Dr. Becky Mingyao Ma is a Clinical Assistant Professor at the Department of Medicine, University of Hong Kong. She completed her Postdoctoral Research Fellowship at the Center for Precision Medicine and Genomics, Columbia University. Her research interests include clinical utility of genetic diagnostics in nephrology, genotype-phenotype correlation in patients with Autosomal Dominant Polycystic Kidney Disease, and Alport syndrome.  

Chronic kidney disease (CKD) affects more than 10% of the global population. Identifying the underlying cause of CKD is the very first step in optimizing care for these patients. However, in many circumstances the etiology of kidney failure remains unknown or uncertain, hence the term chronic kidney disease of unknown etiology (CKDUE). A recently published Spanish renal registry study showed that the cause of kidney failure remains unknown in approximately 18% of patients with CKD. Common clinical scenarios include patients who present late to the health care system due to silent or vague disease manifestations, those in whom performing a kidney biopsy is no longer helpful, and other investigations such as serology is unyielding in unravelling the underlying cause of kidney failure.  Other scenarios include patients in whom performing a kidney biopsy is too risky, or biopsy is unrevealing.

Rapid advancement in molecular diagnostics have paved a new pathway towards unravelling the underlying etiology in these CKDUE patients. Various cohort studies examining the diagnostic yield of next-generation sequencing-based testing in patients with CKDUE have reported a diagnostic yield ranging from 12% to 56%.These cohorts are heterogenous in terms of patient inclusion criteria, age at presentation, proportion with positive family history, ethnicity, number of genes in the kidney disease gene panel and number of participating renal centers. Offering genetic testing on a national scale to young patients with CKDUE has not been comprehensively studied.

The recently published GENSEN Study assessed the diagnostic utility of genetic testing in CKDUE on a nationwide scale in Spain. 818 patients aged <=45 years with CKDUE and either an estimated glomerular filtration rate of <15 mL/min/1.73m² or on maintenance dialysis or transplantation were recruited from 51 Spanish centers.  All participants had genetic testing done for 529 genes associated with inherited nephropathies. The diagnostic yield, which is defined by a pathogenic or likely pathogenic variant concordant with the inheritance pattern, is almost 25%. The most frequently identified variants are in the one of the type IV collagen genes (COL4A5, COL4A4, COL4A3, 35% of total gene variants), followed by NPHP1, PAX2, UMOD, MUC1, and INF2; corresponding to the most common undiagnosed diseases: Alport syndrome spectrum (35%), genetic podocytopathies (19%), nephronophthisis (11%), autosomal dominant tubulointerstitial kidney disease (7%), and congenital anomalies of the kidney and urinary tract (5%).

It has become increasingly clear that an accurate molecular diagnosis has numerous clinical benefits in patients with CKDUE and can alter patient management plans. A genetic diagnosis ends the diagnostic odyssey and allows early initiation of disease-modifying therapy, such as enzyme replacement therapy in patients with Fabry’s disease. Another example is using coenzyme Q10 (CoQ10) replacement in patients with steroid-resistant nephrotic syndrome due to recessive mutations in genes that encode proteins in the CoQ10 biosynthesis pathway. The genetic diagnosis also precludes patients from futile and potentially harmful treatment such as avoidance of prolonged immunosuppressive therapies in patients with Alport syndrome, who are not uncommonly misdiagnosed as focal segmental glomerulosclerosis (FSGS). Early initiation of renin-angiotensin-aldosterone system blockades in patients with autosomal recessive Alport syndrome or males with X-linked Alport syndrome have been shown to delay end-stage kidney disease. Moreover, the genetic finding better informs disease prognosis. Autosomal dominant polycystic kidney disease (ADPKD) patients with PKD1 protein-truncating variants are associated with worse kidney outcomes compared to patients harboring non-protein-truncating variants or variants on the PKD2 gene. Emerging studies also demonstrated a milder clinical phenotype among those harboring variants on atypical ADPKD genes such as IFT140.

Sometimes kidney failure is only part of the clinical manifestations and the genetic finding may prompt physicians to look for extra-renal manifestations such as diabetes mellitus in patients harboring pathogenic variants in HNF1B gene or retinitis pigmentosa in patients with Senior-Loken syndrome.

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Furthermore, the genetic diagnosis can be useful in kidney transplant evaluation. For example, monogenic forms of FSGS typically do not recur after kidney transplant. On the other hand, in patients with atypical hemolytic uremic syndrome, various genetic variants are associated with different risks of post-transplant disease recurrence rates. There is an enhanced risk of anti-glomerular basement disease in Alport patients with protein-truncating variant receiving kidney transplant and this information is important for transplant physicians to better manage the patients. A definitive genetic diagnosis may also guide living-related kidney donor workups. For example, it is recommended that relatives who harbor the same familial pathogenic variant as the proband with Alport syndrome should not act as living donors due to an enhanced lifelong risk of kidney failure. Last but not least, a definitive genetic diagnosis is important to guide reproductive counselling and enable prenatal or preimplantation diagnosis.

The GENSEN Study result has significant clinical implication, supporting the widespread consideration of genetic panel testing independent of the underlying phenotype for CKDUE in younger patients. This paves the way for nationwide initiatives to promote personalized genomic medicine in nephrology.