The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD

Abstract

BACKGROUND. A treatment option for autosomal dominant polycystic kidney disease (ADPKD) has highlighted the need to identify rapidly progressive patients. Kidney size/age and genotype have predictive power for renal outcomes, but their relative and additive value, plus associated trajectories of disease progression, are not well defined. METHODS. The value of genotypic and/or kidney imaging data (Mayo Imaging Class; MIC) to predict the time to functional (end-stage kidney disease [ESKD] or decline in estimated glomerular filtration rate [eGFR]) or structural (increase in height-adjusted total kidney volume [htTKV]) outcomes were evaluated in a Mayo Clinic PKD1/PKD2 population, and eGFR and htTKV trajectories from 20-65 years of age were modeled and independently validated in similarly defined CRISP and HALT PKD patients. RESULTS. Both genotypic and imaging groups strongly predicted ESKD and eGFR endpoints, with genotype improving the imaging predictions and vice versa; a multivariate model had strong discriminatory power (C-index = 0.845). However, imaging but not genotypic groups predicted htTKV growth, although more severe genotypic and imaging groups had larger kidneys at a young age. The trajectory of eGFR decline was linear from baseline in the most severe genotypic and imaging groups, but it was curvilinear in milder groups. Imaging class trajectories differentiated htTKV growth rates; severe classes had rapid early growth and large kidneys, but growth later slowed. CONCLUSION. The value of imaging, genotypic, and combined data to identify rapidly progressive patients was demonstrated, and reference values for clinical trials were provided. Our data indicate that differences in kidney growth rates before adulthood significantly define patients with severe disease.

Characteristics of Patients with End-Stage Kidney Disease in ADPKD

“…When patients were stratified according to disease severity reflected by the MIC, those with the most severe disease (MIC 1E patients) had fully penetrant PKD mutations (92%) and were predominately men (70%). This suggests that PKD mutation strength and male gender are major determinants of rapid cystic expansion and is consistent with the results of the CRISP study 5 , 6 and the aggravating effect of testosterone in several rodent models of PKD. 26 , 27 , 28 , 29 In contrast, most patients with ESKD with class MIC 1B or 2B were women (82%) with fewer fully penetrant PKD mutations (55%).…”

“…Understanding the characteristics associated with age of ESKD onset is critical, given its implication on modifying the disease course. Despite the phenotypic variability, observational studies of large ADPKD cohorts, including CRISP 5 , 6 , 7 , 8 and pooled registry datasets, 24 , 25 have shown that HtTKV strongly predicts the risk of GFR decline and progression to ESKD. The number of patients who reached ESKD in these cohorts was relatively low at the time of analysis (42 [18.6%] and 88 [5.4%]).…”

“…PKD1 NT mutations were subcategorized to PKD1 NT1 and PKD1 NT2 . 4 , 5 PKD1 T and PKD1 NT1 are defined as fully penetrant PKD mutations. A total of 185 of the 290 (63.8%) patients included in this study had genetic testing for PKD1 or PKD2 mutations.…”

“… 3 More recently, PKD1 missense mutations have been subdivided into likely fully penetrant ( PKD1 NT1 ) or hypomorphic ( PKD1 NT2 ). 4 , 5 The severity of PKD1 NT1 disease is similar to that of PKD1 T , whereas the severity of PKD1 NT2 disease is closer to PKD2 . 5 …”

“… 4 , 5 The severity of PKD1 NT1 disease is similar to that of PKD1 T , whereas the severity of PKD1 NT2 disease is closer to PKD2 . 5 …”