The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.

Background: Potassium (K⁺) is the major intracellular cation, with 98% of the total pool being located in the cells at a concentration of 140-150 mmol/l, and only 2% in the extracellular fluid, where it ranges between 3.5 and 5 mmol/l. A fine regulation of the intracellular-extracellular gradient is crucial for life, as it is the main determinant of membrane voltage; in fact, acute changes of K⁺ plasma levels may have fatal consequences. Summary: An integrated system including an ‘internal' and ‘external' control prevents significant fluctuations of plasma levels in conditions of K⁺ loading and depletion. The internal control regulates the intra-extracellular shift, a temporary mechanism able to maintain a constant K⁺ plasma concentration without changing the total amount of body K⁺. The external control is responsible for the excretion of the ingested K⁺, and it has the kidney as the major player. The kidney excretes nearly 90% of the daily intake. Along the proximal tubule and the thick ascending limb on Henle's loop, the amount of K⁺ reabsorption is quite fixed (about 80-90%); conversely, the distal nephron has the ability to adjust K⁺ excretion in accordance with homeostatic needs. The present review analyzes: (1) the main molecular mechanisms mediating K⁺ reabsorption and secretion along the nephron; (2) the pathophysiology of the principal K⁺ derangements due to renal dysfunction, and (3) the effect of ingested K⁺ on blood pressure and renal electrolyte handling. Key Messages: Maintaining plasma K⁺ levels in a tight range is crucial for life; thus, multiple factors are implicated in K⁺ homeostasis, including kidney function. Recent studies have suggested that K⁺ plasma levels, in turn, affect renal salt absorption in animal models; this effect may underlie the reduction of blood pressure observed in hypertensive subjects under K⁺ supplementation.

Genetic testing for pathogenic COL4A3–5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3–COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

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