Genomic testing can benefit patients with chronic kidney disease (CKD) as more causative genes are identified and evidence for clinical utility is discovered.
Genomic testing for treating chronic kidney disease (CKD) has seen progress in the areas in which genomes can inform treatment. A review published in Current Opinion in Nephrology and Hypertension found that genomic testing could be applied in the treatment of CKD.
The first area that genomic testing can be valuable in CKD care is in the understanding of which genes are associated with CKD or its phenotypes. This sector has expanded in recent years, and there is potential for each new gene discovered to work toward diagnosing a monogenic cause for CKD. Pathogenic variants in mtDNA causing a Gitelman-like syndrome brings together understanding and the identification of biallelic variants.
The identification of biallelic variants that are related to hypokalemic syndrome can fortify tubular potassium channel understanding and further link to extrarenal phenotypes. De novo heterozygous variant discovery can bring hypokalemic and hypomagnesemic kidney syndromes with dilated cardiomyopathy together.
Iterative progress continues in heritable structural kidney disorders. There are some challenges to whether the genetic variation in these genes relates to heritable phenotypes. Evidence for biallelic pathogenic LAMA5 has emerged to suggest there is a causative relationship in various glomerular phenotypes, including nonsyndromic nephrotic syndromes and syndromic complex kidney phenotypes.
Biallelic variants in TTC21B have been identified resulting in mixed glomerular and tubulointerstitial kidney disease; TULP3 has been identified as linking disease entities with hepatic, kidney, and cardiac components. These gene relationships are helping to identify kidney ciliopathies.
Clinical effects of genomic testing for CKD have also been revealed through studies. A cohort of autosomal dominant tubulointerstitial kidney disease (ADTKD) families found that 29 of 45 achieved a genetic diagnosis through the genes known to be associated with the condition, although 9 of the 45 had diagnostic variants in genes not usually associated with ADTKD.
Researchers will have to collect and analyze cohorts of monogenic kidney disorders to further learn about prognostication factors. This includes in areas of broad genomic testing, which will need to be tested to determine whether it can have a diagnostic role in unexplained CKD or kidney failure.
Exome analysis in a retrospective study found that a broad kidney gene panel found new genetic diagnoses and could have a role in a diagnostic approach. Diagnosable phenocopy disorders could also be more common in genetic diagnosing. Broadened gene panels for complex phenotypes will be needed, as targeted gene panels fail to identify a genetic diagnosis in up to 20% of instances.
Understanding clinical utility for genomic testing is becoming the focus of further research, as there are less than 10 genes that account for many diagnoses made. A way that genomic testing could be applied is by replacing or acting synergistically with a kidney biopsy in certain situations, as some situations could avoid kidney biopsy altogether in favor of genomic testing. Genomic testing in conjunction with a kidney biopsy changes treatment in 1 of 4 patients who receive a genetic diagnosis.
Kidney donor assessment and reproductive planning could also be realizable goals for genomic testing clinical applicability. Key factors that indicate a higher likelihood of a monogenic cause of CKD include making clinical utility clearer. These factors could include the presence of a family history, younger age of onset, extrarenal features, and phenotype-specific factors.
Translating evidence into practice for integration into nephrology practice is the next step for genomic testing. A way that this can be implemented is in clinicians refining prevalence estimates and characterizing rarer subtypes to create revised and condition-specific diagnostic standards around genetic testing.
Digital health approaches to case identification, transcriptomic or RNA sequencing, and globally calibrated and verified gene-phenotype curation for monogenic CKD could be future innovations in genomic testing being applied to CKD.
The author concluded that the benefits of genomic testing and who it can benefit are becoming clearer and more likely to see positive effects than at any other point in history.
Mallett AJ. Which patients with CKD will benefit from genomic sequencing? synthesizing progress to illuminate the future. Curr Opin Nephrol Hypertens. Published online September 8, 2022. doi: 0.1097/MNH.0000000000000836