Gitomer, Berenice Y

Key Points In an observational cohort of mostly non-Hispanic White women, pregnancy was not associated with later-life accelerated kidney function decline. Pregnancy occurring during the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial was not associated with kidney disease progression relative to women who did not become pregnant. Prior evidence indicates that adverse pregnancy outcomes may be involved in autosomal dominant polycystic kidney disease progression; pregnant women should be closely monitored. Background Data are conflicting regarding whether pregnancy influences disease progression in women with autosomal dominant polycystic kidney disease (ADPKD). This study examined whether pregnancy or number of pregnancies was associated with kidney disease progression in women with ADPKD. Methods Women with early- (study A) and late-stage (study B) ADPKD from the HALT Progression of Polycystic Kidney Disease (HALT-PKD) trial were included to examine the association between self-reported number of pregnancies (categorical predictor: no pregnancy versus 1–2 pregnancies and ≥3 pregnancies), annual slope of eGFR, annual percent change in total kidney volume (%ΔTKV), and a composite outcome (kidney failure, 50% decline in eGFR, or death) using multivariable linear regression and Cox proportional hazard models. In addition, women who became pregnant, had full-term pregnancies, and available data during study participation ( n =13) were propensity matched (1:4) to women who were not pregnant during study participation, and a mixed model was applied to determine the association of pregnancy with eGFR slope and %ΔTKV. Results Across all analyses, 455 women with a median age of 45 (interquartile range, 38–50) years and eGFR of 69±25 ml/min per 1.73 m 2 at baseline were included. One hundred ninety-nine women had 1–2 pregnancies, and 165 women had ≥3 pregnancies. There was no association of 1–2 pregnancies or ≥3 pregnancies (versus no pregnancies) with eGFR slope ( β -estimate [95% confidence interval (CI)]; 1–2 pregnancies: 0.22 [−0.44 to 0.89]; ≥3 pregnancies: −0.46 [−1.16 to 0.25]), %ΔTKV ( β -estimate [95% CI]; 1–2 pregnancies: 0.92 [−0.34 to 2.17]; ≥3 pregnancies: 0.69 [−0.67 to 2.04]), or time to composite outcome (hazard ratio [95% CI]; 1–2 pregnancies: 1.04 [0.56 to 1.93]; ≥3 pregnancies: 1.48 [0.78 to 2.77]) in adjusted models. Moreover, there was no difference in annual eGFR slope ( β -estimate: −0.14 [95% CI, −2.72 to 2.44]) and %ΔTKV ( β -estimate: 0.04 [95% CI, −3.74 to 3.82]) in women who became pregnant matched to women who did not became pregnant during their participation in the study. Conclusions Pregnancy was not associated with ADPKD progression among women with early- and late-stage ADPKD enrolled in the HALT-PKD trial.

ABSTRACT Background A decrease in renal blood flow (RBF) precedes estimated glomerular filtration rate (eGFR) decline among patients with autosomal dominant polycystic kidney disease (ADPKD) and inversely associates with disease severity and progression. However, it is unknown whether RBF independently predicts progression to kidney failure in patients with ADPKD. Methods A total of 379 participants with early-stage ADPKD (mean age 36.6 ± 8.5 years; eGFR: 92.9 ± 17.1 ml/min/1.73 m2) who participated in the Halt Progression of Polycystic Kidney Disease Study A (HALT PKD A; NCT00283686) with baseline RBF (phase contrast magnetic resonance imaging) data were included in the primary analysis. Kaplan–Meier survival analysis and multivariate Cox proportional hazard models were used to determine the association of baseline RBF as a continuous and categorical variable with kidney failure risk (during the HALT study and subsequently linked to the US Renal Data System) over a median follow-up period of 13.1 years (interquartile range 7.5–14.5) (primary outcome). All-cause mortality was also considered as a competing risk (Fine and Gray method). The associations of RBF with eGFR slope and the change in height-adjusted total kidney volume (∆htTKV) were evaluated with linear and logistic regression models. Results The kidney failure incidence rate was the highest among those with the lowest RBF tertile {1.90 [95% confidence interval (CI) 1.31–2.78] versus 0.34 [95% CI 0.14–0.83] events/100 person-years in tertile 3}. In the fully adjusted model, the lowest RBF tertile was associated with a higher risk of progression to kidney failure [hazard ratio (HR) 3.19 (95% CI 1.05–9.67] versus the highest tertile]. The association of RBF with kidney failure risk was slightly attenuated in adjusted models. All associations remained similar when considering death as a competing risk [HR 0.82 (95% CI 0.67–1.00) per 100 ml/min/1.73 m2 higher RBF]. Higher RBF was associated with a slower eGFR decline and lower odds of rapid annual ∆htTKV. Conclusions Lower baseline RBF independently associates with a greater risk of progression to kidney failure in early-stage patients with ADPKD.

ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited progressive kidney disease. Time-restricted eating (TRE) is a fasting regimen that restricts eating to a particular window (typically 8 hours/day), which could slow cyst growth based on preclinical models. Methods A 12-month, randomized, controlled, behavioral dietary intervention compared TRE with a control group given healthy eating advice without TRE (HE), without caloric restriction. Participants underwent baseline and 12-month measurements, including adherence (percentage of participants adhering to the 8-hour window; primary outcome), and MRI to determine height-adjusted total kidney volume (htTKV) and adiposity. Results Twenty-nine participants (23 females, mean standard ± deviation 48 ± 9 years) with a body mass index of 31.1±5 kg/m2 were randomized to TRE (n = 14) or HE (n = 15). Of the total participants, 71% (n = 10) of TRE and 87% (n = 13) of HE participants completed the intervention. The eating window was 9.6 ± 3.6 hours for TRE (60% achieving the 8-hour window) and 12.0 ± 2.0 for HE groups (P = .07). At month 12, both groups lost modest weight (−2.4 ± 6.4% and −3.6 ± 5.4% in the TRE and HE groups, respectively). Annual change in htTKV was 3.0 ± 8.5% and 4.6 ± 8.8% in the TRE and HE groups, respectively. Both change in weight (r = 0.67, P < .01) and change in visceral adiposity (r = 0.54, P < .01) were positively correlated with change in htTKV. Conclusion Both the TRE and HE group lost modest weight at 12 months. The targeted TRE adherence of ≥75% of participants was not achieved. Weight and adiposity loss may be more important drivers of kidney growth than the timing of eating.

Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. Background Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least eight others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for ALG8 / ALG9 pathogenic variants. Results Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families—frequencies that were approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%), with enlarged livers (>2L) found in 11 of 62 patients, although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys, but enlarged livers were rare; for both genes, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.