Common arboviruses and the kidney: a review.

Arboviruses are endemic in several countries and represent a worrying public health problem. The most important of these diseases is dengue fever, whose numbers continue to rise and have reached millions of annual cases in Brazil since the last decade. Other arboviruses of public health concern are chikungunya and Zika, both of which have caused recent epidemics, and yellow fever, which has also caused epidemic outbreaks in our country. Like most infectious diseases, arboviruses have the potential to affect the kidneys through several mechanisms. These include the direct action of the viruses, systemic inflammation, hemorrhagic phenomena and other complications, in addition to the toxicity of the drugs used in treatment. In this review article, the epidemiological aspects of the main arboviruses in Brazil and other countries where these diseases are endemic, clinical aspects and the main laboratory changes found, including changes in renal function, are addressed. It also describes how arboviruses behave in kidney transplant patients. The pathophysiological mechanisms of kidney injury associated with arboviruses are described and finally the recommended treatment for each disease and recommendations for kidney support in this context are given.

Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

[Nephropathology of infectious disease]. / Nephropathologie infektiöser Erkrankungen.

Infections can affect the kidney via different pathways. Urinary tract infections can directly involve the renal tissue by spreading along pre-existing canalicular structures. Such an ascending infection can manifest as a highly active and purulent or even abscessing interstitial nephritis or as a chronic-fibrosing process in recurrent pyelonephritis. Viral infections can also use the canalicular route as in polyomavirus nephropathy or spread via the blood stream in a hematogenous manner as in the case of cytomegalovirus or hantavirus infections. Likewise, bacterial infections can reach the kidney via the blood in the case of systemic infection. Another large group of nephropathies taking place as a sequel of infections includes infection-related glomerulonephritides (IRGN), which are mediated by a series of immunological mechanisms. These IRGN can be subdivided according to their temporal association with the infectious process, occurring either after the infection has healed (postinfectious) or accompanying the ongoing infectious process (parainfectious). The latter, in particular, is of increasing importance in the daily practice of nephropathologists, especially in older patients. A number of other glomerulonephritis forms, i.e., membranous or membranoproliferative forms, can occur as a consequence of infection. In addition, infections can trigger nephropathies, such as thrombotic microangiopathy. The present article gives an overview of morphologic changes in renal parenchyma that take place as a consequence of infectious processes, with particular focus on IRGN.

Renal implications of coronavirus disease 2019: insights into viral tropism and clinical outcomes.

In recent years, multiple coronaviruses have emerged, with the latest one, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing a global pandemic. Besides respiratory symptoms, some patients experienced extrapulmonary effects, such as cardiac damage or renal injury, indicating the broad tropism of SARS-CoV-2. The ability of the virus to effectively invade the renal cellular environment can eventually cause tissue-specific damage and disease. Indeed, patients with severe coronavirus disease 2019 exhibited a variety of symptoms such as acute proximal tubular injury, ischemic collapse, and severe acute tubular necrosis resulting in irreversible kidney failure. This review summarizes the current knowledge on how it is believed that SARS-CoV-2 influences the renal environment and induces kidney disease, as well as current therapy approaches.

Concurrent JCPyV-DNAemia Is Correlated With Poor Graft Outcome in Kidney Transplant Recipients With Polyomavirus-associated Nephropathy.

BACKGROUND: Co-infection of JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) is uncommon in kidney transplant recipients, and the prognosis is unclear. This study aimed to investigate the effect of concurrent JCPyV-DNAemia on graft outcomes in BKPyV-infected kidney transplant recipients with polyomavirus-associated nephropathy (PyVAN). METHODS: A total of 140 kidney transplant recipients with BKPyV replication and PyVAN, 122 without concurrent JCPyV-DNAemia and 18 with JCPyV-DNAemia were included in the analysis. Least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to identify prognostic factors for graft survival. A nomogram for predicting graft survival was created and evaluated. RESULTS: The median tubulitis score in the JCPyV-DNAemia-positive group was higher than in JCPyV-DNAemia-negative group ( P  = 0.048). At last follow-up, the graft loss rate in the JCPyV-DNAemia-positive group was higher than in the JCPyV-DNAemia-negative group (50% versus 25.4%; P  = 0.031). Kaplan-Meier analysis showed that the graft survival rate in the JCPyV-DNAemia-positive group was lower than in the JCPyV-DNAemia-negative group ( P  = 0.003). Least absolute shrinkage and selection operator regression and multivariate Cox regression analysis demonstrated that concurrent JCPyV-DNAemia was an independent risk factor for graft survival (hazard ratio = 4.808; 95% confidence interval: 2.096-11.03; P  < 0.001). The nomogram displayed favorable discrimination (C-index = 0.839), concordance, and clinical applicability in predicting graft survival. CONCLUSIONS: Concurrent JCPyV-DNAemia is associated with a worse graft outcome in BKPyV-infected kidney transplant recipients with PyVAN.

Risk of kidney and liver diseases after COVID-19 infection: A systematic review and meta-analysis.

COVID-19 is not only associated with substantial acute liver and kidney injuries, but also with an elevated risk of post-acute sequelae involving the kidney and liver system. We aimed to investigate whether COVID-19 exposure increases the long-term risk of kidney and liver disease, and what are the magnitudes of these associations. We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, and the Living Overview of the Evidence COVID-19 Repository for cohort studies estimating the association between COVID-19 and kidney and liver outcomes. Random-effects meta-analyses were performed to combine the results of the included studies. We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Fifteen cohort studies with more than 32 million participants were included in the systematic review COVID-19 was associated with a 35% greater risk of kidney diseases (10 more per 1000 persons; low certainty evidence) and 54% greater risk of liver disease (3 more per 1000 persons; low certainty evidence). The absolute increases due to COVID-19 for acute kidney injury, chronic kidney disease, and liver test abnormality were 3, 8, and 3 per 1000 persons, respectively. Subgroup analyses found no differences between different type of kidney and liver diseases. The findings provide further evidence for the association between COVID-19 and incident kidney and liver conditions. The absolute magnitude of the effect of COVID-19 on kidney and liver outcomes was, however, relatively small.

Cultured Renal Proximal Tubular Epithelial Cells Resemble a Stressed/Damaged Kidney While Supporting BK Virus Infection.

BK virus (BKV; human polyomavirus 1) infections are asymptomatic in most individuals, and the virus persists throughout life without harm. However, BKV is a threat to transplant patients and those with immunosuppressive disorders. Under these circumstances, the virus can replicate robustly in proximal tubule epithelial cells (PT). Cultured renal proximal tubule epithelial cells (RPTE) are permissive to BKV and have been used extensively to characterize different aspects of BKV infection. Recently, lines of hTERT-immortalized RPTE have become available, and preliminary studies indicate they support BKV infection as well. Our results indicate that BKV infection leads to a similar response in primary and immortalized RPTE. In addition, we examined the patterns of global gene expression of primary and immortalized RPTE and compared them with uncultured PT freshly dissociated from human kidney. As expected, PT isolated from the healthy kidney express a number of differentiation-specific genes that are associated with kidney function. However, the expression of most of these genes is absent or repressed in cultured RPTE. Rather, cultured RPTE exhibit a gene expression profile indicative of a stressed or injured kidney. Inoculation of cultured RPTE with BKV results in the suppression of many genes associated with kidney stress. In summary, this study demonstrated similar global gene expression patterns and responses to BKV infection between primary and immortalized RPTE. Moreover, results from bulk transcriptome sequencing (RNA-seq) and SCT experiments revealed distinct transcriptomic signatures representing cell injury and stress in primary RPTE in contrast to the uncultured, freshly dissociated PT from human kidney. IMPORTANCE Cultured primary human cells provide powerful tools for the study of viral infectious cycles and host virus interactions. In the case of BKV-associated nephropathy, viral replication occurs primarily in the proximal tubule epithelia in the kidney. Consequently, cultured primary and immortalized renal proximal tubule epithelial cells (RPTE) are widely used to study BKV infection. In this work, using bulk and single-cell transcriptomics, we found that primary and immortalized RPTE responded similarly to BKV infection. However, both uninfected primary and immortalized RPTE have gene expression profiles that are markedly different from healthy proximal tubule epithelia isolated directly from human kidney without culture. Cultured RPTE are in a gene expression state indicative of an injured or stressed kidney. These results raise the possibility that BKV replicates preferentially in injured or stressed kidney epithelial cells during nephropathy.

Determining host factors contributing to the reactivation of JC virus in kidney transplant recipients.

BACKGROUND AND AIMS: The John Cunningham virus (JCV) is the established etiological agent of the polyomavirus-associated nephropathy among renal transplant recipients. In the present study, we aimed to determine the probable predictive factors leading to JCV replication in renal transplant patients. MATERIAL AND METHODS: Urine and plasma samples were collected from a total of 120 consecutive renal-transplanted patients without preliminary screening from Jan 2018 to Mar 2019. After DNA extraction, the simultaneous detection and quantification of JCV and BK polyomavirus (BKV) were conducted using a Real-time quantitative PCR method. Moreover, statistical analyses were performed using the statistical software packages, SPSS version 21. RESULTS: The prevalence of JCV viruria and viremia among renal transplant recipients were 26 (21.67%) and 20 (16.67%), respectively. A significant association was observed between the JCV and two risk factors, diabetes mellitus (P = 0.002) and renal stones (P = 0.015). The prevalence of JCV viremia among recipients who were grafted near time to sampling was significantly higher (P = 0.02). There was a statistically significant coexistence between BK and JC viruses among our patients (P = 0.029). The frequency of JCV viruria in males was reported almost three times more than in females (P = 0.005). The JCV shedding in urine was significantly associated with the tropical steroids like prednisolone acetate, which have been the standard regimen (P = 0.039). Multivariable analysis revealed duration of post-transplantation (OR, 0.89; P = 0.038), diabetes mellitus (OR, 1.85; P = 0.034), and renal stone (OR 1.10; P = 0.04) as independent risk factors associated with JCV viremia post-renal transplantation. CONCLUSION: It seems that the discovery of potential risk factors, including immunological and non-immunological elements, may offer a possible preventive or therapeutic approach in the JCV disease episodes. The results of this study may also help clarify the probable clinical risk factors involving in progressive multifocal leukoencephalopathy development.

JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1 signaling in glomerular cells and podocytopathy in human kidney organoids.

COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.

Chain Mediation Model of Perceived Stress, Resilience, and Social Support on Coping Styles of Chinese Patients on Hemodialysis During COVID-19 Pandemic Lockdown.

BACKGROUND The recurrence of COVID-19 and the continuous escalation of prevention and control policies can lead to an increase in mental health problems. This study aimed to investigate the perceived stress, coping style, resilience, and social support among patients on maintenance hemodialysis (MHD) during the COVID-19 epidemic lockdown in China. MATERIAL AND METHODS This cross-sectional observational study enrolled 197 patients on MHD from the Guangdong Province Traditional Chinese Medical Hospital and the Hedong Hospital of Guangzhou Liwan District People's Hospital during July 2021. AMOS 24.0 and PROCESS Macro 3.1 model 6 were used for analyses of moderating mediating effects. RESULTS Perceived stress was negatively correlated with positive coping style (r=-0.305, P<0.001) and resilience (r=-0.258, P<0.001), whereas resilience (r=0.631, P<0.001) and social support (r=0.300, P<0.001) were positively correlated with positive coping style among patients on MHD. In the moderated mediating model, perceived stress had significant direct predictive effects on positive coping style (95% CI -0.33, -0.07), and perceived stress had significant indirect predictive effects on positive coping styles through resilience (95% CI -0.26, -0.06) or social support (95% CI 0.01, 0.06). Perceived stress had significant indirect predictive effects on positive coping style through both resilience and social support (95% CI -0.04, -0.01). CONCLUSIONS Perceived stress not only predicted coping style directly, but also indirectly predicted coping style through resilience and social support. Coping style was affected by internal and external factors during the COVID-19 pandemic lockdown period.

Spectrum of Kidney Injury Following COVID-19 Disease: Renal Biopsy Findings in a Single Italian Pathology Service.

The onset of coronavirus disease (COVID-19) as a pandemic infection, has led to increasing insights on its pathophysiology and clinical features being revealed, such as a noticeable kidney involvement. In this study, we describe the histopathological, immunofluorescence, and ultrastructural features of biopsy-proven kidney injury observed in a series of SARS-CoV-2 positive cases in our institution from April 2020 to November 2021. We retrieved and retrospectively reviewed nine cases (two pediatric and seven adults) that experienced nephrotic syndrome (six cases), acute kidney injury (two cases), and a clinically silent microhematuria and leukocyturia. Kidney biopsies were investigated by means of light microscopy, direct immunofluorescence, and electron microscopy. The primary diagnoses were minimal change disease (four cases), acute tubular necrosis (two cases), collapsing glomerulopathy (two cases), and C3 glomerulopathy (one case). None of the cases showed viral or viral-like particles on ultrastructural analysis. Novel and specific histologic features on kidney biopsy related to SARS-CoV-2 infection have been gradually disclosed and reported, harboring relevant clinical and therapeutic implications. Recognizing and properly diagnosing renal involvement in patients experiencing COVID-19 could be challenging (due to the lack of direct proof of viral infection, e.g., viral particles) and requires a proper integration of clinical and pathological data.

Renal consequences of the novel coronavirus disease 2019 (COVID-19) and hydrogen sulfide as a potential therapy.

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H2S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H2S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H2S as a potential COVID-19 therapy.

Latin American registry of renal involvement in COVID-19 disease. The relevance of assessing proteinuria throughout the clinical course.

The Latin American Society of Nephrology and Hypertension conducted a prospective cohort, multinational registry of Latin American patients with kidney impairment associated to COVID-19 infection with the objective to describe the characteristics of acute kidney disease under these circumstances. The study was carried out through open invitation in order to describe the characteristics of the disease in the region. Eight-hundred and seventy patients from 12 countries were included. Median age was 63 years (54-74), most of patients were male (68.4%) and with diverse comorbidities (87.2%). Acute kidney injury (AKI) was hospital-acquired in 64.7% and non-oliguric in 59.9%. Multiorgan dysfunction syndrome (MODS) due to COVID-19 and volume depletion were the main factors contributing to AKI (59.2% and 35.7% respectively). Kidney replacement therapy was started in 46.2%. Non-recovery of renal function was observed in 65.3%. 71.5% of patients were admitted to ICU and 72.2% underwent mechanical ventilation. Proteinuria at admission was present in 62.4% of patients and proteinuria during hospital-stay occurred in 37.5%. Those patients with proteinuria at admission had higher burden of comorbidities, higher baseline sCr, and MODS was severe. On the other hand, patients with de novo proteinuria had lower incidence of comorbidities and near normal sCr at admission, but showed adverse course of disease. COVID-19 MODS was the main cause of AKI in both groups. All-cause mortality of the general population was 57.4%, and it was associated to age, sepsis as cause of AKI, severity of condition at admission, oliguria, mechanical ventilation, non-recovery of renal function, in-hospital complications and hospital stay. In conclusion, our study contributes to a better knowledge of this condition and highlights the relevance of the detection of proteinuria throughout the clinical course.

The effect of BKV reactivation on cytokines behavior in kidney transplanted patients.

BACKGROUND: BK virus associated nephropathy (BKVAN) is one of the common causes of graft loss among kidney transplanted recipients (KTRs). The current treatment for BKV nephropathy is decreasing the immunosuppressive regimen in KTRs. Interleukin-27 (IL-27) is a multifunctional cytokine that might be the front-runner of an important pathway in this regard. Therefore, in current study it is tried to evaluate the changes in the expression level of IL-27 and some related molecules, resulting from BKV reactivation in KTR patients. METHODS: EDTA-treated blood samples were collected from all participants. Patients were divided into two groups, 31 kidney transplant recipients with active and 32 inactive BKV infection, after being monitored by Real time PCR (Taq-Man) in plasma. Total of 30 normal individuals were considered as healthy control group. Real time PCR (SYBR Green) technique is used to determine the expression level of studied genes. RESULTS: The results of gene expression comparisons showed that the expression level of IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 genes was significantly higher in inactive group in comparison to active group. The expression level of TLR4 was lower in both active and inactive groups in comparison to control group. ROC curve analysis showed that IL-27 and IRF7 are significantly different amongst other studied genes. Finally, the analyses revealed that the expression level of most of the studied genes (except for TNF-α and TLR4) have significant correlation with viral load. CONCLUSIONS: Our findings revealed that IL-27, IFN-γ, TNF-α, TNFR2 and IRF7 expression level is higher in inactive group and TLR4 expression level is lower in patients' groups in comparison to control group. Also, ROC curve analysis showed IL-27 and IRF7 can significantly differentiate studied groups (BKV active vs. inactive). Therefore, these results might help elucidating the pattern in charge of BKV reactivation in kidney transplanted patients.

COVID-19 impact on the renal system: Pathophysiology and clinical outcomes.

Coronavirus disease (COVID-19) causes many deleterious effects throughout the body. Prior studies show that the incidence of acute kidney injury in COVID-19 patients could be as high as 25%. There are also autopsy reports showing evidence of viral tropism to the renal system. In this regard, COVID-19 can damage the kidneys and increase a patient's risk of requiring dialysis. Available evidence suggests that renal involvement in COVID-19 infection is not uncommon, and there has been an increased incidence of chronic kidney disease related to the pandemic. In this literature analysis, we address COVID-19 and its effects on the renal system, including the pathophysiologic mechanisms. We also address current studies on the causes of injury to the renal system, the cause of kidney failure, its effect on mortality, the impact on dialysis patients, and the impact on renal transplant patients. COVID-19 disease may have unique features in individuals on chronic dialysis and kidney transplant recipients, requiring increased vigilance in limiting viral transmission in perioperative, in-patient, and dialysis center settings.

Kidney Outcomes in Long COVID.

BACKGROUND: COVID-19 is associated with increased risk of post-acute sequelae involving pulmonary and extrapulmonary organ systems-referred to as long COVID. However, a detailed assessment of kidney outcomes in long COVID is not yet available. METHODS: We built a cohort of 1,726,683 US Veterans identified from March 1, 2020 to March 15, 2021, including 89,216 patients who were 30-day survivors of COVID-19 and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE). MAKE was defined as eGFR decline ≥50%, ESKD, or all-cause mortality. We used inverse probability-weighted survival regression, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates, including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory. RESULTS: Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR, 1.94; 95% CI, 1.86 to 2.04), eGFR decline ≥30% (aHR, 1.25; 95% CI, 1.14 to 1.37), eGFR decline ≥40% (aHR, 1.44; 95% CI, 1.37 to 1.51), eGFR decline ≥50% (aHR, 1.62; 95% CI, 1.51 to 1.74), ESKD (aHR, 2.96; 95% CI, 2.49 to 3.51), and MAKE (aHR, 1.66; 95% CI, 1.58 to 1.74). Increase in risks of post-acute kidney outcomes was graded according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared with non-infected controls, 30-day survivors of COVID-19 exhibited excess eGFR decline (95% CI) of -3.26 (-3.58 to -2.94), -5.20 (-6.24 to -4.16), and -7.69 (-8.27 to -7.12) ml/min per 1.73 m2 per year, respectively, in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection. CONCLUSIONS: Patients who survived COVID-19 exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should include attention to kidney disease.