Is genetic testing needed in all cases of Chronic Kidney Disease (CKD) where a clear etiology is not identified?

Genetic Testing in CKD of Unknown Etiology

Genetic testing is not routinely needed in all cases of CKD without a clear etiology, but should be strongly considered in specific clinical scenarios where identification of pathogenic variants can lead to actionable treatment or prevention strategies. 1

When to Pursue Genetic Testing

The 2022 KDIGO Controversies Conference established that genetic testing should be targeted rather than universal, focusing on situations where results will change management. 1

High-Priority Scenarios for Genetic Testing

• Early-onset CKD (age <50 years) without traditional risk factors warrants genetic evaluation, as there is no upper age limit for monogenic CKD but younger patients have higher pre-test probability. 1

• Family history of kidney disease strongly suggests hereditary nephropathy and justifies genetic testing, particularly when multiple family members are affected across generations. 1

• Steroid-resistant nephrotic syndrome or FSGS in children should prompt genetic testing, as children with genetic FSGS are less likely to respond to glucocorticoids and have lower recurrence risk after transplantation. 1

• Atypical clinical presentations including absence of hypertension, minimal proteinuria, or chronic tubulointerstitial pattern on biopsy may indicate monogenic causes requiring genetic evaluation. 1, 2

• Reproductive counseling or family planning represents an actionable indication, as genetic diagnosis enables informed decisions about inheritance risks. 1

When Genetic Testing Can Be Deferred

• Typical diabetic or hypertensive CKD patterns in older adults (>60 years) with appropriate risk factors and disease progression do not require routine genetic testing. 3, 4

• CKD with clear acquired etiology (documented long-standing diabetes, hypertension with target organ damage, known nephrotoxin exposure) makes genetic testing low-yield. 3, 2

Implementation Framework

The KDIGO conference recommends a three-tiered organizational model for genetic testing implementation. 1

Tier 1: Primary Nephrology Level

• All nephrologists should maintain basic genetic literacy to recognize patterns suggesting hereditary kidney disease. 1
• Initial evaluation includes detailed three-generation family history, age of onset, extrarenal manifestations, and response to standard therapies. 1

Tier 2: Collaborative Care

• Clinical connections between nephrologists and geneticists/genetic counselors should be established for case consultation. 1
• Interdisciplinary expert boards should review potential genetic findings before ordering tests. 1

Tier 3: Centers of Expertise

• Complex cases require nephrologists with genetic expertise collaborating with geneticists and genetic counselors. 1
• These centers should handle variant interpretation, particularly variants of uncertain significance (VUS), which lack consensus reporting standards. 1

Critical Considerations Before Testing

Actionable Genes Concept

• Testing should prioritize "actionable genes" where pathogenic variant identification leads to specific clinical actions for treatment or prevention based on evidence. 1
• Examples include PKD1/PKD2 (tolvaptan eligibility), COL4A3/4/5 (Alport syndrome with hearing/vision monitoring), and UMOD (ADTKD-UMOD with specific counseling). 1

Limitations and Pitfalls

• Prevalence estimates of monogenic CKD remain imprecise due to selection bias in studied populations, making pre-test probability calculations difficult. 1
• The term "CKD of unknown etiology" lacks clear consensus definition, creating ambiguity about when genetic testing is appropriate. 1
• VUS reporting standards are not established, meaning testing may yield inconclusive results requiring periodic reanalysis. 1

Special Population Considerations

APOL1 testing in African ancestry populations requires careful consideration, as high-risk genotypes have moderate positive likelihood ratios for FSGS (LR ~10-29) but only 1.5-fold risk for general CKD. 1 A negative APOL1 test is more useful for ruling out APOL1-related disease than a positive test is for ruling it in. 1

CKD of uncertain etiology (CKDu) in agricultural communities from Mesoamerica, Sri Lanka, and India likely represents environmental/occupational disease rather than genetic causes, making genetic testing low-yield unless family clustering is present. 5, 2, 6

Practical Testing Approach

Preferred Testing Methodology

• Whole-exome sequencing is more comprehensive than targeted gene panels when no specific mutation is known, particularly for conditions like FSGS with over 50 causative genes. 1
• Next-generation sequencing panels are appropriate when clinical phenotype suggests specific gene groups (e.g., ciliopathy genes for cystic disease). 1

Alternative to Genetic Testing

• Imaging-based diagnosis remains preferred for ADPKD using age-related ultrasound criteria, reserving genetic testing for inconclusive imaging, early severe presentation, negative family history, or reproductive counseling. 1

Workforce and Infrastructure Requirements

Successful implementation requires expanded workforce with expertise in kidney genetics, genomics, and computational research. 1 Education of the nephrology workforce is necessary before widespread genetic testing adoption. 1

A standardized reference kidney disease gene list and variant reporting standards are needed but not yet established. 1 Periodic reanalysis of unsolved cases should be implemented as variant databases expand. 1