Chronic Kidney Disease of unexplained cause (CKDx): a consensus statement by the Genes & Kidney Working Group of the ERA

Abstract

Chronic kidney disease of unexplained cause (CKDx) is a diagnosis of exclusion. With an estimated global prevalence of at least 16-20% among CKD patients, CKDx poses a significant challenge to the field. To date, there is no established consensus on the definition of CKDx. Additionally, guidance on the diagnosis and reporting of CKDx remains lacking. CKDx is characterized by the inability to identify a specific etiology after comprehensive diagnostic evaluation, including laboratory tests, imaging, and histological or genetic analyses. This condition encompasses diverse clinical scenarios, which vary depending on the availability of diagnostic resources across healthcare systems. Notably, as the diagnostic yield of genetic testing in CKDx ranges from 11 to over 30% in the literature, it has become an integral part of the diagnostic armamentarium for patients with CKDx. This consensus statement of the working group 'Genes&Kidney' of the European Renal Association proposes a definition of CKDx, along with recommendations for the diagnostic approach and diagnostic reporting standards, including guidance on genetic workup as a key tool in a large proportion of such cases. Improved reporting standards, including the systematic documentation of diagnostic tests performed, are essential to avoid the negative therapeutic consequences of misdiagnoses, address the diagnostic gap in CKDx, and inform future research. By fostering a cause-directed approach, this work aims to enhance patient care and lay the foundation for further advancements in nephrology.

Keywords: CKD; CKD of unknown etiology; CKDx; chronic kidney disease; genetic kidney disease.

Figure 1:

CKDx assessment flow chart (for guidance with genetic testing, see Supplementary data, Fig. S1).

Figure 2:

Sunburst-like plot showing possible extrarenal and renal features associated with genetic kidney conditions. (Of note: pie-size does not reflect real frequency; not all possible extrarenal features are listed here nor all genetic kidney diseases are covered.) Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; ARPKD, autosomal recessive polycystic kidney disease; ADTKD, autosomal dominant tubulointerstitial kidney disease; BOR, branchio-oto-renal; CAKUT, congenital anomalies of the kidneys and urinary tract; C3G, C3 glomerulopathy; HANAC, hereditary angiopathy with nephropathy, aneurysms and cramps (COL4A1 gene); HNF1b, gene coding for hepatic nuclear factor 1-beta; FAN1, FANCD2/FANCI-associated nuclease 1; MELAS, mitochondrial encephalopathy, lactic acidosis, stroke-like episodes; MUC1, gene coding for mucin 1; MYH9, gene coding for myosin heavy chain 9; OFD1, orofaciodigital syndrome 1; PH, primary hyperoxaluria; REN, gene coding for renin; SALL1, gene coding for spalt-like transcription factor 1 (Townes-Brockes syndrome); SEC61A1, gene coding for Sec61 subunit alpha isoform 1; TMA, thrombotic microangiopathy; TSC, tuberous sclerosis complex; TULP3, gene coding for TUB like protein 3 (hepatorenocardiac syndrome), UMOD—gene coding for uromodulin; VHL, von Hippel Lindau disease, WT1, Wilms’ tumour suppressor gene. Explanations: 1. The term ‘ciliopathies’ refers to broad spectrum of multisystemic disorders originating from primary cilia disorder with kidney, nervous system, skeleton, eye and other organs affection. (e.g. nephronophtysis, Senior-Loken syndrome, Joubert syndrome, Alström syndrome, Bardet-Biedl, etc.). Ciliopathies may include disorders like ADPKD, ARPKD and OFD1-related disease, although in this figure they are shown separately. 2. The term ‘tubulopathies’ refers to broad spectrum of diseases caused by renal tubular disfunction resulting in electrolyte (K, P, Ca, Mg, Na, Cl) and/or renal acid-base disorders with common systemic implications (e.g. Gitelman syndrome, Bartter syndrome, renal hypophosphatemia, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, etc.).