Loss Of Graft Function Research Articles

Identification of mitophagy-related gene signatures for predicting delayed graft function and renal allograft loss post-kidney transplantation

BackgroundIschemia-reperfusion injury (IRI) is an unavoidable consequence post-kidney transplantation, which inevitably leads to kidney damage. Numerous studies have demonstrated that mitophagy is implicated in human cancers. However, the function of mitophagy in kidney transplantation remains poorly understood. This study aims to develop mitophagy-related gene (MRGs) signatures to predict delayed graft function (DGF) and renal allograft loss post-kidney transplantation. MethodsDifferentially expressed genes (DEGs) were identified and intersected with the MRGs to obtain mitophagy-related DEGs (MRDEGs). Functional enrichment analyses were conducted. Subsequently, random forest and SVM-RFE machine learning were employed to identify hub genes. The DGF diagnostic prediction signature was constructed using LASSO regression analysis. The renal allograft prognostic prediction signature was developed through univariate Cox and LASSO regression analysis. In addition, ROC curves, immunological characterization, correlation analysis, and survival analysis were performed. ResultsNineteen MRDEGs were obtained by intersecting 61 DEGs with 4897 MRGs. Seven hub genes were then identified through machine learning. Subsequently, a five-gene DGF diagnostic prediction signature was established, with ROC curves indicating its high diagnostic value for DGF. Immune infiltration analysis revealed that many immune cells were more abundant in the DGF group compared to the Immediate Graft Function (IGF) group. A two-gene prognostic signature was developed, which accurately predicted renal allografts prognosis. ConclusionsThe mitophagy-related gene signatures demonstrated high predictive accuracy for DGF and renal allograft loss. Our study may provide new perspectives on prognosis and treatment strategies post-kidney transplantation.

MiR-199a-5p aggravates renal ischemia-reperfusion and transplant injury by targeting AKAP1 to disrupt mitochondrial dynamics.

Renal ischemia-reperfusion injury (IRI) is a complex pathophysiological process and a major cause of delayed graft function (DGF) after transplantation. MicroRNA (miRNA) has important roles in the pathogenesis of IRI and may represent promising therapeutic targets for mitigating renal IRI. miRNA sequencing was performed to profile microRNA expression in mouse kidneys after cold storage and transplantation (CST). Lentivirus incorporating a miR-199a-5p modulator was injected into mouse kidney in situ before syngenetic transplantation and unilateral IRI to determine the effect of miR-199a-5p in vivo. miR-199a-5p mimic or inhibitor was transfected cultured tubular cells before ATP depletion recovery treatment to examine the role of miR-199a-5p in vitro. Sequencing data and microarray showed upregulation of miR-199a-5p in mice CST and human DGF samples. Lentivirus incorporating a miR-199a-5p mimic aggravated renal IRI, and protective effects were obtained with a miR-199a-5p inhibitor. Treatment with the miR-199a-5p inhibitor ameliorated graft function loss, tubular injury, and immune response after CST. In vitro experiments revealed exacerbation of mitochondria dysfunction upon ATP depletion and repletion model in the presence of the miR-199a-5p mimic, whereas dysfunction was attenuated when the miR-199a-5p inhibitor was applied. miR-199a-5p was shown to target A-kinase anchoring protein 1 (AKAP1) by double luciferase assay and miR-199a-5p activation reduced dynamin-related protein 1 (Drp1)-s637 phosphorylation and mitochondrial length. Overexpression of AKAP1 preserved Drp1-s637 phosphorylation and reduced mitochondrial fission. miR-199a-5p activation reduced AKAP1 expression, promoted Drp1-s637 dephosphorylation, aggravated the disruption of mitochondrial dynamics, and contributed to renal IRI.NEW & NOTEWORTHY This study identifies miR-199a-5p as a key regulator in renal ischemia-reperfusion injury through microRNA sequencing in mouse models and human delayed graft function. miR-199a-5p worsens renal IRI by aggravating graft dysfunction, tubular injury, and immune response, while its inhibition shows protective effects. miR-199a-5p downregulates A-kinase anchoring protein 1 (AKAP1), reducing dynamin-related protein 1 (Drp1)-s637 phosphorylation, increasing mitochondrial fission, and causing dysfunction. Targeting the miR-199a-5p/AKAP1/Drp1 axis offers therapeutic potential for renal IRI, as AKAP1 overexpression preserves mitochondrial integrity by maintaining Drp1-s637 phosphorylation.

Analyzing the Impact of CIT on the Largest Reported Cohort of Robotic Kidney Transplantation From the Deceased Donors.

Robotic-assisted kidney transplant (RAKT) has proven to be a successful approach for patients with morbid obesity and more centers are encouraged to apply robotic approach also for deceased donor kidney transplantation. Prolonged cold ischemia time (CIT) is accompanied by delayed graft function (DGF) and early graft loss after traditional open kidney transplant (OKT). This study examines the impact of CIT after robotic kidney transplantation on settings of deceased donation. We present a single-center retrospective analysis of 115 cases of RAKT and 128 cases of OKT from deceased donors performed from deceased donor from 2009 to July 2022. Cohort was divided in 3 groups based on CIT ("high" CIT > 15 h, n = 43; "medium" CIT 11-15 h, n = 38; "low" CIT< 11 h, n = 40). The subgroup analysis of DGF and CIT was performed. The median CIT in the cohort was 13.46 (7) h, and overall rate of DGF was 30.6%. The correlation between CIT and DGF was statistically significant (P = 0.008), and DGF negatively correlated with 1-y graft survival (P = 0.04). The rate of DGF was significantly different between the groups (P = 0.05). Results from our study demonstrate that the effect of CIT on DGF in settings of RAKT follows a similar pattern as in traditional OKT.

Polyethylene glycol and caspase inhibitor emricasan alleviate cold injury in primary rat hepatocytes

Current methods of storing explanted donor livers at 4 °C in University of Wisconsin (UW) solution result in loss of graft function and ultimately lead to less-than-ideal outcomes post transplantation. Our lab has previously shown that supplementing UW solution with 35-kilodalton polyethylene glycol (PEG) has membrane stabilizing effects for cold stored primary rat hepatocytes in suspension. Expanding on past studies, we here investigate if PEG has the same beneficial effects in an adherent primary rat hepatocyte cold storage model. In addition, we investigated the extent of cold-induced apoptosis through treating cold-stored hepatocytes with pan caspase inhibitor emricasan. In parallel to storage at the current cold storage standard of 4 °C, we investigated the effects of lowering the storage temperature to −4 °C, at which the storage solution remains ice-free due to the supercooling phenomenon. We show the addition of 5 % PEG to the storage medium significantly reduced the release of lactate dehydrogenase (LDH) in plated rat hepatocytes and a combinatorial treatment with emricasan maintains hepatocyte viability and morphology following recovery from cold storage. These results show that cold-stored hepatocytes undergo multiple mechanisms of cold-induced injury and that PEG and emricasan treatment in combination with supercooling may improve cell and organ preservation.

Continuous renal surface cooling technique (CSCT) in robotic-assisted kidney transplantation: technique and outcomes from a high-volume center: a prospective cohort study.

Robot-assisted kidney transplantation (RAKT) surgery is an advanced minimally invasive technique, albeit with extended surgical and kidney ischemia time. To safeguard kidney function, the authors have devised a continuous surface cooling method (CSCT) for intraoperative kidney cooling. Patients receiving RAKT were divided into CSCT group and conventional group. The CSCT is a custom-designed apparatus composed of a single-layer plastic bag, featuring an inflow and an outflow that create a closed circuit for the continuous flow of cooling saline. The conventional group utilized ice slush for kidney graft cooling (Vattikuti Urology Institute-Medanta Technique, VUIMT). Patients who underwent open renal transplantation during the same period were also included in the study. All patients were subject to a minimum 2-month follow-up. And 1:3 propensity score matching was used to minimize selection bias. A total of 144 patients underwent CSCT, 47 underwent VUIMT, and 196 underwent open surgery were included in the study, while after matching, 129, 43, 129 patients were included in the three groups, respectively. The median follow-up time was 19 months. None of the patients experienced delayed graft function, patient mortality, or graft loss. After introducing the kidney into the abdominal cavity for 20 minutes, the surface temperature of the kidney in the CSCT group was notably lower compared to the VUIMT group (15.42±0.88 vs. 21.74±2.53°C, P =0.001). This temperature disparity became more pronounced at 65 min (19.74±1.61 vs. 29.82±1.63°C, P <0.001). At both 3 and 7 days post-transplantation, creatinine levels in the VUIMT group were significantly higher than those in the CSCT and open surgery groups (at 3days, 244.13±45.61 vs. 182.51±55.47 in CSCT group, P <0.001, or vs. 182.77±61.32 in the open surgery group, P <0.001; at 7days, 162.42±54.86 vs. 143.11±44.32 in the CSCT group, P <0.001, or vs. 135.23±45.27 in the open surgery group, P <0.001). No differences were observed in blood creatinine, estimated glomerular filtration rate, and perioperative complications between the CSCT and open surgery groups. The CSCT presents a significant advantage over the traditional VUIMT method in terms of kidney cooling and early postoperative kidney function preservation. Additional research is required to ascertain whether the CSCT can enhance the long-term prognosis of kidney transplant recipients.

2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

Inhibition of Toll-like Receptor 4 Using Small Molecule, TAK-242, Protects Islets from Innate Immune Responses.

Islet transplantation is a therapeutic option to replace β-cell mass lost during type 1 or type 3c diabetes. Innate immune responses, particularly the instant blood-mediated inflammatory reaction and activation of monocytes, play a major role in the loss of transplanted islet tissue. In this study, we aimed to investigate the inhibition of toll-like receptor 4 (TLR4) on innate inflammatory responses. We first demonstrate a significant loss of graft function shortly after transplant through the assessment of miR-375 and miR-200c in plasma as biomarkers. Using in vitro models, we investigate how targeting TLR4 mitigates islet damage and immune cell activation during the peritransplant period. The results of this study support the application of TAK-242 as a therapeutic agent to reduce inflammatory and innate immune responses to islets immediately following transplantation into the hepatic portal vein. Therefore, TLR4 may serve as a target to improve islet transplant outcomes in the future.

Imlifidase in kidney transplantation.

Kidney transplantation, the gold-standard therapeutic approach for patients with end-stage kidney disease, offers improvement in patient survival and quality of life. However, broad sensitization against human leukocyte antigens often resulting in a positive crossmatch against the patient's living donor or the majority of potential deceased donors in the allocation system represents a major obstacle due to a high risk for antibody-mediated rejection, delayed graft function and allograft loss. Kidney-paired donation and desensitization protocols have been established to overcome this obstacle, with limited success. Imlifidase, a novel immunoglobulin G (IgG)-degrading enzyme derived from Streptococcus pyogenes and recombinantly produced in Escherichia coli, is a promising agent for recipients with a positive crossmatch against their organ donor with high specificity towards IgG, rapid action and high efficacy in early pre-clinical and clinical studies. However, the rebound of IgG after a few days can lead to antibody-mediated rejection, making the administration of potent immunosuppressive regimens in the early post-transplant phase necessary. There is currently no comparative study evaluating the efficiency of imlifidase therapy compared with conventional desensitization protocols along with the lack of randomized control trials, indicating the clear need for future large-scale clinical studies in this field. Besides providing a practical framework for the clinical use of the agent, our aim in this article is to evaluate the underlying mechanism of action, efficiency and safety of imlifidase therapy in immunologically high-risk kidney transplant recipients.

“Eculizumab First” in the Management of Posttransplant Thrombotic Microangiopathy

IntroductionPost-transplant thrombotic microangiopathy (PT-TMA) is an uncommon event that characterizes approximately 3-14% of kidney transplants (KT), and that is associated with a higher risk of delayed graft function and graft loss. PT-TMA occurs more frequently within the first three months after transplant and can be a manifestation of de novo disease or the recurrence of previous atypical hemolytic uremic syndrome (aHUS). Abnormalities in complement regulation genes could explain the increased susceptibility of some patients to PT-TMA. Eculizumab is a humanized monoclonal antibody that inhibits the formation of the membrane attack complex C5b-9. The aim of this study is to evaluate the efficacy of eculizumab as treatment for PT-TMA. MethodsWe retrospectively analyzed clinical records of 45 KT patients who received eculizumab immediately after the clinical diagnosis of PT-TMA. ResultsKidney biopsy was performed in 91.1% of patients and complement genetic study in 64.4%. 85.4% of kidney biopsies showed signs of TMA; genetic analysis revealed one pathogenetic variant, two variants of uncertain significance, one likely benign variant, 8 risk polymorphisms, 27 risk haplotypes.After two weeks from the treatment starting, hemoglobin and platelets significantly increased. A remarkable improvement in kidney function was also observed. After six months, 28.8% of patients had a complete renal recovery while 44.4% had a partial recovery. ConclusionThis is, to our knowledge, the largest series of KT patients with PT-TMA treated with eculizumab. These data suggest that eculizumab is associated with a normalization of hemolysis indices and an important and progressive improvement of graft function.

BLADDER TRANSPLANTATION: THE NEW FRONTIER IN ABDOMINAL ORGAN TRANSPLANTATION.

Lower urinary tract abnormalities are directly implicated in the etiology of renal dysfunction in 6 to 24% of dialytic patients. These patients require bladder capacity and compliance readjustment before being considered viable candidates for renal transplantation. Vesical augmentation surgeries often involve the use of intestinal segments. Although these procedures can effectively restore bladder capacity and compliance, they present various issues related to maintaining mucous absorption and secretion capacity. Acidosis, recurrent urinary tract infections, and stone formation are extremely common, leading to frequent hospitalizations and graft function loss. Urinary tissue is certainly ideal for these reconstructions; however, bladder augmentation using ureter and renal pelvis are feasible only in a minority of cases. Experimental studies have been conducted to establish the groundwork for vascularized bladder transplantation. Last year, for the first time, this procedure was performed on a brain-dead patient. During this intervention, cystectomy was performed with preservation the vascular pedicle, followed by organ reimplantation. The graft remained viable for a period of 12 hours post-transplant. However, this intervention utilized a robotic platform, making it less reproducible in a multi-organ procurement setting as well as for most transplant centers. Moreover, it is debatable whether the benefits of exclusive bladder transplantation outweigh the risks associated with immunosuppression. For patients needing renal transplantation and requiring lower urinary tract reconstruction, however, utilizing the donor's bladder may offer an attractive alternative, avoiding the inherent complications of enterocystoplasty without increasing immunological risk. Combined kidney and bladder transplantation has the potential to emerge as the next frontier in abdominal organ transplants.

Clinical and Immunological Factors Associated with Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis Patients

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely recognized as the sole curative treatment for myelofibrosis (MF). However, patients with MF often experience graft function impairment despite successful engraftment and absence of relapse signs. Although it has been reported that poor graft function can have a negative impact on the outcomes of patients with MF after HSCT, the specific factors that can influence poor graft function are not yet clearly understood. In this background, we analyzed various clinical and immunological factors that may contribute to poor graft function after transplantation. The study included 93 patients who underwent HSCT for the treatment of MF at Seoul St. Mary's Hospital between the years 2000 and 2022. By cumulative incidence analysis of poor graft function (death, relapse, graft failure, and loss of chimerism as competing risks), we evaluated which pre-HSCT factors has significant impact on poor graft function after HSCT. The definition of poor graft function and graft failure in this study followed the criteria set by the European Society for Blood and Marrow Transplantation (EBMT). We measured the longitudinal diameter of spleen up to 2 months prior to HSCT, and classified the patients into pre-HSCT splenomegaly (≥ 14cm) or not. Next, we investigated the association of immune-related gene expression signature in bone marrow immune-microenvironment with the occurrence of poor graft function, by performing targeted gene expression profiling and gene set enrichment analysis using a custom NanoString panel composed of 579 immune-related genes in pre- and post-HSCT BM samples from patients with poor graft function and good graft function (total 24 samples). A median age of 93 patients was 57 years, and 55.9% were male. Secondary MF was observed in 30.1% of the cases. Fifty-three (57.0%) received graft from a matched sibling donor graft and 40 (43.0%) from a matched unrelated donor. Sixty-three (67.7%) patients were classified to the pre-HSCT splenomegaly group. In terms of ABO match, 45 (48.4%) patients were matched, 10 (10.8%) had bi-directional mismatch, 17 (18.3%) had major mismatch, and 19 (20.4%) had minor mismatch. The median infused CD34 (+) cell dose was 6.4 x 10^6/kg (Interquartile range 5.3 x 10^6/kg-8.3 x 10^6/kg). In our patients, cumulative incidence of poor graft function after 5 years from HSCT was 32.0% (95% CI: 23.4-42.7). Infused CD34 (+) cell dose, the presence of splenomegaly before HSCT were revealed to have an impact on the occurrence of poor graft function after HSCT. The other significant factor associated with poor graft function was ABO mismatch, in particular, with a substantial difference between matched patients and patients with bi-directional ABO mismatch. (Figure A). In NanoString panel analysis, although the expression of immune-related genes mostly upregulated after HSCT, genes related to processes such as complement system, inflammasomes, phagocytosis and degradation, and MHC class II antigen presentation pathways were significantly downregulated in PGF. Whereas, oxidative stress, inflammasomes, and autophagy pathways were downregulated in GGF (Figure B). In this study, we could observe that a significant proportion of MF patients undergoing HSCT experienced poor graft function. Factors that significantly associated with the occurrence of poor graft function included the CD34 (+) cell dose at the time of HSCT, the presence of splenomegaly before HSCT, and ABO mismatch. Interestingly, distinct gene expression signatures present in IME between pre- and post-SCT in both PGF and GGF. Further research is warranted to investigate the impact of poor graft function caused by these factors on outcomes such as transfusion requirements and quality of life.

Difficult-to-Treat Rejections in Kidney Transplant Recipients: Our Experience with Everolimus-Based Quadruple Maintenance Therapy.

All chronic and treatment-resistant acute rejections are "difficult-to-treat" and lead to progressive loss of graft function in kidney transplant recipients (KTR), as no effective treatment exists for such rejections to date. We review our experience with a novel strategy to treat such rejections by adding everolimus as a "rescue" to conventional triple maintenance therapy with prednisolone, mycophenolate mofetil and calcineurin inhibitor. We retrospectively analysed data in 28 KTR who received everolimus-based quadruple therapy at our institution for biopsy-proven chronic active T cell-mediated or antibody-mediated rejection (n = 19) or treatment-resistant acute rejections (n = 9) between 2011-2017. The primary outcome was 5-year death-censored graft survival. Main secondary outcomes were response to treatment defined by stable or improved graft function, 5-year patient survival and discontinuation rate of treatment. The Kaplan-Meier estimate for 5-year death-censored graft survival was 79% in all patients, 90% for patients with chronic active T cell-mediated rejections, 78% for chronic active antibody-mediated rejection and 67% for acute rejections. Response to treatment was achieved in 43% and 5-year patient survival was 94%. Treatment was stopped in 12 (43%) patients due to adverse events. Everolimus-based maintenance quadruple therapy, despite high rate of everolimus discontinuation due to adverse events, may be a valid approach in a subset of kidney transplant recipients with such difficult-to-treat rejections, which otherwise would lead to a high rate of graft loss.

Donor-derived myeloid sarcoma in a kidney transplant recipient: clinical case study and relevance of a multidisciplinary approach in therapy and diagnosis

Background. Malignant tumors are one of the main causes of unfavorable outcomes in solid organ transplant recipients in the long term after transplantation. Localization of these tumors in a transplanted organ may cause loss of graft function. After chronic graft dysfunction and infections, malignant neoplasms come next as one of the leading causes of late kidney graft loss. The incidence of different types of malignancies varies according to the transplanted organ. Knowledge of etiology, pathogenesis, peculiarities of diagnosis and treatment of malignant tumors in solid organ transplant recipients is a significant part of screening at any stage of post-transplant period. Late diagnosis of malignancies in a transplanted kidney amidst disconnected stages of treatment and follow-up leads not only to graft loss, but also jeopardizes the life of recipients.Clinical case description. The patient is a 29-year-old female. History: IgA nephropathy with nephrosclerosis. Renal replacement therapy (RRT) with long-term hemodialysis since March 2019. Kidney transplantation from a deceased donor to the right external iliac vessels on March 13, 2019. Graft function is immediate. In October 2020, a tumor in the transplanted kidney was detected for the first time. In November 2021, an emergency graft nephrectomy was performed for health reasons. Antibacterial, antifungal therapy was carried out. Results of morphological study of the removed renal graft with immunohistochemistry (IHC) were obtained. The structure and phenotype of the tumor are consistent with myeloid sarcoma. Trephine biopsy: normocellular bone marrow.Conclusion. The 29-year-old patient was diagnosed with donor-derived myeloid sarcoma in her kidney transplant with the development of paraneoplastic syndrome and multi-organ failure. Currently, the patient is receiving RRT by long-term scheduled hemodialysis. Organ recipients need to be managed by a multidisciplinary team of specialized and highly specialized specialists, taking into account comorbid status and features of the course of the underlying disease.

Performance of Scores Predicting Adverse Outcomes in Procurement Kidney Biopsies From Deceased Donors With Organs of Lower-Than-Average Quality.

Several scores have been devised for providing a prognosis of outcomes after kidney transplantation. This study is a comprehensive test of these scores in a cohort of deceased donors with kidneys of lower-than-average quality and procurement biopsies. In total, 15 scores were tested on a retrospective cohort consisting of 221 donors, 223 procurement biopsies, and 223 recipient records for performance on delayed graft function, graft function, or death-censored graft loss. The best-performing score for DGF was the purely clinical Chapal score (AUC 0.709), followed by the Irish score (AUC 0.684); for graft function, the Nyberg score; and for transplant loss, the Snoeijs score (AUC 0.630) and the Leuven scores (AUCs 0.637 and 0.620). The only score with an acceptable performance was the Chapal score. Its disadvantage is that knowledge of the cold ischemia time is required, which is not known at allocation. None of the other scores performed acceptably. The scores fared better in discarded kidneys than in transplanted kidneys. Our study shows an unmet need for practical prognostic scores useful at the time of a decision about discarding or accepting deceased donor kidneys of lower-than-average quality in the Eurotransplant consortium.

Evaluation of risk factors and clinical outcomes of acute respiratory failure from post renal transplant recipients: A five-year data of a single center

Acute Respiratory Failure (ARF) requiring Intensive Care Unit (ICU) admission is a common complication following renal transplant and is a diagnostic and therapeutic challenge. This study aimed to evaluate etiological factors and clinical outcomes of ARF following a renal transplant. This was a retrospective observational study. Data was recruited from last five –years’ records of Renal Transplant Unit of Dow University of Health Sciences, Karachi, Pakistan. Patients who developed ARF after renal transplantation whether requiring hospitalization (both in ICU or in ward) were included and their severity, etiologic diagnosis, and clinical outcomes were evaluated. During past five years (June 2017 till June 2023) a total of 450 kidney allografts were done and 35 patients (7.8%) developed ARF. Out of which 15 patients were shifted to the ICU. Mortality of female patients was higher as compared to males (26.1% versus 20.4%). Hypertension was found to be the most common comorbidity whereas glomerulonephritis was the most common cause of End Stage Renal Disease (ESRD). Acute rejection was observed in 20.89% (n = 94) of recipients. Bacterial pneumonia was the most common cause of ARF, one patient needed on mechanical ventilation whereas two patients were dialysis dependent survivors. ARF following renal transplant is associated with higher mortality and loss of graft function because of compromised immunity. Anti-bacterial prophylaxis and early intensive management appears to help in improving the outcome while integrating the graft function.

The Association between CDKAL1 Gene rs10946398 Polymorphism and Post-Transplant Diabetes in Kidney Allograft Recipients Treated with Tacrolimus.

Post-transplant diabetes mellitus (PTDM) is a common complication that occurs in kidney transplant patients, increasing the risk of infection, cardiovascular disease and loss of graft function. Currently, factors that increase the risk of this complication are being sought, among them polymorphisms in genes that regulate carbohydrate metabolism and influence pancreatic β-cell function. The aim of this study was to evaluate the association of selected polymorphisms of genes affecting carbohydrate metabolism, such as CDKAL1 rs10946398, GCK rs1799884, GCKR rs780094 and DGKB/TMEM195 rs2191349, with the development of post-transplant diabetes in kidney transplant patients. This study included 201 Caucasian patients after kidney transplantation treated with tacrolimus. An association was observed between the CDKAL1 rs10946398 gene polymorphism and PTDM. Among patients with PTDM, there was an increased prevalence of the CC genotype in the PTDM group compared to the group without PTDM. The chance of PTDM in those with the CC genotype was 2.60 times higher compared to those with the AC + AA genotypes (CC vs. AC + AA OR (95% CI): 2.60 (1.02-6.61), p = 0.040). Multivariate logistic regression analysis showed that advanced age and the CC genotype (rare homozygote) of CDKAL1 rs10946398 were risk factors for the development of PTDM at 1 year after transplantation. There was no statistically significant association between GCK rs1799884, GCKR rs780094 or DGKB/TMEM195 rs2191349 polymorphisms and the development of post-transplant diabetes mellitus in kidney transplant patients. The results of this study suggest that the CDKAL1 rs10946398 CC genotype is associated with the increased risk of PTDM development in patients after kidney graft transplantation treated with tacrolimus.

#6566 A STUDY OF CLINICAL PRESENTATION AND OUTCOME OF COVID 19 INFECTION IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Novel coronavirus 19 (coronavirus disease-19 [COVID-19]) disproportionately affects patients with various kidney diseases. Patients with kidney transplant are at higher risk of complications of COVID-19 infection. Our aim of this analysis was to study the clinical profile and outcome of COVID-19 infections in KTRs from Kashmir. Method Here we present a cohort study of 122 KTRs with polymerase chain reaction-confirmed COVID-19 positivity from March 31, 2020 to October 31, 2022. We detailed demographics, immunosuppression regimen, clinical profile, Covid 19 vaccination status, treatment given, and outcomes (acute kidney injury, graft failure and death) of our study population. Results Median age of the patients was 41 years and median age of disease was 2.9 years after transplant. Most common comorbidities included hypertension (65.6%) and diabetes (35.3%); presenting symptoms at the time of COVID-19 included fever (82.7%) and breathlessness (66.4%). Covid-19 vaccination was given to 81 patients (66.4%) with two doses in 26 patients and 55 patients received one dose. Clinical severity ranged from asymptomatic (4.1%), mild (36.1%), and moderate (28.7%), to severe (31.1%). Acute kidney injury developed in 46.7% of patients and mortality in 21 patients. Risk factors for mortality included higher age, severe disease, allograft dysfunction before COVID-19 infection, Obesity, acute kidney injury, absence of covid-19 vaccination (Table 1). At 3 months of follow-up, loss of graft function was seen in 19 patients of survivors. Conclusion Mortality rates in COVID-19-positive KTR appear to be higher than those in nonimmunosuppressed patients. Risk factors for mortality included higher age, severe disease, allograft dysfunction before COVID-19 infection, Obesity, acute kidney injury, absence of covid-19 vaccination.

#4585 POST-TRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER: COMPARISON OF RISK AND PROGNOSTIC FACTORS BETWEEN KIDNEY AND OTHER ORGAN TRANSPLANT RECIPIENTS

Abstract Background and Aims Post-transplantation lymphoproliferative disorder (PTLD) is a potentially fatal complication of transplantation, pathogenesis of which remains to be fully understood. In solid organ transplant recipients, the risk of disease development is associated with graft type and is lowest for kidney (KTR), intermediate for liver (LTR) and high for lung (LngTR) transplant recipients. The aim of this study was to investigate the factors contributing to the development and treatment outcomes of PTLD and compare their impact on the populations of KTRs, LTRs and LngTRs. Method In this retrospective cohort study we have included all KTRs, LTRs and LngTRs diagnosed with PTLD at four transplantation centers in Poland between 2002 and 2022. The following data were collected from the patients’ medical records: immunosuppression (IS), viral infections, PTLD type, treatment and outcomes. Mann-Whitney U-test was used to assess the differences in group composition, and univariate Cox regression was used to determine the impact of variables upon PTLD time of onset and patient survival. p-values below 0.05 were considered statistically significant. Results We identified 31 KTRs, 31 LTRs and 5 LngTRs who fulfilled the inclusion criteria. Among the patients of the transplantation center leading this study, PTLD was diagnosed in 22 (0.82%) out of 2699 KTRs and 29 (2.03%) out of 1386 LTRs. Two thirds of the patients were male, the median age at first transplantation was 39 years and the median age at PTLD diagnosis was 48 years. KTRs and LTRs significantly differed in IS treatment: more KTRs used steroids (GCS, p = 0.042) and cyclosporin (CsA, p = 0.001), more LTRs used tacrolimus (TAC, p&amp;lt;0.001) and anti-CD25 induction (p = 0.003). KTRs developed PTLD later than LTRs (141 months after transplantation vs 53 months, p = 0.004) and LngTRs (5 months after transplantation, p = 0.001). Monomorphic PTLD was the most frequent in KTRs (80.6%, p = 0.032). Initial IS treatment reduction was used in 91% of all patients. The groups did not significantly differ in the type of PTLD treatment. TAC had the opposite effect on PTLD time of onset in KTRs (HR = 2.92, 95%CI 1.35-6.34, p = 0.007) and LTRs (HR = 0.18, 95%CI 0.04-0.89, p = 0.036). At the end of the observation period 16.7% of KTRs, 51.6% of LTRs and 80% of LngTRs were alive. Complete remission was achieved in 48.4% of KTRs, 61.3% of LTRs and 80% of LngTRs. KTRs had the highest rate of loss to follow up at 41.4%. Patient survival was longer in patients who were treated with anti-CD20 monotherapy (HR = 0.28, 95%CI 0.08-0.96, p = 0.042) and surgery (HR = 0.33, 95%CI 0.12-0.91, p = 0.031). Conclusion KTRs develop PTLD significantly later than LTRs and LngTRs, and disease onset is associated with TAC use. Low KTR survival rate is related to the high rate of loss to follow up (e.g. loss of graft function and return to hemodialysis). Surgical treatment, used mainly in focal PTLD improves patients’ survival. The positive effect of anti-CD20 monotherapy on patients’ survival reflects the efficacy of current stratified treatment regimens for PTLD.

#5551 THE TROPONIN LEVEL AND ITS INFLUENCE ON RENAL AND CARDIOVASCULAR EFFECTS IN RENAL TRANSPLANT RECIPIENTS

Abstract Background and Aims Cardiovascular (CV) morbidity and mortality are highly prevalent in renal transplant recipients (RTRs). As such, assessments of CV status using troponin concentrations could help to identify patients at risk for death or CV events and as a predictor for deterioration of graft function. The aim of the study was to investigate the biomarker troponin for the prediction of adverse renal and cardiovascular outcomes in stable RTRs. Method 305 stable RTRs with a median age of 53 years, (60.6% male) transplanted between 1994 and 2018 were enrolled in the study. General characteristics are shown in Table 1. At baseline, troponin, NT-pro BNP, carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP) were measured. Troponin was measured during a routine baseline visit in stable RTR without cardiac symptoms. The median troponin concentration (11 ng/l) was used as cut-off. Patients were divided into two groups high (≥11 ng/l) and low (&amp;lt;11 ng/l) troponin and followed for 54 months. During this time CV events (stroke, myocardial infarction, peripheral artery thrombosis) death, graft loss and deterioration of renal graft function (increasing creatinine ≥30%) or proteinuria (urine protein creatinine ratio UPCR ≥500 mg/g) were monitored. Results At baseline, significant differences were observed between groups in terms of creatinine, eGFR, troponin, UPCR, PP, and PWV. In the group with baseline troponin ≥11ng/l, more patients had coronary artery disease/peripheral obliterans artery disease (CAD/POAD), heart failure (HF), and diabetes. Baseline troponin correlated only weakly with age (R = 0.47), cfPWV (R = 0.41), eGFR (R = −0.52). During follow-up, patients with high troponin experienced more frequently an increase in creatinine ≥30% (32.9% vs 13%), doubling creatinine (11.2% vs 3.1%), an increase in UPCR (22.4% vs 9.2%), graft loss (16.1% vs 1,8%), death (13.3% vs 0%), and CV events (6.3% vs 4.9%). Conclusion 1. Age, arterial stiffness, and eGFR only have a weakly impact on troponin in stable RTR. 2. Higher troponin is associated with poor outcomes and might be useful not only for the identification of patients with high-risk CV events but also for the deterioration of allograft function.

Diagnosis and treatment of allograft rejection in islet transplantation

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [−59.1% to −91.6%]; ΔC-peptide:glucose, −76.3% [−49.2% to −90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.