clinical impact.

Re-Hospitalization in First Six Months After Live Related Renal Transplantation: Risk Factors, Burden, Causes and Outcomes.

ObjectiveThe aim of our study was to evaluate the incidence, causes, risk factors, outcomes, and cost of hospital readmission after live related renal transplantation (LRRT).MethodsWe conducted a cross-sectional study and followed patients’ re-admissions for six months whose LRRT was done in our center between September 2019 and June 2020.ResultsWe recruited 53 patients, 40 (75.5%) were male. The mean age was 36.9 ± 11.9 years. Donor gender was similar, and their mean age was 31.6 ± 9.2 years. The mean length of hospital stay after LRRT was 14 ± 2.2 days. A total of 81.1% were readmitted after LRRT within the first six months, with a total of 113 readmissions. The median time of readmission after LRRT was 66 days. The median readmission hospital stay was four days. The causes of readmission were surgical in 11 (9.7%), medical in 89 (78.8%), and combined medical and surgical in 13 (11.5%). Infection was the most common medical cause, followed by rejection. Statistically significant difference between readmission and non-readmission groups was found in estimated glomerular filtration rate (eGFR) at six month 61.3 ± 25.9 vs. 84.3 ± 36.1 mL/min/1.73 m2 respectively (p = 0.02). The median cost of readmission was PKR 40629, equivalent to USD 261.ConclusionOver three-fourths of the patients were readmitted after LRRT within the first six months. The most common causes were infection and rejection. Readmissions after LRRT are associated with lower graft function at six months and a significant cost burden on the health system.

High soluble HLA-DQB2 levels in posttransplant serum are associated with kidney graft dysfunction.

HLA-DQB2 is a gene of limited polymorphism, with unknown function that presents at least two transcript variants: v1, which encodes the full-length beta-chain, and v2, which lacks exon 4 and could give rise to a soluble protein. We previously showed a strong correlation between high v2 expression in preimplantation biopsies (PIB) of kidneys from young (18- to 49-year olds) but not from old, deceased donors and 1-year posttransplant low (estimated glomerular filtration rate<45ml/min/1.73 m2 ) graft function (GF). In this study, we aimed to investigate the impact of posttransplant soluble HLA-DQB2 (sDQB2) serum levels, v1 expression in PIB, and recipient HLA-DQB2 rs7453920 A/G polymorphism on GF. sDQB2 was evaluated by enzyme-linked immunosorbent assay in sera from 114 recipients, collected at least 1 year (median 2.1 years) after transplantation. Higher sDQB2 levels were observed in recipients of kidneys from young, but not from old, donors that had a ≥30% decline in GF within 1 year after blood collection for sDQB2 determination. Among the 15 recipients of kidneys from young donors with sDQB2 ≥ 1.52ng/ml, 40% presented a ≥30% decline in GF, whereas this occurred in none of the 43 recipients with lower sDQB2 levels (p=0.007; OR: 36.5). Expression of HLA-DQB2 variant 1, measured by reverse transcription-polymerase chain reaction (RT-PCR) in 92 PIB from young or old donors, did not significantly differ between transplants with high or low 4-year GF. HLA-DQB2 rs7453920 single nucleotide polymorphism (SNP) frequencies did not significantly differ between recipients with low or high 4-year GF. We conclude that HLA-DQB2 variant 1 expression in PIB and recipient rs7453920 SNP polymorphism are not associated with graft outcome. On the other hand, the association, in transplants of kidneys from young donors, between high posttransplant serum sDQB2 levels and decline in GF is a very interesting finding that deserves a validation study in a larger cohort.

Safety and metabolic advantages of steroid withdrawal after 6 months posttransplant in de novo kidney transplantation: A 1‐year prospective cohort study

IntroductionThis prospective multicenter study aimed at investigating the safety and metabolic advantages of steroid withdrawal (SW) therapy in kidney transplant recipients with tacrolimus–mycophenolate mofetil‐based immunosuppression.MethodsWe analyzed 179 recipients who received kidney transplantation from March 2016 and September 2018. In 179 recipients, 114 patients maintained an immunosuppressive regimen including steroids (steroid continuation [SC] group). The remaining 65 patients were determined to withdraw steroid therapy after 6 months posttransplant (SW group). Metabolic parameters and graft functions of the two groups were evaluated.ResultsThe estimated glomerular filtration rates at 12 months posttransplant were 67.29 ± 20.29 ml/min/1.73 m2 in SC group and 73.72 ± 17.57 ml/min/1.73 m2 in SW group (p < .001). The acute rejection occurred to four recipients in the SC group (3.5%) and no acute rejection occurred to SW group recipients during the 6–2 months posttransplant period. Oral glucose tolerance tests revealed that recipients in the SW group were more improved in glucose metabolism than the SC group during 6–12 months posttransplant. In addition, cholesterol levels and blood pressure decreased after the withdrawal of steroids in the SW group.ConclusionIn conclusion, a 6‐month withdrawal of steroids in recipients with low immunological risk and stable graft function can be safely conducted and result in improvement of metabolic profiles. Stable recipients without biopsy‐proven acute rejection and proteinuria can safely withdraw from steroids out of a maintenance immunosuppressive regimen 6‐months posttransplant. A long‐term follow‐up study is needed to verify our results.

Gastroesophageal Reflux and Esophageal Motility Disorder After Lung Transplant: Influence on the Transplanted Graft

Esophageal pathology has been identified as a bad prognostic factor in lung transplantation (LTx). This study aims to assess the esophageal disorders present post-LTx, under treatment with proton pump inhibitors, and their putative impact on the graft. Prospective, observational study of LTx patients. Digestive factors were assessed by manometry and pH-metry at 6 months post-LTx and under proton pump inhibitor treatment. We assessed the association between esophageal disorders and graft function and acute rejection (AR) and chronic lung allograft dysfunction (CLAD). Out of 76 post-LTx patients, 27% showed gastroesophageal reflux disease (GERD), 55% showed inadequate gastric inhibition, and 59% showed esophageal motility disorders (EMDs). We observed a greater incidence of AR from 3 months post-LTx in the presence of EMD (P ≤ .05). No significant differences were observed in GERD or EMD prevalence or in survival between patients with or without CLAD. The maximum forced expiratory volume in 1 second (FEV1) achieved after bilateral LTx was significantly (P=.022) lower in patients with EMD vs without EMD. At 6 months post-LTx, there is a high percentage of esophageal disorders (GERD and EMDs). No esophageal disorder is associated with CLAD or with survival, although EMDs are associated with a greater incidence of AR and lower graft function.

Clinical factors and comorbidities affecting health-related quality of life in postrenal transplant patients.

Background:Health-related quality of life is different among different transplant cohorts with respect to different variables which predict mortality and graft survival. The aim of this study was to identify the effects of clinical factors on the health-related quality of life in postrenal transplant patients.Methods:This census study was conducted at the Institute of Kidney Diseases Peshawar, Pakistan. Data were collected on a questionnaire “ Kidney Diseases Quality of Life-Short Form-1.3 Urdu version” and were analyzed in the 3 main domains, for example, physical component summary (PCS), mental component summary, and kidney disease component summary using SPSS version 21. Mean scores for patients with diabetes mellitus (DM), hypertension, levels of hemoglobin, and serum creatinine were compared by unpaired t-test.Results:A total of 277 men (87.9%) and 38 (12.1%) women participated in the study. Mean age was 37.26 (±10.14) years (range 18–65 years). Hypertension was reported in 72.2% and DM in 10.8%. Hemoglobin was <12.5g% in 26.0% patients. Patients with DM had significant lower PCS (P = .001) and mental component summary (MCS; P = .001) scores. Patients with hypertension had significant lower MCS score (P = .01). Patients with hemoglobin <12.5g% had significantly lower PCS (P = .001) score than those with hemoglobin >12.5 g%. The PCS score in patients with serum creatinine level >2 mg% was significantly lower (P = .02) than those with serum creatinine <2 mg%.Conclusion:Lower graft function and DM were associated with lower PCS and MCS scores. Hypertension was associated with lower MCS score and anemia with lower PCS score.

Autoreactive T cell profiles are altered following allogeneic islet transplantation with alemtuzumab induction and re-emerging phenotype is associated with graft function.

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6m posttransplant: 38%; 7-12m: 44%; 13-24m: 47%; and >24m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10+ cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function.

Plasma Homocysteine and Glutathione Are Independently Associated With Estimated Glomerular Filtration Rates in Patients With Renal Transplants

BackgroundElevated levels of plasma homocysteine could, through homocysteine oxidation, induce the overproduction of reactive oxygen species, leading to a reduction in glutathione-related antioxidants, and may impair graft functions in patients with renal transplants. The purpose of this study was to determine whether plasma homocysteine, glutathione, or its related antioxidants were related to graft functions in patients with renal transplants. Patients and MethodsWe recruited 66 patients (mean age 48.4 years) with renal transplants (mean transplant duration 8.3 years). Patients were divided into 2 groups, based on their estimated glomerular filtration rate (eGFR): the moderate graft function group (eGFR ≥ 60 mL/min/1.73 m2, n = 37) and low graft function group (eGFR < 60 mL/min/1.73 m2, n = 29). We then determined their fasting levels of the following: malondialdehyde (MDA), homocysteine, cysteine, pyridoxal 5′-phosphate (PLP), glutathione (GSH), oxidized glutathione (GSSG), GSH/GSH ratio, glutathione peroxidase (GSH-Px) activity. ResultsWe found in the low graft function group significantly higher levels of plasma homocysteine, cysteine, GSH, and GSH/GSSG ratios. But an intergroup difference was not found regarding levels of MDA, PLP, GSSG, and GSH-Px activity. After adjusting for potential confounders, the increased plasma homocysteine and GSH levels were independently associated with lower eGFR. No interaction existed between homocysteine and GSH levels in association with eGFR. ConclusionIncreased plasma homocysteine and GSH levels appeared to be independent indicators of decreased graft functions in patients with renal transplants.

Development and validation of a new prediction model for graft function using preoperative marginal factors in living-donor kidney transplantation

Recently, living-donor kidney transplantation from marginal donors has been increasing. However, a simple prediction model for graft function including preoperative marginal factors is limited. Here, we developed and validated a new prediction model for graft function using preoperative marginal factors in living-donor kidney transplantation. We retrospectively investigated 343 patients who underwent living-donor kidney transplantation at Kyushu University Hospital (derivation cohort). Low graft function was defined as an estimated glomerular filtration rate of < 45mL/min/1.73m2 at 1year. A prediction model was developed using a multivariable logistic regression model, and verified using data from 232 patients who underwent living-donor kidney transplantation at Tokyo Women's Medical University Hospital (validation cohort). In the derivation cohort, 89 patients (25.9%) had low graft function at 1year. Donor age, donor-estimated glomerular filtration rate, donor hypertension, and donor/recipient body weight ratio were selected as predictive factors. This model demonstrated modest discrimination (c-statistic = 0.77) and calibration (Hosmer-Lemeshow test, P = 0.83). Furthermore, this model demonstrated good discrimination (c-statistic = 0.76) and calibration (Hosmer-Lemeshow test, P = 0.54) in the validation cohort. Furthermore, donor age, donor-estimated glomerular filtration rate, and donor hypertension were strongly associated with glomerulosclerosis and atherosclerotic vascular changes in the "zero-time" biopsy. This model using four pre-operative variables will be a simple, but useful guide to estimate graft function at 1year after kidney transplantation, especially in marginal donors, in the clinical setting.

Baseline graft status is a critical predictor of kidney graft failure after diarrhoea.

Diarrhoea is one of the most frequent complications after kidney transplantation (KT). Non-infectious diarrhoea has been associated with reduced graft survival in kidney transplant recipients. However, the risk factors for renal allograft loss following diarrhoea remain largely unknown. Between January 2010 and August 2011, 195 consecutive KT recipients who underwent standardized microbiological workups for diarrhoea at a single centre were enrolled in this retrospective study. An enteric pathogen was readily identified in 91 patients (47%), while extensive microbiological investigations failed to find any pathogen in the other 104. Norovirus was the leading cause of diarrhoea in these patients, accounting for 30% of the total diarrhoea episodes. The baseline characteristics were remarkably similar between non-infectious and infectious diarrhoea patients, with the exception that the non-infectious group had significantly lower graft function before diarrhoea (P = 0.039). Infectious diarrhoea was associated with a longer duration of symptoms (P = 0.001) and higher rates of acute kidney injury (P = 0.029) and hospitalization (P < 0.001) than non-infectious diarrhoea. However, the non-infectious group had lower death-censored graft survival than the infectious group (Gehan-Wilcoxon test, P = 0.038). Multivariate analysis retained three independent predictors of graft failure after diarrhoea: diarrhoea occurring ≥5 years after KT [hazard ratio (HR) 4.82; P < 0.001], re-transplantation (HR 2.38; P = 0.001) and baseline estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR 11.02; P < 0.001). Our study shows that pre-existing conditions (re-transplantation, chronic graft dysfunction and late occurrence) determine the primary functional long-term consequences of post-transplant diarrhoea.

Long-term effects of delayed graft function duration on function and survival of deceased donor kidney transplants.

Introduction:Delayed graft function (DGF) is a frequent complication after deceased donor kidney transplantation with an impact on the prognosis of the transplant. Despite this, long-term impact of DGF on graft function after deceased donor kidney transplantation has not been properly evaluated.Objective:The main objective of this study was to evaluate risk factors for DGF and the impact of its occurrence and length on graft survival and function.Methods:A retrospective cohort study was performed in 517 kidney transplant recipients who received a deceased donor organ between January 2008 and December 2013.Results:The incidence of DGF was 69.3% and it was independently associated with donor's final serum creatinine and age, cold ischemia time, use of antibody induction therapy and recipient's diabetes mellitus. The occurrence of DGF was also associated with a higher incidence of Banff ≥ 1A grade acute rejection (P = 0.017), lower graft function up to six years after transplantation and lower death-censored graft survival at 1 and 5 years (P < 0.05). DGF period longer than 14 days was associated with higher incidence of death-censored graft loss (P = 0.038) and poorer graft function (P < 0.001). No differences were found in patient survival.Conclusions:The occurrence of DGF has a long-lasting detrimental impact on graft function and survival and this impact is even more pronounced when DGF lasts longer than two weeks.

Urinary Liver Type Fatty Acid Binding Protein Is Negatively Associated With Estimated Glomerular Filtration Rate in Renal Transplant Recipients With Graft Loss

BackgroundLiver type fatty acid binding protein (L-FABP) is abundant not only in the liver but also in the kidney and is excreted in urine. Its primary function is to facilitate intracellular long chain fatty acid transport and it might also act as an endogenous antioxidant molecular. The purpose of this study was to investigate whether plasma or urinary L-FABP levels were associated with graft function in renal transplant recipients. Patients and methodsSixty-seven renal transplant recipients with a mean age of 48.8 years were recruited. The mean duration of renal transplantation was 4131 days. Recipients were divided into 2 groups based on their estimated glomerular filtration rate (eGFR) values: moderate graft function (eGFR ≥60 mL/min/1.73 m2) and low graft function (eGFR <60 mL/min/1.73 m2). Fasting plasma and urinary L-FABP levels were measured. ResultsThere was no significant difference in plasma L-FABP level between the 2 groups, although recipients in the low graft function group had significantly lower urinary L-FABP level when compared with recipients in the moderate graft function group. Plasma and urinary L-FABP levels were not associated with eGFR in the 67 recipients; however, urinary L-FABP level (β = −1.24, P = .037) and level adjusted by urinary creatinine (β = −0.75, P = .046) were significantly negatively associated with eGFR in recipients with low graft function after adjusting for potential confounders. ConclusionIncreased urinary L-FABP level seems to be a significant indicator of decreased graft function in renal transplant recipients with loss of graft function.