Browsing by Subject "ADPKD"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD
    (Wolters Kluwer, 2022) Nowak, Kristen L.; Farmer-Bailey, Heather; Wang, Wei; You, Zhiying; Steele, Cortney; Cadnapaphornchai, Melissa A.; Klawitter, Jelena; Patel, Nayana; George, Diana; Jovanovich, Anna; Soranno, Danielle E.; Gitomer, Berenice; Chonchol, Michel; Pediatrics, School of Medicine
    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.
  • Thumbnail Image
    Item
    Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease
    (Elsevier, 2014) Wallace, Darren P.; White, Corey; Savinkova, Lyudmyla; Nivens, Emily; Reif, Gail A.; Pinto, Cibele S.; Raman, Archana; Parnell, Stephen C.; Conway, Simon J.; Fields, Timothy A.; Pediatrics, School of Medicine
    In renal cystic diseases, sustained enlargement of fluid-filled cysts is associated with severe interstitial fibrosis and progressive loss of functioning nephrons. Periostin, a matricellular protein, is highly overexpressed in cyst-lining epithelial cells of autosomal-dominant polycystic disease kidneys (ADPKD) compared with normal tubule cells. Periostin accumulates in situ within the matrix subjacent to ADPKD cysts, binds to αVβ3 and αVβ5 integrins, and stimulates the integrin-linked kinase to promote cell proliferation. We knocked out periostin (Postn) in pcy/pcy mice, an orthologous model of nephronophthisis type 3, to determine whether periostin loss reduces PKD progression in a slowly progressive model of renal cystic disease. At 20 weeks of age, pcy/pcy:Postn(-/-) mice had a 34% reduction in kidney weight/body weight, a reduction in cyst number and total cystic area, a 69% reduction in phosphorylated S6, a downstream component of the mTOR pathway, and fewer proliferating cells in the kidneys compared with pcy/pcy:Postn(+/+) mice. The pcy/pcy Postin knockout mice also had less interstitial fibrosis with improved renal function at 20 weeks and significantly longer survival (51.4 compared with 38.0 weeks). Thus, periostin adversely modifies the progression of renal cystic disease by promoting cyst epithelial cell proliferation, cyst enlargement, and interstitial fibrosis, all contributing to the decline in renal function and premature death.
  • Thumbnail Image
    Item
    Prospects for mTOR Inhibitor Use in Patients with Polycystic Kidney Disease and Hamartomatous Diseases
    (American Society of Nephrology, 2010-07) Torres, Vicente E.; Boletta, Alessandra; Chapman, Arlene; Gattone, Vincent; Pei, York; Qian, Qi; Wallace, Darren P.; Weimbs, Thomas; Wüthrich, Rudolf P.; Anatomy and Cell Biology, School of Medicine
    Mammalian target of rapamycin (mTOR) is the core component of two complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and analogues. mTORC2 is impeded only in some cell types by prolonged exposure to these compounds. mTOR activation is linked to tubular cell proliferation in animal models and human autosomal dominant polycystic kidney disease (ADPKD). mTOR inhibitors impede cell proliferation and cyst growth in polycystic kidney disease (PKD) models. After renal transplantation, two small retrospective studies suggested that mTOR was more effective than calcineurin inhibitor-based immunosuppression in limiting kidney and/or liver enlargement. By inhibiting vascular remodeling, angiogenesis, and fibrogenesis, mTOR inhibitors may attenuate nephroangiosclerosis, cyst growth, and interstitial fibrosis. Thus, they may benefit ADPKD at multiple levels. However, mTOR inhibition is not without risks and side effects, mostly dose-dependent. Under certain conditions, mTOR inhibition interferes with adaptive increases in renal proliferation necessary for recovery from injury. They restrict Akt activation, nitric oxide synthesis, and endothelial cell survival (downstream from mTORC2) and potentially increase the risk for glomerular and peritubular capillary loss, vasospasm, and hypertension. They impair podocyte integrity pathways and may predispose to glomerular injury. Administration of mTOR inhibitors is discontinued because of side effects in up to 40% of transplant recipients. Currently, treatment with mTOR inhibitors should not be recommended to treat ADPKD. Results of ongoing studies must be awaited and patients informed accordingly. If effective, lower dosages than those used to prevent rejection would minimize side effects. Combination therapy with other effective drugs could improve tolerability and results.