Calcineurin Inhibitor Toxicity Research Articles

Renal Allograft Biopsy Findings in Live-related Renal Transplant Recipients.

To determine the pattern of histopathology in living-related, kidney transplant recipients (KTRs) from a transplant centre in Khyber Pakhtunkhwa (KPK), Pakistan. Descriptive, observational study. Institute of Kidney Diseases, Peshawar, from August 2008 to July 2018. A retrospective review of graft biopsy reports and clinical charts from living-related, kidney transplant recipients was carried out. Allograft biopsies were done for graft dysfunction with no apparent cause. The biopsy pathology was classified according to updated Banff classifications. The descriptive statistics were used to tabulate the results. Out of the 55 biopsies, 51 (92.73%) were from males with mean age of 34.35±9.40 years. Out of 52 percutaneous biopsies, 10 (19.23%) belonged to the normal category. Category 2 (borderline rejection) and 3 (acute/active cellular rejection) were seen in three (5.7%) and one (1.9%) cases, respectively. Interstitial fibrosis/tubular atrophy (Banff Category 5) was observed in 18 (34.62%) cases. Banff Category 6 (others) was seen in 19 (36.5%) cases, in which calcineurin inhibitors (CNI) toxicity was commonest (17 [89.4%] of 19 cases). Mixed lesions were found in 19 (36.5%) cases. Out of the 19 mixed category cases, 12 (63.16%) showed both Category 3 and Category 5 changes with most of the cases showing mild to moderate IF/TA; while one case had severe IF/TA. Three graft nephrectomies were done, one each for recurrent oxalosis, nephroblastoma and fungal infection. Among the studied specimens, mixed lesions were the predominant findings, followed by others (mostly CNI toxicity) and IFTA categories. The frequency of acute/active rejections was low and that of chronic changes higher, in keeping with delayed biopsies. Key Words: Allograft biopsy, Graft dysfunction, Rejection, Kidney.

Posttransplant renal allograft dysfunction – A retrospective observational study

Background: In India, a large number of end-stage renal disease patients are undergoing renal replacement therapy. A successful renal transplantation relives the burden of dialysis with improved quality of life and a productive life thereafter. This also reduces the cost of health care to the government and the society. Graft dysfunction is an important cause of graft loss.The objective of this retrospective study is to evaluate the graft dysfunction and its impact on patient and graft survival. Methods: We did a retrospective record-based analysis of 83 cases (including both deceased and live-related renal transplants) from 2014 to 2019 who were on triple immunosuppression (tacrolimus, mycophenolate mofetil, and steroids) as maintenance therapy. Patients who had graft dysfunction, underwent graft biopsy and were analyzed subsequently. Results: The most common causes for graft dysfunction on biopsy were acute rejection, acute tubular injury, and calcineurin inhibitor toxicity. About 39% of the patients had infections, predominantly bacterial and viral infections. The rejections were associated with poor patient survival (statistically significant). The overall patient survival at our center after 1 year and 3 years was 88% and 84%, respectively, while the death-censored graft survival was 86% and 81%, respectively. Conclusion: In our center, following renal transplantation, patients had a fairly successful outcome. However, early detection and prompt management of the graft dysfunction can improve the graft and the patient survival.

Clinico-Histological Features of Thrombotic Microangiopathy in Renal Biopsies: A Retrospective Study.

Thrombotic microangiopathy (TMA) is often first detected on a renal biopsy performed for renal manifestations. Apart from hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura, there are various secondary conditions associated with TMA. This study analyzes the clinico-pathological spectrum, etiological factors and renal outcome of TMA diagnosed on renal biopsy. A retrospective evaluation of renal biopsies for TMA over 5.5 years was performed. Clinical and laboratory data was collected from patient records. A total of 40 biopsies from 39 patients showed TMA comprising 33 native and 7 transplant biopsies. Malignant hypertension (n=13) was the most common etiology in native biopsies followed by postpartum TMA (n=7), atypical HUS (aHUS) (n=7), and lupus nephritis (n=6). TMA in transplant biopsies was due to acute rejection (n=4) and CNI toxicity (n=3). Serum creatinine was high in most patients (mean 5.6 + 2.5 mg/ dl). aHUS showed the highest mean LDH levels and the lowest average platelet counts. Renal biopsies in malignant hypertension and postpartum TMA showed isolated arterial changes while aHUS and lupus nephritis showed both glomerular and arterial involvement. Postpartum TMA and aHUS had poor renal outcome requiring renal replacement therapy. Most postpartum TMA and aHUS had systemic features of TMA while malignant hypertension and lupus nephritis showed 'isolated renal TMA'. This emphasizes the importance of careful evaluation of renal biopsies even in the absence of systemic features of TMA.

Tacrolimus intrapatient variability in BK virus nephropathy and chronic calcineurin toxicity in kidney transplantation.

Intrapatient variability (IPV) in tacrolimus has been increasingly acknowledged as a risk factor for poor graft survival after kidney transplantation. Although past studies have mainly accounted for IPV in acute or chronic rejection states as due to underimmunosuppression, this is not yet clear. So far, tacrolimus IPV for BK virus-associated nephropathy (BKVN) and chronic calcineurin inhibitor toxicity (CNIT) has not been investigated. Here, we evaluated IPV in tacrolimus for BKVN and chronic CNIT, which are mainly considered as overimmunosuppression states. In this case-control study, kidney allograft biopsies conducted between 1998 and 2018 were included, with patients grouped by biopsy results as BKVN alone group, CNIT alone group, and normal graft function (control group). IPV was estimated as mean absolute deviation. Our study groups included 25 kidney transplant recipients with BKVN alone, 91 patients with CNIT alone, and 60 patients with normal 5-year graft survival (control group). In analyses of IPV in tacrolimus six months before graft biopsy, IPV was highest in the BKVN group (P = 0.001). The BKVN group also had the highest IPV in tacrolimus at 12 months after biopsy (P = 0.001), with all pairwise comparisons statistically different between groups. At 12 months after biopsy, five patients (20%) in the BKVN group and 10 patients (10.9%) in the CNIT group had graft loss. Among other risk factors, BKVN and chronic CNIT are consequences related to high IPV. Quantification of IVP for tacrolimus in clinical practice would help to optimize kidney transplant outcomes.

Microangiopatía trombótica en el trasplante renal, el tacrolimus como causante

La microangiopatía trombótica (MAT) es una complicación poco frecuente asociada al uso de tacrolimus en el trasplante renal. Puede estar relacionado a infecciones, rechazo mediado por anticuerpos (RMA), recurrencia de enfermedad o MAT de novo y a toxicidad por inhibidores de la calcineurina. Por lo general, se presenta como formas incompletas, lo que hace difícil su diagnóstico, por lo que puede provocar lesiones irreversibles. El caso presentado comparte la presencia de infección viral, datos sugerentes de rechazo concomitantemente con el uso de tacrolimus. El tratamiento incluye plasmaferesis y anticuerpos monoclonales como eculizumab. Sin embargo, en el caso presentado la suspensión o cambio del tacrolimus fue una medida más costo-efectiva.

Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts

BackgroundIn kidney transplantation, fibrosis represents the final and irreversible consequence of the pathogenic mechanisms that lead to graft failure, and in the late stages it irremediably precedes the loss of renal function. The invasiveness of kidney biopsy prevents this condition from being frequently monitored, while clinical data are rather unspecific. The objective of this study was to find noninvasive biomarkers of kidney rejection.MethodsWe carried out proteomic analysis of the urinary Extracellular Vesicles (uEVs) from a cohort of kidney transplant recipients (n = 23) classified according to their biopsy-based diagnosis and clinical parameters as interstitial fibrosis and tubular atrophy (IFTA), acute cellular rejection (ACR), calcineurin inhibitors toxicity (CNIT) and normal kidney function (NKF).ResultsShotgun mass spectrometry of uEV-proteins identified differential expression of several proteins among these different groups. Up to 23 of these proteins were re-evaluated using targeted proteomics in a new independent cohort of patients (n = 41) classified in the same diagnostic groups. Among other results, we found a differential expression of vitronectin (VTN) in patients displaying chronic interstitial and tubular lesions (ci and ct mean > 2 according to Banff criteria). These results were further confirmed by a pilot study using enzyme-linked immunosorbent assay (ELISA).ConclusionUrinary vitronectin levels are a potential stand-alone biomarker to monitor fibrotic changes in kidney transplant recipients in a non-invasive fashion.

Glomerular Neovascularization in Nondiabetic Renal Allograft Is Associated with Calcineurin Inhibitor Toxicity

Introduction: Extra efferent arterioles, also known as polar vasculosis (PV), are often observed in the glomerular vascular pole and are associated with glomerular hypertrophy, indicating early recurrent diabetic kidney disease (DKD) in renal allografts. However, its significance in patients without diabetes remains uncertain. Methods: A total of 9,004 renal allograft biopsy specimens obtained between January 2007 and December 2017 at Tokyo Women’s Medical University were retrospectively analyzed to examine the clinical and pathological significance of PV in renal allografts. PV was identified in 186 biopsy specimens obtained from 165 patients. The PV group comprised 46 patients; 35 patients without DKD and 11 patients with DKD as the initial cause of ESRD, whose clinical information was available and treated with the calcineurin inhibitor (CNI) tacrolimus. The non-PV group comprising patients with renal allografts matched for age and postoperative day included 93 patients without DKD and 16 patients with DKD as the initial cause of ESRD. Results: In patients with nondiabetic renal allografts, systolic blood pressure was significantly higher in the PV group than in the non-PV group. The trough tacrolimus levels during the overall study period and at 2 weeks, 1 month, and 2 years after transplantation were significantly higher in the PV group compared with the non-PV group. Glomerulomegaly was significantly more common. Moreover, ah and aah scores in Banff score were significantly higher in the PV group than in the non-PV group. In those with diabetic renal allografts, although the clinical parameters and tacrolimus trough levels in all time periods were not significantly different between the PV and non-PV groups, the ah score was significantly higher in the PV group. Conclusion: PV was associated with CNI toxicity in nondiabetic but not in diabetic renal allografts. The pathogenesis of PV in renal allografts is considered to be multifactorial.

Prevention of acute rejection after rescue with Belatacept by association of low-dose Tacrolimus maintenance in medically complex kidney transplant recipients with early or late graft dysfunction.

Increased acute rejection risk in rescue protocols with Belatacept may limit its use particularly in medically complex patients where preexisting increased risk of rejection couples with CNI toxicity. Retrospective analysis was performed in 19 KTs shifted to a Belatacept-based immunosuppression with low-dose Tacrolimus (2-3 ng/mL) after evidence of allograft disfunction, including patients with primary non-function (PNF), chronic-active antibody-mediated rejection (cAMR), history of previous KTs and/or other concomitant transplants (liver, pancreas). Evaluation of CD28+ CD4+ effector memory T cell (TEM) before conversion was performed in 10/19. Kidney function significantly improved (median eGFR 16.5 ml/min/1.73m2 before vs 25 ml/min after; p = 0.001) at a median time after conversion of 12.5 months (9.1-17.8). Overall graft and patient survival were 89.5% and 100% respectively. Definitive weaning from dialysis in 5/5 KTs with PNF was observed, whereas 7/8 patients lost their graft within first year in a control group. eGFR significantly ameliorated in re-trasplants (p = 0.001) and stabilized in KTs with other organ transplants or cAMR. No acute rejection episodes occurred, despite the significant risk suggested by high frequency of CD28+ CD4+ TEM in most patients. Opportunistic infections were limited and most common in early vs late-converted. Rescue association of Belatacept with low-dose Tacrolimus in medically complex KTs is a feasible option that allows prevention of acute rejection and amelioration of graft function.

Proteomic Characterization of Urinary Extracellular Vesicles from Kidney-Transplanted Patients Treated with Calcineurin Inhibitors.

Use of immunosuppressive drugs is still unavoidable in kidney-transplanted patients. Since their discovery, calcineurin inhibitors (CNI) have been considered the first-line immunosuppressive agents, in spite of their known nephrotoxicity. Chronic CNI toxicity (CNIT) may lead to kidney fibrosis, a threatening scenario for graft survival. However, there is still controversy regarding CNIT diagnosis, monitoring and therapeutic management, and their specific effects at the molecular level are not fully known. Aiming to better characterize CNIT patients, in the present study, we collected urine from kidney-transplanted patients treated with CNI who (i) had a normal kidney function, (ii) suffered CNIT, or (iii) presented interstitial fibrosis and tubular atrophy (IFTA). Urinary extracellular vesicles (uEV) were enriched and the proteome was analyzed to get insight into changes happening during CNI. Members of the uroplakin and plakin families were significantly upregulated in the CNIT group, suggesting an important role in CNIT processes. Although biomarkers cannot be asserted from this single pilot study, our results evidence the potential of uEV as a source of non-invasive protein biomarkers for a better detection and monitoring of this renal alteration in kidney-transplanted patients.

Long-Term Infectious and Noninfectious Outcomes of Monthly Alemtuzumab as a Calcineurin Inhibitor- and Steroid-Free Regimen for Pancreas Transplant Recipients.

Multiple doses of alemtuzumab for immunosuppressive therapy of patients with hematologic malignancies and hematopoietic stem cell transplant have been associated with a high rate of infection. In transplantation, limited alemtuzumab dosing has been successfully used as induction immunosuppression. The effect of multiple doses of alemtuzumab, used as maintenance therapy to minimize steroid and/or calcineurin inhibitor toxicity in solid organ transplant recipients, is unknown. We evaluated the infectious and noninfectious outcomes of 179 pancreas transplant recipients treated with alemtuzumab for induction and maintenance therapy (extended alemtuzumab exposure (EAE)) from 2/28/2003 through 8/31/2005, compared with 159 pancreas transplant recipients with standard induction and maintenance (SIM) therapy performed before (1/1/2002 until 12/31/2002) and after (1/1/2006 until 12/31/2006) the implementation of EAE. EAE was associated with higher risk of overall infections (hazard ratio (HR) 1.33 (1.06–1.66), P=0.01), bacterial infections (HR 1.33 (1.05–1.67), P=0.02), fungal infections (HR 1.86 (1.28–2.71), P < 0.01), and cytomegalovirus infections (HR 2.29 (1.39–3.77), P < 0.01). In addition, EAE was associated with higher risk of acute cellular rejection (HR 2.09 (1.46–2.99), P < 0.01). In conclusion, while a limited alemtuzumab dosing is safe and effective for induction therapy in pancreas transplantation, EAE combined with steroid and calcineurin minimization is associated with a high risk of infectious complications and acute cellular rejection.

Abdominal Distention in a Patient on Peritoneal Dialysis.

A 66-year-old Caucasian man with a failing cardiac transplant, transfusion-dependent myelodysplastic syndrome, and ESKD from calcineurin inhibitor toxicity on peritoneal dialysis (PD) was admitted with complaints of acute onset of shortness of breath after suspected aspiration, and progressive abdominal distention. Physical examination revealed crepitations in the right lung base and distended abdomen that was dull on percussion in the flanks, as well as bilateral inguinal hernias. Chest x-ray confirmed right lower lobe patchy pneumonitis consistent with aspiration along with mild cardiomegaly. Because his symptoms persisted despite antibiotics and achieving daily ultrafiltration in excess of 1 L with PD, a computed tomography (CT) abdomen scan with oral contrast was performed that showed extensive …

Significance of revised criteria for chronic active T cell-mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P<.001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P<.001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.

N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury.

Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.

Evaluation of Longitudinal Exposure to Tacrolimus as a Risk Factor of Chronic Kidney Disease Occurrence Within the First-year Post-Liver Transplantation.

Renal failure is predictive of mortality in the early postliver-transplantation period and calcineurin inhibitors toxicity is a main challenge. Our aim is to assess the impact of longitudinal tacrolimus exposure (TLE) and other variables on chronic kidney disease (CKD)-free 1-year-survival. Retrospective data of consecutive patients transplanted between 2011 and 2016 and treated with tacrolimus were collected. TLE and all relevant pre- and post-liver transplantation (LT) predictive factors of CKD were tested and included in a time-to-event model. CKD was defined by repeated estimated glomerular filtration rate (eGFR) values below 60 mL/min/1.73m2 at least for the last 3 months before M12 post-LT. Data from 180 patients were analyzed. CKD-free survival was 74.5% and was not associated with TLE. Pre-LT acute kidney injury (AKI) and eGFR at 1-month post-LT (eGFRM1) <60 mL/min/1.73m2 were significant predictors of CKD. By distinguishing 2 situations within AKI (ie, with or without hepatorenal syndrome [HRS]), only HRS-AKI remained associated to CKD. HRS-AKI and eGFRM1 <60 mL/min/1.73m2 increased the risk of CKD (hazard ratio, 2.5; 95% confidence interval, 1.2-4.9; hazard ratio, 4.8; 95% confidence interval, 2.6-8.8, respectively). In our study, TLE, unlike HRS-AKI and eGFRM1, was not predictive of CKD-free survival at 1-year post-LT. Our results once again question the reversibility of HRS-AKI.

Sporotrichosis in renal transplant patients: two case reports and a\xa0review of the\xa0literature

IntroductionSporotrichosis is a rare fungal infection in transplant patients; among these patients, it occurs mostly in renal transplant patients. Sporothrix schenkii is the primary pathogen responsible. A high index of suspicion is required to make the diagnosis keeping important differential diagnoses in mind. History of trauma through recreational or occupational exposure to the fungus may assist in making the diagnosis. Treatment is difficult, with long-term use of potentially nephrotoxic and cytochrome P450 inhibitor antifungal agents leading to potential calcineurin inhibitors toxicity. We describe two renal transplant patients presenting with distinct sporotrichosis infection: “Case 2” being only the second reported case ever of meningeal sporotrichosis. We subsequently review the general aspects of sporotrichosis, specifically in renal transplant patients as described in the medical literature.Case presentationCase 1, a 43-year-old mixed ancestry male patient presented with a non-healing ulcer on the left arm for 1 year, he was diagnosed with cutaneous sporotrichosis and was successfully treated with itraconazole monotherapy. Case 2, a 56-year-old mixed ancestry male patient presented with a slow decline in functions, confusion, inappropriate behavior, rigors and significant loss of weight and appetite over the past 4 months, he was diagnosed with meningeal sporotrichosis and was successfully treated with a combination of deoxycholate amphotericin B and itraconazole.ConclusionPhysicians taking care of renal transplant patients should have a high index of suspicion for sporotrichosis infection particularly when conventional therapy for common conditions fails. Susceptibility testing is recommended to identify the most effective antifungal agent and its dose. The slow nature of growth of Sporothrix schenkii necessitates patients to be on amphotericin B until the time results are available. Finally, there is a need to be aware of potential drug-drug interactions of the azoles with calcineurin inhibitors and the required dose adjustments to prevent therapy related adverse events.

Characterizing the frequency of modifiable histological changes observed on surveillance biopsies in pediatric kidney allograft recipients.

Rejection is responsible for just under 50% of graft loss in the pediatric kidney transplant population. Early identification and treatment of allograft injury, specifically modifiable pathologies such as subclinical rejection (SCR), calcineurin inhibitor toxicity, and BK virus nephropathy, may improve allograft survival. Protocol surveillance biopsy (SB) currently offers the earliest opportunity for targeted interventions. This is a single-center retrospective review of 215 kidney SBs obtained from 2008 to 2016 in 97 pediatric kidney transplant recipients. SBs were obtained at 6, 12, and 24 months post-transplantation. Frequency of abnormal histologic findings, estimated glomerular filtration rate at time of SB, and SB-related complications were recorded. Data were analyzed to investigate possible time trends and the presence of demographic or clinical associations with abnormal histologic findings. Potentially modifiable histologic findings were seen in 38.1% of all SBs. SCR was found with increasing frequency across all time points with an estimated 49% increase in the odds of a SCR finding per additional 6 months post-transplantation (aOR 1.49, 95% CI 1.06-2.09, p = 0.022). Among follow-up biopsies in patients who underwent treatment for SCR, 50% had no SCR and 18.8% showed histologic improvement. The complication rate associated with SB was 1.9% (4/215 SBs) and consisted of only minor complications. SBs are safe and offer the opportunity to identify and treat modifiable histologic changes in the pediatric kidney transplant population. The performance of SBs for up to 2 years after transplantation can have meaningful clinical impact.

Thirty Years of Tacrolimus in Clinical Practice.

Tacrolimus was discovered in 1984 and entered clinical use shortly thereafter, contributing to successful solid organ transplantation across the globe. In this review, we cover development of tacrolimus, its evolving clinical utility, and issues affecting its current usage. Since earliest use of this class of immunosuppressant, concerns for calcineurin-inhibitor toxicity have led to efforts to minimize or eliminate these agents in clinical regimens but with limited success. Current understanding of the role of tacrolimus focuses more on its efficacy in preventing graft rejection and graft loss. As we enter the fourth decade of tacrolimus use, newer studies utilizing novel combinations (as with the mammalian target of rapamycin inhibitor, everolimus, and T-cell costimulation blockade with belatacept) offer potential for enhanced benefits.

P1772CONVERSION TO BELATACEPT IMPROVES RENAL GRAFT FUNCTION OF PATIENTS WITH SEVERE HISTOLOGICAL AND FUNCTIONAL INVOLVEMENT. LONG-TERM UNICENTRIC EXPERIENCE

Abstract Background and Aims Belatacept selectively blocks the costimulation signal of T cells. Its use, both de novo and in conversion, is associated with a better renal graft function compared to the regimens that include a calcineurin inhibitor (CNI). We expose our experience with belatacept as a rescue therapy in patients who present moderate-severe dysfunction after renal transplantation and compare the evolution with those patients who received the contralateral kidney graft without change to belatacept. Method Adult kidney transplanted patients, with graft dysfunction and renal biopsy with CNI toxicity or chronic vascular lesions who are changed from CNI to belatacept were included. Efficacy (creatinine, proteinuria, TFGe, acute rejection tested by biopsy, anti HLA) and safety (adverse events, tumors or infections) variables were recorded before and after the change. Results 11 patients were included. The change to belatacept was made at a median of 13 months from the transplant (range 1-62 months) and the duration of the treatment ranged between 6 and 74 months. Renal function improved from a mean creatinine of 3.04±1.34 mg/dl before the change to 1.9±0.3 mg/dl at 6 and 12 months after conversion (p = 0.016), being the last average creatinine (December 2019) of 1.7±0.3 mg/dl. Belatacept was withdrawn in one case, at one year, due to the development of specific donor antibodies without evidence of acute rejection. There were no cases of post-transplant lymphoproliferative syndrome. Two patients developed VBK replication controlled with immunosuppression modification and three patients developed CMV infection controlled with valganciclovir. There was no episode of acute rejection after conversion. In 5 cases the contralateral kidney graft was not implanted, while in 6 cases it was implanted in another recipient who was not given belatacept and was taken on CNI therapy. The last average creatinine (December 2019) of patients without belatacept was 3.3±1.6 mg/dl vs. 1.6±0.2 mg/dl in patients with belatacept (p = 0.03). Conclusion The change to belatacept improves the renal function of all patients, even in those with severe histological and functional involvement. The improvement of renal function remains stable in the medium/long term and is significantly better than the renal function of patients with CNI.

P0589ACUTE KIDNEY INJURY IN PATIENTS UNDERGOING LIVING DONOR LIVER TRANSPLANT-INCIDENCE ,RISK FACTORS AND SHORT TERM PATIENT OUTCOMES ,A PROSPECTIVE SINGLE CENTER STUDY

Abstract Background and Aims AKI is a major concern in the management of candidates for liver transplantation. Post-LT AKI is associated with worse short- and long-term recipient and graft outcomes and the subsequent development of chronic kidney disease (CKD ).Most of the studies done on this are on deceased donor Liver transplant ,or if done on Living donor are retrospective in nature &amp; there is inconsistency in studies regarding definition of AKI To assess incidence, risk factor and outcomes of patient developing acute kidney injury(AKI) in patients undergoing living donor liver transplant(LT). Method This is a single center prospective study. Patients over age of 18 years undergoing living donor liver transplant were selected consecutively from Jan 19 to April 19, prospectively followed for 1 month post op to assess incidence of AKI(Early-&amp;lt;=7,Late &amp;gt;7 to &amp;lt;30) &amp; reassessed at 3 months for persistence of renal dysfunction .Patients with fulminant liver failure, those undergoing combined liver kidney transplant &amp; who died within first 72 hour post-LT were excluded .AKI was defined by KDIGO criteria. Preoperative, Intraoperative &amp; Post operative variables were analysed for risk factor &amp; patient outcomes by regression analysis. Results 62 patients underwent LDLT between period of Jan 2019 to April 2019 .22(35%) patients developed AKI .15 (68%) had stage 1 AKI ,5 (23%) Stage 2 &amp; 2(9%) had stage 3 AKI requiring CRRT.14 (64 %) patients had early AKI ,8 (36%) had late AKI.Acute CNI toxicity (3,14%) was most common cause of early AKI.Most common cause of Late AKI was Sepsis (7,11%).Use of vasopressors intra op &amp; Past history of AKI (HRS) were the only statistically significant(p &amp;lt;0.001) risk factors for AKI .The mean ICU stay among patients with AKI was 7.2 ±4.2 days vs 4.5±1.2 days in patients without AKI .Median days to normalization of liver enzymes in non AKI group was 10 days vs 20 days in AKI group.2 (3.2%)patient had persistence of renal dysfunction at 3 month. 7(11.2%) patients died during analysis period, 2(3%) of them from AKI group. Conclusion - Incidence of AKI (35%) was higher in our study as compared to other cohort but lead to CKD in 2 patients . Past history of AKI (HRS) was a significant risk factor for Post op AKI though pre transplant e GFR did not differ in both group. Although AKI was transient but it lead to increase ventilator stay ,ICU stay and prolonged normalization of graft function in patients undergoing Living donor liver transplant.

P0125ELECTRON MICROSCOPIC DESCRIPTION OF A SENSITIVE DIAGNOSTIC PROXIMAL EPITHELIAL LYSOSOMAL LESION IN PATIENTS WITH CINAC/CKDU/MEN AND CNI NEPHROTOXICITY

Abstract Background and Aims In CINAC patients from Sri Lanka, we recently observed a sensitive constellation of proximal tubular cell findings including cellular/tubular atrophy, cell fragment shedding and, by electron microscopy (EM), the presence of an increased number of enlarged lysosomes. Here we focused on precisely defining the EM lysosomal phenotype and evaluating its presence in CINAC/MeN/CKDu cases and controls from other countries. Method Thirthy-two renal biopsies (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with a diagnosis of CINAC (CKD 1-3A, 3B) were examined by electron microscopy (EM) in comparison to renal biopsies of normal kidneys at implantation, patients with calcineurin inhibitor (CNI) toxicity (n=17), proteinuric nephropathies (n=15), light chain disease (n=4), several cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and patients with reduced renal function of various causes (n=20). Results The aberrant lysosomal phenotypes can be defined as enlarged (&amp;gt;1.2µm) and dysmorphic with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound round to irregular shaped “aggregates”. In addition, indicative clusters of 4-6 smaller lysosomes with the same features could be observed. No cristae or other features of mitochondria, autophagic vacuoles, lipofuscin/ceroid droplets, peroxisomes (marginal plate), lysosomal myeloid bodies (aminoglycoside nephropathy) or electron dense laminated lysosomal inclusions (Fabry disease) were observed. Patients with calcineurin inhibitor nephrotoxicity and several cases on nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can either directly or indirectly be linked to calcineurin inhibition, presented the same lesions. We present an image set demonstrating the phenotypical consistency of the diagnostic lysosomal lesion versus similar features that are non-diagnostic. Conclusion A rather sensitive constellation of lysosomal lesions in renal proximal tubular cells was detected associated with CINAC/CKDu/MeN and CNI nephrotoxicity in several countries, suggesting a common new pathomechanistic paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity.