Diagnostic Approach in Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian disorder of the kidney and affects all racial groups worldwide. It is characterized by focal development of renal and extrarenal cysts in an age-dependent manner. Typically, only a few renal cysts are detected in most affected individuals before 30 yr of age. However, by the fifth decade of life, hundreds to thousands of renal cysts will be found in the majority of patients. ADPKD is genetically heterogeneous. Mutations of two genes, PKD1 and PKD2, account for approximately 85 and 15% of cases, respectively. Although the clinical manifestations of these two genotypes overlap completely, patients with PKD1 have much more severe renal disease compared with those with PKD2, as evidenced by their ESRD occurring approximately 15 yr earlier. Renal ultrasonography commonly is used for the assessment of ADPKD, and age-dependent ultrasound diagnostic criteria with high sensitivity and specificity have been established for individuals who are born with 50% risk for PKD1. Although these diagnostic criteria are used widely for genetic counseling and for the evaluation of at-risk individuals as living-related kidney donors to their affected relatives, their application to individuals who are at risk for PKD2 or have undefined genotype needs to be refined further. Molecular genetic testing is available for ADPKD and may be useful for evaluation of at-risk individuals with equivocal imaging results, younger at-risk individuals as a living-related kidney donor, and individuals with atypical or de novo renal cystic disease.

Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

“…Highly sensitive and specific diagnostic criteria based on renal cyst number have been derived for this purpose (12)(13)(14). A family history, however, may be absent in 10 to 20% of new patients in whom the diagnosis of ADPKD is first suspected from imaging studies performed to evaluate otherwise unexplained hematuria, abdominal mass, flank pain, or renal insufficiency (1,2,12). In these cases, the finding of ADPKD can be due to a de novo mutation or ascertainment of a small family with PKD2 and mild renal disease, which is often underdiagnosed (12,21).…”

“…In the latter case, the proband's younger brother would be expected to be affected because the presence of even a single renal cyst is highly unusual in his age group (12). Gene-based mutation screening was informative and provided strong evidence suggesting that the proband had de novo PKD2 and that his brother had a simple renal cyst.…”

“…The diagnosis of ADPKD is generally straightforward when affected individuals present with a positive family history and enlarged kidneys with multiple cysts (12). Renal ultrasound is a sensitive method for this purpose, and age-dependant criteria based on cyst number have been derived for individuals who are born with 50% risk for PKD1 (13); however, because cyst formation is an age-dependent process, the false-negative rate of ultrasound-based diagnosis is higher in younger at-risk individuals or in those who are affected by PKD2, which is associated with later onset disease (14).…”

“…Renal ultrasound is a sensitive method for this purpose, and age-dependant criteria based on cyst number have been derived for individuals who are born with 50% risk for PKD1 (13); however, because cyst formation is an age-dependent process, the false-negative rate of ultrasound-based diagnosis is higher in younger at-risk individuals or in those who are affected by PKD2, which is associated with later onset disease (14). Equivocal imaging results can be a source of diagnostic uncertainty in the clinic because the underlying gene type for most patients is unknown.…”

“…Equivocal imaging results can be a source of diagnostic uncertainty in the clinic because the underlying gene type for most patients is unknown. In addition, renal cystic disease without a family history of ADPKD and evaluation of younger at-risk individuals as living-related kidney donors are clinical scenarios that often pose diagnostic challenges (12). Using a case series, we illustrate the utility and limitations of molecular diagnostics for ADPKD in the clinical setting.…”