CI-1040 has no effect on blood pressure, kidney function and albuminuria after SNx.

<p>CI-1040 does not improve kidney function in the SNx rat; systolic blood pressure (SBP) (<b>a</b>), urinary albumin excretion (<b>b</b>), serum creatinine (<b>c</b>) and creatinine clearance (<b>d</b>) after 18 weeks treatment with either CI-1040 60mg/kg/d (closed triangles) or vehicle (closed circles) (n = 11 per group). Vertical bars indicate ± SEM, * p<0.05, ** p<0.001, *** p<0.0001 vs sham controls (open circles).</p

Myofibroblast number after treatment with CI-1040.

<p>Myofibroblast number as indicated by α-SMA staining. Representative sections of glomeruli (400x) from terminal kidney tissue (90 day) stained with α-SMA obtained from (<b>a</b>) sham (<b>c</b>) SNx and (<b>e</b>) SNx plus CI-1040 60mg/kg/day rats. Group data are quantified in (<b>g</b>). Representative sections of the tubulointerstitium (200x) from terminal kidney tissue (90 day) stained with α-SMA obtained from (<b>b</b>) sham (<b>d</b>) SNx and (<b>f</b>) SNx plus CI-1040 60mg/kg/day rats. Group data are quantified in (<b>h</b>). Bars represent mean ± SEM, n = 7–11 per group. * p<0.05, *** p<0.001 vs sham controls.</p

CI-1040 inhibits phospho-ERK1/2 expression after SNx and upregulates p38, cJun and PAI-1.

<p>(<b>a</b>) terminal kidney homogenates were western blotted for pERK1/2, phospho-p38 (p-p38), phospho-cJun (p-c-Jun) and PAI-1 with calnexin and total ERK1/2 acting as loading controls. (<b>b</b>) Densitometry values plotted with data representing mean +/- SEM, n = 6–11 per group. Statistical significance determined by one-way ANOVA. ***p<0.0001.</p

CI-1040 inhibits pERK1/2 activation and proliferation in rat fibroblasts.

<p>NRK49F cells were serum starved overnight together with increasing concentrations of the MEK inhibitor CI-1040 prior to stimulation with 10% foetal bovine serum. pERK1/2 expression was assessed by western blotting with calnexin as a loading control (1a). CI-1040 treatment leads to a dose-dependent reduction in pERK1/2 expression as a percentage of control (n = 3). Cell proliferation as assessed by BrdU ELISA (1b) shows CI-1040 at doses between 100nM and 10,000nM has no significant effect on cell proliferation (closed circles). Viability assays (1b, closed triangles) determined CI-1040 was cytotoxic at doses higher than 10,00nM (assay performed 3 times in triplicate. V to refers vehicle only. + refers to FBS-stimulated cells and–refers to non-stimulated cells.</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