Citations

Significance Statement Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, is also an independent marker for incidence and progression of renal diseases. Mechanistically, it has been shown to activate podocytes in glomerular diseases. In this study, the authors provide the first description linking suPAR levels with disease progression for a major genetic renal disease that mainly affects the extraglomerular compartment, autosomal dominant polycystic kidney disease (ADPKD). They found an association between suPAR levels and height-adjusted total kidney volume, independent of age, sex, race, hypertension, and eGFR. In addition, patients with suPAR levels >2.82 ng/ml had a 3.38-fold increase in risk of incident ESRD. These findings suggest that suPAR levels may be useful for early identification of patients with ADPKD at high risk of disease progression. Background Levels of soluble urokinase plasminogen activator receptor (suPAR), an inflammation marker, are strongly predictive of incident kidney disease. Patients with autosomal dominant polycystic kidney disease (ADPKD) experience progressive decline in renal function, but rates of decline and outcomes vary greatly. Whether suPAR levels are predictive of declining kidney function in patients with ADPKD is unknown. Methods We assessed suPAR levels in 649 patients with ADPKD who underwent scheduled follow-up for at least 3 years, with repeated measurements of height-adjusted total kidney volume and creatinine-derived eGFR. We used linear mixed models for repeated measures and Cox proportional hazards to characterize associations between baseline suPAR levels and follow-up eGFR or incident ESRD. Results The median suPAR level was 2.47 ng/ml and median height-adjusted total kidney volume was 778, whereas mean eGFR was 84 ml/min per 1.73 m 2 . suPAR levels were associated with height-adjusted total kidney volume ( β =0.02; 95% confidence interval, 0.01 to 0.03), independent of age, sex, race, hypertension, and eGFR. Patients in the lowest suPAR tertile (<2.18 ng/ml) had a 6.8% decline in eGFR at 3 years and 22% developed CKD stage 3, whereas those in the highest tertile (suPAR>2.83 ng/ml) had a 19.4% decline in eGFR at 3 years and 68% developed CKD stage 3. suPAR levels >2.82 ng/ml had a 3.38-fold increase in the risk of incident ESRD. Conclusions suPAR levels were associated with progressive decline in renal function and incident ESRD in patients with ADPKD, and may aid early identification of patients at high risk of disease progression.

Background and objectives To evaluate the growth pattern of kidney cyst number and cyst volume in association with kidney size, demographics, and genotypes in autosomal dominant polycystic kidney disease. Design, setting, participants, & measurements Kidney cyst number and cyst volume were measured from serial magnetic resonance images, giving a maximum follow-up of 14.23 years, from 241 patients with autosomal dominant polycystic kidney disease (15–46 years old at baseline). The growth pattern was analyzed, in association with sex, age, height-adjusted total kidney volume, and genotype, using linear mixed models of repeated measurements and tests of interactions with age (as a time-dependent covariate) to assess rates of change over time. Models were also fit using Irazabal class. Genotypic groups were characterized as either ( 1 ) PKD1 truncating, PKD1 nontruncating, and PKD2 plus patients with no mutation detected; or ( 2 ) in combination with PKD1 mutation strength groups. Results Imaging and genetic data were collected (at least one visit) for 236 participants. The mean height-adjusted total cyst number increased exponentially over time from a baseline value of 762 to 1715 at the last clinic visit, while the mean height-adjusted total cyst volume increased exponentially from 305 to 770 ml. Height-adjusted total kidney volume, height-adjusted total cyst number, and height-adjusted total cyst volume were all highly correlated over time. Female participants and participants with larger height-adjusted total kidney volume at baseline showed smaller rates of change in the log of height-adjusted total cyst number and cyst volume. PKD1 was associated with significant increases in both cyst number and volume at a given age, but genotype did not significantly affect the rate of growth. Conclusions Both height-adjusted total cyst number and height-adjusted total cyst volume increased exponentially and more than doubled over 14.23 years of follow-up. Compared with PKD2 plus no mutation detected, PKD1 was associated with a greater cyst number and volume at a given age, but no significant difference in the rate of growth.

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height–adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.