In this large cohort study from a single geographic region, we documented a prevalence of atypical polycystic kidney disease by imaging of 8.8% (46/543) which is very similar to that reported in the discovery cohort used for the Mayo Clinic Imaging Classification.10 In the original report, patients with atypical patterns were excluded from subsequent analyses. Compared to patients with typical imaging patterns, patients with atypical imaging patterns were older, and less likely to have a family history of ADPKD, a detectable PKD1 or PKD2 mutation, or progression to CKD stage 3 or stage 5. Thus, patients with atypical polycystic kidney disease by imaging have an excellent prognosis with a very low risk for ESKD. Failure to appropriately identify patients with atypical patterns and invalid Mayo Clinic Imaging Classification can lead to erroneous CKD risk stratification. If unrecognized as atypical, 41% of our patients with atypical kidney imaging patterns would have been misclassified as being at high risk for progression to ESKD (i.e., Mayo Clinic Imaging Class 1C-1E).
To fully capture all observed atypical kidney imaging patterns, we added two additional patterns to the Mayo Clinic Imaging Classification. Firstly, a "segmental sparing” pattern, characterized by bilateral and diffuse cystic disease with sparing of one pole of one or both kidneys, which is relatively common (i.e., 5/46 or 10.9%) in this study. Secondly, a “mild lopsided” pattern, where 15–49% of TKV is attributable to 2–5 cysts (similar to the “lopsided” pattern where ≥ 50% of TKV is attributable to 2–5 cysts); it is the most common atypical imaging pattern in our cohort (i.e., 20/46 or 43.5%). Both of these patterns were strongly associated with the clinical and genetic features of atypical polycystic kidney disease, namely low probability of a positive family history, low probability of a detectable mutation, or slowly progressive kidney disease.
Forty-five of the 46 patients with atypical polycystic kidney disease (1 unilateral, 10 asymmetrical, 29 lopsided, and 5 segmental sparing) showed complete sparing of cystic disease with normal parenchyma in one or more parts of the kidneys. Sparing of multiple portions of the kidney is a common finding (40/46 or 87.0% in this cohort) and is suspicious of somatic mosaicism.14,15 Mosaicism refers to the occurrence of two genetically distinct cell populations within an individual, due to the somatic mutation of a single pluripotent stem cell during embryogenesis or development.16,17 Due to dilution and variable involvement of the affected cells, a mosaic individual with ADPKD often presents with de novo cystic kidney disease with atypical imaging (i.e. focal, unilateral, or asymmetrical) patterns, as exemplified by the proband of TOR135 we previously reported.18 However, diagnosis of mosaicism is technically challenging and frequently missed by Sanger sequencing, which is frequently used for ADPKD, due to dilution of the mutation signal from the admixture of normal and mutant cells – a difficulty that can be overcome by next-generation sequencing with high-read depth.19 Indeed, by using next-generation sequencing, a recent study of 387 PKD1 and PKD2 mutation-negative patients with ADPKD identified 20 PKD1 somatic mosaics, with at least 6 of them displaying atypical kidney imaging patterns.15 In addition to somatic mosaicism, PKD2 (n = 5) and PKD1 non-truncating (n = 3) mutations, which are typically associated with mild cystic kidney disease, were found in 8 of 9 (88.9%) mutation-positive patients with atypical imaging patterns in our study. Next-generation sequencing for mutation screening of additional genes, such as PRKCSH, GANAB, ALG8, ALG9, SEC61B, SEC63, DNAJB11, and HNF1B, which may be associated with mild or atypical polycystic kidney disease, may allow for further elucidation of the genetic causes of atypical polycystic kidney disease by imaging.14
In conclusion, 8.8% of a large cohort of patients with ADPKD displayed atypical polycystic kidney disease by imaging. Compared to patients with typical kidney imaging patterns, they were older, and less likely to have a family history of ADPKD, a detectable mutation in PKD1 and PKD2, or progression to advanced CKD. The causes of atypical polycystic kidney disease by imaging are heterogeneous and may include somatic mosaicism, mild disease associated with PKD1 non-truncating or PKD2 mutations, as well as mutations in other cystic disease genes. Lack of identification of atypical imaging patterns can lead to inappropriate risk stratification. Elucidating the genetic causes of atypical polycystic kidney disease by imaging by next-generation sequencing will advance our understanding of this clinical syndrome and help clinicians counsel patients on the most appropriate management strategy.