Literature

Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published August 14, 2024

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Why is genetic testing in patients with cystic kidney disease considered important?

Genetic causes of chronic kidney disease (CKD) are increasingly recognized. Read the NEJM Review Article here.

Clinical Pearls

Q: Are genetic kidney diseases rare?

A: It has long been known that many common and diverse causes of CKD cluster in families, indicating genetic contributions. Furthermore, disparities among racial and ethnic groups have suggested genetic contributions. Most genetic kidney diseases are rare. Collectively, however, they contribute substantially to the global prevalence of CKD.

Q: How would you approach establishing a genetic diagnosis in a patient with CKD?

A: The first step in establishing a genetic diagnosis is comprehensive phenotyping. Obtaining a detailed family history and a three-generation pedigree are also important steps. A negative family history of kidney disease does not preclude CKD of genetic origin. The diagnostic yield of genetic testing in CKD is variable and depends on the disease phenotype, associated coexisting conditions, ethnicity, consanguinity, family history, and age at onset. Multiple studies support a list of major indications that should prompt clinicians to consider genetic analysis for their patients with CKD. Once genetic test results are received, even if they are negative, genetic consultation is important for clinical reassessment and consideration of broader or complementary genetic testing. Further diagnostic steps are often required, and correct interpretation of the results is important.

Morning Report Questions

Q: Why is genetic testing in patients with cystic kidney disease considered important?

A: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease worldwide, affecting 4 to 8% of all patients with kidney failure. A systemic disorder with variable clinical expression, ADPKD may include extrarenal manifestations such as liver cysts, cerebral aneurysms, and cardiac valvular disease. The main causes of ADPKD are pathogenic variants in two genes, PKD1 (in approximately 78% of cases) or PKD2 (in approximately 15% of cases), which encode the polycystin 1 and polycystin 2 proteins, respectively. Until recently, routine clinical genetic testing in persons with ADPKD was seldom performed. Nonetheless, a diagnosis at the genetic level is important, since mutations in more than 15 different genes can mimic an ADPKD phenotype. Thus, genetic testing in patients with cystic kidney disease can inform clinical management and family planning and reclassify patients on the ADPKD spectrum.

Q: What is the 2nd most common genetic cause of CKD after ADPKD?

A: Variants in the genes encoding the α3, α4, and α5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively) are the second most common genetic cause of CKD after ADPKD, accounting for approximately 2 to 3% of cases in adults with advanced CKD. More than 30 years ago, alterations in type IV collagen, a major component of the glomerular basement membrane, were identified in patients with Alport’s syndrome (so-called familial nephritis). Subsequent studies have shown wide phenotypic variation among patients with collagen variants, often associated with modes of inheritance and the location and types of variants within the genes encoding type IV collagen. Clinical features range from classic Alport’s syndrome (glomerular hematuria, hearing loss, and eye abnormalities) to disease confined solely to the kidneys, with a thin basement membrane seen on electron microscopy, or focal segmental glomerulosclerosis. Multiple studies show that previously underappreciated variants in genes encoding type IV collagen are responsible for many cases of CKD in adults who do not have the classic extrarenal features of Alport’s syndrome. Such patients may initially have persistent, isolated hematuria or proteinuria, with subsequent development of progressive CKD.

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