Nowak, Kristen L

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.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. In addition, the long-term consequences of these dietary interventions, including their effect on adverse events in patients with ADPKD, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal body weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction seems particularly beneficial for patients with overweight or obesity because it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in patients with ADPKD. Notably, β -hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for patients with ADPKD. In summary, dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term effects. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD.

Background Higher serum intact fibroblast growth factor 23 (iFGF23) was associated with disease progression in participants with autosomal dominant polycystic kidney disease (ADPKD) in the HALT-PKD Studies. PKD mutation is also an important determinant of progression. We hypothesized that serum levels of iFGF23 and vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH) 2 D] and 25-hydroxyvitamin D [25[OH]D]) differ according to ADPKD mutation and differentially predict clinical end points according to genotype (significant interaction between genotype and mineral metabolites). Methods A total of 864 individuals with ADPKD who participated in the HALT-PKD Study A or B and had measurements of mineral metabolites (1,25[OH] 2 D, 25[OH]D, iFGF23) were categorized by PKD mutation (PKD1 truncating, PKD1 nontruncating, PKD2, or no mutation detected [NMD]). The association of the interactions of genotype × iFGF23, genotype × 1,25(OH)2D, and genotype × 25(OH)D with ( 1 ) annualized change in eGFR; ( 2 ) mean annualized percentage change in height-corrected total kidney volume (Study A only); and ( 3 ) time to a composite of 50% reduction in eGFR, ESKD, or death were evaluated using linear regression and Cox proportional hazards regression. Results Median (interquartile range) iFGF23 differed (PKD1 truncating, 55.8 [40.7–76.8]; PKD1 nontruncating, 49.9 [37.7–71.0]; PKD2, 49.0 [33.8–70.5]; NMD, 50.3 [39.7–67.4] pg/ml; P =0.03) and mean±SD 1,25(OH) 2 D differed (PKD1 truncating, 32.8±12.8; PKD1 nontruncating, 33.4±12.5; PKD2, 34.1±13.1; NMD, 38.0±14.6 pg/ml; P =0.02) according to PKD genotype. There was a significant interaction between iFGF23 and genotype ( P =0.02) for the composite end point in fully adjusted models, but no significant interaction between 1,25(OH) 2 D or 25(OH)D and genotype for clinical end points. Conclusions ADPKD genotype interacts significantly with FGF23 to influence clinical end points. Whereas the worst outcomes were in individuals with a PKD1-truncating or -nontruncating mutation and the highest iFGF23 tertile, risk of the composite end point differed according to iFGF23 the most in the PKD1-nontruncating and PKD2 groups.