Design of Clinical Trials in Acute Kidney Injury: A Report from an NIDDK Workshop-Prevention Trials
Division of Nephrology, University of Virginia Health System, Charlottesville, VA 22908-0133, USA.Clinical Journal of the American Society of Nephrology (Impact Factor: 4.61). 03/2012; 7(5):851-5. DOI: 10.2215/CJN.12811211
AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.
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ABSTRACT: The maintenance of normal metabolism and body defenses depends on the balance between cellular antioxidant and anti-inflammatory factors. This balance can be disrupted by agents/mechanisms in the extracellular milieu that induce excess reactive oxygen species (ROS) and inflammation. Cytopathic advanced glycation endproducts, present in ever increasing amounts in the modern diet, are one of the major environmental factors that cause excess ROS and/or inflammation at all ages and induce complications in aging, such as chronic kidney disease (CKD) and type 2 diabetes. Increased ROS and/or inflammation are present in both aging and CKD, and are associated with reduced cellular defenses against ROS and/or inflammation. Affected individuals have reduced defenses against further stress and are predisposed to organ failure, now a well-known phenomenon in aging. Thus, new methods are urgently needed to safely reduce ROS and/or inflammation in the aging type 2 diabetes patient with CKD. Studies of both normal aging and diabetic patients with kidney disease underline the fact that increased ROS and/or inflammation can be managed in these conditions by economical, safe, and effective interventions that reduce the uptake of advanced glycation endproducts by either modifying preparation of food or an oral drug. This communication reviews these data and adds new information on the efficacy of a drug, sevelamer carbonate, required to reduce ROS and/or inflammation in the aging type 2 diabetes patient complicated by CKD. If larger and longer studies confirm the hypothesis that one or both of these interventions reduce progression of CKD, it could represent a new paradigm in the management of complications in the type 2 diabetes patient with CKD.The Journals of Gerontology Series A Biological Sciences and Medical Sciences 10/2012; 67(12). DOI:10.1093/gerona/gls195 · 5.42 Impact Factor
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ABSTRACT: Males have higher prevalence of hypertension and renal injury than females, which may be attributed in part to androgen-mediated effects on renal hemodynamics. Tubuloglomerular feedback (TGF) is an important mechanism in control of renal microcirculation. The present study examines the role of testosterone in the regulation of TGF responses. TGF was measured by micropuncture (change of stop flow pressure, ΔPsf) in castrated SD rats. Addition of testosterone (10-7mol/L) into the lumen increased the ΔPsf from 10.1±1.2 to 12.2±1.2 mmHg. To determine if androgen receptors (AR) are involved, mRNA of AR was measured in the macula dense cells isolated by laser capture microdissection from kidneys, and a macula-densa like cell line (MMDD1). AR mRNA was expressed in the macula densa of rats and in MMDD1 cells. We next examined the effects of the AR blocker, flutamide (10-5mol/L) on the TGF response. Addition of flutamide blocked the effects of testosterone on TGF. Addition of tempol (10-4mol/L), or PEG-SOD (100 u/ml), to scavenge superoxide blocked the effect of testosterone to augment TGF. We then applied apocynin to inhibit NAD(P)H oxidase and oxypurinol to inhibit xanthine oxidase and found the testosterone-induced augmentation of TGF was blocked. In additional experiments in MMDD1 cells, we found that testosterone increased O2- generation. Apocynin or oxypurinol blocked the testosterone-induced increases of O2- while blockade of COX-2 with NS-398 had no effect. These findings suggest that testosterone enhances TGF response by stimulating O2- production in macula densa via an AR-dependent pathway.AJP Regulatory Integrative and Comparative Physiology 03/2013; 304(9). DOI:10.1152/ajpregu.00341.2012 · 3.11 Impact Factor
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ABSTRACT: Diabetes mellitus and decreased renal function are important risk factors for contrast-induced nephropathy (CIN) in which oxidative stress damage may play a role. Alkalinization with sodium bicarbonate (NaHCO3) has been proposed as a means of reducing free-radical mediated renal injury; however, the effectiveness of NaHCO3 treatment to prevent CIN in high-risk patients remains uncertain. We performed a prospective, randomized, double blind, sodium chloride (NaCl) hydration-controlled study of NaHCO3 in 120 diabetic patients with impaired renal function (serum creatinine ≥100μmol/L) undergoing an elective procedure with use of low-osmolar contrast media. The primary endpoint was the incidence of CIN defined as creatinine increase of ≥25% and/or ≥44μmol/L within 2 days after contrast. Secondary end-points were maximal changes in serum creatinine and estimated glomerular filtration rate. Urine F2-isoprostane levels were also assessed as measure of oxidative stress. There were no significant group differences in baseline characteristics except for the marginally lower age of the NaHCO3 treated patients (63±11 vs. 67±10 years; p=0.05). CIN occurred in 7 (11.5%) and 5 (8.5%) patients of the NaHCO3 and NaCl groups, respectively (p=0.76; incidence rate ratio 1.35; 95% CI 0.37-5.41). No significant differences were seen in secondary outcome measures and changes in the parameter of oxidative stress. In diabetic patients with renal function impairment sodium bicarbonate does not confer protection against contrast-induced nephropathy greater than sodium chloride-based hydration. Its specific role in mitigating oxidative stress damage in CIN is also not supported by our data.Diabetes research and clinical practice 07/2013; 101(3). DOI:10.1016/j.diabres.2013.05.015 · 2.54 Impact Factor
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