The spectrum of kidney biopsies in hospitalized patients with COVID-19, acute kidney injury, and/or proteinuria.

We report a multicentric retrospective case series of patients with COVID-19 who developed acute kidney injury and/or proteinuria and underwent a kidney biopsy in the Paris and its metropolitan area. Forty-seven patients (80.9% men) with COVID-19 who underwent a kidney biopsy between March 08 and May 19, 2020 were included. Median age was 63 years IQR [52-69]. Comorbidities included hypertension (66.0%), diabetes mellitus (27.7%), obesity (27.7%), history of chronic kidney (25.5%), cardiac (38.6%) and respiratory (27.3%) diseases. Initial symptoms were fever (85.1%), cough (63.8%), shortness of breath (55.3%), and diarrhea (23.4%). Almost all patients developed acute kidney injury (97.9%) and 63.8% required renal replacement therapy. Kidney biopsy showed two main histopathological patterns, including acute tubular injury in 20 (42.6%) patients, and glomerular injury consisting of collapsing glomerulopathy and focal segmental glomerulosclerosis in 17 (36.2%) patients. Two (4.3%) patients had acute vascular nephropathy, while eight (17%) had alternative diagnosis most likely unrelated to COVID-19. Acute tubular injury occurred almost invariably in the setting of severe forms of COVID-19, whereas patients with glomerular injury had various profiles of COVID-19 severity and collapsing glomerulopathy was only observed in patients harboring a combination of APOL1 risk variants. At last follow-up, 16 of the 30 patients who initially required dialysis were still on dialysis, and 9 died. The present study describes the spectrum of kidney lesions in patients with COVID-19. While acute tubular injury is correlated with COVID-19 severity, the pattern of glomerular injury is intimately associated with the expression of APOL1 risk variants.

Blocking TGF-ß Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRß+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats.

BACKGROUND: The platelet-derived growth factor receptor ß (PDGFRß)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target. AIMS: In this regard, we first confirmed the presence of PDGFRß+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor ß (TGFß) inhibition in a rat model of AAN. MATERIALS AND METHODS: Neutralizing anti-TGFß antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily. RESULTS: At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro. CONCLUSIONS: The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRß+ pericytes-derived myofibroblasts accumulation.

Reappraisal of treatment-induced renal dysfunction in patients receiving antiangiogenic agents in phase I trials.

BACKGROUND: Several phase I trials are currently evaluating new antiangiogenic compounds. While hypertension and proteinuria have been largely reported as a class side effect of these agents, data on renal function [i.e. the glomerular filtration rate (GFR)] in patients (pts) treated with new antiangiogenic compounds in phase I trials are much scarcer. PATIENTS AND METHODS: Between November 2005 and March 2008, we identified 72 pts with solid tumors who had been included in four Phase I trials testing antiangiogenic or related compounds. Thirty-two pts had received a pan-HER/VEGFR inhibitor (A), 29 had received a vascular-disrupting agent (B) and 11 had received a pan-VEGFR inhibitor in combination with CPT11 (C). For each patient, we retrospectively analyzed the serum creatinine level (SCr), Cr clearance (CrCl) calculated by both the Cockcroft and Gault and aMDRD equations at baseline, during treatment and at the end of treatment. Acute renal failure (ARF) was defined as a decrease of >25% in CrCl, and severe renal failure (SRF) as a decrease of >50% in CrCl. Chronic renal failure (CRF) was defined according to the KDOQI-KDIGO classification. Renal dysfunction was defined as Cl <60 ml/min with a normal Cr level (<125 µmol/l). RESULTS: Each pt had received an average of 4 cycles of treatment (1 to 12). During treatment, the incidence of ARF ranged from 40.2% to 44.4% (A = 11/32, B = 19/29, C = 2/11). Seven to 9.7% of these cases were severe (A = 1/32, B = 6/29, C = 0/11). Moreover, 26.4 to 27.7% of the pts had exhibited persistent renal insufficiency at the end of the study (A = 5/32, B = 15/29, C = 0/11). From the start till the end of treatment, ARF had been documented in 20.8% to 22.2% of the pts. The average reduction in clearance was 9.8 to 11.6 ml/min/1.73 m2 between baseline and the end of treatment. CONCLUSION: The incidence of renal toxicity in phase I pts treated with antiangiogenic compounds was much higher than expected. Simple screening of Cr levels appears to be insufficient and careful nephrologic monitoring at baseline and during treatment should be implemented in early clinical trials assessing the risk/benefit ratio of new antiangiogenic compounds.