The burden of kidney replacement therapy (KRT) due to inherited kidney diseases (IKD) is underestimated. Polycystic kidney disease (PKD), diagnosed by imaging, is the most common IKD. PKD is the only IKD commonly represented in summary reports of KRT registries, whereas other inherited kidney diseases are typically grouped within nonspecific or miscellaneous categories.1 This limited visibility contributes to the underutilization of genetic studies in chronic kidney disease (CKD), as inherited kidney diseases other than PKD may be perceived as too uncommon to be routinely considered in the differential diagnosis or to prompt genetic testing. Grouping inherited kidney diseases together with congenital anomalies of the kidney and urinary tract (CAKUT), many of which have a genetic basis, provides a more accurate estimate of their true burden. This burden is substantially larger than previously recognized, although it remains underestimated due to limited access to genetic testing. In the ERA Registry and the Spanish REDYT, 9–10% of incident patients on KRT had IKD (IKD/CAKUT in ERA), ranking as the fourth most commonly known cause of CKD2,3 (Fig. 1A). However, the burden of IKD is best assessed in prevalent KRT, i.e., patients on KRT today that contribute to the current personal and societal costs of KRT. In the ERA Registry, IKD/CAKUT represents the most frequent cause of prevalent KRT among women and individuals younger than 45 years and the second most common cause overall and among men2 (together with diabetic nephropathy) (Fig. 1B). Out of >500,000 people on KRT in the European Union,4 nearly 100,000 are estimated to have IKD/CAKUT, as compared to roughly 80,000 whose cause was diabetes.2 However, in ≈90,000 of individuals the cause of kidney failure was unknown, a condition now termed CKD of unexplained cause (CKDx).5 In the absence of genetic testing, many people with IKD may remain invisible, being classified as CKDx or misdiagnosed (e.g., “familial IgA nephropathy without biopsy” or “hypertensive nephropathy”).6 The Spanish GENSEN study, in line with other reports, identified genetic conditions potentially explaining kidney failure in ≈25% of young (<45-year-old) prevalent patients on KRT with CKDx.7,8 In the United States, APOL1-associated nephropathy—an inherited kidney disease—has traditionally been labeled as hypertensive nephropathy and is approximately six-fold more prevalent among African Americans, who may carry APOL1 risk variants, than among White individuals.9

Fig. 1.

Causes of kidney failure requiring kidney replacement therapy (KRT). (A) Causes of incident kidney failure requiring KRT in the European Renal Association (ERA) Registry and the Spanish Dialysis and Transplant Registry (REDYT). (B) Causes of prevalent kidney failure requiring KRT in the ERA Registry. Data expressed as % of patients with each cause of chronic kidney disease (CKD) among incident or prevalent patients on KRT. Data for the figure obtained from references (Refs.2,3). Note that diagnosed IKD/CAKUT (REDYT only shows IKD data) has a larger contribution to the burden of KRT (prevalence) than DM and hypertension. Note also the high contribution of unknown cause, which includes CKDx. The GENSEN study recently showed that 25% of prevalent kidney failure on KRT among young (<45-year-old) people with CKDx in Spain has a pathogenic or likely pathogenic genetic variant that may explain the condition (Ref.8). Abbreviations: CKD: chronic kidney disease; CKDx: CKD of unexplained cause; DM: diabetes mellitus; GN: glomerulonephritis; IKD/CAKUT: inherited kidney disease/congenital anomalies of the kidney and urinary tract; KRT: kidney renal therapy; TI: tubulointerstitial. IKD/CAKUT is color-coded red and unknown pink. The number (#) within a square above each column indicates rank among known causes of kidney failure requiring KRT.

The burden of IKD extends beyond the number of people on KRT. Patients with IKDs are younger, and the negative impact on life expectancy of kidney failure on KRT is larger in the young. Remaining life expectancy is 44 years shorter in young women on dialysis than in the general population, 22 years shorter if transplanted.10,11 Additionally, many IKDs do not lead to kidney failure but still significantly impair quality of life.

The Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines on CKD,12 establish the cause of CKD using clinical context, personal and family history, social and environmental factors, medications, physical examination, laboratory measures, imaging, and also genetic diagnosis. Thus, nephrologists should take the lead in initiating genetic testing for patients, with collaboration from genetic counselors and clinical geneticists as needed.12 Nephrologists are best suited to identify individuals who may benefit from genetic testing and explain the rationale to both the patient and their family members. Genetic testing has become an essential component in the evaluation of CKD, reflecting the increasing recognition that monogenic etiologies account for a substantial proportion of both pediatric and adult kidney disorders.13 More than 600 monogenic causes of CKD have been described, with pathogenic variants explaining approximately 30–50% of CKD in children and 10–30% in adults, depending on the cohort studied. Diagnostic yields range from around 10% in unselected adults with CKD to 20–40% when next-generation sequencing (NGS) approaches are applied.14–21 Parallel implementation research demonstrates that although genetic testing has high diagnostic and clinical utility, it remains underused in routine practice and is often performed too late in the diagnostic pathway.14,22 The key clinical indications for genetic testing are summarized in Fig. 223:

Fig. 2.

Genetic testing in kidney disease: indications and clinical benefits. Abbreviations: CKD: chronic kidney disease; CKDx: unexplained chronic kidney disease.

Early-onset, familial kidney diseaseor consanguinity remain one of the most reliable clinical clues to a IKD.14,24,25 A detailed family pedigree is therefore essential. Even subtle patterns of early onset hypertension, hearing impairment, kidney cysts, or hematuria among relatives can point toward syndromic or hereditary conditions. Consanguinity further raises the probability of autosomal recessive diseases, many of which manifest with progressive CKD early in life and affect only one generation.

Syndromic or extra-renal manifestations are a strong indicator of an underlying IKD and should prompt early genetic evaluation.24 Features affecting the auditory, ocular, neurological, hepatic, or connective tissue systems often accompany inherited nephropathies such as Alport syndrome, ciliopathies or Fabry disease among many others disorders. Evidence from kidney genetics clinics further shows that patients presenting with syndromic phenotypes achieve some of the highest diagnostic yields with genomic testing, underscoring the clinical value of recognizing these red flags early in the diagnostic pathway.26

Clinical categories with high monogenic prevalence, such as cystic kidney diseases and tubulopathies consistently show high diagnostic yields in genomic studies.24 Identifying a molecular cause in these disorders has substantial therapeutic implications, improving patient management and guiding family counseling. While for other conditions such as CAKUT, steroid-resistant nephrotic syndrome, tubulointerstitial kidney disease, atypical hemolytic uremic syndrome (aHUS) have more variable or overall lower yields, particularly in the absence of syndromic features or family history.

CKDx represents a clinical scenario in which genomic testing offers substantial diagnostic value. Recent national studies demonstrate that early genetic evaluation can identify a molecular cause in approximately 25–32% of young patients with advanced CKDx.8,27–30 These results underline that genomic testing should be prioritized when CKD remains unexplained after standard evaluation (inconclusive prior work-up, including kidney biopsy).

Guidance of therapy and treatment decisions: Identifying a molecular cause of CKD has substantial therapeutic implications, enabling the use of targeted interventions, such as Renin–Angiotensin–Aldosterone System (RAAS) blockade in COL4A3–5-related disease, enzyme replacement in Fabry disease, or disease specific treatments for complement mediated aHUS.31–33 Genetic results can also prevent futile or harmful treatments (e.g., prolonged immunosuppression in genetic podocytopathies) and inform prognosis. Studies show management changes in over 90% of patients following positive genetic results in specialized kidney genetics clinics.23

Kidney transplantation planning: Genetic testing plays a central role in kidney transplantation planning, especially when the cause of kidney disease is unclear or IKD is suspected.12 For transplant candidates, establishing a monogenic diagnosis is crucial because conditions such as aHUS/thrombotic microangiopathy (TMA) or primary hyperoxaluria carry a high risk of post-transplant recurrence. A precise molecular diagnosis allows clinicians to anticipate these risks, adjust peri-transplant management, and improve long term graft outcomes. It is equally important to evaluate related living donors when IKD is suspected or confirmed, as early genetic screening prevents the inadvertent selection of donors who carry pathogenic variants, reducing future disease risk for the donor and complications for the recipient.34 Incorporating genomic testing early in the transplant pathway therefore enhances both donor safety and graft success, reinforcing its role as a standard component of modern transplant assessment.

Ensuring equitable access to genetic testing is increasingly central in nephrology. Implementation studies show that mainstreaming models, in which nephrologists lead the testing process with support from embedded genetic counselors, help overcome under referral and diagnostic delays. These pathways are further strengthened by electronic consultation (e-consult) systems that provide rapid expert input and reduce dependence on in person genetics appointments. Together, nephrology led testing, integrated counseling, and e-consult platforms have been shown to increase diagnostic yield, shorten time to diagnosis, and facilitate timely incorporation of genomic information into CKD care.23,25

Nowadays, next-generation sequencing (NGS) enables rapid and increasingly affordable genetic testing for IKD. Although Sanger sequencing remains useful in specific situations, it has largely been replaced by NGS. The main genetic testing techniques currently in use are:

Multigene NGSPanels35,38 are first line tools in nephrogenetics.36 They enable the simultaneous evaluation of hundreds of clinically relevant genes, detect single nucleotide variants (SNVs), small insertions/deletions (indels), and copy number variants (CNVs) and offer high depth of coverage and low false—positive/negative rates. In CKDx, panels achieve diagnostic yields of 6–30% in adults and ∼30% in children. Panels are especially valuable in genetically heterogeneous disorders such as tubulopathies, cystic kidney diseases, focal segmental glomerulosclerosis (FSGS), and CAKUT.

Multigene panels can be performed either by targeting a predefined set of genes, allowing higher depth of coverage and a more tailored approach, or by using whole exome sequencing (WES) with analysis restricted to a predefined gene set (virtual gene panel). The latter approach is the most widely used in general hospitals, as the same sequencing workflow is applied to all samples, while the analysis is customized according to the clinical specialty, such as nephrology. This approach combines the breadth of WES data generation with the focused interpretation of a gene panel, while preserving the possibility of reanalysis as new disease-associated genes are identified.36

Table 1 summarizes the available genetic testing options, their main indications, and their advantages and limitations. The choice of panel should be tailored to the clinical context and local expertise, with the option of using either large comprehensive kidney gene panels (up to 500 genes) or more focused phenotype-driven panels, depending on the suspected diagnosis and laboratory approach.37 The diagnostic yield of multigene panels in CKD varies depending on the population studied. In adults, yields range from approximately 6% to 30%, whereas in early-onset, familial, or syndromic cases, the yield can reach up to 65%.38–40

Whole Exome Sequencing (WES)14,41 sequences and analyzes all protein-coding regions of the genome. WES may be used when a gene panel is negative, but suspicion remains high for hereditary disease; the phenotype is atypical, syndromic, or poorly defined; or broader interrogation is necessary due to overlap between phenotypes. WES captures all coding regions of the genome. KDIGO highlights the importance of advanced genomic tools for refining CKD etiologies and capturing rare or novel variants.42

Whole Genome Sequencing (WGS) sequences the entire genome, including coding and non-coding regions. Its advantages include more comprehensive detection of structural variants, CNVs, and deep intronic mutations that may alter gene function and potentially higher diagnostic yield in unresolved CKD cases. Long-read (LR) sequencing provides new approaches to resolve complex genetic defects, including pseudogenic regions (PKD1), large tandem repeats (MUC1), haplotypes, structural rearrangements. While not yet standard in routine nephrology practice, WGS is gaining relevance due to expanding understanding of non-coding regulatory variants, however, the large number of DNA variants detected makes result interpretation increasingly challenging. KDIGO emphasizes the need for future research and data integration to improve classification and interpretation of genome-wide variation in CKD.42

Copy number variant (CNV) analysis includes complementary techniques for detecting deletions and duplications, such as SNP arrays, array CGH, and multiplex ligation-dependent probe amplification (MLPA). They are clinically relevant for conditions such as Hepatocyte Nuclear Factor 1-Beta (HNF1B)-related disease, which often involves whole-gene deletions. However, currently, many modern NGS panels can detect CNVs with high accuracy.

Long-Range PCR (LR-PCR) is used for Technically Challenging Genes, such as PKD1, which have high homology with pseudogenes that complicates standard sequencing. LR-PCR improves specificity for unique genomic regions prior to sequencing. However, many modern NGS panels can now accurately detect variants across the PKD1 gene, including regions with high homology.

Targeted variant Testing focuses on identifying a known pathogenic variant previously detected in a family member. It is the recommended test for relatives undergoing cascade testing due to its high specificity and sensitivity for a defined variant, as well as its low cost.

Single-gene testing is used when the patient's phenotype clearly matches the clinical criteria for a specific disorder and the causative gene is of limited size, making targeted analysis efficient (e.g., Fabry disease, cystinosis).

Nowadays, comprehensive genomic (exome or genome) sequencing is preferred over sequential single gene testing, given the genetic heterogeneity of CKD (>600 implicated genes). This approach enables detection of diverse variant types, future reanalysis and the use of virtual panel filtering to improve diagnostic precision.25 In this regard, genetic tests have inherent limitations, including incomplete coverage of certain genomic regions, the need for regular panel updates as new genes are discovered, and the possibility of inconclusive results (e.g., variants of uncertain significance, VUS), which should not be used for clinical decision-making.42 Thus, a negative genetic test should not be interpreted as definitive exclusion of a genic cause. Periodic reanalysis of existing exome or genome data is strongly recommended, as novel gene–disease associations and reclassification of VUS may resolve previously negative cases.43,44 In persistently unresolved cases with strong clinical suspicion, referral to specialized undiagnosed diseases programs should be considered.

Understanding inheritance patterns and genetic variants is essential for interpreting genetic test results in CKD. In clinical practice, both are closely linked, as they help establish the diagnosis, assess prognosis, and guide family counseling. Four main inheritance patterns are recognized in monogenic IKD: autosomal dominant (AD), autosomal recessive (AR), X-linked, and mitochondrial (Fig. 3).

Fig. 3.

Mendelian inheritance patterns in monogenic kidney diseases.

Adapted from Ref.42

AD inheritance is observed in conditions such as ADPKD, caused by pathogenic variants in PKD1 or PKD2, and autosomal dominant tubulointerstitial kidney disease (ADTKD), associated with UMOD, MUC1, or REN variants, and other genes. In these disorders, a single altered copy of the gene is sufficient to cause disease, often with adult onset, incomplete penetrance and variable expressivity, and the possibility of de novo variants.14,36,45

AR inheritance requires two pathogenic variants, usually one inherited from each parent, who are typically asymptomatic carriers. This pattern is seen in diseases such as autosomal recessive polycystic kidney disease and nephronophthisis, which usually present in childhood or adolescence and often show a strong genotype–phenotype correlation.46,47 Consanguinity or occurrence in siblings with unaffected parents may raise clinical suspicion. AR diseases typically show a horizontal pattern of inheritance, affecting siblings within a single generation, although they may appear in multiple generations, particularly in families with more than one consanguinity.

X-linked inheritance is exemplified by Alport syndrome due to COL4A5 pathogenic variants and Fabry disease caused by disease-causing variants in GLA. Males are generally more severely affected, while females present with a spectrum ranging from asymptomatic to severe disease due to random X-chromosome inactivation within each cell, resulting in a mosaicism of healthy and diseased cells.14,46 Mitochondrial inheritance, less frequent, is transmitted exclusively through the maternal line and may be associated with multisystem disorders that include renal involvement, such as certain tubulopathies.48

The interpretation of genetic variants is standardized by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) criteria. Variants are classified into five categories: pathogenic, likely pathogenic, VUS, likely benign, and benign49 (Fig. 4). A positive result corresponds to pathogenic or likely pathogenic variants that explain the phenotype and can guide clinical management. Importantly, the identification of a pathogenic variant does not always imply full clinical expression, as penetrance and expressivity may vary significantly. A negative result indicates the absence of a clearly causative variant but does not exclude a genetic etiology.

Fig. 4.

American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) Classification of DNA Sequence Variants.

Adapted from Ref.84

VUS represent a major challenge. They lack sufficient evidence to determine their clinical relevance and should not be used to guide medical decisions. However, they may become clinically relevant over time, particularly after reclassification or in the context of segregation studies. Their classification may change over time as new data emerge, including population frequency, functional studies, in silico predictions, and familial segregation analysis.49

In some conditions, genotype–phenotype correlations may help predict disease severity, progression, or extrarenal manifestations, although this relationship is variable and gene-dependent.

Accurate identification of inheritance patterns and careful interpretation of genetic variants are fundamental for diagnosis, prognosis, and genetic counseling in IKD. A comprehensive understanding of these aspects is essential to translate genetic findings into meaningful clinical decision-making and personalized patient care.14,35,41,49

NGS Bioinformatic Analysis pipelines already classify variants as pathogenic, likely pathogenic, VUS, likely benign, or benign. Additionally, genetic testing reports include interpretive comments to clarify potential clinical significance. However, multidisciplinary interpretation remains essential, integrating clinical, family pedigree, bioinformatic, and histologic data. Kidney genetics clinics and variant review boards help avoid misinterpretation, especially for VUS, which should not drive management decisions without expert review.26,49 KDIGO emphasizes the need for improved clinical interpretation, bioinformatic tools, and global data resources for variant classification.

As the number of treatable IKD grows, identifying the underlying genetic etiology has become a clinical imperative rather than a mere academic exercise (Table 2). Genetic testing in nephrology has evolved from a research tool to a clinical instrument with direct implications for patient management. Positive genetic diagnoses have the following clinical benefits:

Diagnostic reclassification and cessation of unnecessary treatments. One of the most immediate and impactful consequences of a positive genetic diagnosis is the reclassification of the underlying etiology of CKD. In an Australian cohort study, clinical exome sequencing achieved a molecular diagnosis in 39% of patients with suspected monogenic IKD, changing the clinical diagnosis in 39%.16 Similar results were reported from the United States.18,20 The Renasight CARE study, the largest prospective interventional study to date in adults with CKD, reported a 20.8% positive rate using a 385-gene panel, with direct implications for clinical management.21

A paradigmatic example is the reclassification of patients initially diagnosed with chronic glomerulonephritis who, upon genetic testing, are found to carry pathogenic COL4A3/COL4A4/COL4A5 variants consistent with Alport syndrome.50 Several case reports have documented reclassification of FSGS to Dent‘s disease, a hereditary tubulopathy.51,52 In these cases, immunosuppressive therapy—which carries significant side effects and no expected benefit—can be safely discontinued. Similarly, genetic testing in children with suspected tubulopathies allows accurate discrimination between phenotypically overlapping conditions such as Bartter and Gitelman syndromes, directly informing electrolyte replacement strategies.19,53

Systematic screening for extrarenal manifestations. A confirmed genetic diagnosis triggers a targeted evaluation for extrarenal involvement. In Alport syndrome, this includes audiological and ophthalmological surveillance.50 In ADPKD, hepatic and cerebrovascular screening may be indicated depending on the genotype and family history. In Fabry disease, a genetic diagnosis prompts evaluation of cardiac, neurological and dermatological involvement and enables specific treatment. This systematic approach ensures early detection and treatment of complications that might otherwise be overlooked.

Assessment of transplant recurrence risk and donor selection. Genetic diagnosis is particularly relevant in the transplant setting. Diseases with a high risk of post-transplant recurrence—such as complement-mediated aHUS and primary hyperoxaluria—require specific pre-transplant planning and, in some cases, prophylactic therapy.54 Conversely, diseases such as Alport syndrome or ADPKD do not recur after transplantation, which has reassuring implications for patients and clinicians alike. Furthermore, genetic characterization of AR conditions enables safe identification of heterozygous carrier family members as potential living donors, as demonstrated in COQ8B nephropathy.55

Access to targeted therapies and clinical trials. The number of genotype-specific therapies for hereditary kidney diseases is rapidly expanding. Enzyme replacement therapy and chaperone therapy are available for Fabry disease. Complement-targeted agents (eculizumab, ravulizumab among others) have transformed outcomes in complement-mediated aHUS. RNA interference therapies (lumasiran, nedosiran) represent a breakthrough for primary hyperoxaluria type 1. SGLT2 inhibitors are under investigation in pediatric Alport syndrome, with the ongoing DOUBLE PRO-TECT trial56 as well as for ADPKD (STOP-PKD trial). Variant-specific therapies are being tested for ADPKD (NCT07161037). A positive genetic diagnosis is the gateway to these therapies and trials.

Genetic counseling and family planning. All individuals with a genetic condition should undergo genetic counseling as explained in the next section.57

Well-trained nephrologists are best suited to identify individuals who may benefit from genetic testing, explain the rationale to patients and their family members and provide follow-up care for result interpretation. Consultation with a clinical geneticist or genetic counselor is recommended when additional expertise is required.

Genetic counseling is a structured, bidirectional communication process that helps patients and families understand the genetic basis of CKD, the implications of testing, and options for management and family planning. It involves both pre-test counseling and test selection and coordination as well as post-test counseling.

Prior to testing, genetic studies must ensure compliance with the principles of justice (equity, accessibility), non-maleficence (proportionality in balancing benefits and harms), confidentiality (privacy and informed consent), and autonomy (self-determination).58 Potential benefits, limitations, and risks of genetic testing, including incidental findings and VUS, should be explained.59 Family history, inheritance patterns, likelihood of a monogenic cause, and implications for relatives (cascade testing) should be discussed.12,60,61 The ethical and legal implications of establishing a genetic diagnosis of CKD should be discussed, as the consequences are not invariably beneficial. Depending on healthcare systems, and societal and personal values, potential implications may include effects on family, social, and professional relationships, feelings of guilt related to disease transmission, and concerns regarding access to insurance and employment (e.g., in the U.S.).21,62

The choice of genetic test depends on clinical suspicion and may include single-gene testing, targeted variant testing, gene panels, exome, or genome sequencing (Table 1).21,62

Post-test counseling involves interpreting results within clinical context, including pathogenic, likely pathogenic, and variants of uncertain significance.59 It also includes discussion of prognosis, implications for treatment, transplant planning, and screening of at-risk relatives; as well as a balanced discussion of the limitations of current genomic knowledge and evolving reclassification of genetic variants.

Genetic counseling should be integrated early and strategically in the evaluation of people with CKD59,63,64 with suspected monogenic etiology65 or CKDx,8 before performing cascade testing in family members once a pathogenic variant is identified in the index case,60,66 prior to kidney donation evaluation67 to potential living donors with a family history of CKD or a known familial pathogenic variant and during pregnancy planning to inform reproductive options when IKD is known or suspected.60

The routine and systematic implementation of genetic testing in nephrology remains limited by several barriers, resulting in inequitable access that may exacerbate disparities in CKD diagnosis and outcomes.68 The main barriers are economic, structural, educational and ethical.

Economic limitations (cost-effectiveness). Although the cost of genetic sequencing has decreased dramatically over the past decade, it remains substantial in many healthcare systems, especially when broad gene panels, WES, or WGS are employed. However, the improved diagnostic accuracy achieved through genetic testing may also reduce costs through21,69 reduced use of invasive or redundant diagnostic procedures (e.g., kidney biopsy or repeated imaging), avoidance of ineffective or potentially harmful treatments, optimized genetic counseling and cascade testing and improved outcomes for living kidney donors.

Although the clinical benefit of genetic testing is not always immediate or easily quantifiable, an increasing body of evidence demonstrates that genetic testing is cost-effective in both adult and pediatric populations.70,71 Health economic analyses across diverse cohorts show that targeted genomic testing can reduce overall healthcare costs by approximately 20%, and up to 40% in selected populations with high pre-test probability.72 These findings strongly support the incorporation of genetic testing as a value-based diagnostic strategy rather than a purely technological expense.

Need for a specialized multidisciplinary nephrogenetics team. Another major barrier is the lack of structured multidisciplinary teams capable of interpreting and applying genetic information appropriately.25 Genetic data are inherently complex, with frequent identification of VUS and incidental findings. In the absence of specialized expertise, there is a risk of misinterpretation, inappropriate clinical decisions, and ethical challenges. Optimal implementation requires close collaboration between nephrologists, clinical geneticists, genetic counselors, and, when necessary, molecular pathologists. Recognizing this need, the KDIGO Controversies Conference proposed a three-tier implementation framework.

• –

  Basic level: All nephrologists should acquire foundational genetic literacy, enabling appropriate family history assessment and identification of patients who may benefit from genetic testing. However, there is a significant educational gap in genetics within nephrology training programs, resulting in variable confidence among clinicians when ordering or interpreting genetic tests.73

• –

  Intermediate level: Establishment of collaborative networks between nephrologists and genetic specialists through multidisciplinary clinics, courses, and joint conferences.

• –

  Advanced level: The development of expert nephrogenetics centers, functioning as referral hubs for complex cases and research initiatives, is essential. ERKNet assesses European centers for this purpose and lists the approved ones on its website.

Ethical considerations. Genetic testing raises concerns related to informed consent, incidental findings, psychosocial impact, and data privacy. These issues further emphasize the importance of genetic counseling and standardized protocols within nephrology services.68,74

Implementing genetic testing in Nephrology requires pragmatic and stepwise strategies, prioritizing genetic testing in scenarios with a high diagnostic yield and creating nephrogenetics units or committees. A detailed family history should be obtained in all individuals with CKD and once available, should be periodically updated (e.g., annually).

Nephrogenetics units or committees at hospital, regional or inter-hospital levels allow expertise to be centralized and resources to be optimized, as well as ensuring homogeneous interpretation of results. In practice, this could start with appointing a reference nephrologist who has received specific training in renal genetics, and the establishment of a formal collaboration with the Genetics Unit. The nephrologist would be responsible for patient selection and longitudinal care, while genetic counselors and geneticists would lead family counseling and variant interpretation. Regular multidisciplinary meetings should be held, initially at an institutional level and later expanding to regional forums, to discuss cases, harmonize interpretation criteria and generate local evidence.25 However, especially complicated cases should still be referred to expert centers.

The perspective of patients living with IKD is a central pillar of clinical care. Current guidelines advocate for shared decision-making and integration of patient-reported outcomes (PROs) into practice.75 In IKDs, the lived experience extends beyond organ dysfunction to encompass the psychological burden of inheritance, reproductive dilemmas and the quest for equitable access to care.

The diagnostic odyssey is a recurrent theme. Qualitative studies in primary hyperoxaluria type 1 have documented prolonged diagnostic delays driven by low disease awareness.76 Patients with aHUS describe similar uncertainty and lack of information at diagnosis.77 These accounts underscore the need for clinician education and accessible and reliable educational resources that effectively support patients’ life-planning and facilitate informed, therapy-assisted decision-making.

Patients consistently express three core expectations: a timely diagnosis, understandable information about their condition, and meaningful participation in treatment decisions.77 In IKDs, an additional emotional burden arises from the awareness that the disease may be transmitted to offspring. Reproductive decisions in ADPKD are profoundly influenced by the genetic nature of the disease, with patients expressing a clear desire for better access to reproductive counseling and preimplantation genetic testing.78 Disease burden reported by patients—pain, fatigue and anxiety—remains underrecognised, as shown by patient-powered registries.79,80

Significant disparities exist in access to genetic testing and genotype-specific therapies. Ensuring equitable access to genetic diagnosis should be regarded as a patient right. Inequity may persist even in Spain despite its universal public health system, and longstanding national strategy for CKD.81,82 Access to genetic testing still varies across regional health systems and even at hospital or clinician level.

On the other hand; patients express legitimate concerns regarding genetic data privacy. The perceived risk of discrimination in insurance or employment constitutes a barrier to testing uptake. Robust legal frameworks for genetic data protection, together with informed consent understood as an ongoing process—rather than a one-time act—are essential for building patient trust.

Patient advocacy organizations play a transformative role. The IgA Nephropathy Foundation illustrates how patient-driven initiatives evolve from information-sharing to active participation in research and regulatory dialog.83 Fostering patient networks for IKD in Spain and Europe should be a priority of the nephrology community.

• •

  IKD and CAKUT, which may also have a genetic cause, are one of the leading cause of prevalent KRT in Europe.

• •

  A substantial proportion (around 25%) of CKDx likely has a genetic basis, especially in younger patients.

• •

  Genetic testing should be performed early rather than as a last diagnostic step, particularly in cases with early onset, family history, syndromic features, or unexplained disease.

• •

  A positive genetic diagnosis has major clinical impact, including reclassification of disease, avoidance of inappropriate treatments, access to targeted therapies, improved transplant planning, and informed family counseling.

• •

  Genetic testing leads to changes in clinical management in most patients in specialized settings.

• •

  Genetic testing is increasingly cost-effective, reducing unnecessary procedures and inappropriate treatments despite initial costs.

• •

  Next-generation sequencing approaches, including gene panels, whole-exome sequencing, and whole genome sequencing (currently in research setting) are now preferred due to the high genetic heterogeneity of kidney diseases.

• •

  Interpretation of genetic results requires a multidisciplinary approach.

• •

  VUS should not guide clinical decisions and, if there is a high suspicion of a genetic condition, should be revisited after some time.

• •

  Key barriers to genetic testing include limited access, lack of training, and insufficient multidisciplinary structures.

• •

  Implementation should focus on high-yield clinical scenarios, nephrologist-led testing models, and the creation of nephrogenetics units.

• •

  The future of nephrology increasingly points toward precision medicine, with genetic diagnosis becoming a standard component of chronic kidney disease care.

• •

  Patients emphasize the need for earlier diagnosis, clear information, and equitable access to genetic testing and therapies.

Fig. 5.

The practical management of inherited kidney diseases: driving clinical changes. Abbreviations: CAKUT: congenital anomalies of the kidney and urinary tract; CKD: chronic kidney disease; CKDx: unexplained chronic kidney disease IKD: inherited kidney diseases; NGS: next generation sequencing; WES: whole exome sequencing; WGS: whole genome sequencing.

Borja Quiroga: 0000-0001-5730-1929

Alberto Ortiz: 0000-0002-9805-9523

Mónica Furlano: 0000-0003-1025-3901

Miquel Blasco: 0000-0003-0789-7992

María Vanessa Pérez-Gómez: 0000-0003-4558-5236

Ana Sánchez Horrillo: 0009-0002-1171-7069

María Marques Vidas: 0000-0001-9691-2546

Daniel Gallego Zurro: 0000-0002-7596-3974

Patricia de Sequera: 0000-0001-7705-9228

Roser Torra: 0000-0001-8714-2332

María Auxiliadora Bajo: 0000-0001-7364-557X

BQ, ASH and MAB research are funded by Instituto de Salud Carlos III (ISCIII): RICORS program to RICORS2040-Renal (RD24/0004/0028) co-funded by European Union (FEDER funds) and public research grants (PI25/00413). MB research is supported by Instituto de Salud Carlos III (ISCIII): RICORS program to RICORS2040-Renal (RD24/0004/0013) and public research grants (PI22/00240; PI25/00300). AO research is supported by Comunidad de Madrid en BiomedicinaP2022/BMD-7223, CIFRA_COR-CM. Instituto de Salud Carlos III (ISCIII) (PI22/00469, PI22/00050, PI21/00251, PI25/00145, ERA-PerMed-JTC2022 (SPAREKID AC22/00027), RICORS program to RICORS2040-renal (RD24/0004/0001) co-funded by European Union and SPACKDcPMP21/00109, FEDER funds; COST Action PERMEDIK CA21165 supported by COST (European Cooperation in Science and Technology); PREVENTCKD Consortium Project ID 101101220 Programme EU4H DG/Agency HADEA; KitNewCare Project ID 101137054, Call HORIZON-HLTH-2023-CARE-04, Programme HORIZON, DG/Agency HADEA; PICKED Project ID 101168626 HORIZON-MSCA-2023-DN-01-01 MSCA Doctoral Networks 2023. JPP and MM research are supported by the Instituto de Salud Carlos III (ISCIII) through public research grants PI25/01000, PI23/01518 and by the RICORS programs to RICORS2040-Renal (RD24/0004/0028) co-funded by European Union (FEDER funds). MF and RT research are supported by the Instituto de Salud Carlos III (grants PI22/00361 and PI24/00823), AC23_2/00043 and co-funded research from the Instituto de Salud Carlos III and the European Union (RICORS2040-Renal, RD24/0004/002). MVPG research is supported by Project PI22/01168, PI25/01565 funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union; ISCIII RICORS program to RICORS2040 (RD24/0004/0001) co-funded by European Union. PS research is supported by Instituto de Salud Carlos III (ISCIII): RICORS program to RICORS2040-Renal (RD24/0004/0020).

BQ reports honorarium for conferences, consulting fees and advisory boards from Bayer, Novo Nordisk, Novartis, Genzyme-Sanofi, AstraZeneca, Boehringer and CSL-Vifor.

MAB reports honorarium for conferences, consulting fees or travel support from Fresenius Medical Care, Laboratorio Rubió, SPA Farma Ibérica and CSL-Vifor.

MB has received speaking fees, served on advisory boards, and received funding to attend courses and conferences from Otsuka, Chiesi, Novartis, Sobi, AstraZeneca, Vifor and Alexion.

PDS has received speaking fees, served on advisory boards, and received funding to attend courses and conferences from Payment or fees for conferences, presentations from, Amgen, Astellas, Astra Zeneca, Braun, Fresenius, Nipro, Otsuka, Vantive and Vifor Pharma.

AO has received consultancy or speaker fees or travel support from Astellas, Astrazeneca, Bioporto, Boehringer Ingelheim, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Sobi, Menarini, Lilly, Chiesi, Otsuka, Novo-Nordisk, Sysmex and CSL-Vifor and Spafarma.

RT has received travel support or consulting/lecturing fees from Alnylam, Amicus, AstraZeneca, Boehringer Ingelheim, Chiesi, CSL Vifor, Kyowa Kirin, Otsuka, Sanofi-Genzyme, Takeda.

ASH, JP, MF, MM, MVPG and DG declare no conflicts of interest relevant to this manuscript.