Genes, kidneys, and the future: transforming chronic kidney disease management through genomic insights
Article information
Abstract
Chronic kidney disease (CKD) affects over 800 million individuals globally and demonstrates significant genetic diversity. Advances in next-generation sequencing have identified over 600 genes associated with inherited kidney disorders, with monogenic variants accounting for 10% to 20% of adult and up to 50% of pediatric CKD cases. Genetic diagnostics, including gene panels, whole-exome sequencing, and whole-genome sequencing, improve diagnostic accuracy, enhance prognostication, and support personalized care. These tools apply to inherited nephropathies such as autosomal dominant polycystic kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, autosomal dominant tubulointerstitial kidney disease, and monogenic nephrotic syndromes. Beyond monogenic disorders, polygenic influences have emerged through genome-wide association studies, but their clinical utility remains to be fully established. Genetic insights not only support diagnosis but also guide treatment strategies, facilitate familial risk assessment, and can eliminate the need for invasive procedures like renal biopsy. Nevertheless, challenges remain, including the interpretation of variants of uncertain significance, limited understanding of genetics among clinicians, and inadequate access to genetic counseling. Despite these obstacles, genetic testing remains essential for deepening our understanding of CKD mechanisms and advancing a personalized approach in nephrology.
Introduction
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.
Genetics and CKD
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].
Genetic testing for CKD
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].
Indications for genetic testing in suspected monogenic CKD
Monogenic kidney diseases and associated genes
Cystic kidney diseases
Cystic kidney disorders comprise a diverse array of inherited conditions characterized by the development of renal cysts that distort renal parenchyma. Over 100 genes have been linked to these diseases, many of which are involved in primary cilia of renal tubular cells, classifying them as ciliopathies [15]. Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease globally, predominantly associated with pathogenic variants in PKD1 or PKD2 [7]. Patients harboring truncating PKD1 mutations often reach end-stage kidney disease (ESKD) in their 50s, while those with non-truncating variants may progress more slowly, often reaching ESKD in their 60s. Mutations in PKD2 generally correlate with even later onset, typically preserving kidney function into the 70s or 80s [13]. Conversely, autosomal recessive polycystic kidney disease, caused by mutations in PKHD1, usually manifests in infancy or childhood, though milder variants can present later in life depending on the specific mutation [16]. In a cohort study, 8.1% of patients clinically diagnosed with ADPKD had causative mutations in genes other than PKD1 or PKD2, indicating genetic heterogeneity [17]. Genetic evaluation is increasingly vital for prognosis, disease classification, and reproductive planning in cystic kidney conditions, particularly ADPKD [7].
Glomerular diseases
Genetic glomerulopathies often arise from defects in proteins critical to the glomerular basement membrane or podocyte integrity. These disorders typically present with proteinuria and/or hematuria [15]. Mutations in type IV collagen genes, especially COL4A3, COL4A4, and COL4A5, are the second most common genetic cause of adult-onset progressive CKD after ADPKD, accounting for 2%–3% of cases. Originally described in Alport syndrome, these mutations exhibit significant phenotypic variation depending on inheritance pattern, mutation type, and gene location. Notably, such variants can cause CKD even in the absence of syndromic features [7]. Timely molecular diagnosis assists in guiding treatment decisions, identifying suitable kidney donors, and conducting family screening [18]. Podocyte-related disorders, or podocytopathies, are linked to over 50 genes and are major contributors to nephrotic-range proteinuria and glomerular damage [19]. Although commonly diagnosed in childhood, adult-onset presentations occur. For instance, NPHS2 mutations (encoding podocin) can lead to focal segmental glomerulosclerosis (FSGS) in adults [20]. Other genetic contributors to adult-onset FSGS include ACTN4, INF2, and TRPC6 mutations [21-23].
Congenital anomalies of the kidney and urinary tract
Congenital anomalies of the kidney and urinary tract (CAKUT) represents the leading cause of CKD in children and is responsible for a subset of adult ESKD. It includes anatomical abnormalities like renal agenesis, dysplasia, hydronephrosis, and reflux. Syndromic forms often involve extrarenal anomalies. Genetic defects disrupting nephrogenesis underlie many CAKUT cases, with over 50 monogenic causes and numerous copy number variants reported [7,24]. However, the correlation between genotype and phenotype remains inconsistent, complicating gene discovery and counseling. Current estimates suggest that only 16%–20% of CAKUT cases receive definitive genetic diagnoses, pointing to the involvement of unknown genes and complex gene–environment interactions [25].
Tubulointerstitial kidney diseases
Inherited tubular disorders include more than 50 syndromes, often due to mutations in genes encoding ion channels or transport proteins [26]. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by progressive tubulointerstitial fibrosis with minimal glomerular involvement. Clinically, it presents as slowly progressive CKD with minimal proteinuria and a family history suggestive of dominant inheritance [27]. The two most common genetic forms of ADTKD are associated with UMOD and MUC1 mutations [28]. UMOD encodes uromodulin, the most abundant urinary protein, produced in the thick ascending limb, where it maintains tubular integrity, inhibits stone formation, and supports sodium transport via Na+-K+-2Cl- cotransporter 2 and renal outer medullary potassium channel 2 [29,30]. UMOD mutations account for about 3% of monogenic CKD cases, ranking sixth among inherited renal disorders [2]. These variants often cause hyperuricemia and gout. MUC1 mutations, the second most common subtype, are associated with a slightly shorter renal survival and a longer gout-free survival time compared to UMOD-related disease [29].
Atypical hemolytic uremic syndrome
Hemolytic uremic syndrome (HUS) is a form of thrombotic microangiopathy characterized by the triad of hemolytic anemia, thrombocytopenia, and acute kidney injury. Atypical HUS (aHUS) is known to result from excessive activation of the complement system triggered by genetic mutations in complement-related proteins, leading to uncontrolled inflammatory responses [31]. Approximately 50%–60% of patients with aHUS have identifiable Mendelian genetic mutations, with pathogenic variants in the CFH gene, which encodes complement factor H, being the most frequently observed. In addition, mutations can be found in other genes involved in complement regulation, including MCP (membrane cofactor protein), C3, CFI (complement factor I), and CFB (complement factor B) [32]. About 50% of aHUS patients progress to end-stage renal disease requiring dialysis, and prognosis varies depending on the specific genetic mutation involved [31]. Eculizumab, a humanized monoclonal antibody targeting complement protein C5, is an approved treatment for aHUS. In patients with mutations affecting the carboxy terminus of CFH, long-term therapy with eculizumab may be necessary. As complement-targeted therapies become increasingly personalized, genetic testing is gaining importance in clinical decision-making [32]. Moreover, non-complement-mediated genetic forms of atypical HUS have been associated with mutations in MMACHC (leading to cobalamin C deficiency), DGKE, and VTN. Although rare, identifying these conditions is clinically significant, as eculizumab is often ineffective in such cases, and targeted therapies are available for cobalamin C deficiency [7].
Nephropathies with complex genetic bases
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].
Kidney disease-associated genes
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].
Clinical utility of genetic testing
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].
Limitations and considerations of genetic testing
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].
Conclusions
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].
Notes
Conflicts of interest
The authors declare no conflicts of interest related to this manuscript.
Funding
None.
Author contributions
Conceptualization: SYK,YNK, HSS, YJ, HR
Data curation: SYK, WSY, YNK, HSS
Formal analysis: all authors
Investigation: all authors
Methodology: all authors
Project administration: all authors
Visualization: all authors
Writing–original draft: all authors
Writing–review & editing: SYK, WSY, HSS, HR
All authors read and approved the final manuscript.