Genetic testing in chronic kidney disease of uneXplained cause (CKDx): clinical insights and evolving diagnostic paradigms

Abstract

Chronic kidney disease (CKD) represents a significant global health burden, with diverse etiologies and often complex clinical presentations. Among these, a notable subset of CKD patients present without a clear underlying cause despite extensive diagnostic evaluation. For this subgroup, the term CKDx - chronic kidney disease of unexplained cause, has recently been proposed. A major element of the diagnostic workup of CKDx is genetic testing, for which the methodology has greatly improved in the last years.

Figure 1:

Schematic on diagnostic strategies for identification of the underlying cause in a patient with CKD. (A) Conventionally, kidney biopsy is the gold standard for establishing the underlying kidney disorder by providing clinicians with a histological diagnosis. In cause of undetermined findings upon histology (CKDx h+ g-), genetic testing serves as an 2^nd tier diagnostic tool to establish the definite cause. In cases of unestablished etiology despite histological and genetic investigation, the term CKDx with the suffices h+ and g+ has been proposed. (B) In a “Genetics-first” approach, genetic testing is considered the 1^st tier diagnostics for establishing the underlying cause. In unresolved cases (CKDx h+ g+), re-analysis, for instance by long-read sequencing, will be indicated (Figure created with Biorender). Legend: ADPKD – autosomal dominant polycystic kidney disease; ADTKD – autosomal dominant tubulointerstitial kidney disease; ARAS – autosomal recessive Alport Syndrome; CAKUT – congenital anomalies of the kidneys and urinary tract; CKDx – chronic kidney disease of unexplained cause; C3GN – Complement factor 3 glomerulonephritis; FSGS – focal segmental glomerulosclerosis; IgAN – IgA Nephropathy; MCD – minimal change disease; MPGN – membranoproliferative glomerulonephritis; NPH – nephronophthisis; TMA – thrombotic microangiopathy.