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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.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%).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.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.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.

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).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.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.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.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.

The chronic use of immunosuppressive drugs is a key risk factor of death because of coronavirus disease 2019 (COVID-19) in kidney transplant recipients (KTRs), although no evident association between the class of immunosuppressive and outcomes has been observed. Thus, we aimed to compare COVID-19-associated outcomes among KTRs receiving 3 different immunosuppressive maintenance regimes.This study included data from 1833 KTRs with COVID-19 diagnosed between March 20 and April 21 extracted from the national registry before immunization. All patients were taking calcineurin inhibitor associated with mycophenolate acid (MPA, n = 1258), azathioprine (AZA, n = 389), or mammalian targets of rapamycin inhibitors (mTORi, n = 186). Outcomes within 30 and 90 d were assessed.Compared with patients receiving MPA, the 30-d (79.9% versus 87.9% versus 89.2%; P0.0001) and 90-d (75% versus 83.5% versus 88.2%; P0.0001) unadjusted patient survivals were higher in those receiving AZA or mTORi, respectively. Using adjusted multivariable Cox regression, compared with patients receiving AZA, the use of MPA was associated with a higher risk of death within 30 d (adjusted hazard ratio [aHR], 1.70; 95% confidence interval [CI], 1.21-2.40; P = 0.003), which was not observed in patients using mTORi (aHR, 0.78; 95% CI, 0.45-1.35; P = 0.365). At 90 d, although higher risk of death was confirmed in patients receiving MPA (aHR, 1.46; 95% CI, 1.09-1.98; P = 0.013), a reduced risk was observed in patients receiving mTORi (aHR, 0.59; 95% CI, 0.35-0.97; P = 0.04) compared with AZA.This national cohort data suggest that, in KTRs receiving calcineurin inhibitor and diagnosed with COVID-19, the use of MPA was associated with higher risk of death, whereas mTORi use was associated with lower risk of death.

BACKGROUND Metrics for evaluating low-quality kidneys have failed to predict outcomes or reduce the kidney refusal and discard rates. Kidneys from extended-criteria donors (ECDs) and kidneys with ≥85% kidney donor profile indexes (KDPIs) might have different sensitivities to the proinflammatory milieu generated by brain death. We aimed to identify gene expression profile differences in innate immunity pathways between low-quality and ideal kidneys. METHODS Preimplantation kidney biopsies from ECD (n = 41) and standard-criteria donor (n = 39) were evaluated for real-time quantitative polymerase chain reaction gene expression using the TaqMan Gene Expression Array Plates system for genes Toll-like receptor-4 (TLR4), high-mobility group box 1, nuclear factor kappa beta, myeloid differentiation primary response 88, interferon (IFN)-γ, interleukin (IL)1-β, tumor necrosis factor alpha, caspase-1 (CASP1), intercellular adhesion molecule 1, IL-10, heme oxygenase 1 hypoxia-inducible factor 1 (HIF-1), monocyte chemotactic protein 1, transforming growth factor beta 1, TIR-domain containing adapter inducing interferon-β (TRIF), TRIF-related adaptor molecule, interferon regulatory factor 3 (IRF-3), receptor-interacting protein 1, IFNβ-1, and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex. Gene expression was also evaluated in kidneys with KDPI ≥85. RESULTS ECD biopsies showed significantly higher expression of IL-10, TLR4, high-mobility group box 1, IFN-γ, TRIF-related adapter molecule, IRF-3, HIF-1, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex, CASP1, and IL-1β (P < 0.05) compared with standard-criteria donor biopsies. IRF-3, HIF-1, and CASP1 were exclusively upregulated in ECD kidneys. Compared with kidneys with KDPIs

Made available in DSpace on 2022-04-28T19:47:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-01 Background Atypical Hemolytic Uremic Syndrome (aHUS) is an ultra-rare disease that potentially leads to kidney graft failure due to ongoing Thrombotic Microangiopathy (TMA). The aim was evaluating the frequency of TMA after kidney transplantation in patients with aHUS in a Brazilian cohort stratified by the use of the specific complement-inhibitor eculizumab. Methods This was a multicenter retrospective cohort study including kidney transplant patients diagnosed with aHUS. We collected data from 118 transplant centers in Brazil concerning aHUS transplanted patients between 01/01/2007 and 12/31/2019. Patients were stratified into three groups: no use of eculizumab (No Eculizumab Group), use of eculizumab for treatment of after transplantation TMA (Therapeutic Group), and use of eculizumab for prophylaxis of aHUS recurrence (Prophylactic Group). Results Thirty-eight patients with aHUS who received kidney transplantation were enrolled in the study. Patients' mean age was 30 years (24-40), and the majority of participants was women (63% of cases). In the No Eculizumab Group (n = 11), there was a 91% graft loss due to the TMA. The hazard ratio of TMA graft loss was 0.07 [0.01-0.55], p = 0.012 in the eculizumab Prophylactic Group and 0.04 [0.00-0.28], p = 0.002 in the eculizumab Therapeutic Group. Conclusion The TMA graft loss in the absence of a specific complement-inhibitor was higher among the Brazilian cohort of kidney transplant patients. This finding reinforces the need of eculizumab use for treatment of aHUS kidney transplant patients. Cost optimization analysis and the early access to C5 inhibitors are suggested, especially in low-medium income countries. Department of Internal Medicine-UNESP Univ Estadual Paulista Departamento de Pediatria Hospital de Clinicas Universidade Estadual de Campinas, SP Transplant Unit São Jose Rio Preto/FAMERP Transplant Unit Santa Casa de Misericórdia de Porto Alegre-ISCMPA Santa Casa de Belo Horizonte Department of Internal Medicine-UNESP Univ Estadual Paulista

BackgroundChronic kidney disease (CKD) is a global public health problem. Cell therapy using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD.MethodsWe transplanted mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitor cells (RPCs) into a CKD rat model system. The RPC and hiPSC cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology, and immunohistochemistry were evaluated 45 days post-surgery.ResultsWe successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker α-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups.ConclusionsIn conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seem to be more efficient than RPCs, possibly due to a paracrine effect triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improves clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD.Graphical abstract

Background The risk factors associated with delayed graft function (DGF) and its impact in kidney transplant (KTx) outcomes remains controversial; it is possible that donor renal characteristics influence the initial graft function in KTx. Objective Evaluate risk factors associated with DGF and its impact in KTx outcomes. Methods One hundred six mate KTx mate recipients performed in a single center were grouped according to the presence or absence of DGF. Results Donors were predominantly men (58%); 70% were standard criteria type, with a mean Kidney Donor Profile Index (KDPI) of 62% ± 28%, median age of 42 ± 15 and presenting hospitalization time of 6 ± 5 days. KTx recipients presented an overall DGF rate of 82%, lasting 12 ± 7 days. Pairs presenting DGF were older than pairs without DGF (P = .008), while cold ischemia time (CIT) was significantly shorter in the group without DGF compared to those presenting DGF (P = .003). The KDPI of the KTx pairs was significantly higher in pairs with DGF versus without DGF (P = .04). No statistically significant differences in 1 year allograft and patient survival were observed. Recipient age (odds ratio = 6.3, confidence interval = 1.5–25.8; P = .009) and CIT (odds ratio = 4.6, confidence interval = 1.2–17.7; P = .002) were significantly associated with DGF. Conclusion This study suggests that recipient age, cold ischemic time, and KDPI are factors associated with DGF. In addition, DGF had no impact on 1-year renal function, allograft, and patient survival. In the transplant conditions of our country, Brazil, CIT seems to represent an important variable to be managed, and the aim should be to reduce this factor as much as possible.

Introduction Longer cold ischemia time (CIT) is a deleterious factor for kidney transplant (KTx) outcomes and may lead Tx teams to graft discard. Because the CIT in Brazil is overall very high, the objective of this study was to compare outcomes among mate recipients of KTx with distinct CIT. Methods We studied 106 mate recipients of KTx in a single center followed for 1-year post-Tx. Mate kidneys were analyzed comparing the first and the second recipient to be transplanted. In a second analysis, we grouped mate recipients according to the CIT: ≤ 20 hours, > 20 hours, and mixed CIT. Results Seventy percent were standard criteria donors, with a mean Kidney Donor Profile Index (KDPI) of 61.5 ± 28%. KTx recipients presented an overall delayed graft function (DGF) rate of 82%, lasting 12 ± 7 days. The analysis of pairs considering the first and second recipient to be transplanted resulted in a longer CIT for the second (23.6 h vs 27 h; P = .001), and we did not find differences of outcomes after 1-year follow-up. Comparing pairs according to CIT (> 20h and ≤ 20h), DGF was higher in the CIT group > 20 hours (87.5% vs 58%; P = .002), with no differences of outcomes in 1-year follow-up. The logistic regression analysis shows that CIT > 20 hours is a risk factor for DGF in our study. Conclusion CIT > 20 hours is a risk factor for DGF, therefore strategies to reduce the CIT are always necessary.

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

The therapeutic effect of induced pluripotent stem cells (iPSs) on the progression of chronic kidney disease (CKD) has not yet been demonstrated. In this study, we sought to assess whether treatment with iPSs retards progression of CKD when compared with bone marrow mesenchymal stem cells (BMSCs). Untreated 5/6 nephrectomized rats were compared with CKD animals receiving BMSCs or iPSs. Renal function, histology, immunohistochemistry, and gene expression were studied. Implanted iPSs were tracked by the SRY gene expression analysis. Both treatments minimized elevation in serum creatinine, significantly improved clearance, and slowed down progression of disease. The proteinuria was reduced only in the iPS group. Both treatments reduced glomerulosclerosis, iPSs decreased macrophage infiltration, and TGF-βwas reduced in kidneys from the BMSC group. Both types of treatments increased VEGF gene expression, TGF-βwas upregulated only in the iPS group, and IL-10 had low expression in both groups. The SRY gene was found in 5/8 rats treated with iPSs. These 5 animals presented tumors with histology and cells highly staining positive for PCNA and Wilms’ tumor protein antibody characteristics of Wilms’ tumor. These results suggest that iPSs may be efficient to retard progression of CKD but carry the risk of Wilms’ tumor development.

Dengue infection (DI) is the most important arboviral infection in the world. The majority of immunocompetent patients will have asymptomatic or mild infections, but the degree of dengue severity in kidney transplant recipients (KTx) is unknown. In this study, we report the clinical profile and outcomes of 39 dengue cases in KTx. From a total of 1,186 KTx outpatients in follow-up we reviewed clinical and laboratory records of 60 (5%) patients admitted with suspected DI initially screened by NS-1, IgM, and when possible, multiplex nested PCR. The prevalence of DI in KTx was 3% (39/1,118), with symptoms leading to hospital admission being fever, myalgia, malaise, and headache. Laboratory tests showed leucopenia, thrombocytopenia, and liver enzyme elevation. DI was confirmed by positivity of NS-1 (33%), IgM (69%), and/or RT-PCR (59%). Twenty-three patients (59%) had dengue with warning signs, and 15% had severe dengue, 2 of them with a fatal course. Acute graft dysfunction occurred in 59% (mean nadir serum creatinine: 2.9 ± 2.6mg/dL), 4 of them requiring dialysis. CMV coinfection diagnosed in 19% of the cases and patients was associated with worse clinical presentation. Our results suggest that KTx with DI presented initial physical and laboratorial profile similar to the general population. However, DI in KTx seems to have a higher risk for graft dysfunction, severe dengue, and death. Because CMV coinfection aggravates the DI clinical presentation and recovery, it must be evaluated in all cases.

The 5/6 nephrectomy, mimics the stages of human chronic renal failure (CRF), but the procedure causes severe renal functional and morphological damage that could interfere with the evaluation of therapies for slowing the progression of the disease. This study summarizes the results of renal function, histology, and immunohistochemical findings in rats undergoing a 2/3 nephrectomy.The rats were distributed in groups according to the type of nephrectomy: CRF5/6: induced by a 5/6 renal mass reduction and CRF2/3: less severe CRF. The body weight and blood pressure were monitored, and the serum creatinine (SCr), creatinine clearance (CCr), urine osmolality, and 24-h proteinuria (PT24h) were measured. CRF progression was evaluated by the rate of decline of CCr (RCCr). Histology and immunohistochemistry were performed in the remnant kidneys. Statistical analysis was done by unpaired t-test, and a P-value0.05 was taken as a statistical significance.Compared to the CRF5/6 group, the CRF2/3 model had a lower SCr, PT24h, CCr, and variations of the SCr from baseline. The disease progression was also significantly slower. The renal histopathological findings revealed fewer chronic lesions in rats with CRF2/3. Similarly, we observed less macrophage accumulation as well as lower proliferative activity and expression of fibronectin and a-smooth muscle-actin in the CRF2/3 model.The CRF2/3 model presented with a pattern of less severe CRF, functionally and morphologically, compared to the classical CRF5/6 model, and the CRF2/3 model may be useful for evaluating therapeutic interventions that target the early stages of CRF.

Background. Donors after brain death develop a systemic proinflammatory state that may predispose the kidneys to injury after transplantation. Because it is not known whether this inflammatory environment similarly affects the kidneys from expanded criteria donor (ECD) and standard criteria donors (SCD), we sought to evaluate differences in the gene expression of inflammatory cytokines in preimplantation biopsies (PIBx) from ECD and SCD kidneys. Methods. Cytokines gene expression was measured in 80 PIBx (SCD, 52; ECD, 28) and associated with donor variables. Results. Normal histology and chronic histological lesions were not different between both types of kidneys. ECD kidneys showed significant increase in the transcripts of MCP-1, RANTES, TGF-β1, and IL-10 when compared with SCD. Kidneys presenting normal histology had similar inflammatory profile except by a higher expression of RANTES observed in ECD (P = 0.04). Interstitial fibrosis and tubular atrophy (interstitial fibrosis and tubular atrophy ≥ 1) were associated with higher expression of TGF-β1, RANTES, and IL-10 in ECD compared with SCD kidneys. Cold ischemia time of 24 hours or longer was significantly associated with upregulation of FOXP3, MCP-1, RANTES, and IL10, whereas longer duration of donor hospitalization significantly increased gene expression of all markers. High FOXP3 expression was also associated with lower level of serum creatinine at 1 year. Donor age was not associated with any of the transcripts studied. Conclusions. PIBx of ECD exhibit a higher gene expression of inflammatory cytokines when compared with SCD kidneys. This molecular profile may be a specific ECD kidney response to brain death and may help to predict the posttransplant outcomes of ECD recipients.

Made available in DSpace on 2018-11-26T17:34:42Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-06-01 Background. This study compared the use of static cold storage versus continuous hypothermic machine perfusion in a cohort of kidney transplant recipients at high risk for delayed graft function (DGF). Methods. In this national, multicenter, and controlled trial, 80 pairs of kidneys recovered from brain-dead deceased donors were randomized to cold storage or machine perfusion, transplanted, and followed up for 12 months. The primary endpoint was the incidence of DGF. Secondary endpoints included the duration of DGF, hospital stay, primary nonfunction, estimated glomerular filtration rate, acute rejection, and allograft and patient survivals. Results. Mean cold ischemia time was high but not different between the 2 groups (25.6 +/- 6.6 hours vs 25.05 +/- 6.3 hours, 0.937). The incidence of DGF was lower in the machine perfusion compared with cold storage group (61% vs. 45%, P = 0.031). Machine perfusion was independently associated with a reduced risk of DGF (odds ratio, 0.49; 95% confidence interval, 0.26-0.95). Mean estimated glomerular filtration rate tended to be higher at day 28 (40.6 +/- 19.9 mL/min per 1.73 m(2) vs 49.0 +/- 26.9 mL/min per 1.73 m(2); P = 0.262) and 1 year (48.3 +/- 19.8 mL/min per 1.73 m(2) vs 54.4 +/- 28.6 mL/min per 1.73 m(2); P = 0.201) in the machine perfusion group. No differences in the incidence of acute rejection, primary nonfunction (0% vs 2.5%), graft loss (7.5% vs 10%), or death (8.8% vs 6.3%) were observed. Conclusions. In this cohort of recipients of deceased donor kidneys with high mean cold ischemia time and high incidence of DGF, the use of continuous machine perfusion was associated with a reduced risk of DGF compared with the traditional cold storage preservation method. Univ Fed Sao Paulo, Hosp Rim, Sao Paulo, SP, Brazil Escola Paulista Med, Org Procura Orgaos, Sao Paulo, SP, Brazil Univ Sao Paulo, Fac Med, Hosp Clin, Sao Paulo, SP, Brazil Hosp Israelita Albert Einstein, Kidney Transplant Unit, Sao Paulo, SP, Brazil Hosp Samaritano, Sao Paulo, SP, Brazil Santa Casa Sao Paulo, Sao Paulo, SP, Brazil Hosp Bandeirantes, Sao Paulo, SP, Brazil Hosp Servidor Publ Estadual, Sao Paulo, SP, Brazil Hosp Beneficencia Portuguesa, Sao Paulo, SP, Brazil Hosp Dante Pazzanese, Sao Paulo, SP, Brazil Hosp Base Sao Jose do Rio Preto, Sao Jose Do Rio Preto, SP, Brazil Univ Estadual Paulista, UNESP, Dept Internal Med, Rubiao Jr S-N, Sao Paulo, Brazil Santa Casa Ribeirao Preto, Ribeirao Preto, SP, Brazil Hosp Alemao Oswaldo Cruz, Sao Paulo, SP, Brazil Hosp Santa Marcelina, Sao Paulo, SP, Brazil Univ Estadual Paulista, UNESP, Dept Internal Med, Rubiao Jr S-N, Sao Paulo, Brazil