Development and validation of a simple web-based tool for early prediction of COVID-19-associated death in kidney transplant recipients.

This analysis, using data from the Brazilian kidney transplant (KT) COVID-19 study, seeks to develop a prediction score to assist in COVID-19 risk stratification in KT recipients. In this study, 1379 patients (35 sites) were enrolled, and a machine learning approach was used to fit models in a derivation cohort. A reduced Elastic Net model was selected, and the accuracy to predict the 28-day fatality after the COVID-19 diagnosis, assessed by the area under the ROC curve (AUC-ROC), was confirmed in a validation cohort. The better calibration values were used to build the applicable ImAgeS score. The 28-day fatality rate was 17% (n = 235), which was associated with increasing age, hypertension and cardiovascular disease, higher body mass index, dyspnea, and use of mycophenolate acid or azathioprine. Higher kidney graft function, longer time of symptoms until COVID-19 diagnosis, presence of anosmia or coryza, and use of mTOR inhibitor were associated with reduced risk of death. The coefficients of the best model were used to build the predictive score, which achieved an AUC-ROC of 0.767 (95% CI 0.698-0.834) in the validation cohort. In conclusion, the easily applicable predictive model could assist health care practitioners in identifying non-hospitalized kidney transplant patients that may require more intensive monitoring. Trial registration: ClinicalTrials.gov NCT04494776.

Collaborative Brazilian pediatric renal transplant registry (CoBrazPed-RTx): A report from 2004 to 2018.

The Brazilian collaborative registry for pediatric renal transplantation began in 2004 as a multicenter initiative aimed at analyzing, reporting, and disseminating the results of pediatric renal transplantation in Brazil. Data from all pediatric renal transplants performed from January 2004 to May 2018 at the 13 participating centers were analyzed. A total of 2744 pediatric renal transplants were performed in the thirteen participating centers. The median age at transplantation was 12.2 years, with the majority being male recipients (56%). The main underlying diseases were CAKUT (40.5%) and glomerulopathy (28%). 1981 (72%) of the grafts were from deceased donors (DD). Graft survival at one year (censored by death) was 94% in the live donor group (LD) and 91% in the DD group (log-rank test P < 0.01). The patient's survival at one and 5 years was 97% and 95% for the LD group and 96% and 93% for the DD group (log-rank test P = 0.02). The graft loss rate was 19% (n = 517), more frequently caused by vascular thrombosis (n = 102) and chronic graft nephropathy (n = 90). DD recipients had 1.6 (1.0-2.2) times greater chance of death and 1.5 (1.2-1.8) times greater chance of graft loss compared to LD recipients. The mortality rate was 5.4% (n = 148), mainly due to infection (n = 69) and cardiovascular disease (n = 28). The results of this collaborative pediatric renal transplant record are comparable to other international registries, although we still have a high infection rate as a cause of death.

Prediction, prevention, and management of delayed graft function: where are we now?

Delayed graft function (DGF) remains a major barrier to improved outcomes after kidney transplantation. High-risk transplant recipients can be identified, but no definitive prediction model exists. Novel biomarkers to predict DGF in the first hours post-transplant, such as neutrophil gelatinase-associated lipocalin (NGAL), are under investigation. Donor management to minimize the profound physiological consequences of brain death is highly complex. A hormonal resuscitation package to manage the catecholamine "storm" that follows brain death is recommended. Donor pretreatment with dopamine prior to procurement lowers the rate of DGF. Hypothermic machine perfusion may offer a significant reduction in the rate of DGF vs simple cold storage, but costs need to be evaluated. Surgically, reducing warm ischemia time may be advantageous. Research into recipient preconditioning options has so far not generated clinically helpful interventions. Diagnostic criteria for DGF vary, but requirement for dialysis and/or persistent high serum creatinine is likely to remain key to diagnosis until current work on early biomarkers has progressed further. Management centers on close monitoring of graft (non)function and physiological parameters. With so many unanswered questions, substantial reductions in the toll of DGF in the near future seem unlikely but concentrated research on many levels offers long-term promise.

Comparative effects of mesenchymal stem cell therapy in distinct stages of chronic renal failure.

BACKGROUND: The therapeutic potential of adult stem cells in the treatment of chronic diseases is becoming increasingly evident. In the present study, we sought to assess whether treatment with mesenchymal stem cells (MSCs) efficiently retards progression of chronic renal failure (CRF) when administered to experimental models of less severe CRF. METHODS: We used two renal mass reduction models to simulate different stages of CRF (5/6 or 2/3 mass renal reduction). Renal functional parameters measured were serum creatinine (SCr), creatinine clearance (CCr), rate of decline in CCr (RCCr), and 24-h proteinuria (PT24h). We also evaluated renal morphology by histology and immunohistochemistry. MSCs were obtained from bone marrow aspirates and injected into the renal parenchyma of the remnant kidneys of both groups of rats with CRF (MSC5/6 or MSC2/3). RESULTS: Animals from groups MSC5/6 and CRF2/3 seemed to benefit from MSC therapy because they showed significantly reduction in SCr and PT24h, increase in CCr and slowed the RCCr after 90 days. Treatment reduced glomerulosclerosis but significant improvement did occur in the tubulointerstitial compartment with much less fibrosis and atrophy. MSC therapy reduced inflammation by decreasing macrophage accumulation proliferative activity (PCNA-positive cells) and fibrosis (α-SM-actin). Comparisons of renal functional and morphological parameters responses between the two groups showed that rats MSC2/3 were more responsive to MSC therapy than MSC5/6. CONCLUSION: This study showed that MSC therapy is efficient to retard CRF progression and might be more effective when administered during less severe stages of CRF.

Influence of HLA-A, B, and -DRB1 genes and panel-reactive antibodies on the waitlist time for kidney transplantation in the state of Sao Paulo-Brazil.

BACKGROUND: Brazil ranks second in the absolute number of transplants. However, the supply remains insufficient to meet the demands, resulting in a lengthy waitlist. This study aimed to analyze whether the frequency of human leukocyte antigen (HLA) and the value of calculated panel reactive antibody (cPRA) would influence the waiting time for kidney transplantation. METHODS: The HLA-A, B, and -DRB1 frequencies and the cPRA value were analyzed in 11,186 kidney transplant candidates included in the waitlist from 2006 to 2016. RESULTS: The most frequent alleles were HLA-A*02, HLA-B*35, and HLA-DRB1*13. The overall mean length of stay on the list was 986 ± 1001 days. The mean waiting time for the three most frequent alleles of the HLA-A and B loci showed no significant difference when compared with the least frequent alleles; however, for the HLA-DRB1 locus, the most frequent alleles showed a shorter waiting time. In the association between HLA and PRA, the average length of stay on the list increased according to the candidate's degree of sensitization, regardless of the analyzed HLA frequency. CONCLUSION: The length of stay on the waitlist is influenced by the frequency of the HLA alleles of the DRB1 locus and the degree of sensitization.

Analysis of COVID-19 Infection in Kidney Transplant Recipients.

BACKGROUND: COVID-19, caused by SARS-CoV-2, was responsible for higher morbidity and mortality in renal transplant recipients (RTx). The objective of the study was to evaluate the impact of COVID-19 infection on RTx in a single center in Brazil. METHODS: A cohort of 135 RTx was evaluated between December 2019 and June 202l, and demographics, clinical, and laboratory profiles were analyzed from deceased donors with COVID-19. RESULTS: Diabetic and RTx from extended criterion donors presented more frequently the severe form of the disease. Serum creatinine (sCr) after 3 months of diagnosis of COVID-19 varied according to the severity of infection. The lethality rate was higher in the group with severe symptoms (65%) compared with those with mild infection (1.5%). CONCLUSION: The increase in sCr was associated with disease severity. The lethality rate for COVID-19 was 26.6%. These rates are 10-20 times higher than those reported in the general population and suggest that rigorous observation, early diagnosis, and disease prevention measures are crucial in RTx.

Use of Machine Perfusion to Increase the Number of Expanded Criteria Deceased Donor Kidney Transplants: A Pharmacoeconomic Analysis.

Background: The discard of expanded criteria donor (ECD) kidneys is unacceptably high, considering the growing demand for transplantation. Using machine perfusion may reduce the discard rate, increase the number of transplants, and reduce mortality on the waiting list. Methods: We developed a 5-y Markov model to simulate incorporating the pulsatile perfusion machine into the current government-funded healthcare system. The model compared the universal use of static cold storage for all kidneys with the selective use of machine perfusion for ECD kidneys. Real-life data were used to compose the cohort characteristics in this model. This pharmacoeconomic analysis aimed to determine the cost-effectiveness and budgetary impact of using machine perfusion to preserve ECD kidneys. Results: Compared with the universal use of static cold storage, the use of machine perfusion for ECD kidneys was associated with an increase in the number of kidney transplants (n = 1123), a decrease in the number of patients on the waiting list (n = 815), and decrease in mortality (n = 120), with a cost difference of US dollar 4 486 009 in the period. The budget impact analysis revealed an additional cost of US dollar 4 453 749 >5 y. The budget impact analysis demonstrated a progressive reduction in costs, becoming cost-saving during the last year of the analysis. Conclusions: This stochastic model showed that incorporating machine perfusion for ECD kidneys is most often a dominant or cost-effective technology associated with an increase in the number of transplants and a reduction in the number of patients on the waiting list, reducing mortality on the waiting list.

Different Patterns of Foxp3 Gene Expression in Pre-and Post-Transplantation Kidney Biopsies and the Effect of Use Mammalian Target of Rapamycin Inhibitors.

BACKGROUND: Trafficking of regulatory T cells (Tregs) modulates the inflammatory response after kidney transplantation (KTx). There is scarce information on whether circulating and intragraft Tregs are similarly affected by immunosuppressive drugs and the type of deceased kidney donor. METHODS: FOXP3 gene expression was measured in the pretransplant kidney biopsies (PIBx) from donors who met extended (ECD) and standard (SCD) criteria donors. In the third month after KTx, the patients were divided according to tacrolimus (Tac) or everolimus (Eve) and the type of kidney they had received. FOXP3 gene expression in the peripheral blood (PB) and kidney biopsies (Bx) was analyzed using real-time polymerase chain reaction. RESULTS: FOXP3 gene expression in the PIBx was higher in ECD kidneys. FOXP3 gene expression in the PB and Bx was greater in Eve- than in Tac-treated patients. However, SCD recipients treated with Eve (SCD/Eve) had higher FOXP3 expression than ECD/Eve. CONCLUSION: Pretransplant kidney biopsies from ECD kidneys had higher FOXP3 gene expression than SCD, and the use of Eve may affect the expression of the FOXP3 gene only in SCD kidneys.

Clinical outcomes of COVID-19 in patients undergoing chronic hemodialysis and peritoneal dialysis.

BACKGROUND: The reported incidence and fatality rate of the severe acute respiratory syndrome coronavirus 2 in patients receiving chronic dialysis are higher than in the general population. We sought to study the outcomes following coronavirus disease 2019 (COVID-19) diagnosis in patients undergoing chronic hemodialysis (HD) or peritoneal dialysis (PD) in a single center in Brazil. METHODS: Of the 522 patients on dialysis evaluated between March 1, 2020, and October 1, 2021, those presenting symptoms or with a history of close contact with COVID-19 patients were tested with reverse-transcription polymerase chain reaction of samples from nasopharyngeal swabs. RESULTS: Of the 522 patients, 120 were positive for COVID-19 infection, of which 86% were on HD and 14% in the PD program. The incidence per 10,000 inhabitants was higher in the HD group than in the PD group (2,423.5 vs. 1,752.5). The mortality per 10,000 inhabitants (470.5 vs. 927.8) and the fatality rate (19.4 vs. 52.9%, p = 0.005) were higher in the PD group. The PD group also had a higher need for hospitalization, intensive care, and mechanical ventilation. CONCLUSIONS: We advise caution when considering strategies to transfer patients from HD to the PD program to minimize the risk of COVID-19 for patients on HD.

Paired kidney donation: are we going beyond reasonable limits in living-donor transplantation?

The growing demand for transplant kidneys requires strategies to increase organ supply and avoid long waiting periods on the list. The increase in the number of transplants from living donors involves the growth in the use of unrelated donors and paired kidney donation. Most of these transplants are performed in the USA, where they already represent, respectively, 34% and 16% of total transplants from living donors. In Latin America, and especially in Brazil, there is no collective enthusiasm for these modalities, either at the request of transplanters or that of the community, with the region's priority being to increase transplants from deceased donors, which growth can be up to three-fold. Concerning transplants from matched donors, the possible conflicting results between donors can generate public challenges and they risk compromise the concepts of equal opportunities for transplant candidates, with the possibility of generating resistance to organ donation, especially in regions with socioeconomic limitations and disparities in access to qualified health care and education. This donation model involves challenging ethical and logistical issues, which are subject to questionings, starting with an act of exchange between two pairs until reaching embarrassing proposals, which can compromise the altruistic character of organ donation, and thus not be universally incorporated.

Effect of the COVID-19 Pandemic on Kidney Transplant and on Chronic Dialysis Patients.

BACKGROUND: The reported fatality rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients receiving maintenance dialysis or kidney transplant are higher than in the general population. The aim of this study was to evaluate the impact of SARS-CoV-2 infection in chronic dialysis patients (DPs) compared with kidney transplant recipients (KTxRs). METHODS: A study evaluating 266 COVID-19-positive patients (112 DPs and 154 KTxRs) was conducted in a single center from March 1, 2020, to June 30, 2021. All patients were confirmed for COVID-19 infection by reverse transcription polymerase chain reaction or antigen test. RESULTS: KTxRs were younger (49 ± 12.4 vs 61 ± 14.6 years; P < .0001) and had significantly fewer coexisting disorders than the DPs. A higher percentage of KTxRs required hospitalization (70% vs 49.4%, P = .002) and intensive care unit admission (39% vs 25%, P = .01). The fatality rate was 24% in both groups. DISCUSSION: There is no consensus among studies about the higher fatality rate between KTxRs and DPs who develop COVID-19. In our study, we also did not find a different fatality rate. CONCLUSION: In spite of KTxRs being younger and having fewer coexisting disorders, compared with DPs, they presented a higher hospitalization and intensive care unit necessity rate but a similar fatality rate.

Impact of an Electronic Alert in Combination with a Care Bundle on the Outcomes of Acute Kidney Injury.

Early diagnosis is essential for the appropriate management of acute kidney injury (AKI). We evaluated the impact of an electronic AKI alert together with a care bundle on the progression and mortality of AKI. This was a single-center prospective study that included AKI patients aged ≥ 18 years, whereas those in palliative care, nephrology, and transplantation departments were excluded. An AKI alert was issued in electronic medical records and a care bundle was suggested. A series of classes were administered to the multidisciplinary teams by nephrologists, and a clinical pharmacist audited prescriptions. Patients were categorized into pre-alert and post-alert groups. The baseline characteristics were comparable between the pre-alert (n = 1613) and post-alert (n = 1561) groups. The 30-day mortality rate was 33.6% in the entire cohort and was lower in the post-alert group (30.5% vs. 36.7%; p < 0.001). Age, pulmonary disease, malignancy, and ICU admission were associated with an increase in 30-day mortality. The electronic AKI alert together with a care bundle and a multidisciplinary education program was associated with a reduction in 30-day mortality in patients with AKI.

Distinct global DNA methylation and NF-κB expression profile of preimplantation biopsies from ideal and non-ideal kidneys.

BACKGROUND: Epigenetic mechanisms may affect the ideal and non-ideal kidneys selected for transplantation and their inflammatory gene expression profile differently and may contribute to poor clinical outcomes. OBJECTIVE: Study the Global DNA methylation and the expression profiles of the DNA methyltransferases (DNMTs) and nuclear factor kappa B (NF-κB) in preimplantation kidney biopsies from ideal and non-ideal kidneys (expanded criteria donor (ECD) and with KDPI > 85%). METHODS: In a sample consisting of 45 consecutive pre-implantation biopsies, global DNA methylation levels were detected by LINE-1 repeated elements using bisulfite pyrosequencing. DNMT gene expression was assessed by real-time quantitative polymerase chain reaction, and NF-κB protein expression by immunofluorescence. RESULTS: ECD kidneys displayed increased methylation levels in LINE-1, and DNMT1 and DNMT3B expression was upregulated when comparing ECD to standard criteria donor kidneys. Similarly, kidneys with KDPI > 85% exhibited increased LINE-1 methylation and DNMT1 upregulation when compared to a KDPI ≤ 85%. NF-κB protein expression levels were greatly increased in both types of non-ideal kidneys compared to ideal kidneys. Moreover, hypermethylation of LINE-1 was associated with cold ischemia time > 20 h and ECD kidney classification. CONCLUSIONS: This study shows that global DNA hypermethylation and high expression of NF-κB occurred in both types of non-ideal kidneys and were associated with prolonged cold ischemia time. Global DNA methylation can be a useful tool to assess non-ideal kidneys and hence, could be used to expand the pool of kidneys donors.

Reasons for Disparities in Access to Kidney Transplantation.

Clinical Background: Kidney transplantation (KT) is the best treatment for most patients with end-stage kidney disease (ESKD), providing better survival and quality of life and lower cost when compared to dialysis. Epidemiology: Despite robust evidence showing the superiority of KT over dialysis, a significant percentage of ESKD patients worldwide do not access this treatment. Challenges: Barriers resulting in inequalities and inequities in access to KT involves chronic kidney disease (CKD) diagnosis and management, including difficulties in accessing dialysis therapy before KT; suboptimal referral and enlistment to KT; and imbalance between supply and demand for organs. Low socioeconomic status has an important role in that scenario. Prevention and Treatment: Strategies to minimize disparities in access to KT involve public policies to ensure access to CKD diagnosis and treatment, health education, continuous training of health providers, infrastructure, and allocation policies.

SARS-CoV-2 assessment in an outpatient dialysis facility of a single center in Brazil.

BACKGROUND: The reported incidence and fatality rates of SARS-CoV-2 infection in patients receiving maintenance dialysis are higher than those of the general population. OBJECTIVE: This study sought to characterize the clinical characteristics and outcomes following COVID-19 infection in this population in a single center in Brazil. METHODS: Out of 497 dialysis patients evaluated between March 1st, 2020 and February 1st, 2021, those presenting symptoms or history of close contact with COVID-19 patients were tested. Disease severity was categorized as mild, moderate, or severe. RESULTS: Out of the 497 patients, 8.8% tested positive for COVID-19. These patients were predominantly male (59%), mean age 57.5 ± 17. Hospitalization was required for 45.4% of patients and 15.9% received mechanical ventilation. Symptoms such as fever, cough, dyspnea and asthenia were more frequent in the severe group. Neutrophil to lymphocyte ratio, C- reactive protein, glutamic oxalacetic transaminase and lactic dehydrogenase were significantly higher in the severe group, while hemoglobin and lymphocyte counts were significantly lower. Chest CT >50% of ground glass lesions was the risk factor associated with severe disease and need for hospitalization. The incidence of a thromboembolic event was of 22.7% in this population. The incidence, mortality, and case fatality rates were 954.4/10,000 patients, 151.8/10,000 patients, and 15.9%, respectively. CONCLUSIONS: The incidence, mortality and case fatality rates in our cohort were significantly higher than those reported for the general population. To institute appropriate control measures and early vaccination in dialysis facilities is imperative to prevent the spread of COVID-19 infection.

High mortality among kidney transplant recipients diagnosed with coronavirus disease 2019: Results from the Brazilian multicenter cohort study.

BACKGROUND: Kidney transplant (KT) recipients are considered a high-risk group for unfavorable outcomes in the course of coronavirus disease 2019 (COVID-19). AIM: To describe the clinical aspects and outcomes of COVID-19 among KT recipients. METHODS: This multicenter cohort study enrolled 1,680 KT recipients diagnosed with COVID-19 between March and November 2020, from 35 Brazilian centers. The main outcome was the 90-day cumulative incidence of death, for the entire cohort and according to acute kidney injury (AKI) and renal replacement therapy (RRT) requirement. Fatality rates were analyzed according to hospitalization, intensive care unit (ICU) admission, and mechanical ventilation (MV) requirement. Multivariable analysis was performed by logistic regression for the probability of hospitalization and death. RESULTS: The median age of the recipients was 51.3 years, 60.4% were men and 11.4% were Afro-Brazilian. Comorbidities were reported in 1,489 (88.6%), and the interval between transplantation and infection was 5.9 years. The most frequent symptoms were cough (54%), myalgia (40%), dyspnea (37%), and diarrhea (31%), whereas the clinical signs were fever (61%) and hypoxemia (13%). Hospitalization was required in 65.1%, and immunosuppressive drugs adjustments were made in 74.4% of in-hospital patients. ICU admission was required in 34.6% and MV in 24.9%. In the multivariable modeling, the variables related with the probability of hospitalization were age, hypertension, previous cardiovascular disease, recent use of high dose of steroid, and fever, dyspnea, diarrhea, and nausea or vomiting as COVID-19 symptoms. On the other hand, the variables that reduced the probability of hospitalization were time of COVID-19 symptoms, and nasal congestion, headache, arthralgia and anosmia as COVID-19 symptoms. The overall 90-day cumulative incidence of death was 21.0%. The fatality rates were 31.6%, 58.2%, and 75.5% in those who were hospitalized, admitted to the ICU, and required MV, respectively. At the time of infection, 23.2% had AKI and 23.4% required RRT in the follow-up. The cumulative incidence of death was significantly higher among recipients with AKI (36.0% vs. 19.1%, P < 0.0001) and in those who required RRT (70.8% vs. 10.1%, P < 0.0001). The variables related with the probability of death within 90 days after COVID-19 were age, time after transplantation, presence of hypertension, previous cardiovascular disease, use of tacrolimus and mycophenolate, recent use of high dose of steroids, and dyspnea as COVID-19 symptom. On the other hand, the variables that reduced the risk of death were time of symptoms, and headache and anosmia as COVID-19 symptoms. CONCLUSION: The patients diagnosed with COVID-19 were long-term KT recipients and most of them had some comorbidities. One in every five patients died, and the rate of death was significantly higher in those with AKI, mainly when RRT was required.

Randomized trial of early corticosteroid reduction vs. regular-dose corticosteroid maintenance in combination with tacrolimus and mycophenolate mofetil in living donor kidney transplant recipients: the Brazilian CORRETA trial.

This multicenter, randomized trial aimed to compare the safety and efficacy of an early reduction in corticosteroid dose vs. long-term maintenance in Brazilian patients on an immunosuppressive regimen based on tacrolimus and mycophenolate mofetil (MMF). In the control arm, prednisone was progressively reduced from days 8 to 90 and then kept for 12 months. In the experimental arm, prednisone was given for 12 months at the dose of 5 mg every other day. Endpoints were the composite occurrence of death, graft loss, or Banff III acute rejection, and safety. A total of 83 patients were enrolled, and 77 were analyzed for efficacy safety. One death occurred in each group. There were no cases of graft loss and one case of grade 3 acute rejection in the early reduction arm. There was no difference in the rate of the composite primary endpoint between both arms (p=0.215), and there were no significant differences between both arms in terms of adverse events. Except for higher incidence of hypertriglyceridemia levels among patients in the regular-dose arm, there were no significant differences between both arms in terms of adverse events. The results of this trial suggest that early reduction of corticosteroid can be feasible and safe within a timeframe of 12 months in patients receiving tacrolimus and MMF.