Table 4.

Case study

Case Presentation

GF is a 42-yr-old male with a history of diabetes and hypertension who presents with end-stage kidney disease (ESKD). He reports that his grandmother, mother, and maternal aunt, all of whom are deceased, reached ESKD before the age of 50 yrs, which was presumed to be secondary to diabetes and hypertension. Serum electrolytes and complement studies are unremarkable, and urinalysis shows bland sediment and low-grade proteinuria. Renal imaging reveals shrunken, hyperechogenic kidneys; given these findings and his advanced kidney disease, renal biopsy is not performed. His 51-yr-old sister, KF, wants to donate her kidney to him. KF reports being in good health. She is normotensive and has no anomalies on renal imaging. KF’s laboratory values show serum creatinine 0.8 (estimated glomerular filtration rate of 84 ml/min per 1.73 m2) and fasting glucose of 75 mg/dl; urinalysis is within normal limits. KF notes their family identifies as African American, and she has read that individuals of Western African ancestry may be at higher risk of developing kidney disease. GF and KF ask if any additional tests could help them understand why GF and other members of their family have kidney disease and whether KF can safely donate a kidney to GF.

Genetic Differential Diagnosis

Although diabetic and hypertensive nephropathy are on the differential, GF’s personal and family history of ESKD before the age of 50 yrs supports considering monogenic etiologies for his kidney disease. Although his clinical presentation is not specific for a particular category of genetic kidney disease, the absence of certain features can help narrow the differential, for example, the negative complement studies disfavoring a typical hemolytic uremic syndrome or other complement-mediated renal diseases. Given the cooccurrence of diabetes and renal disease in his family, HNF1B nephropathy is a possibility: though classically associated with cystic renal disease and diabetes, there is variable expressivity, with some individuals displaying only isolated renal hypoplasia or no structural renal anomalies on imaging.146,147 In addition, given that GF is an African American of Western African ancestry, APOL1 nephropathy should also be considered, because approximately 13% of African Americans harbor 2 APOL1 risk alleles.148 Although the APOL1 risk genotype substantially increases kidney disease risk, a minority of individuals with APOL1 risk genotypes develop kidney disease, suggesting that a “second hit,” such as other genetic variant(s) and/or systemic or environmental factors, may be needed to produce disease. A study of over 15,000 individuals with kidney disease found that nearly 10% of individuals with APOL1 risk genotypes harbored a diagnostic variant for a monogenic form of kidney disease, supporting genetic testing in individuals with suggestive features for monogenic forms of kidney disease even if they are known to have an APOL1 risk genotype.149

Clinical Utility of Genetic Testing

For GF, genetic testing has the potential to pinpoint a specific cause of disease and thereby inform living-related donor selection and posttransplant prognosis and management.26 Next-generation sequencing –based genetic testing has been reported to identify a monogenic cause in approximately 10% of adults with ESKD of unknown etiology.150, 151, 152 Knowledge of the transplant recipient's primary kidney disease can help determine recurrence risk in the allograft and also identify individuals at increased risk of other common posttransplant complications (e.g., malignancy for WT1-associated focal segmental glomerulosclerosis, diabetes among individuals with HNF1B nephropathy), helping guide surveillance and choice of posttransplant therapy. In addition, by ascertaining whether family members harbor the disease-causal variant, genetic testing can help determine eligible living-related donors. If genetic testing includes investigation for the APOL1 risk genotypes and/or other medically actionable disorders,37 these findings may have clinical utility. For example, knowledge of the APOL1 risk genotype status can inform about the recurrence risk in the allograft153 and the donor’s risk of developing CKD postdonation.14

Although not causal for an individual’s renal disease, secondary findings in genes deemed medically actionable can inform management, for example, detection of a hereditary cancer predisposition syndrome informing immunosuppression regimen or identification of a pathogenic variant in KCNQ1, associated with long QT syndrome, prompting avoidance of QT-prolonging medications such as macrolide and quinolone antibiotics and azole antifungals.122 Therefore, individuals should be counseled about the possible utility of receiving medically actionable secondary findings should they choose to pursue genome-wide testing.

Options for Genetic Testing

ESKD of unclear etiology and no specific familial form of kidney disease support a broad approach to genetic testing (Figure 2). GF’s options include a broad targeted panel of genes associated with monogenic forms of CKD, virtual panel testing, or genome-wide testing (i.e., exome sequencing [ES] or genome sequencing). Becauseeach of these tests is a reasonable first-line approach,35 GF and his nephrologist engage in shared decision-making. His nephrologist writes a letter of medical necessity describing how GF has kidney disease of unknown etiology with a family history of kidney disease and the clinical utility of genetic testing in his case and obtains insurance coverage for ES for him.

Results and Next Steps

ES reveals that GF has a pathogenic variant in the HNF1B gene. GF is given a genetic diagnosis of HNF1B nephropathy, which has meaningful implications for his clinical management. Identification of HNF1B nephropathy warrants targeted evaluation and surveillance for extrarenal manifestations, which include liver dysfunction, neuropsychiatric disease, and exocrine pancreatic insufficiency.147,154 Moreover, because affected individuals have an increased risk of diabetes posttransplant, avoidance of tacrolimus and reduced corticosteroid usage in immunosuppression regimens is advised, and, for those with ESKD and diabetes, combined kidney-pancreas transplant can be considered.

In addition to the pathogenic HNF1B variant, GF’s ES report notes that he harbors the APOL1 G1/G1 risk genotype and has a heterozygous pathogenic variant in the LDLR gene, associated with autosomal dominant familial hypercholesterolemia. His sister, KF, is found to be negative for the HNF1B variant, but does harbor the APOL1 G1/G1 risk genotype and LDLR pathogenic variant. She is counseled that, per population-based studies, individuals with APOL1 risk genotypes have an ∼2-fold increased risk of ESKD post donation, with the caveat that her risk may be lower because the lifetime risk of ESKD decreases as donors age.155 Despite harboring the APOL1 risk genotype, she still meets institutional cutoffs for acceptable lifetime risk and decides to proceed with donating her kidney.

As individuals with heterozygous familial hypercholesterolemia, GF and KF are referred to a cardiologist specialized in hereditary dyslipidemias for recommended management, including stringent lipid profile monitoring with a low threshold for initiating pharmacotherapy (e.g., with statins, ezetimibe, or PCSK9 inhibitors).156 In addition, their familial hypercholesterolemia also informs immunosuppression regimen via supporting minimizing corticosteroid use, given corticosteroids’ negative impact on lipid profile.