Genetic testing and glomerular hematuria-A nephrologist's perspective

Abstract

Alport syndrome is an inherited disorder of the kidneys that results from variants in three collagen IV genes-COL4A3, COL4A4, and COL4A5. Early diagnosis and pharmacologic intervention can delay the progression of chronic kidney disease and the onset of kidney failure in patients with Alport syndrome. This article describes the evolution of approaches to the diagnosis and early treatment of Alport syndrome.

Keywords: Alport syndrome; basement membranes; collagen IV; genetic kidney disease.

FIGURE 1

An approach to diagnosis of individuals with persistent glomerular hematuria using genetic testing and/or kidney biopsy (adapted from Kashtan, 2021). This algorithm presents a possible approach to diagnosis of individuals with persistent glomerular hematuria using genetic testing and/or kidney biopsy. Genetic testing is suggested when clinical findings and/or family history suggest a diagnosis of Alport syndrome. When other clinical findings suggestive of Alport syndrome are absent and family history is negative, but kidney function and urine protein excretion are normal, genetic testing prior to kidney biopsy would be a reasonable choice (dotted arrow). However, when a patient who has no clinical findings or family history suggestive of Alport syndrome but has proteinuria and/or abnormal kidney function, kidney biopsy may provide a more rapid approach to obtaining diagnostic information. If kidney biopsy shows findings suggestive of Alport syndrome, genetic testing can be undertaken to confirm the diagnosis. *The genetic testing approach may vary based on the level of suspicion of a diagnosis of Alport syndrome. When suspicion is high, next‐generation sequencing (NGS) of COL4A3, COL4A4, and COL4A5 is indicated. When suspicion of a diagnosis of Alport syndrome is moderate or low, a broad NGS panel including loci for focal segmental glomerulosclerosis, complement regulatory disorders and polycystic kidney disease, or whole‐exome sequencing, should be considered. **Kidney biopsy should, if possible, always include routine transmission electron microscopy (TEM). When TEM shows glomerular basement membrane changes suggestive of Alport syndrome, or when TEM is not available, studies of collagen IV alpha‐chain expression can provide useful diagnostic and prognostic information. ***See Kashtan and Gross, for clinical practice recommendations. ACEi, angiotensin‐converting enzyme inhibitor; VUS, variant of uncertain significance