Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis - Fig 5

<p>(A) Levels of renal IL-17 by qCR were not different between the 3 experimental groups. (B) Flow cytometry analysis of IL-17 receptor expression in splenocytes from unmanipulated WT and IL-17^-/- mice. Shaded area represents PE isotype control. Dotted line represents WT splenocytes and superimposed solid line represents IL-17^-/-splenocytes. There was no difference in expression of the IL-17 receptor in splenocytes from healthy WT and IL-17^-/- mice (B).</p

IL-17^-/- mice are protected from NTN.

<p>IL17^-/- mice had significantly (A) lower serum urea (p<0.01), (B) less proteinuria (p<0.001) and (C) less thrombosis (p<0.05) compared to WT mice. There was no difference in humoral responses between the groups either for (D) total serum mouse anti-sheep IgG or (E) glomerular deposition of mouse anti-sheep IgG. There was no significant difference in cellular infiltration of glomeruli by either (F) CD4+ T cells or (G) CD68+ macrophages. Analysis by Two-Way ANOVA and non-parametric Mann-Whitney U test. Bars represent median and range. Lines represent median. * = p<0.05; ** = p<0.01; *** = p<0.001. Differences are non-significant unless otherwise stated. Data shows combined results from 2 experiments of at least 4 mice per group.</p

Transplantation of WT bone marrow to IL-17^-/- mice restores and augments disease susceptibility.

<p>(A) Haematopoietic reconstitution of bone marrow transplant mice. DNA extracted from blood was analysed by PCR for WT and IL-17^-/- alleles. All mice reconstituted >90% donor bone marrow. WT to IL-17^-/- mice have (B) significantly greater tubular injury (p<0.01) and (C) more glomerular thrombosis (p<0.05) than WT to WT mice. Renal function is worse as measured by serum urea (D) than the other two groups. WT to IL-17^-/- mice had more proteinuria than IL-17^-/- to WT mice (p<0.05) (E), but not statistically more than WT to WT mice due to small numbers, many of the severely affected mice were oligo-anuric and produced insufficient urine to quantify. Humoral immune responses and infiltrating cell numbers were similar between the groups despite differences in disease outcomes. (F) There was no difference in glomerular mouse IgG between the groups. (G) Serum showed no differences in total anti-sheep IgG produced. (H) There was significantly less IgG2b in WT to IL-17^-/- mice in the first experiment and a similar tendency in the second experiment. There was no difference in numbers of (I) CD4+ T cells or (J) CD68+ macrophages in the glomeruli. Analysis by Two-Way ANOVA and non-parametric Mann-Whitney U test. Bars represent median and range. Lines represent median. * = p<0.05; ** = p<0.01; *** = p<0.001. Representative data shown from 1 experiment of 2 separate experiments of at least 6 mice per group.</p

There were significant differences in cytokine levels and macrophage phenotype between the groups.

<p>The most severely affected group, WT to IL-17^-/- bone marrow transplants had significantly less renal (A)IL-10, (B)IL-1β, (C) IL-23 by qPCR compared to WT to WT transplant mice. They also had a different macrophage phenotype with significantly less (D) mannose receptor and (F) iNOS. Although arginase levels had a tendency to be lower in WT to IL-17^-/- bone marrow transplants, this was not statistically significant (E). Analysis by Two-Way ANOVA and non-parametric Mann-Whitney U test. Lines represent median. * = p<0.05; ** = p<0.01; *** = p<0.001. Data shows combined results from 2 separate experiments of at least 6 mice per group.</p

Mast cells persist following irradiation and produce IL-17.

<p>Mast cells persist following irradiation and retain the ability to produce IL-17 following stimulation with LPS. (A) Numbers of intra-renal mast cells are unchanged following irradiation. (B) In contrast, CD45+ splenocytes are completely removed by irradiation. (C) Production of IL-17 by mast cells is unaffected by irradiation. (D) Confocal microscopy images from renal cortex. (i) In the absence of irradiation, mast cells (red), CD45+ splenocytes (blue) and IL-17 (green) are demonstrated. (ii) Following irradiation, CD45+ leucocytes are absent. Mast cells and IL-17 production are unaffected and co-localise (yellow). X1200. Data presented are representative of two independent experiments of at least 6 mice per group.</p

Representative histological sections from the 3 bone marrow transplant groups with NTN.

<p>(A) PAS-stained sections of renal histology. The WT to IL-17^-/- group have severe glomerular thrombosis with profound tubular dilatation and casts, significantly more than the other groups. (B) and (C) Immunofluorescence for glomerular deposition of sheep and mouse IgG respectively. There was no difference between the groups. (D) and (E) Representative glomerular staining for CD68 and CD4 respectively. Magnification x400.</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

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