Background and objectives: On the basis of earlier observations, we evaluated the association between overweight and obesity and rapid progression of autosomal dominant polycystic kidney disease in participants in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial. More importantly, we also determined whether efficacy of tolvaptan was attenuated in individuals with baseline overweight or obesity. Design, setting, participants, & measurements: A total of 1312 study participants with relatively early-stage autosomal dominant polycystic kidney disease (mean eGFR 78±22 ml/min per 1.73 m²) who were at high risk of rapid progression were categorized by body mass index (BMI; calculated using nonkidney weight) as normal weight (18.5–24.9 kg/m²; n=670), overweight (25.0–29.9 kg/m²; n=429), or obese (≥30 kg/m²; n=213). Linear and multinomial logistic regression models were used to determine the association of baseline overweight and obesity with change in total kidney volume (TKV) over the 3-year study period. Results: In fully adjusted models, higher BMI was associated with greater annual percent change in TKV (difference of 1.20 [95% confidence interval (95% CI), 0.85 to 1.55] per five-unit higher BMI). Overweight and obesity were associated with higher odds of annual percent change in TKV of ≥7% versus <5% (overweight: odds ratio, 2.04 [95% CI, 1.45 to 2.87]; obese: odds ratio, 4.31 [95% CI, 2.83 to 6.57] versus normal weight). eGFR decline did not differ according to BMI (fully adjusted difference in decline of −0.95 [95% CI, −2.32 to 0.40] ml/min per 1.73 m² per year per five-unit higher BMI). The three-way interaction (treatment×time×BMI group) was not statistically significant in linear mixed models with an outcome of TKV (log-transformed estimated coefficient comparing the treatment effect for overweight versus normal weight: 0.56% [95% CI, −0.70% to 1.84%] per year; P=0.38; obese versus normal weight: 0.07% [95% CI, −1.47% to 1.63%] per year; P=0.93) or eGFR (estimated coefficient comparing overweight versus normal weight: −0.07 [95% CI, −0.95 to 0.82] ml/min per 1.73 m² per year; P=0.88; obese versus normal weight: 0.22 [95% CI, −0.93 to 1.36] ml/min per 1.73 m² per year; P=0.71). Conclusions: Overweight and particularly obesity are strongly and independently associated with kidney growth, but not eGFR slope, in the TEMPO 3:4 trial, and tolvaptan efficacy is irrespective of BMI categorization. Clinical Trial registry name and registration number: Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4, NCT00428948

Patients with chronic kidney disease (CKD) commonly experience sex hormone disturbances, which may be associated with the risk of cardiovascular disease (CVD) and mortality. This review aimed to systematically evaluate current findings on the association of sex hormone levels with the risk of CVD events and mortality (CVD and all‐cause) in the CKD population. Articles were systematically searched in CINAHL, Cochrane, and PubMed. A total of 1739 articles were independently screened by two reviewers and 17 prospective cohort studies were included. The clinical conditions of the patients were those with non‐dialysis CKD [mean/median estimated glomerular filtration rate (eGFR) between 15–51 ml/min/1.73 m²] and those on chronic dialysis (mean/median vintage between 6–125 months). The sample size ranged from 111 to 2419 and the mean/median age of subjects ranged from 52 to 72 years. The sex hormones studied were testosterone, estradiol, prolactin, dehydroepiandrosterone sulfate, and relaxin. A random‐effects model was used to generate a pooled hazard ratio (HR) to evaluate the association of total testosterone levels with the risk of CVD and all‐cause mortality. Most studies examined total testosterone levels (11 out of 17 studies) and studied only male patients (12 out of 17 studies). A lower total testosterone level was associated with a higher risk of CVD mortality [HR 4.37 (95% CI 1.40–13.65)] and all‐cause mortality [1.96 (1.35–2.83)] in males with CKD. To conclude, there is a strong need for additional studies examining the association of sex hormones with cardiovascular and mortality risk in female patients with CKD.

Background and objectives: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. Design, setting, participants, & measurements: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6–25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m² were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. Results: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, −0.84 to 3.13; placebo: 0.33; 95% confidence interval, −1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, −1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, −25.7 to 26.9; placebo: 6.5; 95% confidence interval, −20.4 to 33.5; estimated difference for change: −5.9; 95% confidence interval, −35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. Conclusions: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. Clinical Trial registry name and registration number: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3

Patients with chronic kidney disease (CKD) are more likely to die of cardiovascular diseases, including cerebrovascular disease, than to progress to end‐stage kidney disease. Cerebrovascular dysfunction, characterized by reduced cerebrovascular reactivity, cerebral hypoperfusion, and increased pulsatile flow within the brain, precedes the onset of dementia and is linked to cognitive dysfunction. However, whether impaired cerebrovascular function is present in non‐dialysis dependent CKD is largely unknown. Using transcranial Doppler, we compared middle cerebral artery (MCA) blood velocity response to hypercapnia (normalized for blood pressure and end‐tidal CO₂; a measure of cerebrovascular reactivity) and MCA pulsatility index (PI; a measure of cerebrovascular stiffness) in patients with stage 3–4 CKD vs. age‐matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function), measured carotid‐femoral pulse‐wave velocity (PWV; aortic stiffness), and assessed ex vivo nitric oxide (NO) and reactive oxygen species (ROS) production from human brain endothelial cells incubated with serum obtained from study participants. MCA PI was higher in patients with CKD vs. controls; however, normalized MCA blood velocity response to hypercapnia did not differ between groups. Similar results were observed in a validation cohort of midlife and older adults divided by the median estimated glomerular filtration rate (eGFR). MCA PI was associated with greater large‐elastic artery stiffness (carotid‐femoral PWV), worse executive function (trails B time), lower eGFR, and higher ex vivo ROS production. These data suggest that impaired kidney function is associated with greater cerebrovascular stiffness, which may contribute to the known increased risk for cognitive impairment in patients with CKD.