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Background Acute kidney injury is common in patients with COVID-19, however mechanisms of kidney injury remain unclear. Since cytokine storm is likely a cause of AKI and glomerular disease, we investigated the two major transcription factors, STAT3 and NF-kB, which are known to be activated by cytokines. Methods This is an observational study of the postmortem kidneys of 50 patients who died with COVID-19 in the Mount Sinai Hospital during the first pandemic surge. All samples were reviewed under light microscopy, electron microscopy, and immunofluorescence by trained renal pathologists. In situ hybridization evaluation for SARS-CoV-2 and immunostaining of transcription factors STAT3 and NF-kB were performed. Results Consistent with previous findings, acute tubular injury was the major pathological finding, together with global or focal glomerulosclerosis. We were not able to detect SARS-CoV-2 in kidney cells. ACE2 expression was reduced in the tubular cells of patients who died with COVID-19 and did not co-localize with TMPRSS2. SARS-CoV-2 was identified occasionally in the mononuclear cells in the peritubular capillary and interstitium. STAT3 phosphorylation at Tyr705 was increased in 2 cases in the glomeruli and in 3 cases in the tubulointerstitial compartments. Interestingly, STAT3 phosphorylation at Ser727 increased in 9 cases but only in the tubulointerstitial compartment. A significant increase in NF-kB phosphorylation at Ser276 was also found in the tubulointerstitium of the two patients with increased p-STAT3 (Tyr705). Conclusions Our findings suggest that, instead of tyrosine phosphorylation, serine phosphorylation of STAT3 is commonly activated in the kidney of patients with COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s40620-021-01173-0.

Here we present the first case of newly diagnosed IgA nephropathy (IgAN) after a SARS-CoV-2 vaccination. A 30-year-old man with no known past medical history presented with gross hematuria and subnephrotic proteinuria 24 hours after the second dose of the mRNA-1273 SARS-CoV-2 vaccine. A kidney biopsy showed IgAN. He was started on an angiotensin receptor blocker, resulting in proteinuria reduction. Similar to natural infection of SARS-CoV-2, persons who receive 2 mRNA-based vaccines demonstrate robust antibodies against the receptor-binding domain (RBD) of the S1 protein. Given the uniqueness of glycosylation of RBD and potent stimulation of immune response from mRNA-based vaccine compared to other vaccines, we hypothesize that our patient developed de novo antibodies, leading to IgA-containing immune-complex deposits. This case highlights the urgency of understanding the immunological responses to novel mRNA-based SARS-CoV-2 vaccines in more diverse populations. Despite the lack of clear causality, nephrologists should be alerted if any new-onset hematuria or proteinuria is observed.

Recent case reports suggest that coronavirus disease 2019 (COVID-19) is associated with collapsing glomerulopathy in African Americans with apolipoprotein L1 gene (APOL1) risk alleles; however, it is unclear whether disease pathogenesis is similar to HIV-associated nephropathy. RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19–associated collapsing glomerulopathy and APOL1 risk alleles (G1/G1) revealed similar levels of APOL1 and angiotensin-converting enzyme 2 (ACE2) messenger RNA transcripts as compared with 12 control kidney samples downloaded from the GTEx (Genotype-Tissue Expression) Portal. Whole-genome sequencing of the COVID-19–associated collapsing glomerulopathy kidney sample identified 4 indel gene variants, 3 of which are of unknown significance with respect to chronic kidney disease and/or focal segmental glomerulosclerosis. Molecular profiling of the kidney demonstrated activation of COVID-19–associated cell injury pathways such as inflammation and coagulation. Evidence for direct severe acute respiratory syndrome coronavirus 2 infection of kidney cells was lacking, which is consistent with the findings of several recent studies. Interestingly, immunostaining of kidney biopsy sections revealed increased expression of phospho-STAT3 (signal transducer and activator of transcription 3) in both COVID-19–associated collapsing glomerulopathy and HIV-associated nephropathy as compared with control kidney tissue. Importantly, interleukin 6–induced activation of STAT3 may be a targetable mechanism driving COVID-19–associated acute kidney injury.

Aim Predicting progression in diabetic kidney disease (DKD) is critical to improving outcomes. We sought to develop/validate a machine-learned, prognostic risk score (KidneyIntelX™) combining electronic health records (EHR) and biomarkers. Methods This is an observational cohort study of patients with prevalent DKD/banked plasma from two EHR-linked biobanks. A random forest model was trained, and performance (AUC, positive and negative predictive values [PPV/NPV], and net reclassification index [NRI]) was compared with that of a clinical model and Kidney Disease: Improving Global Outcomes (KDIGO) categories for predicting a composite outcome of eGFR decline of ≥5 ml/min per year, ≥40% sustained decline, or kidney failure within 5 years. Results In 1146 patients, the median age was 63 years, 51% were female, the baseline eGFR was 54 ml min−1 [1.73 m]−2, the urine albumin to creatinine ratio (uACR) was 6.9 mg/mmol, follow-up was 4.3 years and 21% had the composite endpoint. On cross-validation in derivation (n = 686), KidneyIntelX had an AUC of 0.77 (95% CI 0.74, 0.79). In validation (n = 460), the AUC was 0.77 (95% CI 0.76, 0.79). By comparison, the AUC for the clinical model was 0.62 (95% CI 0.61, 0.63) in derivation and 0.61 (95% CI 0.60, 0.63) in validation. Using derivation cut-offs, KidneyIntelX stratified 46%, 37% and 17% of the validation cohort into low-, intermediate- and high-risk groups for the composite kidney endpoint, respectively. The PPV for progressive decline in kidney function in the high-risk group was 61% for KidneyIntelX vs 40% for the highest risk strata by KDIGO categorisation (p event for the high-risk group was 41% (p Conclusions KidneyIntelX improved prediction of kidney outcomes over KDIGO and clinical models in individuals with early stages of DKD. Graphical abstract

Background: Dentists have a vital role in detection of the signs and symptoms of obstructive sleep apnea (OSA) as it modifies in anatomy of orofacial structures. Aims and Objectives: This study aims to assess the prevalence of OSA risk in patients attending dental department and explore the factors related with high-risk OSA. Materials and Methods: The study was carried in the Al-Farabi Dental College, Jeddah, Saudi Arabia, on 200 consecutive dental patients from June 1, 2018, to July 31, 2019. Demographic details and the OSA risk were evaluated based on the Berlin questionnaire (Arabic version). Two qualified investigators independently did anthropometric measurements, medical and dental examination. Results: About 3.7% of males and 13.8% of females were found to be at high risk of OSA. Obese individuals almost had twice more likely chance to have OSA symptoms. Conclusion: Our findings confirm that dentists have an important role in recognizing the OSA signs and symptoms.

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4(+)/CD8(+) T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics., Kinase inhibitors used in chemotherapy are known for their adverse effects on kidney physiology. Here, Calizo et al. show that dasatinib is associated with a higher risk of glomerular toxicity compared to other kinase inhibitors, due to deleterious effects on cytoskeletal biomechanics in podocytes.

Analysis of the transcriptional profile of graft biopsies represents a promising strategy to study T cell mediated-rejection (TCMR), also known as acute cellular rejection. However, bulk RNA sequencing of graft biopsies may not capture the focal nature of acute rejection. Herein, we used the whole exome GeoMX Digital Space Profiling platform to study five tubular and three glomerular regions of interest in the kidney graft biopsy from a patient with a chronic-active TCMR episode and in analogous areas from two different normal kidney control biopsies. All kidney sections were from paraffin blocks. Overall, inflammatory genes were significantly upregulated in the tubular areas of the TCMR biopsy and showed an enrichment for gene-ontology terms associated with T cell activation, differentiation, and proliferation. Enrichment analysis of the 100 genes with the highest coefficient of variation across the TCMR tubular regions of interest revealed that these highly-variable genes are involved in kidney development and injury, and interestingly do not associate with the 2019 Banff classification pathology scores within the individual regions of interest. Spatial transcriptomics allowed us to unravel a previously unappreciated variability across different areas of the TCMR biopsy related to the graft response to the alloimmune attack, rather than to the immune cells. Thus, our approach has the potential to decipher clinically relevant, new pathogenic mechanisms, and therapeutic targets in acute cellular rejection and other kidney diseases with a focal nature.

To lay the foundation for the special issue that this research article introduces, we present 1) a systematic review of existing literature on the implications of the use of Artificial Intelligence (AI) in public governance and 2) develop a research agenda. First, an assessment based on 26 articles on this topic reveals much exploratory, conceptual, qualitative, and practice-driven research in studies reflecting the increasing complexities of using AI in government – and the resulting implications, opportunities, and risks thereof for public governance. Second, based on both the literature review and the analysis of articles included in this special issue, we propose a research agenda comprising eight process-related recommendations and seven content-related recommendations. Process-wise, future research on the implications of the use of AI for public governance should move towards more public sector-focused, empirical, multidisciplinary, and explanatory research while focusing more on specific forms of AI rather than AI in general. Content-wise, our research agenda calls for the development of solid, multidisciplinary, theoretical foundations for the use of AI for public governance, as well as investigations of effective implementation, engagement, and communication plans for government strategies on AI use in the public sector. Finally, the research agenda calls for research into managing the risks of AI use in the public sector, governance modes possible for AI use in the public sector, performance and impact measurement of AI use in government, and impact evaluation of scaling-up AI usage in the public sector.

Purpose To investigate the utility of magnetic resonance elastography (MRE) vs. ultrasound (US) point shear wave elastography (pSWE) for the assessment of chronic renal allograft dysfunction, prediction of outcome and determine the correlation with Banff pathology scores. Methods In this IRB approved prospective study, 27 enrolled patients with functional (n = 15) and chronic dysfunctional (n = 12) renal allografts underwent same day 2D MRE and pSWE. Histogram parameters [including mean, median, standard deviation, kurtosis and skewness] of the magnitude of the complex shear modulus (MRE) and median Young’s modulus (pSWE) were measured in the cortex (MRE and pSWE) and combined corticomedullary regions (MRE). Histopathology was available for 16 patients (4 functional, 12 dysfunctional). Results MRE and pSWE stiffness were not significantly different between functional and dysfunctional groups (p range 0.139-0.347). The skewness of MRE corticomedullary stiffness was significantly lower (p = 0.04) in patients with chronic dysfunction and correlated significantly with Banff histopathologic scores (range r=-0.518–0.567, p = 0.035–0.040). MRE cortical and corticomedullary mean stiffness showed strong performance in predicting graft loss/relist (AUC 0.958, p = 0.011 for both). Reliable pSWE measurements were obtained in 13 patients (48 %). pSWE stiffness did not correlate with Banff scores and did not predict outcome. Conclusions The skewness of MRE corticomedullary stiffness is sensitive to changes in chronic allograft dysfunction, while mean/median MRE renal stiffness and median US stiffness did not differentiate patients with stable function vs those with chronic renal allograft dysfunction. MRE corticomedullary mean stiffness appears to be a predictor of graft loss/relist. pSWE was not found to be a useful method for assessing renal allografts.

Urinary plasminogen/plasmin, or plasmin(ogen)uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin(ogen) as a “second hit” in kidney disease progression has yet to be demonstratedin vivo, and the association between plasmin(ogen)uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin(ogen)uria and urinary endothelin-1 (ET1). In a glomerular disease biorepository cohort (n=128), we measured time-of-biopsy albuminuria, proteinuria, and plasmin(ogen)uria for correlations with renal outcomes. Increased glomerular plasmin(ogen) was found in PAN rats and FSGS patients. PAN nephropathy was associated with increases in plasmin(ogen)uria, proteinuria, and urinary ET1. Amiloride was protective against PAN-induced glomerular injury, reducing urinary ET1 and oxidative stress. In patients, we found associations between plasmin(ogen)uria and edema status as well as eGFR. Our study demonstrates a role for plasmin(ogen)-induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte-protective properties. In one of largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin(ogen)uria and eGFR. Together, these findings suggest a role for plasmin(ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte-sparing treatments.TRANSLATIONAL STATEMENTProteinuria is associated with CKD progression, and increased cardiovascular morbidity and mortality. The underlying mechanisms of podocyte injury, the hallmark of proteinuric kidney disease, are poorly understood with limited, non-specific therapeutic options. This study adds to the evidence that plasmin(ogen) in the urine of proteinuric patients is associated with podocyte injury, edema, and impaired renal function. Previously published results from us and others, taken together with our current rodent model and human data, suggest that urinary plasmin(ogen) is a potential targetable biomarker. Efforts to decrease plasmin(ogen)-mediated podocyte injury could be part of a novel therapeutic strategy for glomerular disease.

Current guidelines encourage administering pneumococcal vaccine Prevnar-13 to patients with lupus, but whether such vaccinations affect disease severity is unclear. To address this issue, we treated 3-month-old MRL-lpr mice, that spontaneously develop a lupus-like syndrome, with Prevnar-13 or vehicle control. After 3 months, we quantified circulating anti-Pneumococcal polysaccharide capsule (PPS) antibodies and signs of disease severity, including albuminuria, renal histology and skin severity score. We also compared immunophenotypes and function of T and B cells from treated and untreated animals. Prevnar-13 elicited the formation of anti-pneumococcal IgM and IgG. Prevnar-13 treated animals showed reduced albuminuria, renal histological lesions, and milder dermatitis compared to vehicle-treated controls. Mitigated disease severity was associated with reduced and increased T follicular helper cells (TFH) and T follicular regulatory cells (TFR), respectively, in Prevnar-treated animals. T cells from Prevnar-13 vaccinated mice showed differential cytokine production after aCD3/aCD28 stimulation, with significantly decreased IL-17 and IL-4, and increased IL-10 production compared to non-vaccinated mice. In conclusion, pneumococcal vaccination elicits anti-pneumococcal antibody response and ameliorates disease severity in MRL-lpr mice, which associates with fewer TFH and increased TFR. Together, the data support use of Prevnar vaccination in individuals with SLE.

Diabetic kidney disease (DKD) is characterized by progressive glomerulosclerosis (GS). ROP mice have a sclerosis-prone phenotype. However, they develop severe, rapidly progressive GS when rendered diabetic. Since GS also develops in aged C57Bl6 mice, and can be reversed using bone marrow from young mice which have lower oxidative stress and inflammation (OS/Infl), we postulated that this might also apply to DKD. Therefore, this pilot study asked whether reducing OS/Infl in young adult sclerosis-prone (ROP) diabetic mice leads to resolution of existing GS in early DKD using safe, FDA-approved drugs.After 4 weeks of stable streptozotocin-induced hyperglycemia 8-12 week-old female mice were randomized and treated for 22 weeks as follows: 1) enalapril (EN) (n = 8); 2) pyridoxamine (PYR)+EN (n = 8); 3) pentosan polysulfate (PPS)+EN (n = 7) and 4) PPS+PYR+EN (n = 7). Controls were untreated (non-DB, n = 7) and hyperglycemic (DB, n = 8) littermates. PPS+PYR+EN reduced albuminuria and reversed GS in DB. Treatment effects: 1) Anti-OS/Infl defenses: a) PPS+PYR+EN increased the levels of SIRT1, Nrf2, estrogen receptor α (ERα) and advanced glycation endproduct-receptor1 (AGER1) levels; and b) PYR+EN increased ERα and AGER1 levels. 2) Pro-OS/Infl factors: a) PPS+PYR+EN reduced sTNFR1, b) all except EN reduced MCP1, c) RAGE was reduced by all treatments. In summary, PYR+PPS+EN modulated GS in sclerosis-prone hyperglycemic mice. PYR+PPS+EN also decreased albuminuria, OS/Infl and the sclerosis-prone phenotype. Thus, reducing OS/Infl may reverse GS in early diabetes in patients, and albuminuria may allow early detection of the sclerosis-prone phenotype.

Proliferation of glomerular epithelial cells, including podocytes, is a key histologic feature of crescentic glomerulonephritis. We previously found that retinoic acid (RA) inhibits proliferation and induces differentiation of podocytes by activating RA receptor-α (RARα) in a murine model of HIV-associated nephropathy. Here, we examined whether RA would similarly protect podocytes against nephrotoxic serum–induced crescentic glomerulonephritis and whether this effect was mediated by podocyte RARα. RA treatment markedly improved renal function and reduced the number of crescentic lesions in nephritic wild-type mice, while this protection was largely lost in mice with podocyte-specific ablation of Rara (Pod-Rara knockout). At a cellular level, RA significantly restored the expression of podocyte differentiation markers in nephritic wild-type mice, but not in nephritic Pod-Rara knockout mice. Furthermore, RA suppressed the expression of cell injury, proliferation, and parietal epithelial cell markers in nephritic wild-type mice, all of which were significantly dampened in nephritic Pod-Rara knockout mice. Interestingly, RA treatment led to the coexpression of podocyte and parietal epithelial cell markers in a small subset of glomerular cells in nephritic mice, suggesting that RA may induce transdifferentiation of parietal epithelial cells toward a podocyte phenotype. In vitro , RA directly inhibited the proliferation of parietal epithelial cells and enhanced the expression of podocyte markers. In vivo lineage tracing of labeled parietal epithelial cells confirmed that RA increased the number of parietal epithelial cells expressing podocyte markers in nephritic glomeruli. Thus, RA attenuates crescentic glomerulonephritis primarily through RARα-mediated protection of podocytes and in part through the inhibition of parietal epithelial cell proliferation and induction of their transdifferentiation into podocytes.

Kidney podocytes represent a key constituent of the glomerular filtration barrier. Identifying the molecular mechanisms of podocyte injury and survival is important for better understanding and management of kidney diseases. KIBRA ( ki dney bra in protein), an upstream regulator of the Hippo signaling pathway encoded by the Wwc1 gene, shares the pro-injury properties of its putative binding partner dendrin and antagonizes the pro-survival signaling of the downstream Hippo pathway effector YAP (Yes-associated protein) in Drosophila and MCF10A cells. We recently identified YAP as an essential component of the glomerular filtration barrier that promotes podocyte survival by inhibiting dendrin pro-apoptotic function. Despite these recent advances, the signaling pathways that mediate podocyte injury remain poorly understood. Here we tested the hypothesis that, similar to its role in other model systems, KIBRA promotes podocyte injury. We found increased expression of KIBRA and phosphorylated YAP protein in glomeruli of patients with biopsy-proven focal segmental glomerulosclerosis (FSGS). KIBRA/WWc1 overexpression in murine podocytes promoted LATS kinase phosphorylation, leading to subsequent YAP Ser-127 phosphorylation, YAP cytoplasmic sequestration, and reduction in YAP target gene expression. Functionally, KIBRA overexpression induced significant morphological changes in podocytes, including disruption of the actin cytoskeletal architecture and reduction of focal adhesion size and number, all of which were rescued by subsequent YAP overexpression. Conversely, constitutive KIBRA knockout mice displayed reduced phosphorylated YAP and increased YAP expression at baseline. These mice were protected from acute podocyte foot process effacement following protamine sulfate perfusion. KIBRA knockdown podocytes were also protected against protamine-induced injury. These findings suggest an important role for KIBRA in the pathogenesis of podocyte injury and the progression of proteinuric kidney disease.

We report five fetuses and a child from three families who shared a phenotype comprising cerebral ventriculomegaly and echogenic kidneys with histopathological findings of congenital nephrosis. The presenting features were greatly elevated maternal serum alpha-fetoprotein (MSAFP) or amniotic fluid alpha-fetoprotein (AFAFP) levels or abnormalities visualized on ultrasound scan during the second trimester of pregnancy. Exome sequencing revealed deleterious sequence variants in Crumbs, Drosophila, Homolog of, 2 (CRB2) consistent with autosomal-recessive inheritance. Two fetuses with cerebral ventriculomegaly and renal microcysts were compound heterozygotes for p.Asn800Lys and p.Trp759Ter, one fetus with renal microcysts was a compound heterozygote for p.Glu643Ala and p.Asn800Lys, and one child with cerebral ventriculomegaly, periventricular heterotopias, echogenic kidneys, and renal failure was homozygous for p.Arg633Trp in CRB2. Examination of the kidneys in one fetus showed tubular cysts at the corticomedullary junction and diffuse effacement of the epithelial foot processes and microvillous transformation of the renal podocytes, findings that were similar to those reported in congenital nephrotic syndrome, Finnish type, that is caused by mutations in nephrin (NPHS1). Loss of function for crb2b and nphs1 in Danio rerio were previously shown to result in loss of the slit diaphragms of the podocytes, leading to the hypothesis that nephrosis develops from an inability to develop a functional glomerular barrier. We conclude that the phenotype associated with CRB2 mutations is pleiotropic and that the condition is an important consideration in the evaluation of high MSAFP/AFAFP where a renal cause is suspected.