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Articles by V. E Torres
Total Records ( 3 ) for V. E Torres
  V. E Torres , L Bankir and J. J. Grantham
 

Autosomal dominant polycystic disease (ADPKD) is an inherited disorder characterized by the development within renal tubules of innumerable cysts that progressively expand to cause renal insufficiency. Tubule cell proliferation and transepithelial fluid secretion combine to enlarge renal cysts, and 3'-5'-cyclic adenosine monophosphate (cAMP) stimulates that growth. The antidiuretic hormone, arginine vasopressin (AVP), operates continuously in ADPKD patients to stimulate the formation of cAMP, thereby contributing to cyst and kidney enlargement and renal dysfunction. Studies in animal models of ADPKD provide convincing evidence that blocking the action of AVP dramatically ameliorates the disease process. In the current analysis, the authors reason that increasing the amount of solute-free water drunk evenly throughout the day in patients with ADPKD and normal renal function will decrease plasma AVP concentrations and mitigate the action of cAMP on the renal cysts. Potential pitfalls of increasing fluid intake in ADPKD patients are considered, and suggestions for how physicians may prudently implement this therapy are offered.

  A. B Chapman , V. E Torres , R. D Perrone , T. I Steinman , K. T Bae , J. P Miller , D. C Miskulin , F. R Oskoui , A Masoumi , M. C Hogan , F. T Winklhofer , W Braun , P. A Thompson , C. M Meyers , C Kelleher and R. W. Schrier
 

Background and objectives: Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease.

Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m2 were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively.

Results: This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life.

Conclusions: HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD.

  V. E Torres , A Boletta , A Chapman , V Gattone , Y Pei , Q Qian , D. P Wallace , T Weimbs and R. P. Wuthrich
 

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.

 
 
 
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