GENETICS

Introducing routine genetic testing for patients with CKD

Chronic kidney disease (CKD) is often clinically silent and traditional clinical data alone cannot differentiate disease subtypes. A recent study of the genetic basis of CKD in adults that examined the prevalence of monogenic kidney disease aetiologies supports the use of genetic analysis to improve diagnostics and treatment in CKD.

Refers to Groopman, E. E. et al. Diagnostic utility of exome sequencing for kidney disease. N. Engl. J. Med. 380, 142–151 (2019).

Chronic kidney disease (CKD) can be driven by a variety of heterogeneous disease processes that cause progressive deterioration of renal function. The most advanced stage of CKD is end-stage renal disease (ESRD), where patients require renal replacement therapy (RRT) to survive1. CKD has an 8–18% worldwide prevalence and constitutes a major public health challenge1, given the increased risks of all-cause mortality, morbidity and progression to ESRD. In clinical practice, the diagnosis and monitoring of CKD are based on clinical parameters and only rarely entail a kidney biopsy. However, many CKD aetiologies can be clinically ‘silent’ and are difficult to discriminate using clinical data alone. Thus, in many individuals, the precise cause of progressive kidney damage remains unknown and CKD is often diagnosed too late in its course, reducing the opportunity for early therapeutic intervention. Moreover, few current therapeutic approaches are tailored to any given patient or aetiology, but genetic testing might help address this scarcity, as suggested in a recent report by Groopman and colleagues2.

Advances in the field of genetics have enabled substantial progress in understanding the genetic architecture of CKD and ESRD over the past decade. In fact, familial clustering studies3, as well as population disparities across many common CKD aetiologies (for example, the increased incidence of focal segmental glomerulosclerosis among African Americans), have long suggested a genetic risk for CKD. In general, the genetic risk of a trait can be classified according to its penetrance. At one end of the spectrum of genetic causality are Mendelian diseases (that is, monogenic disorders), which have a tight genotype–phenotype correlation as the disease phenotype is almost entirely determined by single-gene mutations. Studies over the past decade suggest that much of CKD in children and young adults is caused by a diverse array of different monogenic disorders4. However, the contribution of single-gene mutations to the full range of adult CKD is largely unknown; it was estimated to be 10–20% in small pilot studies5. At the other end of the spectrum of genetic causality, we find more common conditions for which low penetrance ‘risk alleles’ have been described (Fig. 1a). Some cases of CKD might be partly attributable to low penetrance genetic risk alleles that act in concert with environmental triggers; such risk alleles include the APOL1 locus, the PLA2R locus or the UMOD locus.

Fig. 1: Genetic contribution to CKD.
figure1

a | The contribution of genetic variation to chronic kidney disease (CKD) depends on the disease aetiology. In the majority of cases, a plethora of low penetrance ‘risk alleles’ influences the kidney phenotype. However, for some patients a strong correlation exists between genotype and phenotype as a result of causal single-gene mutations. b | Large-scale studies of DNA sequence variants among patients with end-stage renal disease (ESRD) might be facilitated by existing ESRD registries. Collecting DNA samples for exome sequencing from registered patients, as part of approved research protocols and with consent, might not only benefit the individual patients in confirming a specific diagnosis, but might also provide insights into disease pathogenesis that could benefit a large number of patients.

In their recent study, Groopman and colleagues2 performed exome sequencing on a cohort of 3,315 patients with CKD of varying aetiologies, including congenital or cystic renal disease, glomerulopathy, diabetic nephropathy, hypertensive nephropathy, tubulointerstitial disease and nephropathy of unknown origin. Having prioritized the analysis of 625 nephropathy-associated genes in proband-only exomes, the researchers reported a 9.3% detection rate of genetic diagnostic variants, which included 66 known monogenic kidney disorders. The diagnostic yield was highest for congenital or cystic renal disease (23.9%) and nephropathy of unknown origin (17.1%), and lowest for patients with diabetic nephropathy (1.6%). Of the 66 monogenic disorders detected, mutations in six genes accounted for 198 (63%) of the 312 patients in whom a genetic diagnosis was made: PKD1 (75 patients), PKD2 (22 patients), COL4A3 (27 patients), COL4A4 (21 patients), COL4A5 (44 patients) and UMOD (9 patients).

It is important to note that in the report by Groopman et al., disease causality was not ascertained for novel variants, which would have required segregation and functional analyses of those variants. Nevertheless, an overall 9.3% detection rate probably underestimates the true contribution of genetic variation to CKD and ESRD in adults for several reasons. First, proband-only exome sequencing is known to be less effective in terms of detection rate compared with exome trio-analysis, in which both the affected patient and their parents undergo exome sequencing. Second, exome sequencing has suboptimal coverage of possible relevant regions such as the mitochondrial genome, duplicated gene regions of PKD1 or variants within intergenic and regulatory regions of the genome4,5. Third, exome sequencing cannot detect copy-number variants, which are known to contribute substantially to the underlying aetiology of many kidney diseases5. Last, it is well known that different low penetrance risk alleles, such as the APOL1 (refs6,7) and PLA2R loci8, contribute to the genetic risk of CKD in adults. The contribution of these risk alleles was not included in the reported 9.3% cases with monogenic aetiologies2.

“an overall 9.3% detection rate probably underestimates the true contribution of genetic variation to CKD”

This study highlights the potential of genetic testing for adults with CKD and ESRD. Uncovering the underlying genetic causes of CKD will improve diagnostic accuracy and contribute to ‘precision medicine’ approaches. Obtaining a genetic diagnosis for a patient with CKD might enhance their clinical management, including choice of therapy, and enable targeted disease surveillance; it might also reveal novel disease mechanisms and lead to therapeutic target development which could benefit a vast number of patients. A more widespread use of genetic testing might also avoid unnecessary clinical investigations, including renal biopsies, improve risk prediction and clinical trial stratification of patients with ESRD, and provide opportunities for targeted patient therapy, while guiding advanced medical management on a gene-specific basis9. Importantly, genetic testing might reduce the time to diagnosis and establish the cause of CKD long before the development of ESRD. Even in the case of patients with ESRD, a genetic approach might identify variant signatures that are associated with different disease aetiologies and patient outcomes, which could be used to personalize dialysis treatments or optimize care for transplant recipients. Nevertheless, clinicians must be able to correctly interpret sequencing findings in order to make the best decisions regarding patient care. In this respect, remaining challenges include the attribution of causality for rare variants, as well as the identification and reporting policy of incidental findings. Moreover, the cost effectiveness of this approach should be quantified before it can be established as standard clinical practice.

“a genetic approach might identify variant signatures … associated with different disease aetiologies and patient outcomes”

The recent genetic revolution in the field of nephrology prompts further large-scale investigations into the use of genetic tests to diagnose and guide the treatment of specific groups of patients with CKD — ESRD is a well-defined clinical end point and might actually be the most informative starting point. ESRD registries, which are maintained in many parts of the world, could be adapted to include the collection of DNA samples and offer genetic analysis to all individuals with ESRD (Fig. 1b). Indeed, we and others9 have established national consortiums to enable consenting patients with ESRD to enroll for genome sequencing to advance these aims.

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Correspondence to Asaf Vivante or Karl Skorecki.

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Vivante, A., Skorecki, K. Introducing routine genetic testing for patients with CKD. Nat Rev Nephrol 15, 321–322 (2019). https://doi.org/10.1038/s41581-019-0140-9

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