Long-term trajectory of kidney function in autosomal-dominant polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst and kidney growth, which is hypothesized to cause loss of functioning renal mass and eventually end-stage kidney disease. However, the time course of decline in glomerular filtration rate (GFR) is poorly defined. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study is a 14-year observational cohort study of 241 adults with ADPKD. As an estimate of the rate of kidney growth, participants were stratified into 5 subclasses based on baseline age and MRI measurements of total kidney volume (TKV) according to the method of Irazabal. GFR trajectories spanning over four decades of life were reconstructed and fitted using mixed polynomial models, which were validated using data from the HALT-PKD study. GFR trajectories were nonlinear, with a period of relative stability in most participants, followed by accelerating decline. The shape and slope of these trajectories were strongly associated with baseline Irazabal class. Patients with PKD1 mutations had a steeper GFR decline than patients with PKD2 mutations or with no detected mutation, largely mediated by the effect of genotype on Irazabal class. Thus, GFR decline in ADPKD is nonlinear, and its trajectory throughout adulthood can be predicted from a single measurement of kidney volume. These models can be used for clinical prognostication, clinical trial design, and patient selection for clinical interventions. Our findings support a causal link between growth in kidney volume and GFR decline, adding support for the use of TKV as a surrogate endpoint in clinical trials.

International consensus statement on the diagnosis and management of autosomal dominant polycystic kidney disease in children and young people

“…Although children with very-early-onset ADPKD have poorer outcomes 89 , no studies have examined whether the prediction of 'rapid progressors' by repeated imaging in children is feasible and clinically helpful. Our recommendation (Box 6) would change in the future if paediatric studies show a predictive value of kidney imaging on later progression to end-stage renal disease (ESRD; as has been shown in adults 90 ) and a treatment to slow disease progression is licensed specifically for children who are at risk of early progression to ESRD.…”

Implications of early diagnosis of autosomal dominant polycystic kidney disease: A post hoc analysis of the TEMPO 3:4 trial

“…An increase in TKV is widely accepted as being the dominant feature of ADPKD progression, as TKV www.nature.com/scientificreports www.nature.com/scientificreports/ is inherently linked to the pathogenesis of PKD and represents a primary event rather than a secondary consequence of disease-causing mutations 21 . Indeed, it was recently demonstrated that the proportion of the total effect of gene type that is mediated by Mayo class is 0.73, supporting the notion that PKD mutations cause loss of GFR predominantly by affecting kidney size 17 . A htTKV ≥600 mL/m at baseline predicts the development of stage 3 CKD within 8 years 22 , and patients with higher rates of TKV growth at baseline have an increased frequency of ESRD after 10 years 16 .…”

“…An analysis of CD subjects by reason for diagnosis (subjects diagnosed due to symptoms and other subjects) showed a significant difference between observed and predicted eGFR for tolvaptan-treated subjects but not placebo-treated subjects, possibly due to the small analysis population (Supplementary Table 10). Finally, a sensitivity analysis based on the mixed polynomial prediction model developed by Yu et al 17 found no significant differences in observed versus predicted eGFR in either tolvaptan-or placebo-treated subjects defined by age at diagnosis (Supplementary Table 11).…”

“…The significant difference between observed and predicted eGFR in the CD group must be interpreted within the context of multiple comparisons and the possibility of a chance finding. Although the Mayo prediction equation is validated and commonly used as a clinical tool, a sensitivity analysis based on the mixed polynomial prediction model recently developed by Yu et al 17 found no significant differences in observed versus predicted eGFR in either tolvaptan-or placebo-treated subjects defined by age at diagnosis.…”

“…We performed two sensitivity analyses, the first a linear mixed model with change in eGFR as outcome, adjusted for baseline differences (including AD versus CD) and their interactions with time. Second, we applied a recently developed mixed polynomial model to predict eGFR change over time 17 . The prediction model developed by Irazabal et al assumes a linear relation between age and eGFR slope, whereas kidney function in ADPKD is relatively stable at young age and declines more rapidly later.…”