Jahrestagung der Gesellschaft fur Padiatrische Nephrologie.

The proceedings contain 92 papers. The topics discussed include: cellular and humoral immune responses after SARS-CoV-2 vaccination in pediatric kidney recipients;adult outcomes of childhood-onset idiopathic nephrotic syndrome: findings from a health insurance database;the genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies;translational profiling of developing podocytes during glomerulogenesis;MAGED2 is required under hypoxia for cAMP signaling by inhibiting MDM2-dependent endocytosis of G-Alpha-S;high throughput investigation of the metabolic flux of intact cortical kidney tubules;peritoneal membrane junction and solute transporter expression and function in health, CKD and PD;and Function and interaction of coronavirus ion channel proteins.

On the occasion of world kidney day 2023;renal impacts of COVID-19

World kidney day is an international campaign focused on bringing awareness to kidney health throughout the world and reducing the incidence of renal disease and its related medical complications. This mini-review sought to take a short look on the renal impact of SARS-CoV-2, with a particular focus on post-COVID-19 nephropathy as a new dilemma in the era of nephrology, which can be a new concern for nephrologists that requires more attention and particular strategies. Keywords: SARS-CoV-2 vaccine, Glomerulonephritis, Acute kidney injury, World kidney day, SARS-CoV-2, COVID-19-related nephropathy, APOL1 gene, Collapsing glomerulopathy, Podocyte.Copyright © 2023 The Author(s);Published by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Understanding kidney injury in covid-19, a pressing priority

The 2019 novel coronavirus disease (COVID-19) is a newly defined infectious and highly contagious acute disease caused by the severe acute respiratory syndrome coronavirus 2 ( (SARS-CoV-2). COVID-19 is mainly characterized by an acute respiratory disease however it can also affect multiple other organ systems such as the kidney, gastrointestinal tract, heart, vascular system, and the central nervous system. Kidney involvement is frequent in patients with COVID-19 and this review aims to explore the available data on kidney and COVID-19. In conclusion, COVID-19 infection can affect renal function and may cause acute kidney injury (AKI), due to several mechanisms that need to be fully elucidated. As only supportive management strategies are available for treating AKI in COVID-19, it is necessary to identify and preserve renal function during SARS-CoV-2 infection.Copyright © 2021 The Author(s).

α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier.

BACKGROUND: The cell-matrix adhesion between podocytes and the glomerular basement membrane is essential for the integrity of the kidney's filtration barrier. Despite increasing knowledge about the complexity of integrin adhesion complexes, an understanding of the regulation of these protein complexes in glomerular disease remains elusive. METHODS: We mapped the in vivo composition of the podocyte integrin adhesome. In addition, we analyzed conditional knockout mice targeting a gene (Parva) that encodes an actin-binding protein (α-parvin), and murine disease models. To evaluate podocytes in vivo, we used super-resolution microscopy, electron microscopy, multiplex immunofluorescence microscopy, and RNA sequencing. We performed functional analysis of CRISPR/Cas9-generated PARVA single knockout podocytes and PARVA and PARVB double knockout podocytes in three- and two-dimensional cultures using specific extracellular matrix ligands and micropatterns. RESULTS: We found that PARVA is essential to prevent podocyte foot process effacement, detachment from the glomerular basement membrane, and the development of FSGS. Through the use of in vitro and in vivo models, we identified an inherent PARVB-dependent compensatory module at podocyte integrin adhesion complexes, sustaining efficient mechanical linkage at the filtration barrier. Sequential genetic deletion of PARVA and PARVB induces a switch in structure and composition of integrin adhesion complexes. This redistribution of these complexes translates into a loss of the ventral actin cytoskeleton, decreased adhesion capacity, impaired mechanical resistance, and dysfunctional extracellular matrix assembly. CONCLUSIONS: The findings reveal adaptive mechanisms of podocyte integrin adhesion complexes, providing a conceptual framework for therapeutic strategies to prevent podocyte detachment in glomerular disease.

Multiscale Fractal Shape Cues Support Hierarchical Maturation Of Podocytes Via Curvature induced Extracellular Matrix Patterning

Purpose/Objectives: Nature efficiently self-organizes cells and tissues into complex fractal forms. Whether fractal patterning contributes functionally to maturation, and how cells sense and interpret such shape cues, is not well understood. Methodology: Using kidney podocytes as a model system, bioinspired templating of glomerular histology was leveraged to design controlled fractal 21/2 -D surfaces for cell culture. Results: Microcurvature was associated with charge density gradients in space, found to direct extracellular matrix protein organization resulting in hierarchical assembly of cell structures and fractally-branching podocyte morphology in vitro, that was delineated clearly in vitro with a novel highresolution fluorescent assaying technique. Shape stimulation was uniquely associated with development of mature-like foot processes and organized ECM. In applications of drug testing, coronavirus infection, and a cells-as-sensors approach to patient serum diagnostics, fractally stimulated cells were more responsive than flat cultures. Conclusion/Significance: Fractal frameworks may thus provide a functional role in podocyte maturation and could serve to advance other bioengineered systems.

Traditional Chinese Medicine in Treating Primary Podocytosis: From Fundamental Science to Clinical Research.

Podocytes form a key component of the glomerular filtration barrier. Damage to podocytes is referred to as "podocyte disease." There are many causes of podocyte injury, including primary injury, secondary injury, and gene mutations. Primary podocytosis mostly manifests as nephrotic syndrome. At present, first-line treatment is based on glucocorticoid administration combined with immunosuppressive therapy, but some patients still progress to end-stage renal disease. In Asia, especially in China, traditional Chinese medicine (TCM) still plays an important role in the treatment of kidney diseases. This study summarizes the potential mechanism of TCM and its active components in protecting podocytes, such as repairing podocyte injury, inhibiting podocyte proliferation, reducing podocyte apoptosis and excretion, maintaining podocyte skeleton structure, and upregulating podocyte-related protein expression. At the same time, the clinical efficacy of TCM in the treatment of primary podocytosis (including idiopathic membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis) is summarized to support the development of new treatment strategies for primary podocytosis.

Integrating basic science with translational research: the 13th International Podocyte Conference 2021.

The 13th International Podocyte Conference was held in Manchester, UK, and online from July 28 to 30, 2021. Originally planned for 2020, this biannual meeting was postponed by a year because of the coronavirus disease 2019 (COVID-19) pandemic and proceeded as an innovative hybrid meeting. In addition to in-person attendance, online registration was offered, and this attracted 490 conference registrations in total. As a Podocyte Conference first, a day for early-career researchers was introduced. This premeeting included talks from graduate students and postdoctoral researchers. It gave early career researchers the opportunity to ask a panel, comprising academic leaders and journal editors, about career pathways and the future for podocyte research. The main meeting over 3 days included a keynote talk and 4 focused sessions each day incorporating invited talks, followed by selected abstract presentations, and an open panel discussion. The conference concluded with a Patient Day, which brought together patients, clinicians, researchers, and industry representatives. The Patient Day was an interactive and diverse day. As well as updates on improving diagnosis and potential new therapies, the Patient Day included a PodoArt competition, exercise and cooking classes with practical nutrition advice, and inspirational stories from patients and family members. This review summarizes the exciting science presented during the 13th International Podocyte Conference and demonstrates the resilience of researchers during a global pandemic.

GLOMERULAR HYPERFILTRATION MAY CONTRIBUTE TO RENAL TROPISM AND KIDNEY INJURY IN COVID-19 BY UPREGULATING ACE2 IN HUMAN PODOCYTES

Objective: Apart from the respiratory system, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can potentially infect multiple other organs including podocytes in the kidney. The latter play a crucial role in glomerular filtration. Podocytes can be damaged by increased fluid flow shear stress (FFSS) of the ultrafiltrate in Bowman's space in the setting of glomerular hyperfiltration that occurs in disease states such as hypertension, diabetes or in several forms of chronic kidney disease. These conditions are associated with an increased risk of a more severe course of coronavirus disease 2019 (COVID-19) and mortality. Design and method: To assess the susceptibility of human podocytes (hPC) for SARS-CoV-2 infection in the context of hyperfiltration in vitro, we used a recently established model system (Streamer Shear Stress Device)) to mimic hyperfiltration by exposing hPC to increased FFSS of 1 dyne/cm2 for 2 h. In this setting we nalysed the effects of FFSS on mRNA expression of angiotensin I-converting enzyme 2 (ACE2) as the pivotal entry receptor for SARS-CoV-2 infection in hPC. Moreover, other potential critical host cell factors including transmembrane serine protease 2 (TMPRSS2), furin (FURIN), and neuropilin 1 (NRP1) were also assessed in parallel with changes of the F-actin fiber structure, i.e. an important cytoskeletal marker in hPC. Results: Under control conditions, hPC displayed long, parallel F-actin fibers crossing the entire cell body. After FFSS, an enrichment of cells that express F-actin in a cortically condensed pattern near the cell membrane was observed. FFSS induced a significant upregulation of ACE2 expression (about twofold) and of all other nalysed SARS-CoV-2 entry factors in hPC (p < 0.05, respectively compared to control conditions, Figure 1 with data plotted as log2fold change [FC]). Conclusions: Our data support a potential link between glomerular hyperfiltration, podocyte damage and renal tropism of SARS-CoV-2 that may contribute to kidney damage including albuminuria development in COVID-19 patients.

MINIMAL CHANGE DISEASE SECONDARY TO SARS-COV-2 (COVID-19) INFECTION: A REPORT OF 2 CASES AND REVIEW OF RELATED LITERATURE

BACKGROUND AND AIMS: The COVID-19 pandemic has brought to the forefront a wide spectrum of renal injuries that included glomerulopathies, some of which were recently highlighted in various case reports. These consist of focal and segmental glomerulosclerosis (FSGS) and minimal change disease (MCD).1 These changes were found among seemingly vulnerable populations such as the African American and Caucasian ethnicities with paucity of reports among other races. We present two cases of biopsy-confirmed MCD secondary to COVID-19 infection among adult Filipino patients. METHODS: Case Report RESULTS: Case 1 A 40-year-old Filipino female with a history of right total mastectomy 2 years prior for a low-grade phyllodes tumor and no other medical comorbidities was admitted due to stillbirth. She was noted to have bipedal edema with a positive COVID-19 RT-PCR swab. Further workup revealed a serum creatinine 1.04 mg/dL, urine RBC 1/HPF and a 24-h urine protein of 9.22 g with hypoalbuminemia and dyslipidemia. Serologic workup was noted to be negative. She was started on Losartan, Atorvastatin, and Furosemide. A kidney biopsy was performed which demonstrated unremarkable light microscopy and immunofluorescence and widespread podocyte-foot process effacement. These biopsy findings were interpreted to be consistent with minimal change disease. She was started on Prednisone at 1 mg/kg/day with continuation of both Losartan and Atorvastatin. Six weeks after, the patient achieved complete remission with resolution of both hypoalbuminemia and dyslipidemia. She also reports no further recurrence of edema. Case 2 A 61-year-old Filipino male with a history of type 2 diabetes mellitus, hypertension, dyslipidemia and mild COVID-19 infection 4 months prior now presented with diarrhea. A routine COVID-19 RT-PCR swab revealed a re-infection. Physical examination noted bipedal edema. Further workup demonstrated a serum creatinine 3.39 mg/dL, urine RBC 2/HPF and urine ACR 2.6 g/g. Serologic tests were negative. He was diagnosed with Nephrotic Syndrome and underwent kidney biopsy. Findings showed an unremarkable light microscopy and immunofluorescence with widespread podocyte-foot process effacement. These findings were found to be consistent with minimal change disease and acute tubular injury. He was started on Prednisone (1 mg/kg/day), Losartan, Furosemide and Atorvastatin. Eight weeks later, the patient achieved complete remission with resolution of edema. CONCLUSION: It is currently suspected that APOL1 risk variants found in reported cases of COVID-19-associated glomerulopathies are underlying toxic gain-of-function mutations that drive kidney disease.2 It is interesting to note that APOL1 renal risk variants are found exclusively in African-derived chromosomes and are rarely found among European or Asian chromosomes.3 Even though an APOL1 genotyping was not performed, our case reports provide the first examples of MCD among individuals without a high-risk genotype (APOL1) by epidemiology and enlarge the literature on MCD in COVID-19. We posit that there may be other underlying predispositions or mechanisms that may be driving glomerulopathy formation among COVID-19 patients aside from their inherent APOL 1 risk. Both of our patients were started on steroid therapy with a tapering regimen and achieved complete remission on subsequent follow-up. Existing reports suggest that most cases of COVID-19-associated MCD will often achieve resolution of AKI and proteinuria with steroid therapy, even in those with high-risk APOL1 genotype, emphasizing the need for an accurate histologic classification.4 (Figure Presented).

A CASE OF FSGS IN A PREVIOUSLY HEALTHY MALE AFTER THE SECOND DOSE OF COVID-19 MRNA VACCINE

Case Report Background COVID-19 infection and COVID-19 mRNA vaccines have been associated with the occurrence of de-novo and relapsing glomerulopathies. Although, Focal Segmental Glomerulosclerosis (FSGS) similar HIV associated Nephropathy (HIVAN) has been reported with COVID-19 infection in African American population with Apolipoprotein L1 gene mutation, amongst the few reported cases post-vaccine, Minimal change disease (MCD), IgA nephropathy (IgAN), Anti-Glomerular basement membrane glomerulonephritis (Anti GBM GN), and membranous glomerulonephritis (MGN) have been reported. Case A 26-year-old Caucasian male with a history of tobacco use complained of Frothy urine and edema for 3 weeks post second dose of Moderna COVID-19 vaccine on 06/01/21. He received the first dose on 5/04/21. On his annual wellness visit on 5/18/21, he had no complaints, normal physical examination with serum albumin 5g/dl, and urinalysis significant for trace proteinuria. A repeat urinalysis post-onset of symptoms on 7/18/21 revealed 3+ proteinuria, no RBCs, 24- hour urine revealed 3.2g proteinuria. Further investigations revealed Hypoalbuminemia (2g/dl), persistent proteinuria, and an unremarkable renal ultrasound, ANA, ANCA, Anti-dsDNA, Anti-PLA2R, anti-streptolysin, RF, HIV, hepatitis panel, and serum complement levels. Renal biopsy revealed Tip lesion variant of FSGS with 100% effacement of podocyte foot process. Therapy with Prednisone 60 mg daily was initiated, following which an improvement in edema and serum albumin levels (2.7 g/dl) were noted. Discussion A few de-novo cases of anti-GBM GN, ANCA positive vasculitis, MCD and IgAN, and relapsing cases of IgAN, MCD, MGN, and Thrombotic microangiopathy have been reported post-COVID 19 mRNA vaccination. Most reported cases of MCD occurred after the first dose whereas IgAN flare-up occurred after the second dose. Our case is unique as our Caucasian patient developed FSGS post-second dose of Moderna vaccine. Although the pathogenesis is unclear, it is thought to be related to an acute T-cell immune response involving cytokine production to COVID 19 spike protein which is responsible for inducing or worsening existing podocytopathies. Interestingly fewer cases have been reported following adenovirus vector or inactivated virus vaccination. Most of the reported cases of IgAN flare-up have been mild and a small number of MCN cases required ICU admission for management of fluid overload. As observed in a few prior case reports our patient had a slow response to steroid therapy. Although guidelines on COVID 19 vaccination in patients with existing glomerulopathies remain unclear and are based on case-by-case scenarios, the benefit of COVID 19 vaccination, may in general, outweighs the risk of glomerular diseases. We encourage further studies on this topic, especially in the era of booster doses with ongoing discussion about mixing two types of vaccines.

ScoMorphoFISH: A deep learning enabled toolbox for single-cell single-mRNA quantification and correlative (ultra-)morphometry.

Increasing the information depth of single kidney biopsies can improve diagnostic precision, personalized medicine and accelerate basic kidney research. Until now, information on mRNA abundance and morphologic analysis has been obtained from different samples, missing out on the spatial context and single-cell correlation of findings. Herein, we present scoMorphoFISH, a modular toolbox to obtain spatial single-cell single-mRNA expression data from routinely generated kidney biopsies. Deep learning was used to virtually dissect tissue sections in tissue compartments and cell types to which single-cell expression data were assigned. Furthermore, we show correlative and spatial single-cell expression quantification with super-resolved podocyte foot process morphometry. In contrast to bulk analysis methods, this approach will help to identify local transcription changes even in less frequent kidney cell types on a spatial single-cell level with single-mRNA resolution. Using this method, we demonstrate that ACE2 can be locally upregulated in podocytes upon injury. In a patient suffering from COVID-19-associated collapsing FSGS, ACE2 expression levels were correlated with intracellular SARS-CoV-2 abundance. As this method performs well with standard formalin-fixed paraffin-embedded samples and we provide pretrained deep learning networks embedded in a comprehensive image analysis workflow, this method can be applied immediately in a variety of settings.

MULTISCALE FRACTAL SHAPE CUES SUPPORT HIERARCHICAL ASSEMBLY AND MATURATION OF PODOCYTES VIA CURVATURE-INDUCED EXTRACELLULAR MATRIX PATTERNING

Nature efficiently self-organizes cells and tissues into complex fractal forms. Whether fractal patterning contributes functionally to maturation, and how cells sense and interpret such shape cues, is not well understood. Using kidney podocytes as a model system, bioinspired templating of glomerular histology was leveraged to design controlled fractal 21/2 -D surfaces for cell culture. Microcurvature was associated with charge density gradients in space, found to direct extracellular matrix protein organization resulting in hierarchical assembly of cell structures and fractally-branching podocyte morphology in vitro, outlined with a novel fluorescent assaying technique. Shape simulation was uniquely associated with mature-like foot processes on an organized ECM. In applications of drug testing, coronavirus infection, and a cells-as-sensors approach to patient serum diagnostics, fractally stimulated cells were more responsive than flat cultures. Fractal frameworks may thus provide a functional role in podocyte maturation and could serve to advance other bioengineered systems.

RAGE/Diaph1, Diabetes, and Kidney Disease: Mechanisms and Novel Therapeutic Strategies

In Year Three of the funded grant, we have substantial progress in the following critical areas: 1). As noted in the project narrative, we generated four different lines of mice to directly test the hypothesis that RAGE and DIAPH1 contribute to the pathogenesis of diabetes-associated nephropathy in the podocytes and/or in myeloid cells/macrophages. All of the mouse lines are now generated and largely completed (mice sacrificed) and samples being evaluation by Dr DAgati. There are no new pending mice to generate all are generated and on time course. 2). We have determined that the small molecule RAGE/DIAPH1 antagonist is best administered orally and that the RAGE antagonist survives the medicated chow pelleting, heating and irradiation. Our first data on treated vs. untreated male and female diabetic mice illustrates reduction in mesangial sclerosis, reduced thickening of the glomerular basement membrane and reduction in podocyte effacement in diabetic mice receiving RAGE229 medicated chow (vs vehicle). Additional mice are on study and time course at this time to complete the indicated enrollment.3). For transcriptomics and metabolomics/lipidomics assay, Dr. Ramasamy will be testing the macrophages from the mice through the time course and he has verified all of his experimental systems for the performance of the outlined studies. Dr. Ramasamy identifies substantial progress in the development and validation of metabolomics and lipidomics assays here at NYU and in transcriptomic data (all on macrophages) in order to understand detailed mechanisms of the role of these molecules in the diabetic kidney. Taken together, despite the >3 month shutdown due to COVID19 our work in Year 3 has been productive and we await tissue and other analyses, as above, to render final conclusions.

Inhibition of endoplasmic reticulum stress signaling rescues cytotoxicity of human apolipoprotein-L1 risk variants in Drosophila.

Risk variants of the apolipoprotein-L1 (APOL1) gene are associated with severe kidney disease, putting homozygous carriers at risk. Since APOL1 lacks orthologs in all major model organisms, a wide range of mechanisms frequently in conflict have been described for APOL1-associated nephropathies. The genetic toolkit in Drosophila allows unique in vivo insights into disrupted cellular homeostasis. To perform a mechanistic analysis, we expressed human APOL1 control and gain-of-function kidney risk variants in the podocyte-like garland cells of Drosophila nephrocytes and a wing precursor tissue. Expression of APOL1 risk variants was found to elevate endocytic function of garland cell nephrocytes that simultaneously showed early signs of cell death. Wild-type APOL1 had a significantly milder effect, while a control transgene with deletion of the short BH3 domain showed no overt phenotype. Nephrocyte endo-lysosomal function and slit diaphragm architecture remained unaffected by APOL1 risk variants, but endoplasmic reticulum (ER) swelling, chaperone induction, and expression of the reporter Xbp1-EGFP suggested an ER stress response. Pharmacological inhibition of ER stress diminished APOL1-mediated cell death and direct ER stress induction enhanced nephrocyte endocytic function similar to expression of APOL1 risk variants. We confirmed APOL1-dependent ER stress in the Drosophila wing precursor where silencing the IRE1-dependent branch of ER stress signaling by inhibition with Xbp1-RNAi abrogated cell death, representing the first rescue of APOL1-associated cytotoxicity in vivo. Thus, we uncovered ER stress as an essential consequence of APOL1 risk variant expression in vivo in Drosophila, suggesting a central role of this pathway in the pathogenesis of APOL1-associated nephropathies.

Collapsing Focal Segmental Glomerulosclerosis in Viral Infections.

Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein-Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS.

Minimal change disease (MCD) after Moderna COVID-19 vaccination

Background: Post vaccination minimal change disease with nephrotic syndrome and acute kidney injury has been reported after influenza and Pfizer-BioNTech vaccine. Further research is needed to prove a correlation. Methods: Clinical case, renal biopsy, dialysis Results: We present a case of a 65 years old patient, who developed minimal change disease 8 days following first injection with Moderna COVID-19 vaccine. In his medical history the patient has collagenous colitis and was on treatment with budenofalk. He presented with full blown nephrotic syndrome and developed dialysis dependent acute kidney injury for two weeks. Renal biopsy showed minimal change disease with 90% loss of podocyte processes in electron microscopy. Two weeks of dialysis and immunosupressive therapy over three months after the event lead to recovery of renal function to baseline. The patient received the second COVID-19 vaccination without developing complications or relapse. Conclusions: We present one of the first patients with minimal change disease after Moderna COVID-19 vaccine. There was an association between the timing of the vaccination and clinical manifestation of ne-phrotic syndrome. A definite causal relation still needs to be elucidated. A possible pathomechanism would be, that mRNA vaccines initiate T-cell mediated injury. However further studies are needed to find the im-munological mechanism of action after COVID-19 vaccination. Out of many millions of mRNA vaccines administered so far, to our knowledge, 7 cases of de novo minimal change disease have been described as well as up to 17 other glomerular diseases de novo and relapsing after COVID-19 vaccination.

Evidence For and Against Direct Kidney Infection by SARS-CoV-2 in Patients with COVID-19.

Despite evidence of multiorgan tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV2 can directly infect the kidney is relevant to the understanding of pathogenesis of AKI and collapsing glomerulopathy in patients with COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, RT-PCR, in situ hybridization, and electron microscopy. In our review of studies to date, we found that SARS-CoV-2 in the kidneys of patients with COVID-19 was detected in 18 of 94 (19%) by immunohistochemistry, 71 of 144 (49%) by RT-PCR, and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed because many other studies have been negative for SARS-CoV-2 and it should be noted that when detected, it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19-associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a noninvasive way to evaluate SARS-CoV-2 infection during the evolution of COVID-19-associated kidney disease.

TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling.

BACKGROUND: Injury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 (TrkC) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton. METHODS: Nephron-specific TrkC knockout (TrkC-KO) and nephron-specific TrkC-overexpressing (TrkC-OE) mice were generated to dissect the role of TrkC in nephron development and maintenance. RESULTS: Both TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)-associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue. CONCLUSIONS: Our results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.