Progressive loss of glomerular podocin abundance in the course of disease.

<p>Podocin (green), nidogen (red) and nucleus (blue) staining of glomeruli of healthy and <i>Nphs2</i>^{<i>R140Q/-</i>} animals. (A) Normally expressed podocin in glomerulus of a healthy animal. (B) Partial podocin loss one week after the induction. (C) Immense podocin loss in <i>Nphs2</i>^{<i>R140Q/-</i>} animals four weeks after the induction. (D) Subtotal to total podocin loss at the end stage disease. Magnification, X640.</p

Podocyte foot process effacement in <i>Nphs2</i>^{<i>R140Q/-</i>} mice.

<p>(A) Ultrastructural studies showed regular foot processes (FP) in healthy control animals on the opposite side of endothelial cells (En) lining the capillary lumen (L). (B) Irregularly shaped or fused FPs in <i>Nphs2</i>^{<i>R140Q/-</i>} mice one week after induction (arrow). (C and D) Progression of focal changes to global fusion of FPs in <i>Nphs2</i>^{<i>R140Q/-</i>} animals over time (Magnification, X10000). 3D modelling of glomerular structure showed no GBM denudation in <i>Nphs2</i>^{<i>R140Q/-</i>} animal (F) compared to controls (E). Blue colour represents GBM, pink and green represent FPs of adjacent podocytes. Severely affected FP number and organization in <i>Nphs2</i>^{<i>R140Q/-</i>} animals (G). GBM thickening in <i>Nphs2</i>^{<i>R140Q/-</i>} animals (H) (G and H: analysis is based on 3 animals per group). ** p<0.01, **** p<0.0001.</p

Podocyte loss in <i>Nphs2</i>^{<i>R140Q/-</i>} mice.

<p>(A) Number of podocytes reduced in induced mice with the course of the disease (columns represent 4–6 animals per group and time point). (B) Wt1 labelled podocytes in glomerulus in a healthy animal. Decreased Wt1 signal in <i>Nphs2</i>^{<i>R140Q/-</i>} animals 1 week (C), 2 weeks (D), and 4 weeks after induction (E). Wt1: green, nidogen: red, nucleus: blue. Magnification, X640.</p

Whereas mRNA expression of mutant <i>Nphs2</i> is elevated, podocin protein abundance is diminished.

<p>(A) <i>Nphs2</i>^{<i>R140Q/-</i>} animals showed an elevated expression level of mutated podocin mRNA during the first four weeks following induction (analysis is based on 4–6 animals per group and time point) WT: wild type. (B) Western blot analysis of total kidney extracts showing partial podocin protein loss during first two weeks, subtotal loss after 4–6 weeks and complete loss at attainment of end-stage renal disease (week 12–16) (analysis is based on 4–6 animals per group and time point; p<0.05).</p

<i>Nphs2</i>^{<i>R140Q/-</i>} mice develop focal-segmental glomerulosclerosis (FSGS).

<p>(A) Glomerular sclerosis index (GSI) in healthy and <i>Nphs2</i>^{<i>R140Q/-</i>} mice. (B) Percentage of glomeruli affected by sclerosis in <i>Nphs2</i>^{<i>R140Q/-</i>} mice increased drastically over time (columns represent 4–10 animals per group and time point). (C-F) Evolution of glomerular lesions in induced animals. PAS staining; Magnification, X200.</p

Time course of clinical phenotype in different hereditary podocytopathy mouse models.

<p>Time course of clinical phenotype in different hereditary podocytopathy mouse models.</p

<i>Wt1</i> regulation in induced animals.

<p><i>Wt1</i> expression is significantly reduced in <i>Nphs2</i>^{<i>R140Q/-</i>} animals 4 weeks after disease induction (columns represent 5–7 animals per group and time point). **p = 0.0002.</p

Podocin loss leads to renal damage.

<p>(A) control, (B) week 2, (C) week 4, (D) week 12. (E) Percentage of total kidney area affected by fibrosis in <i>Nphs2</i>^{<i>R140Q/-</i>} mice increased with observation time (columns represent 4–10 animals per group and time point). (F) Proteinuria 2 weeks after induction is correlated with the tubulointerstitial fibrosis score at week 4 (n = 17; p = 0.01). SR staining; Magnification, X150. * p<0.05, ** p<0.001.</p

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window).Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p Background Methods Findings Interpretation Funding</p