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.

Exploring the causes of the high incidence of delayed graft function after kidney transplantation in Brazil: a multicenter study.

This retrospective multicenter (n = 18) cohort study evaluated the incidence, risk factors, and the impact of delayed graft function (DGF) on 1-year kidney transplant (KT) outcomes. Of 3992 deceased donor KT performed in 2014-2015, the incidence of DGF was 54%, ranging from 29.9% to 87.7% among centers. Risk factors (lower-bound-95%CI OR upper-bound-95%CI ) were male gender (1.066 1.2491.463 ), diabetic kidney disease (1.053 1.2961.595 ), time on dialysis (1.005 1.0071.009 ), retransplantation (1.035 1.3971.885 ), preformed anti-HLA antibodies (1.011 1.3831.892 ), HLA mismatches (1.006 1.0661.130 ), donor age (1.011 1.0171.023 ), donor final serum creatinine (sCr) (1.239 1.3171.399 ), cold ischemia time (CIT) (1.031 1.0431.056 ), machine perfusion (0.401 0.5420.733 ), and induction therapy with rabbit antithymocyte globulin (rATG) (0.658 0.8000.973 ). Duration of DGF > 4 days was associated with inferior renal function and DGF > 14 days with the higher incidences of acute rejection, graft loss, and death. In conclusion, the incidence and duration of DGF were high and associated with inferior graft outcomes. While late referral and poor donor maintenance account for the high overall incidence of DGF, variability in donor and recipient selection, organ preservation method, and type of induction agent may account for the wide variation observed among transplant centers.

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation.

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

A high level of urinary retinol-binding protein is associated with cytomegalovirus infection in kidney transplantation.

The indirect effects of cytomegalovirus (CMV) viremia can be related to chronic changes in renal allograft structure, but its real impact in early and late graft function remains speculative. A total of 159 patients undergoing renal transplantation using a preemptive therapeutic strategy to prevent CMV disease were included in the present study. The patients were prospectively followed, with serial measurements of urinary retinol-binding protein (uRBP), a marker of proximal tubule injury. uRBP levels and their dynamic performance were compared according to CMV viremia and the 5-year estimated glomerular filtration rate (eGFR), as measured with the modification of diet in renal disease (MDRD) equation. CMV viremia was detected in 79.9% of the patients, with high uRBP levels being detected in 76.0% of these patients (compared with 40.7% in CMV-, P=0.005). High uRBP was associated with male recipients (P=0.02), the number of mismatches (P=0.02) and CMV infection (P=0.001). Five-year eGFR was worse in patients with high uRBP levels (50.3 ± 25.8 compared with 59.8 ± 26.4 ml/min, P=0.04). In a multivariate model, eGFR <60 ml/min was associated with donor age (P<0.001), the number of mismatches (P=0.04), thymoglobulin dose (P=0.02), the presence of and time with delayed graft function (DGF) (P=0.005 and P=0.04), 1-month tacrolimus levels (P=0.03), and uRBP levels after CMV treatment (P=0.01). Patients with CMV viremia in whom uRBP levels were normalized up to 3 months after treatment showed significantly better 5-year eGFR than those in whom uRBP remained high: 61.0 ± 24.2 compared with 42.3 ± 23.9 ml/min, P<0.001. CMV viremia was associated with high uRBP levels, which represent a profile of proximal tubule injury, and the dynamic performance of uRBP after treatment was associated with long-term kidney graft function.

TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is considered an inflammatory disease in which toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, the present study aimed to evaluate the specific participation of TLR2 and TLR4 molecules on the development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and heme oxygenase-1 (HO-1), a promisor cytoprotective molecule. First, we observed that only the absence of TLR2 but not TLR4 in mice exacerbated the renal dysfunction, tissue injury and mortality rate, even under an immunologically privileged microenvironment. Second, we demonstrated that TLR2 knockout (KO) mice presented lower expression of autophagy-associated markers when compared with TLR4 KO animals. Similar parameter was confirmed in vitro, using tubular epithelial cells derived from both KO mice. To test the cross-talking between HO-1 and TLRs, hemin (an HO-1 internal inducer) was administrated in cisplatin-treated TLR2 and TLR4 KO mice and it was detected an improvement in the global renal tissue parameters. However, this protection was less evident at TLR2 KO mice. In summary, we documented that TLR2 plays a protective role in cisplatin-induced AKI progression, in part, by a mechanism associated with autophagy up-regulation, considering that its interplay with HO-1 can promote renal tissue recover.

Impact of machine perfusion after long static cold storage on delayed graft function incidence and duration and time to hospital discharge.

Delayed graft function (DGF) is very high in our center (70%-80%), and we usually receive a kidney for transplant after more than 22 hours of static cold ischemia time (CIT). Also, there is an inadequate care of the donors, contributing to a high rate of DGF. We decided to test whether machine perfusion (MP) after a CIT improved the outcome of our transplant patients. We analyzed the incidence of DGF, its duration, and the length of hospital stay (LOS) in patients who received a kidney preserved with MP after a CIT (hybrid perfusion-HP). We included 54 deceased donors kidneys preserved with HP transplanted from Feb/13 to Jul/14, and compared them to 101 kidney transplants preserved by static cold storage (CS) from Nov/08 to May/12. The median pumping time was 11 hours. DGF incidence was 61.1% vs 79.2% (P = .02), median DGF duration was 5 vs 11 days (P < .001), and median LOS was 13 vs 18 days (P < .011), for the HP compared to CS group. The observed reduction of DGF with machine perfusion did not occur in donors over 50 years old. In the multivariate analysis, risk factors for DGF, adjusted for CIT, were donor age (OR, 1.04; P = .005) and the absence of use of MP (OR, 1.54; P = .051). In conclusion, the use of HP contributed to faster recovery of renal function and to a shorter length of hospital stay.

Intragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery.

BACKGROUND: Proximal tubular dysfunction (PTD) is associated with a decreased long-term graft survival in renal transplant patients and can be detected by the elevation of urinary tubular proteins. This study investigated transcriptional changes in biopsies from renal transplant patients with PTD to disclose molecular mechanisms underlying graft injury and functional recovery. METHODS: Thirty-three renal transplant patients with high urinary levels of retinol-binding protein, a biomarker of PTD, were enrolled in the study. The initial immunosuppressive scheme included azathioprine, cyclosporine, and steroids. After randomization, 18 patients (group 2) had their treatment modified by reducing cyclosporine dosage and substituting azathioprine for mycophenolate mofetil, while the other 15 patients (group 1) remained under the initial scheme. Patients were biopsied at enrollment and after 12 months of follow-up, and paired comparisons were performed between their intragraft gene expression profiles. The differential transcriptome profiles were analyzed by constructing gene co-expression networks and identifying enriched functions and central nodes in each network. RESULTS: Only the alternative immunosuppressive scheme used in group 2 ameliorated renal function and tubular proteinuria after 12 months of follow-up. Intragraft molecular changes observed in group 2 were linked to autophagy, extracellular matrix, and adaptive immunity. Conversely, gene expression changes in group 1 were related to fibrosis, endocytosis, ubiquitination, and endoplasmic reticulum stress. CONCLUSION: These results suggest that molecular networks associated with the control of endocytosis, autophagy, protein overload, fibrosis, and adaptive immunity may be involved in improvement of graft function.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

AIM: The role of post-reperfusion biopsy findings as a predictor of early and long-term graft function and survival is still a target of research. METHODS: We analyzed data from 136 post-reperfusion biopsies performed in deceased donor renal transplanted patients from November 2008 to May 2012. We analyzed the presence of acute tubular necrosis (ATN), arteriolar hyalinosis (AH), intimal thickness (IT), interstitial fibrosis (IF) and glomerulosclerosis (GS). We also analyzed the impact of donor features on the following outcomes: delayed graft function (DGF) and chronic allograft dysfunction defined as eGFR < 60 mL/min at 1 year. RESULTS: The mean donor age was 41 years, 26% of whom were extended criteria donors (ECD), 33% had hypertension and 50% had cerebral vascular accident (CVA) as the cause of death. ATN was present in 87% of these biopsies, AH in 31%, IF in 21%, IT in 27% and GS in 32%. DGF occurred in 80% and chronic allograft dysfunction was present in 53%. AH was the only histological finding associated with DGF and chronic allograft dysfunction at 1 year. Patients with AH had a lower eGFR at 1 year than patients without it (49.8 mL/min × 64.5 mL/min, P = 0.02). In the multivariate analysis, risk variables for development of chronic graft dysfunction were male sex (odds ratio [OR] = 3.159 [CI: 1.22-8.16]; P = 0.018), acute rejection (OR = 8.91 [CI: 2.21-35.92]; P = 0.002), donor hypertension (OR = 2.94 [CI: 1.10-7.84]; P = 0.031), AH (OR = 3.96 [CI: 1.46-10.70]; P = 0.007) and eGFR at discharge (OR = 0.96 [CI: 0.93-0.98]; P = 0.005). In multivariate analysis, risk factors for AH were donor age ≥ 50 years (OR = 2.46 [CI: 1.10-5.44]; P = 0.027) and CVA as the cause of donor death (OR = 2.33 [CI: 1.05-5.15]; P = 0.007). CONCLUSION: The presence of AH in post-reperfusion biopsies is a marker of ageing and vascular disease and was associated with DGF and a one year poorer renal function. AH in donor biopsies superimposed to long ischaemic time is a predictor of renal function. The management of immunosuppression based on the presence of AH in post-reperfusion biopsy could be useful to improve long term graft function.

Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration.

AIM: Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis. METHODS: Mice were immunized with MOG(35-55) and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry. RESULTS: Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-ß mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1ß secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells. CONCLUSIONS: Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.

Does graft mass impact on pediatric kidney transplant outcomes?

BACKGROUND: The aim of this study is to assess the evolution of renal size and function in pediatric transplant patients according to the graft mass/recipient size ratio. METHODS: Fifty pediatric renal transplant recipients were followed over 2 years. Grafts were weighed, and three different graft mass/m(2) ratios were determined: (1) low graft mass (58 g/m(2), range 31-57 g/m(2)), (2) median (142 g/m(2), range 59-141 g/m(2)) and high (267 g/m(2), range 143-353 g/m(2)). Patients underwent repeated ultrasound Doppler scans and repeated measurements of estimated glomerular filtration rate (eGFR; 1 week and 1, 6, 12 and 24 months), urinary retinol-binding protein (RBP) and proteinuria (1 week and 6, 12 and 24 months). RESULTS: The volume of renal tissue increased by 12 ± 5.6 cm(3) at 24 months (p = 0.035) in the low graft mass and decreased by -14 ± 7 cm(3) (p = 0.046) in the high graft mass. The eGFR increased when either low (30 ± 5 ml/min/1.73 m(2), p < 0.001) or median (19 ± 4 ml/min/1.73 m(2), p < 0.001) graft mass was transplanted but remained stable when high graft mass was transplanted. The resistive index (RI) presented a significant decrease throughout early follow-up in the transplants involving low and median graft mass, whereas a slight rise was observed in those involving high graft mass. A significant difference was apparent 6 months post-transplant. Transplants of low and median graft mass were associated with an initial higher urinary RBP. No significant differences in proteinuria were detected. CONCLUSIONS: Small kidneys undergo increases in volume and function without escalation of either proteinuria or urinary RBP, characterizing an adequate adaptation to the recipient. Children receiving larger kidneys present a reduction in volume, stable GFR and higher RI at 6 months.

Acute kidney injury reduces phagocytic and microbicidal capacities of alveolar macrophages.

BACKGROUND/AIMS: Renal ischaemia-reperfusion injury (IRI) is a systemic inflammatory process in which Th1 responses predominate affecting other organs including the lungs. The present study explored the phagocytic and microbicidal capacity of macrophages in rats with lung inflammation that underwent IRI. METHODS: The alveolar macrophages of rats sensitised to OVA were evaluated for phagocytosis and bacterial killing 24h after antigen challenge in animals with or without prior submission to 60 min of renal ischaemia. RESULTS: Bronchoalveolar lavage had a high level of cellular infiltrate in immunised animals (420%) compared with control animals; IRI significantly reduced this infiltration (52%). Macrophages from animals immunised and challenged with OVA presented a 10x increase in phagocytic capacity compared to the control group, whereas immunised animals subjected to IRI showed a reduction in the phagocytic index of 68%. The killing of Klebsiella pneumoniae by macrophages from immunised animals was higher (56%) compared with the control group but reduced in animals submitted to IRI (45%). Immunised and challenged group showed an increase in gene expression levels of IL-10(450%), HO-1 (259%), INF-γ (460%) and MCP-1 (370%) compared to the immunised group subjected to IRI. CONCLUSIONS: Renal ischaemia and reperfusion injury apparently alters the phagocytic and microbicidal capacity of macrophages, reducing lung inflammation to OVA.

Preemptive kidney transplantation: why, when, and how?

Among renal replacement therapies, preemptive kidney transplantation (PKT) presents the best clinical, social, and economic results. However, it is still infrequently chosen as first therapy for patients with irreversible kidney failure. Initiatives in different parts of the world were developed to identify the reasons why PKT is still not widely used and to facilitate the access of patients with end-stage kidney disease to the advantages associated with it. This article addresses the main advantages and difficulties of PKT and discusses when it should be indicated and how to prepare potential recipients for PKT.

Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial.

BACKGROUND: Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown. METHODS AND RESULTS: In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. CONCLUSIONS: Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level.

MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages.

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4(+) T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (T(H)2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished T(H)2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10(+) and CD206(+) CD11b(high) cells, at 7 d after surgery. We evaluated the role of a T(H)2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-ß levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and T(H)1:T(H)2 balance, as T(H)2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.

Modulation of lung allergic response by renal ischemia and reperfusion injury.

The Th1/Th2 balance represents an important factor in the pathogenesis of renal ischemia-reperfusion injury (IRI). In addition, IRI causes a systemic inflammation that can affect other tissues, such as the lungs. To investigate the ability of renal IRI to modulate pulmonary function in a specific model of allergic inflammation, C57Bl/6 mice were immunized with ovalbumin/albumen on days 0 and 7 and challenged with an ovalbumin (OA) aerosol on days 14 and 21. After 24 h of the second antigen challenge, the animals were subjected to 45 minutes of ischemia. After 24 h of reperfusion, the bronchoalveolar lavage (BAL) fluid, blood and lung tissue were collected for analysis. Serum creatinine levels increased in both allergic and non-immunized animals subjected to IRI. However, BAL analysis showed a reduction in the total cells (46%) and neutrophils (58%) compared with control allergic animals not submitted to IRI. In addition, OA challenge induced the phosphorylation of ERK and Akt and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lung homogenates. After renal IRI, the phosphorylation of ERK and expression of COX-2 and iNOS were markedly reduced; however, there was no difference in the phosphorylation of Akt between sham and ischemic OA-challenged animals. Mucus production was also reduced in allergic mice after renal IRI. IL-4, IL-5 and IL-13 were markedly down-regulated in immunized/challenged mice subjected to IRI. These results suggest that renal IRI can modulate lung allergic inflammation, probably by altering the Th1/Th2 balance and, at least in part, by changing cellular signal transduction factors.

Carbon monoxide inhibits apoptosis during cold storage and protects kidney grafts donated after cardiac death.

Ischemia/reperfusion (I/R) injury remains as a serious deleterious factor in kidney transplantation (KTx). We hypothesized that carbon monoxide (CO), an endogenous potent cytoprotective molecule, inhibits hypothermia-induced apoptosis of kidney grafts. Using the rat KTx model mimicking the conditions of donation after cardiac death (DCD) as well as nontransplantable human kidney grafts, this study examined effects of CO in preservation solution in improving the quality of marginal kidney grafts. After cardiac cessation, rat kidneys underwent 40 min warm ischemia (WI) and 24 h cold storage (CS) in control UW or UW containing CO (CO-UW). At the end of CS, kidney grafts in control UW markedly increased mitochondrial porin release into the cytosol and resulted in increased cleaved caspase-3 and PARP expression. In contrast, grafts in CO-UW had significantly reduced mitochondrial breakdown and caspase pathway activation. After KTx, recipient survival significantly improved with CO-UW with less TUNEL(+) cells and reduced mRNA upregulation for proinflammatory mediators (IL-6, TNF-α, iNOS). Furthermore, when nontransplantable human kidney grafts were stored in CO-UW for 24 h, graft PARP expression, TUNEL(+) cells, and proinflammatory mediators were less than those in control UW. CO in UW inhibited hypothermia-induced apoptosis and significantly improved kidney graft function and outcomes of KTx.

The Mycophenolate-based Immunosuppressive Regimen Is Associated With Increased Mortality in Kidney Transplant Patients With COVID-19.

BACKGROUND: 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. METHODS: 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. RESULTS: Compared with patients receiving MPA, the 30-d (79.9% versus 87.9% versus 89.2%; P < 0.0001) and 90-d (75% versus 83.5% versus 88.2%; P < 0.0001) 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. CONCLUSIONS: 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.

Long-term outcomes after kidney transplant failure and variables related to risk of death and probability of retransplant: Results from a single-center cohort study in Brazil.

BACKGROUND: Returning to dialysis after kidney graft loss (GL) is associated with a high risk of mortality, mainly in the first 3-6 months. The follow-up of patients with GL should be extended to better understand crude patient outcomes, mainly in emerging countries, where the transplantation activity has increased. METHODS: This is a historical single-center cohort study conducted in an emerging country (Brazil) that included 115 transplant patients with kidney allograft failure who were followed for 44.1 (21.4; 72.6) months after GL. The outcomes were death or retransplantation after GL calculated by Kaplan-Meier and log-rank tests. Proportional hazard ratios for death and retransplantation were assessed by Cox regression. RESULTS: The 5-year probability of retransplantation was 38.7% (95% CI: 26.1%-51.2%) and that of death was 37.7% (95% CI: 24.9%-50.5%); OR = 1.03 (95% CI: 0.71-1.70) and P = 0.66. The likelihood of retransplantation was higher in patients who resumed dialysis with higher levels of hemoglobin (HR = 1.22; 95% CI = 1.04-1.43; P = 0.01) and lower in blood type O patients (HR = 0.48; 95% CI = 0.25-0.93; P = 0.03), which was associated with a lower frequency of retransplantation with a subsequent living-donor kidney. On the other hand, the risk of death was significantly associated with Charlson comorbidity index (HR for each point = 1.37; 95% CI 1.19-1.50; P<0.001), and residual eGFR at the time when patients had resumed to dialysis (HR for each mL = 1.14; 95% CI = 1.05-1.25; P = 0.002). The trend toward a lower risk of death when patients had resumed to dialysis using AV fistula access was observed (HR = 0.50; 95% CI 0.25-1.02; P = 0.06), while a higher risk seems to be associated with the number of previous engraftment (HR = 2.01; 95% CI 0.99-4.07; P = 0.05). CONCLUSIONS: The 5-year probability of retransplantation was not less than that of death. Variables related to the probability of retransplantation were hemoglobin level before resuming dialysis and ABO blood type, while the risk of death was associated with comorbidities and residual eGFR.

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.

Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury.

One of the early phases that lead to fibrosis progression is inflammation. Once this stage is resolved, fibrosis might be prevented. Bone marrow mononuclear cells (BMMCs) are emerging as a new therapy for several pathologies, including autoimmune diseases, because they enact immunosuppression. In this study we aimed to evaluate the role of BMMC administration in a model of kidney fibrosis induced by an acute injury. C57Bl6 mice were subjected to unilateral severe ischemia by clamping the left renal pedicle for 1h. BMMCs were isolated from femurs and tibia, and after 6h of reperfusion, 1 x 10(6) cells were administrated intraperitoneally. At 24h after surgery, treated animals showed a significant decrease in creatinine and urea levels when compared with untreated animals. Different administration routes were tested. Moreover, interferon (IFN) receptor knockout BMMCs were used, as this receptor is necessary for BMMC activation. Labeled BMMCs were found in ischemic kidney on FACS analysis. This improved outcome was associated with modulation of inflammation in the kidney and systemic modulation, as determined by cytokine expression profiling. Despite non-amelioration of functional parameters, kidney mRNA expression of interleukin (IL)-6 at 6 weeks was lower in BMMC-treated animals, as were levels of collagen 1, connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta) and vimentin. Protective molecules, such as IL-10, heme oxygenase 1 (HO-1) and bone morphogenetic 7 (BMP-7), were increased in treated animals after 6 weeks. Moreover, Masson and Picrosirius red staining analyses showed less fibrotic areas in the kidneys of treated animals. Thus, early modulation of inflammation by BMMCs after an ischemic injury leads to reduced fibrosis through modulation of early inflammation.