Cohort Of Kidney Transplant Recipients Research Articles

Klotho and Fibroblast Growth Factor 23 Are Independent of Vitamin D, and Unlike Vitamin D, Are Not Associated With Graft- and Patient Survival After Kidney Transplantation.

Vitamin D, sKlotho, and iFGF23 were measured 8 wk and 1 y posttransplant in 132 recipients transplanted between November 2012 and October 2013. Of the 132 kidney transplant recipients, 49 had deficient vitamin D levels (<30 nmol/L) and 83 had nondeficient vitamin D levels (≥30 nmol/L) at 8 wk posttransplant. The mean age was 51 y and the median follow-up was 7.4 y. At 1 y posttransplant, vitamin D increased significantly. There were no significant differences in sKlotho or iFGF23 levels between the 2 vitamin D groups neither at 8 wk nor 1 y. sKlotho increased significantly and iFGF23 decreased significantly in the whole cohort. During the follow-up, there were 36 graft losses (27%) and 27 deaths (20%). Ninety-four percent of the transplant recipients with nondeficient vitamin D levels were alive with a well-functioning graft after 5 y using Kaplan-Meier survival estimates, compared with 84% of the patients with deficient vitamin D levels (P = 0.014). Klotho and FGF23 levels did not influence graft- and patient survival. In this nationwide cohort of kidney transplant recipients, long-term graft- and patient survival were significantly better in patients with vitamin D ≥30 nmol/L 8 wk posttransplant compared with those with vitamin D <30 nmol/L. sKlotho levels increased and iFGF23 levels decreased from 8 wk to 1 y posttransplant. Klotho and FGF23 levels were not associated with graft- and patient survival.

Leukopenia in autosomal dominant polycystic kidney disease: a single-center cohort of kidney transplant candidates with post-transplantation follow-up.

Autosomal dominant polycystic kidney disease (ADPKD) has occasionally been associated with lower peripheral white blood cell (WBC) counts. This study aimed to investigate the peripheral blood cell counts in a large cohort of kidney transplant recipients before and after kidney transplantation and its potential impact on post-transplant outcomes. This was a retrospective study with long-term follow-up data of 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals, of whom 392 had ADPKD. In total, 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals were included, of whom 392 had ADPKD. Both pre- and post-transplantation, ADPKD patients had significantly lower total WBC counts, and more specifically lower neutrophil, lymphocyte and eosinophil counts compared with the non-ADPKD patients. This observation was independent of potential confounders such as level of inflammation, smoking habit, vitamins and pre-transplant medication. Overall survival and kidney transplant survival were significantly better in ADPKD vs non-ADPKD transplant recipients and a longer time to first infection was observed. However, no association between blood cell counts and outcome differences was found. In conclusion, this large single-center study reports a strong and independent association between ADPKD and lower peripheral WBC counts both before and after kidney transplantation. Considering the role of inflammation in disease progression, further investigation into the role of WBC in ADPKD is needed.

Kinetics of humoral immune response and severity of infection after three doses of SARS-CoV-2 mRNA vaccine in a large cohort of kidney transplant recipients

BackgroundCOVID-19 in kidney transplant recipients is associated with high morbidity and mortality. In this study we aimed to evaluate: (i) the seroconversion rate after BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine, (ii) factors associated with humoral response, (iii) clinical outcome of COVID-19 in kidney transplanted patients.MethodsWe enrolled a cohort of 743 kidney transplant recipients followed up from March 2020 until April 2022. A subset of 336 patients, who received three-doses of SARS-CoV-2 vaccine, was analyzed in terms of kinetics of humoral immune response and compared to a control group of 94 healthcare workers. Antibody response was tested before vaccination (T0), 15 and 90 days after the second dose (T1 and T2), on the day of the third dose (T3) and one month after the third dose (T4).ResultsWe observed that 66 out of 743 subjects had COVID-19 infection pre-vaccination: 65.2% had severe symptoms, 27.3% were hospitalized (9 deaths), none were asymptomatic. After three doses, 51 patients had COVID-19 infection, 60.8% were asymptomatic, 27.5% reported mild symptoms, 3.9% showed severe symptoms, 7.8% were hospitalized (2 deaths).In the subset of 336 vaccinated patients, an antibody level > 0.8 U/ml was detected at T1, that increased at T2 and T3, peaking at T4. Independent factors associated with a negative antibody titer at T4 were decreasing estimated glomerular filtration rate, time from transplantation, and antimetabolites (all p < 0.001) and age (p = 0.007).ConclusionsThe kinetics of humoral response after three doses of vaccine in kidney transplant patients is characterized by a late but effective immune response against SARS-CoV-2, reducing morbidity and mortality.Graphical abstract

Association between Kidney Donor Risk Index, kidney graft function and histological changes in early post-transplant graft biopsy.

Proper assessment of donor organ quality is crucial for optimal kidney allocation and best long-term outcomes. The aim of this study was to analyze the association between the Kidney Donor Risk Index (KDRI) and histological parameters in early post-transplant graft biopsy in a Polish cohort of kidney transplant recipients. In 418 consecutive kidney transplant recipients, a histological evaluation of very early [at median 11 (9-13) post-transplant day] protocol core needle biopsy was performed and analyzed according to the Banff classification. Subjects were divided into quartiles of the KDRI value. Kidney graft function, patient and graft survival were also analyzed over a median follow-up period of 44 (26-56) months. There was a significant trend toward greater intensity of chronic histology changes along the KDRI quartiles (χ2=20.8; P<.001), including interstitial fibrosis, tubular atrophy, mesangial matrix increase and arteriolar hyalinosis. Stepwise multivariate regression analysis revealed that only higher KDRI value independently increased the severity of chronic graft injury (rpartial=0.340, P<.001). KDRI values were valuable in the determination of both early and long-term graft function. The KDRI values correlate with chronic histological changes found in early post-implantation kidney biopsies and can also be helpful in the prediction of graft outcome.

#6073 MAGNETIC RESONANCE RADIOMIC ANALYSIS FOR THE PREDICTION OF GRAFT FAILURE IN PATIENTS WITH KIDNEY TRANSPLANTATION

Abstract Background and Aims Prediction of future graft failure with non-invasive investigations is a relevant objective for transplant clinicians. We previously demonstrated a promising discrimination capacity for interstitial fibrosis / tubular atrophy (IFTA) &amp;gt;50% in kidney biopsy of a machine learning (ML) based magnetic resonance imaging (MRI) radiomic algorithm. Aim of the present study is to evaluate accuracy of MRI radiomic-based ML algorithms in predicting future graft failure. Method Single-center retrospective observational cohort study on a previously characterized cohort of kidney transplant recipients who underwent graft biopsy and graft MRI imaging within 6 months from biopsy, both on clinical indication, at the “Azienda Ospedaliero-Universitaria di Modena”, Italy, from 1/1/2012 to 1/3/2021. The primary outcome was to identify the best combination of MRI radiomic features for the prediction of graft failure during follow-up. Segmentation of renal parenchyma, cortex and medulla on MRI sequences was performed using the 3DSlicer software. Radiomic features were then extracted using an in-house software based on pyradiomics applying Wavelet and Gaussian filters. LASSO algorithm was employed to select correlated features with outcome and summarize them in a radiomic signature. Using radiomic signature alone and then merged with meaningful clinical data we trained ML-algorithms using 70% of cases for training/validation, with a 10-fold internal cross-validation, and 30% for model testing. Model performance was assessed using AUC with a 95% confidence interval (CI). Results Seventy coupled tests (63 patients) were included and randomly subdivided into a training/validation cohort (n = 50) and a test cohort (n = 20). Median follow-up was 24.73 months (interquartile range 13.64-46.57). Radiomic model had an AUC of 0.88 (95%_CI 0.70-0.97) in training and 0.57 (95%_CI 0.23-0.86) in test cohort. Radiomic-clinical mixed model had an AUC of 0.90 (95%_CI 0.73-0.98) in training and 0.66 (95%_CI 0.33-0.88) in test cohort. Conclusion We produced an MRI radiomic-based ML algorithm with good prediction ability for future graft failure in patients with kidney transplant. Given the limited number of enrolled patients, validation in larger (and ideally prospective) cohorts is required to confirm our findings. Comparison of radiomic-based ML with histological parameters (i.e., IFTA) for the prediction of graft failure in our cohort is currently under assessment.

Uso de los agonistas del receptor del péptido similar al glucagón tipo 1 en pacientes trasplantados renales

IntroductionIn kidney transplant (KT) recipients, diabetes mellitus (DM) are associated with an increased mortality and a poorer graft survival. Glucagon-like peptide 1 receptor agonists (GLP1-RA) have demonstrated cardiovascular and renal benefits in the general population. However, there is lacking evidence in KT recipients. ObjectiveTo analyze the efficacy and safety of glucagon-like peptide 1 receptor GLP1-RA in a cohort of KT recipients. MethodsMulticenter retrospective cohort study of KT patients with DM who started subcutaneous GLP1-RA in three hospitals in the province of Cádiz between February 2016 and July 2022. Estimated glomerular filtration rate (eGFR), proteinuria, and weight at baseline and after 6 and 12 months were collected. We analyzed glycemic control, blood pressure, lipid profile, and doses and trough levels of tacrolimus. We document episodes of acute rejection (AR), de novo donor-specific antibodies (dnDSA), and adverse effects. ResultsDuring this period, 96 KT with DM started treatment with GLP1-RA, of which 84 had a minimum follow-up of 6 months and 61 were followed for 12 months. A significant reduction was observed in proteinuria (−19.1 mg/g, P = .000; −46.6 mg/g, P = .000), weight (−3.6 kg, P = .000; −3.6 kg, P = .000), glycosylated hemoglobin (−0.7%, P = .000; −0.9%, P = .000), systolic blood pressure (−7.5 mmHg, P = .013; −7.3 mmHg, P = .004), total cholesterol (−11.5 mg/dl, P = .001; −15.6 mg/dl, P = .002) and LDL cholesterol (−9.2 mg/dl, P = .002; −16.8 mg/dl, P = .000) at 6 months and 1 year of follow-up. The eGFR remained stable and the dose and trough levels of tacrolimus did not change. No episodes of AR or development of dnDSA were observed during follow-up. ConclusionsGLP1-RA in KT patients can be a safe and effective option for the management of DM in KT.

Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study

ObjectiveTo compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DesignDevelopment...

Classification of imbalanced data using machine learning algorithms to predict the risk of renal graft failures in Ethiopia

IntroductionThe prevalence of end-stage renal disease has raised the need for renal replacement therapy over recent decades. Even though a kidney transplant offers an improved quality of life and lower cost of care than dialysis, graft failure is possible after transplantation. Hence, this study aimed to predict the risk of graft failure among post-transplant recipients in Ethiopia using the selected machine learning prediction models.MethodologyThe data was extracted from the retrospective cohort of kidney transplant recipients at the Ethiopian National Kidney Transplantation Center from September 2015 to February 2022. In response to the imbalanced nature of the data, we performed hyperparameter tuning, probability threshold moving, tree-based ensemble learning, stacking ensemble learning, and probability calibrations to improve the prediction results. Merit-based selected probabilistic (logistic regression, naive Bayes, and artificial neural network) and tree-based ensemble (random forest, bagged tree, and stochastic gradient boosting) models were applied. Model comparison was performed in terms of discrimination and calibration performance. The best-performing model was then used to predict the risk of graft failure.ResultsA total of 278 completed cases were analyzed, with 21 graft failures and 3 events per predictor. Of these, 74.8% are male, and 25.2% are female, with a median age of 37. From the comparison of models at the individual level, the bagged tree and random forest have top and equal discrimination performance (AUC-ROC = 0.84). In contrast, the random forest has the best calibration performance (brier score = 0.045). Under testing the individual model as a meta-learner for stacking ensemble learning, the result of stochastic gradient boosting as a meta-learner has the top discrimination (AUC-ROC = 0.88) and calibration (brier score = 0.048) performance. Regarding feature importance, chronic rejection, blood urea nitrogen, number of post-transplant admissions, phosphorus level, acute rejection, and urological complications are the top predictors of graft failure.ConclusionsBagging, boosting, and stacking, with probability calibration, are good choices for clinical risk predictions working on imbalanced data. The data-driven probability threshold is more beneficial than the natural threshold of 0.5 to improve the prediction result from imbalanced data. Integrating various techniques in a systematic framework is a smart strategy to improve prediction results from imbalanced data. It is recommended for clinical experts in kidney transplantation to use the final calibrated model as a decision support system to predict the risk of graft failure for individual patients.

The epidemiology of early deep vein thrombosis in kidney transplant recipients.

Because kidney transplant recipients may be at increased risk for deep vein thrombosis (DVT) following transplantation, we investigated the incidence, risk factors, treatments and outcomes of early DVT among kidney transplant recipients. An observational, single-centre cohort study was conducted among adult kidney transplant recipients from Jan. 1, 2005, to Dec. 31, 2016 with 1-year followup. Time to DVT was assessed using the Kaplan-Meier method. Cox proportional hazards and linear regression models were used to analyze risk factors for and outcomes of DVT. The cumulative incidence of DVT was 4.25% at 3 months after transplant. In multivariable analysis, the use of depleting induction agents (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.05-4.35]), white recipient race (HR 1.84. 95% CI 1.08-3.12), the use of kidneys from expanded criteria donors (HR 2.13, 95% CI 1.05-4.32) and lower recipient body mass index (HR 0.95, 95% CI 0.91-1.00) increased the risk for early DVT. Peritransplant DVT prophylaxis was not associated with early DVT. Early DVT was not associated with reduced graft function, death, graft failure or first hospital readmission. Risk factors for early DVT in our cohort of kidney transplant recipients included white recipient race, use of depleting agents, lower recipient body mass index and use of expanded criteria donors. As practice patterns of donor and recipient selection in kidney transplantation evolve, the results of this study may aid in perioperative risk assessments and decision-making about the use of DVT prophylaxis.

Tixagevimab-cilgavimab como tratamiento profiláctico preexposición frente a SARS-CoV-2 en pacientes trasplantados renales

IntroductionIt has been reported that after vaccination with RNAm or viral vectors from SARS-CoV-2 a significant number of solid organ transplant recipients do not develop an effective immune response. In this scenario, the use of tixagevimab-cilgavimab was approved by the European Medicines Agency for COVID-19 prophylaxis in immunocompromised patients in March 2022. We present our experience with a group of kidney transplant recipients who received prophylactic treatment with tixagevimab-cilgavimab. Material and methodsProspective study from a cohort of kidney transplant recipients who had been previously vaccinated with 4 doses and did not achieve a satisfactory immune response to vaccination, presenting antibody titers lower than 260 BAU/mL when measured by ELISA. A total of 55 patients who received a single dose of 150mg of tixagevimab and 150mg of cilgavimab between May and September of 2022 were included in this study. ResultsNo immediate or severe adverse reactions, including worsening of kidney function, were observed after administering the drug or during follow up. All patients who had received the drug 3 months prior presented positive antibody titers (>260 BAU/mL). Seven patients were diagnosed with COVID, and one of those patients had to be admitted to the hospital and died 5 days later from infectious complications and a suspected diagnosis of bacterial coinfection. ConclusionsIn our experience, all kidney transplant recipients reached antibody titers higher than 260 BAU/mL 3 months after receiving prophylactic treatment with tixagevimab-cilgavimab with no severe or irreversible adverse reactions.

Association between NLRP3 rs10754558 and CARD8 rs2043211 Variants and Susceptibility to Chronic Kidney Disease.

Nod-like receptor protein 3 (NLRP3) is a multi-protein complex belonging to the innate immune system, whose activation by danger stimuli promotes inflammatory cell death. Evidence supports the crucial role of NLRP3 inflammasome activation in the transition of acute kidney injury to Chronic Kidney Disease (CKD), by promoting both inflammation and fibrotic processes. Variants of NLRP3 pathway-related genes, such as NLRP3 itself and CARD8, have been associated with susceptibility to different autoimmune and inflammatory diseases. In this study, we investigated for the first time the association of functional variants of NLRP3 pathway-related genes (NLRP3-rs10754558, CARD8-rs2043211), with a susceptibility to CKD. A cohort of kidney transplant recipients, dialysis and CKD stage 3-5 patients (303 cases) and a cohort of elderly controls (85 subjects) were genotyped for the variants of interest and compared by using logistic regression analyses. Our analysis showed a significantly higher G allele frequency of the NLRP3 variant (67.3%) and T allele of the CARD8 variant (70.8%) among cases, compared with the control sample (35.9 and 31.2%, respectively). Logistic regressions showed significant associations (p < 0.001) between NLRP3 and CARD8 variants and cases. Our results suggest that the NLRP3 rs10754558 and CARD8 rs2043211 variants could be associated with a susceptibility to CKD.

Comparing Kidney Transplant Rates and Outcomes Among Adults With and Without Intellectual and Developmental Disabilities

Improving equity in organ transplant access for people with intellectual and developmental disabilities (IDD) is a topic of social discourse in mainstream media, state legislation, and national legislation. However, few studies have compared evaluation rates, transplant rates, and outcomes among adults with and without IDD. To compare rates of kidney transplant and transplant-specific outcomes between propensity-score matched groups of adults with end-stage kidney disease (ESKD [also referred to as end-stage renal disease (ESRD)]) with and without co-occurring IDD. This retrospective cohort study included all Medicare inpatient and outpatient standard analytical files from 2013 through 2020. A total of 1 413 655 adult Medicare beneficiaries with ESKD were identified. Propensity-score matching was used to balance cohorts based on age, sex, race, follow-up duration, and Charlson Comorbidity Index. The matched cohorts consisted of 21 384 adults with ESKD (10 692 of whom had IDD) and 1258 kidney transplant recipients (629 of whom had IDD). Data were analyzed between June 1, 2022, and August 1, 2022. IDD. Evaluation for kidney transplant, receipt of kidney transplant, perioperative complications, readmission, mortality, graft rejection, and graft failure. Of the 21 384 propensity-score matched adults with ESKD, the median (IQR) age was 55 (43-65) years, 39.2% were male, 27.4% were Black, 64.1% were White, and 8.5% identified as another race or ethnicity. After propensity score matching within the ESKD cohort, 633 patients with IDD (5.9%) received a kidney transplant compared with 1367 of adults without IDD (12.8%). Adults with IDD were 54% less likely than matched peers without IDD to be evaluated for transplant (odds ratio, 0.46; 95% CI, 0.43-0.50) and 62% less likely to receive a kidney transplant (odds ratio, 0.38; 95% CI, 0.34-0.42). Among matched cohorts of kidney transplant recipients, rates of perioperative complications, readmission, and graft failure were similar for adults with and without IDD. Using the largest cohort of adult kidney transplant recipients with IDD to date, the study team found that rates of evaluation and transplant were lower despite yielding equivalent outcomes. These data support consideration of adults with IDD for kidney transplant and underscore the urgent need for antidiscrimination initiatives to promote the receipt of equitable care for this population.

Expression of Class II Human Leukocyte Antigens on Human Endothelial Cells Shows High Interindividual and Intersubclass Heterogeneity.

Donor-specific antibodies against class II HLA are a major cause of chronic kidney graft rejection. Nonetheless, some patients presenting with these antibodies remain in stable histological and clinical condition. This study describes the use of endothelial colony-forming cell lines to test the hypothesis of the heterogeneous expression of HLA molecules on endothelial cells in humans. Flow cytometry and immunofluorescence staining revealed substantial interindividual and interlocus variability, with HLA-DQ the most variable. Our data suggest that the expression of HLA class II is predicted by locus. The measurement of endothelial expression of HLA class II in the graft could present a novel paradigm in the evaluation of the alloimmune risk in transplantation and certain diseases. HLA antigens are important targets of alloantibodies and allospecific T cells involved in graft rejection. Compared with research into understanding alloantibody development, little is known about the variability in expression of their ligands on endothelial cells. We hypothesized individual variability in the expression of HLA molecules. We generated endothelial colony forming cell lines from human peripheral blood mononuclear cells ( n =39). Flow cytometry and immunofluorescence staining were used to analyze the cells, and we assessed the relationship between HLA-DQ expression and genotype. Two cohorts of kidney transplant recipients were analyzed to correlate HLA-DQ mismatches with the extent of intragraft microvascular injury. Large variability was observed in the expression of HLA class II antigens, not only between individuals but also between subclasses. In particular, HLA-DQ antigens had a low and heterogeneous expression, ranging from 0% to 85% positive cells. On a within-patient basis, this expression was consistent between endothelial cell colonies and antigen-presenting cells. HLA-DQ5 and -DQ6 were associated with higher levels of expression, whereas HLA-DQ7, -DQ8, and -DQ9 with lower. HLA-DQ5 mismatches among kidney transplant recipients were associated with significant increase in graft microvascular. These data challenge the current paradigm that HLA antigens, in particular HLA class II, are a single genetic and post-translational entity. Understanding and assessing the variability in the expression of HLA antigens could have clinical monitoring and treatment applications in transplantation, autoimmune diseases, and oncology.

Machine learning does not outperform traditional statistical modelling for kidney allograft failure prediction

Machine learning (ML) models have recently shown potential for predicting kidney allograft outcomes. However, their ability to outperform traditional approaches remains poorly investigated. Therefore, using large cohorts of kidney transplant recipients from 14 centers worldwide, we developed ML-based prediction models for kidney allograft survival and compared their prediction performances to those achieved by a validated Cox-Based Prognostication System (CBPS). In a French derivation cohort of 4000 patients, candidate determinants of allograft failure including donor, recipient and transplant-related parameters were used as predictors to develop tree-based models (RSF, RSF-ERT, CIF), Support Vector Machine models (LK-SVM, AK-SVM) and a gradient boosting model (XGBoost). Models were externally validated with cohorts of 2214 patients from Europe, 1537 from North America, and 671 from South America. Among these 8422 kidney transplant recipients, 1081 (12.84%) lost their grafts after a median post-transplant follow-up time of 6.25 years (Inter Quartile Range 4.33-8.73). At seven years post-risk evaluation, the ML models achieved a C-index of 0.788 (95% bootstrap percentile confidence interval 0.736-0.833), 0.779 (0.724-0.825), 0.786 (0.735-0.832), 0.527 (0.456-0.602), 0.704 (0.648-0.759) and 0.767 (0.711-0.815) for RSF, RSF-ERT, CIF, LK-SVM, AK-SVM and XGBoost respectively, compared with 0.808 (0.792-0.829) for the CBPS. In validation cohorts, ML models' discrimination performances were in a similar range of those of the CBPS. Calibrations of the ML models were similar or less accurate than those of the CBPS. Thus, when using a transparent methodological pipeline in validated international cohorts, ML models, despite overall good performances, do not outperform a traditional CBPS in predicting kidney allograft failure. Hence, our current study supports the continued use of traditional statistical approaches for kidney graft prognostication.

Divergent Occurrence of Carotid Intima-Media Thickness and Carotid Arteries Plaques in Stable Kidney Transplant Recipients.

Carotid atherosclerosis is one of the main cerebrovascular complications in kidney transplant recipients (KTRs). We analyzed the relationships between carotid intima-media thickness (IMT) and the occurrence and characteristics of carotid plaques in a cohort of KTRs. In 500 KTRs (aged 49.9 12.0 years), IMT was measured and carotid plaques were semi-qualitatively assessed. Concomitantly, biochemical and hormonal inflammatory, vascular and calcium-phosphate metabolism parameters were also assessed. In 10.2% of patients, a side-to-side IMT difference 0.1 mm was observed, whereas 26.8% of patients with no plaques in one carotid artery had at least one contralateral calcified plaque. Multivariate logistic regression analysis revealed that age ( = 0.409; p 0.001), male sex ( = 0.199; p 0.001), and coronary artery disease ( = 0.139; p 0.01) independently increased IMT ( = 0.25). For the occurrence of calcified carotid plaques, age ( = 0.544; p 0.001), male gender ( = 0.127; p 0.05), and the duration of renal insufficiency prior to transplantation ( = 0.235; p 0.001) were confirmed as independent variables. Substantial side-to-side differences in IMT values and carotid plaques distribution are present in a large percentage of stable KTRs. In addition, there are different clinical risk factors profiles associated with IMT and the presence of calcified plaques. Vascular and calcium-phosphate metabolism biomarkers were not associated with any carotid atherosclerosis characteristics.

Magnetic Resonance Elastography as Surrogate Marker of Interstitial Fibrosis in Kidney Transplantation: A Prospective Study.

Fibrosis progression is a major prognosis factor in kidney transplantation. Its assessment requires an allograft biopsy, which remains an invasive procedure at risk of complications. We assessed renal stiffness by magnetic resonance elastography (MRE) as a surrogate marker of fibrosis in a prospective cohort of kidney transplant recipients compared with the histologic gold standard. Interstitial fibrosis was evaluated by three methods: the semi-quantitative Banff ci score, a visual quantitative evaluation by a pathologist, and a computer-assisted quantitative evaluation. MRE-derived stiffness was assessed at the superior, median, and inferior poles of the allograft. We initially enrolled 73 patients, but only 55 had measurements of their allograft stiffness by MRE before an allograft biopsy. There was no significant correlation between MRE-derived stiffness at the biopsy site and the ci score (ρ=-0.25, P=0.06) or with the two quantitative assessments (pathologist: ρ=-0.25, P=0.07; computer assisted: ρ=-0.21, P=0.12). We observed negative correlations between the stiffness of both the biopsy site and the whole allograft, with either the glomerulosclerosis percentage (ρ=-0.32, P=0.02 and ρ=-0.31, P=0.02, respectively) and the overall nephron fibrosis percentage, defined as the mean of the percentages of glomerulosclerosis and interstitial fibrosis (ρ=-0.30, P=0.02 and ρ=-0.28, P=0.04, respectively). At patient level, mean MRE-derived stiffness was similar across the three poles of the allograft (±0.25 kPa). However, a high variability of mean stiffness was found between patients, suggesting a strong influence of confounding factors. Finally, no significant correlation was found between mean MRE-derived stiffness and the slope of eGFR (P=0.08). MRE-derived stiffness does not directly reflect the extent of fibrosis in kidney transplantation.

Serum Bicarbonate and Graft and Patient Outcomes Among Kidney Transplant Recipients: A Retrospective Cohort Study Evaluating Changes in Serum Bicarbonate Over Time

Identification of treatable risk factors for kidney allograft failure is necessary to improve graft longevity. Metabolic acidosis with either low serum bicarbonate or normal serum bicarbonate (eubicarbonatemic metabolic acidosis) is implicated in native kidney disease progression but its effects in kidney transplant recipients are unclear. Retrospective cohort study. An Integrated Claims-Clinical dataset of US patients with chronic kidney disease (estimated glomerular filtration rates<60mL/min/1.73m2) and serum bicarbonate data were used to generate a cohort of kidney transplant recipients with data from≥1 year before and after transplantation. The primary independent variable was a change in serum bicarbonate from baseline. The primary outcomes were graft failure and all-cause mortality. The secondary outcomes were major adverse cardiac events and all-cause hospitalization. We used adjusted time-dependent Cox proportional hazards models to assess the risk of graft failure, all-cause mortality, major adverse cardiac events, and time to first hospitalization. In this US community-based cohort of 1,915 kidney transplant recipients with a median follow-up of ∼2.5 years, each 1-mEq/L increase in serum bicarbonate was associated with significantly lower hazard of graft loss, death, major adverse cardiac events, and hospitalization by 10%, 8%, 4%, and 8%, respectively. Possible residual confounding. In a US community-based population of kidney transplant recipients, even small incremental increases in serum bicarbonate (1 mEq/L) were significantly associated with reduced hazard of graft loss, all-cause mortality, cardiovascular events, and hospitalization. Interventional trials evaluating the potential benefits of treating metabolic acidosis in kidney transplant recipients are warranted.

Serological Response and Clinical Protection of Anti-SARS-CoV-2 Vaccination and the Role of Immunosuppressive Drugs in a Cohort of Kidney Transplant Patients.

Vaccination against SARS-CoV2 represents a key weapon to prevent COVID-19, but lower response rates to vaccination have frequently been reported in solid organ transplant recipients. The aim of our study was to evaluate the rate of seroconversion to SARS-CoV-2 mRNA vaccines in a cohort of kidney transplant recipients and the potential role of the different immunosuppressive regimens. We conducted an observational retrospective cohort study in kidney transplant patients vaccinated for COVID-19. For each patient, we evaluated IgG anti-S-RBD SARS-CoV-2 titers immediately before the administration of first COVID-19 vaccination dose, 20 days after the first dose and 40 days after the second dose. Moreover, we evaluated the type of immunosuppressive treatment and the incidence of vaccine breakthrough SARS-CoV-2 infection. We enrolled 121 kidney transplant patients vaccinated for COVID-19. At the time of administration of the first vaccine dose, all patients had a negative antibody titer; only 4.1% had positive antibody titers 20 days after the first dose. More than half patients 62 (51%) had protective antibody titers 40 days after the second dose. A total of 18 Solid Organ Transplant Recipients (SOTRs) (14.9%) got a SARS-CoV-2 breakthrough infection during the study period. With regard to immunosuppressive regimen, patients on mycophenolate-based regimen (48.7%) showed the lowest antibody response rates (27.5%) compared to other regimens. Our study confirms that kidney transplant patients show a poor response to two doses of COVID-19 vaccination. Moreover, in our study the use of mycophenolate is significantly associated with a non-response to COVID-19 m-RNA vaccines.

A Narrative Review COVID-19 in Solid-Organ Transplantation: Real-World Evidence From India

Worldwide, India ranks number 2 and 3 for COVID-19 burden and absolute transplant numbers, respectively. Here, we summarized our single and multicenter Indian studies on solid-organ transplant during the COVID-19 pandemic. During the pandemic, solid-organ transplants declined 40% to 50%. The mortality rate in COVID-19-positive kidney transplant recipients (11.6%) was lower in India compared with the developed world during the first wave and lower compared with maintenance hemodialysis patients (13% to 38%) but significantly higher compared with the nonimmunosuppressed general population (1% to 3%) in India. We contributed to National Organ and Tissue Transplant Organization transplant-related guidelines to increase safety and access to solid-organ transplant. We reported the safety and feasibility of remdesivir (n = 57) and convalescent plasma therapy (n = 10) in kidney transplant recipients. We reported 100% patient and graft survival without any complications related to COVID-19 in a large cohort of kidney transplant recipients who recovered from COVID-19 (n = 372) and a large cohort of kidney transplant recipients of living donors (n = 31) who recovered from COVID-19 without any change in induction and maintenance immunosuppression. COVID-19 disease severity and mortality in the second episode (reoccurring infection) was higher (46%) compared with the first episode (11.6%). There was 4.4% incidence of COVID-19-associated mucormycosis in kidney transplant recipients with mortality of 46% in the second wave. We reported COVID-19 vaccine safety with suboptimal efficacy in kidney transplant recipients and dialysis patients compared with the general population. Our report suggested that transplant with carefully selected COVID-19-recovered donors and patients may be feasible and safe, at least over the short term. Continued research is needed on vaccine efficacy, booster doses, and long-term follow up sequelae.

Effect of a Third Dose of SARS-CoV-2 mRNA BNT162b2 Vaccine on Humoral and Cellular Responses and Serum Anti-HLA Antibodies in Kidney Transplant Recipients

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has severely impacted on public health, mainly on immunosuppressed patients, including solid organ transplant recipients. Vaccination represents a valuable tool for the prevention of severe SARS-CoV-2 infection, and the immunogenicity of mRNA vaccines has been evaluated in transplanted patients. In this study, we investigated the role of a third dose of the BNT162b2 vaccine in a cohort of kidney transplant recipients, analyzing both humoral and cell-mediated responses. We observed an increased immune response after the third dose of the vaccine, especially in terms of Spike-specific T cell response. The level of seroconversion remained lower than 50% even after the administration of the third dose. Mycophenolate treatment, steroid administration and age seemed to be associated with a poor immune response. In our cohort, 11/45 patients experienced a SARS-CoV-2 infection after the third vaccine dose. HLA antibodies appearance was recorded in 7 out 45 (15.5%) patients, but none of the patients developed acute renal rejection. Further studies for the evaluation of long-term immune responses are still ongoing, and the impact of a fourth dose of the vaccine will be evaluated.