Diagnosis and screening of autosomal dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and accounts for approximately 5% of ESRD population in the United States. The disorder is characterized by the focal and sporadic development of renal cysts, which increase in size and number with age. Mutations of PKD1 and PKD2 account for most of the cases. Although the clinical manifestations of both gene types overlap completely, PKD1 is associated with more severe disease than PKD2, with larger kidneys and earlier onset of ESRD. In general, renal ultrasonography is commonly used for the diagnosis of ADPKD, and age-dependent criteria have been defined for subjects at risk of PKD1. However, the utility of the PKD1 ultrasound criteria in the clinic setting is unclear because their performance characteristics have not been defined for the milder PKD2 and the gene type for most test subjects is unknown. Recently, highly predictive ultrasound diagnostic criteria have been derived for at-risk subjects of unknown gene type. Additionally, both DNA linkage or gene-based direct sequencing are now available for the diagnosis of ADPKD, especially in subjects with equivocal imaging results, subjects with a negative or indeterminate family history, or in younger at-risk individuals being evaluated as potential living-related kidney donors. Here, we review the clinical utilities and limitations of both imaging- and molecular-based diagnostic tests and outline our approach for the evaluation of individuals suspected to have ADPKD.

Figure 1

The pre-test probability of disease decreases with age in subjects born with 50% risk of ADPKD and differs between PKD1 and PKD2. (A) The prevalence of PKD1 (solid color) and PKD2 (strip color) are assumed to be 85% and 15%, respectively. At birth, the proportion of affected but clinically undiagnosed subjects (green color) is equal to that of at-risk but unaffected subjects (blue color). With increasing age the proportion of affected but clinically undiagnosed subjects (green color) diminishes as increasing proportion of the affected subjects are clinically diagnosed (yellow color). However, a higher proportion of the more severely affected PKD1 subjects will be clinically diagnosed (solid yellow color) compared to affected PKD2 subjects (strip yellow color). (B) The pre-test probability of disease among subjects born with 50% risk for PKD1 (circle) and PKD2 (diamond) diverges with increasing age (Data derived from Lancet 353: 103-7, 1999).

Figure 2

(A) T2 weighted breath-held MRI from a 28 year-old female at-risk of ADPKD performed without contrast injection in one breath-hold showing multiple tiny cysts in a cortical and perihilar distribution (white arrows) in both kidneys (≫10/kidney). (B) Corresponding ultrasound through both kidneys was normal. Only the left kidney ultrasound is shown. DNA testing subsequently detected a truncating PKD2 mutation in her and her other affected family members.

Figure 3

Molecular genetic evaluation of III:3, who had a negative renal ultrasound, as a potential living-related kidney donor. Direct sequencing of PKD1 and PKD2 in her affected father (II:2) identified two unclassifiable PKD1 variants (Q739R and del2763M) of uncertain clinical significance. Although III:3 did not carry these variants, the mutation analysis was considered as indeterminate. Haplotype analysis, on the other hand, showed that only the PKD1 haplotype 3-2-2-3-1 (upper panel), but no single PKD2 haplotype (lower panel), co-segregated with the affected family members indicating that this family was PKD1-linked. Since III:3 did not carry this putative PKD1 disease haplotype, she was considered as unaffected (adapted from C J Am Soc Nephrol 3: 146-52, 2008).

Figure 4

Diagnostic algorithm for the evaluation of an individual suspected to have ADPKD. See text for details.