Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.

Mutations in the ␣-actinin-4 gene (ACTN4) cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS).A mutational analysis was performed of ACTN4 in DNA from probands with a family history of FSGS as well as in individuals with nonfamilial FSGS. The possible contribution of noncoding variation in ACTN4 to the development of FSGS also was assessed. Multiple nucleotide variants were identified in coding and noncoding sequence. The segregation of nonsynonymous coding sequence variants was examined in the relevant families. Only a small number of nucleotide changes that seemed likely to be causing (or contributing to) disease were identified. Sequence changes that predicted I149del, W59R, V801M, R348Q, R837Q, and R310Q changes were identified. For studying their biologic relevance and their potential roles in the pathogenesis of FSGS, these variants were expressed as GFP-fusion proteins in cultured podocytes. F-actin binding assays also were performed. Three of these variants (W59R, I149del, and V801M) showed clear cellular mislocalization in the form of aggregates adjacent to the nucleus. Two of these mislocalized variants (W59R and I149del) also showed an increased actin-binding activity. The I149del mutation segregated with disease; W59R was found to be a de novo mutation in the proband. A total of five ACTN4 mutations that are believed to be disease causing (three reported previously and two novel) as well as a number of variants with unclear contribution to disease now have been identified. The possibility that some of these other variants increase the susceptibility to FSGS cannot be excluded. ACTN4 mutations seem to account for approximately 4% of familial FSGS.

The precise guidelines recommended by the American Heart Association for blood pressure measurement are commonly overlooked by health-care workers, who generally take blood pressure in an arbitrary way. To validate this observation we designed a descriptive and observational study to be carried out in a major hospital. One hundred and seventy-two health-care workers divided into four groups (63 general practitioners, 25 clinical and 25 surgical specialists, and 59 nurses) were evaluated in a two-part test. In the first part (practical), the examinee had to follow all the steps recommended by the American Heart Association to get a passing score. In the second part (theoretical, which came second to avoid influencing the practical), the examinee had to answer correctly 7 of 10 questions based on the American Heart Association's guidelines to obtain a passing score. The highest accepted variation in systolic and diastolic pressures between examinee and observer was +/- 4 mm Hg. None of the examinees followed the American Heart Association's recommendations. Sixty-three percent of systolic and 53% of diastolic readings were out of range. Surgical specialists obtained the best practical results (48% systolic and 64% diastolic within range), and nurses obtained the lowest values (29% and 39%, respectively; P = .03 versus surgical specialists). These two groups showed deficiencies in the theoretical test (nurses, 10% correct answers and surgical specialists, 16%). Clinical specialists obtained the best results on the theoretical test (60% correct; P < .05 versus the other groups) but were deficient in the practical test (32% systolic and 60% diastolic within range).(ABSTRACT TRUNCATED AT 250 WORDS)

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OBJECTIVE Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. We explored whether baseline HbA1c level and insulin treatment influenced outcomes. RESEARCH DESIGN AND METHODS Patients with T2D, urine albumin-to-creatinine ratio (UACR) of 30–5,000 mg/g, estimated glomerular filtration rate (eGFR) of 25 to &lt;75 mL/min/1.73 m2, and treated with optimized renin–angiotensin system blockade were randomly assigned to receive finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c &lt;7.5% (58 mmol/mol) or ≥7.5%. RESULTS Of 5,674 patients, 3,637 (64.1%) received insulin at baseline. Overall, 5,663 patients were included in the analysis for HbA1c; 2,794 (49.3%) had baseline HbA1c &lt;7.5% (58 mmol/mol). Finerenone significantly reduced risk of the kidney composite outcome independent of baseline HbA1c level and insulin use (Pinteraction = 0.41 and 0.56, respectively). Cardiovascular composite outcome incidence was reduced with finerenone irrespective of baseline HbA1c level and insulin use (Pinteraction = 0.70 and 0.33, respectively). Although baseline HbA1c level did not affect kidney event risk, cardiovascular risk increased with higher HbA1c level. UACR reduction was consistent across subgroups. Adverse events were similar between groups regardless of baseline HbA1c level and insulin use; few finerenone-treated patients discontinued treatment because of hyperkalemia. CONCLUSIONS Finerenone reduces kidney and cardiovascular outcome risk in patients with CKD and T2D, and risks appear consistent irrespective of HbA1c levels or insulin use.