Key words : Chronic kidney disease, Genomic sequencing, Precision medicine

Introduction

Precision medicine is described as “the right treatment, for the right patient, in the right place, at the right time.” Artificial intelligence, in which a computer mimics the cognitive function of humans, and Chat GPT are increasingly used in medical practice. Genomic approaches followed by physician planning for targeted treatment are the result of the precision medicine revolution. There are different approaches to genetic testing, which include next-generation sequencing technology, Sanger, targeted, and whole exome sequencing, with different costs for each method.

Value of Genetic Testing in Nephrology and Transplantation

Exome sequencing can provide a diagnostic yield of 9.3% in patients with chronic kidney disease (CKD), as shown in a study of 3315 patients by Elliott and colleagues.¹ Comprehensive genetic testing can provide genetic diagnoses of kidney diseases of unknown etiology and diseases with unexpected phenotypes due to multiple genetic causes, as shown in the examples of kidney relevant monogenic disorders with disease-specific therapies (Figure 1).¹

Early genetic testing (before aged 50 years for recipients) can increase diagnostic accuracy before patients undergo kidney transplant. The SUSPECT Study by the European Working Group of Inherited Kidney Disease highlighted the probability of a positive genetic result in CKD. In a cohort of patients who received a kidney transplant before aged 50 years due to end-stage kidney disease of any cause, the proportion of patients with genetic disease was at a minimum of 21%. This finding shows the relevance of early genetic testing in providing a minimally invasive test that can affect prognosis and treatment, especially for those with CKD of unknown etiology, cystic disease, syndromic disease, congenital kidney abnormalities, and family history of CKD.²

Predicting Complications After Kidney Transplant

The risk of cardiometabolic disease, the long-term cancer risk with immunosuppressive regimens, infections, and thrombosis are associated with genes.³

In a genome-wide association study of hospitalized patients during 2002 to 2019 with acute kidney injury (AKI), 3 loci were associated with AKI, including one (MPPED2), near FTO, that was previously associated with CKD. Thus, FTO may contribute to the risk of AKI independently of body mass index.⁴

In a study of the genetics of idiopathic nephrotic syndrome at the population level, 2009 patients were enrolled and sequenced. The cohort included patients with proteinuric kidney disease with a biopsy showing focal segmental glomerulosclerosis or minimal change disease or nephrotic syndrome without biopsy. Overall, 10.6% of patients were found to have a monogenic variant known to be associated with inherited nephrotic syndrome. There was a significant rate of monogenic variant discovery, including in steroid-sensitive patients. Most of this group featured heterozygous COL4A variants.⁵

Outcome and complications of peritoneal dialysis depend on AQP1 genotypes, which include 3 types (TT, CT, CC). TT has worse prognosis and high rate of technical failure, resulting in transfer to hemodialysis.⁶

Cirillo and colleagues showed that early genetic testing strategy can allow reallocation of resources more efficiently, providing valuable insights for health care policymakers.⁷

Conclusions

Genomic approaches followed by physician planning for targeted treatment of renal disease and transplant are precision medicine tools that can lead to better prognosis and medical outcomes.

References:

1. Elliott MD, Rasouly HM, Gharavi AG. Genetics of kidney disease: the unexpected role of rare disorders. Annu Rev Med. 2023;74:353-367. doi:10.1146/annurev-med-042921-101813
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2. Knoers N, Antignac C, Bergmann C, et al. Genetic testing in the diagnosis of chronic kidney disease: recommendations for clinical practice. Nephrol Dial Transplant. 2022;37(2):239-254. doi:10.1093/ndt/gfab218
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7. Cirillo L, Becherucci F. Genetic testing in nephrology: show your pedigree! Kidney360. 2022;3(12):2148-2152. doi:10.34067/KID.0002732022
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