Chronic kidney disease (CKD) is a progressive condition impacting over 10% of the world’s population, with more than 800 million individuals affected globally [1,2]. It represents a major contributor to global disease burden, associated with high morbidity and mortality rates, as well as significant healthcare costs [1,2]. A major obstacle in managing CKD is the incomplete understanding of its biological mechanisms, which limits the ability to identify precise causes and hampers the development of effective, targeted treatments [3]. Breakthroughs in genomic research have made it possible to combine comprehensive genetic profiles with clinical datasets, providing deeper insight into the molecular pathways that govern kidney physiology and pathology. These scientific advances are increasingly being integrated into clinical settings, enhancing diagnostic accuracy, enabling personalized monitoring, guiding therapeutic planning, and providing genetic counseling for at-risk family members [4,5]. Reflecting this paradigm shift, recent Kidney Disease: Improving Global Outcomes (KDIGO) guidelines highlight the growing importance of genetics in diagnosing and managing CKD, advocating for the use of genetic testing to enhance diagnostic clarity and support individualized patient care [6]. CKD, as defined by the KDIGO guidelines, is characterized by structural or functional abnormalities of the kidney persisting for at least 3 months, with implications for health. The definition includes decreased glomerular filtration rate (GFR), elevated albumin-to-creatinine ratio, and additional markers of kidney damage such as albuminuria, urinary sediment abnormalities, persistent hematuria, electrolyte disturbances due to tubular dysfunction, histologic abnormalities, structural changes on imaging, and a history of kidney transplantation [6]. In light of recent advances in genetics, this review briefly summarizes the genomic links to diseases implicated in chronic kidney damage.

While hereditary kidney disorders have long been recognized as primary causes of pediatric CKD, their significance in adult-onset CKD has only recently come to light [7]. Genetic contributions to CKD exist along a continuum of penetrance, which describes the likelihood that individuals carrying a specific genetic alteration will exhibit clinical signs of disease. Monogenic conditions with high penetrance usually involve pathogenic mutations in a single gene and are often associated with predictable genotype-phenotype patterns. Conversely, variants with reduced penetrance, although sometimes inherited in a Mendelian fashion, may not lead to overt clinical disease but still carry increased risk compared to the general population. In addition, common risk alleles tend to act synergistically with environmental influences, shaping an individual’s overall vulnerability to CKD [7].

Over 600 genes have been linked to renal pathologies, and monogenic causes are now believed to underlie 10%–20% of adult cases and as many as 30%–50% of pediatric CKD cases [7,8]. A notable study found that among patients who developed CKD before age 30 without a clear etiology, 65% received a genetic diagnosis, with most cases involving mutations in just seven genes: COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2, and PKHD1 [9]. Beyond single-gene disorders, polygenic inheritance also plays a meaningful role in CKD predisposition. For example, heritability estimates for major CKD traits are significant, with around 44% for estimated GFR and 20% for urinary albumin excretion [10]. Environmental exposures—such as occupational hazards, tobacco use, infections, and socioeconomic disparities—further influence CKD development. Although variations in CKD incidence between regions often mirror environmental conditions, familial aggregation in certain groups points to a genetic susceptibility component [5,11,12].

A variety of next-generation sequencing (NGS) strategies are currently utilized to diagnose inherited kidney disorders. Among these, Sanger sequencing is often employed when a specific pathogenic variant is suspected, as it targets selected regions within known genes. More comprehensive are targeted gene panels, which sequence the exonic regions of multiple genes implicated in particular renal conditions. Whole-exome sequencing (WES) broadens the scope by analyzing nearly all protein-coding regions in the genome, while whole-genome sequencing (WGS) extends coverage to include both coding and non-coding sequences throughout the entire genome [13]. Genetic evaluation should be considered for patients in whom a hereditary kidney condition is suspected, particularly after detailed clinical examination and family history review [14]. Table 1 presents the scenarios in which genetic testing should be considered for suspected monogenic CKD, as recently highlighted by the KDIGO Controversies Conference and National Kidney Foundation [5,14].

Nephrolithiasis is influenced by both genetic and metabolic factors and is increasingly viewed as a systemic disease. Genetic testing is advised in individuals with early-onset, recurrent stones, nephrocalcinosis, or stone-related CKD. Approximately 30 genes have been implicated, with genetic causes found in 16%–29% of pediatric and 11% of adult stone cases [33,34]. While most forms of nephrolithiasis are polygenic, severe or early-onset cases may reflect monogenic conditions—such as adenine phosphoribosyltransferase deficiency, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, or primary hyperoxaluria—that are often associated with an increased risk of progression to kidney failure (Table 2) [7].

Genome-wide association studies (GWAS) are powerful tools for investigating the genetic architecture of complex diseases by simultaneously analyzing hundreds of thousands to millions of single-nucleotide polymorphisms across thousands of individuals. GWAS are based on the "common disease–common variant" hypothesis, which posits that common diseases are influenced, at least in part, by common alleles present in more than 1%–5% of the population [36]. Through GWAS, independent risk loci have been identified for decreased GFR, albuminuria, idiopathic membranous nephropathy, and immunoglobulin A nephropathy. Genetic risk scores based on these loci have also been developed [37-42]. However, further research is needed to validate the clinical utility of such polygenic information and risk stratification in diagnosis, prognosis, and therapeutic response prediction [7,39].

Establishing a genetic diagnosis begins with thorough clinical evaluation and family history. Genetic identification aids in diagnostic clarification, prognosis, and management decisions [7]. An approximately 40% diagnostic yield has been reported, with 17% of cases receiving a new diagnosis, particularly in patients with previously unexplained CKD [43]. Notably, testing remains informative across age groups [8,43]. Genetic diagnosis also facilitates cascade testing and reproductive planning [7,43]. While variants of uncertain significance (VUS) are common, they should not inform treatment per American College of Medical Genetics and Genomics guidelines [13]. Periodic reanalysis may reclassify VUS as new evidence emerges, emphasizing the need for data integration [44]. Genetic testing may reduce the need for invasive diagnostics. For instance, confirming Alport syndrome via genetic testing may preclude biopsy in patients and relatives [45]. It also informs therapy—e.g., halting ineffective immunosuppression in genetic steroid-resistant nephrotic syndrome, or applying targeted treatments in complement-mediated nephropathies such as aHUS or metabolic nephropathies like primary hyperoxaluria [13].

Despite its benefits, genetic testing has limitations. WES and WGS remain costly and resource-intensive [4]. VUS interpretation varies by lab, and unclear results can cause distress or therapeutic ambiguity [4,13]. Moreover, diagnoses without available treatments may induce frustration. The shortage of trained clinicians and genetic counselors presents an additional barrier [4].

NGS and genomic advances have improved the precision of diagnosis, prognostication, and treatment in CKD, while reducing costs [13]. Genetic insights are enhancing our understanding of CKD pathophysiology [46]. Clinicians, including nephrologists and geneticists, must understand the complexities of interpreting genotype-phenotype relationships and managing phenotypic variability, even when identical genetic variants are present [5,13]. Effective integration of genomic data into personalized clinical care is crucial for advancing precision nephrology and achieving the objectives of precision medicine [47].