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The Combined Effect of High Ambient Temperature and Antihypertensive Treatment on Renal Function in Hospitalized Elderly Patients.
Sagy, I, Vodonos, A, Novack, V, Rogachev, B, Haviv, YS, Barski, L
PloS one. 2016;(12):e0168504
Abstract
BACKGROUND The aging kidney manifests structural, functional as well as pharmacological changes, rendering elderly patients more susceptible to adverse environmental influences on their health, dehydration in particular. HYPOTHESIS Higher temperature is associated with renal function impairment in patients 65 years and older who routinely take thiazide and/or ACE-inhibitors/ARBs. METHODS We obtained health data of patients older than 65 who were admitted to a large tertiary center during the years 2006-2011, with a previous diagnosis of hypertension, and treated with thiazide, ACE-inhibitors/ARBs or both. We collected environmental data of daily temperature, available from collaborative public and governmental institutions. In order to estimate the effect of daily temperature on renal function we performed linear mixed models, separately for each treatment group and creatinine change during hospital admission. RESULTS We identified 26,286 admissions for 14, 268 patients with a mean age of 75.6 (±6.9) years, of whom 53.6% were men. Increment in daily temperature on admission of 5°C had significant effect on creatinine increase in the no treatment (baseline creatinine adjusted 0.824 mg/dL, % change 1.212, % change 95% C.I 0.082-2.354) and dual treatment groups (baseline creatinine adjusted 1.032mg/dL, % change 3.440, % change 95% C.I 1.227-5.700). Sub-analysis stratified by advanced age, chronic kidney disease and primary diagnosis on hospital admission, revealed a significant association within patients admitted due to acute infection and treated with dual therapy. CONCLUSION Whereas previous studies analyzed sporadic climate effects during heat waves and/or excluded older population taking anti-hypertensive medications, the present study is novel by showing a durable association of temperature and decreased renal function specifically in elderly patients taking anti-hypertensive medications.
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Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.
Heerspink, HJ, Johnsson, E, Gause-Nilsson, I, Cain, VA, Sjöström, CD
Diabetes, obesity & metabolism. 2016;(6):590-7
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AIMS: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. METHODS We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. RESULTS Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. CONCLUSIONS Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.
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Risk of hyperkalemia in patients with moderate chronic kidney disease initiating angiotensin converting enzyme inhibitors or angiotensin receptor blockers: a randomized study.
Espinel, E, Joven, J, Gil, I, Suñé, P, Renedo, B, Fort, J, Serón, D
BMC research notes. 2013;:306
Abstract
BACKGROUND Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are renoprotective but both may increase serum potassium concentrations in patients with chronic kidney disease (CKD). The proportion of affected patients, the optimum follow-up period and whether there are differences between drugs in the development of this complication remain to be ascertained. METHODS In a randomized, double-blind, phase IV, controlled, crossover study we recruited 30 patients with stage 3 CKD under restrictive eligibility criteria and strict dietary control. With the exception of withdrawals, each patient was treated with olmesartan and enalapril separately for 3 months each, with a 1-week wash-out period between treatments. Patients were clinically assessed on 10 occasions via measurements of serum and urine samples. We used the Cochran-Mantel-Haenszel statistics for comparison of categorical data between groups. Comparisons were also made using independent two-sample t-tests and Welch's t-test. Analysis of variance (ANOVA) was performed when necessary. We used either a Mann-Whitney or Kruskal-Wallis test if the distribution was not normal or the variance not homogeneous. RESULTS Enalapril and olmesartan increased serum potassium levels similarly (0.3 mmol/L and 0.24 mmol/L respectively). The percentage of patients presenting hyperkalemia higher than 5 mmol/L did not differ between treatments: 37% for olmesartan and 40% for enalapril. The mean e-GFR ranged 46.3 to 48.59 ml/mint/1.73 m2 in those treated with olmesartan and 46.8 to 48.3 ml/mint/1.73 m2 in those with enalapril and remained unchanged at the end of the study. The decreases in microalbuminuria were also similar (23% in olmesartan and 29% in enalapril patients) in the 4 weeks time point. The percentage of patients presenting hyperkalemia, even after a two month period, did not differ between treatments. There were no appreciable changes in sodium and potassium urinary excretion. CONCLUSIONS Disturbances in potassium balance upon treatment with either olmesartan or enalapril are frequent and without differences between groups. The follow-up of these patients should include control of potassium levels, at least after the first week and the first and second month after initiating treatment. TRIAL REGISTRATION The trial EudraCT "2008-002191-98".
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Long-term antiproteinuric effect of dual renin-angiotensin system blockade.
Robles, NR, Fernandez Carbonero, E, Romero, B, Sánchez Casado, E, Cubero, JJ
Cardiovascular therapeutics. 2009;(2):101-7
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We evaluated the long-term changes on overt proteinuria induced by dual blockade of the renin-angiotensin system (RAS). Dual blockade was produced by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an angiotensin converting enzyme (ACE) inhibitor in proteinuric patients. A total of 28 patients (19 men and 9 women) with proteinuria higher than 1 g/24 h were enrolled in this trial of treatment with the ARB candesartan (from 4 up to 32 mg daily) added to existing treatment with an ACE inhibitor. At 6, 12, 24, and 36 months, we evaluated proteinuria in 24-h urinary collections, office blood pressure (BP), plasmatic creatinine (Cr), serum potassium (K), and 24 h urine collection creatinine clearance (CrC). During monoblockade of the RAS by ACE inhibitor treatment, albuminuria was 2.94 +/- 1.92 mg/24 h; BP was 137/76 mmHg; K+ was 4.8 +/- 0.5 mmol/l, Cr was 1.76 +/- 0.67 mg/dL, and CrC was 62 +/- 31.9 mL/min. After 6 months, dual blockade of the RAS albuminuria was 2.18 +/- 2.29 mg/24 h (P < 0.01 vs. baseline) and BP was 133/75 mmHg (not significant). At 36 months, albuminuria was 2.21 +/- 2.20 mg/24 h (P < 0.05 vs. baseline); BP was 133/73 mmHg (not significant). CrC was not changed along the follow up. A small increment of Cr was detected at 24 months (2.11 +/- 1.06 mg/mL, P < 0.05). The antiproteinuric effect of dual renin-angiotensin system blockade combining candesartan and ACE inhibitors remain after 36 months without losing its initial effect. Blood pressure changes seem not to explain this long-term antiproteinuric effect.
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Increased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes.
Thomas, MC, Jerums, G, Tsalamandris, C, Macisaac, R, Panagiotopoulos, S, Cooper, ME, ,
Kidney international. 2005;(6):2494-9
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BACKGROUND The tubular excretion of creatinine significantly contributes to its clearance. Administration of an angtiotensin-converting enzyme (ACE) inhibitor is associated with increased organic ion clearance in experimental diabetes. This study examines the effect and implications of chronic ACE inhibition on renal organic ion excretion in patients with type 1 diabetes. METHODS Samples were obtained from the Melbourne Diabetic Nephropathy Study Group (MDNSG) that randomized patients to receive perindopril (N= 11), nifedipine (N= 11), or placebo (N= 8). Albumin excretion rate, creatinine clearance, and isotopic glomerular filtration rate (GFR) were assessed at baseline and after 24 months. In addition, the clearance of the endogenous cations N-methylynicotinamide (NMN), creatinine, and the anion hippurate were determined by high-performance liquid chromatography (HPLC). RESULTS Following treatment with the ACE inhibitor, perindopril, renal clearance of NMN was increased (+96%) (P < 0.05). There was no difference in patients treated with nifedipine (P= 0.25) and NMN clearance fell in the placebo-treated patients (-26%) (P < 0.05). Changes in NMN clearance were unaffected after adjusting for the effects of perindopril on GFR. However, they were attenuated after adjusting for hippurate clearance, a marker of renal blood flow. This effect of perindopril on NMN clearance was seen in both men and women, regardless of baseline clearance and was correlated with reduced albuminuria following perindopril treatment. CONCLUSION Organic ion clearance is increased in patients with diabetes following chronic ACE inhibition. This is consistent with experimental models showing increased ion transporter expression and improved tubular blood flow, following blockade of the renin-angiotensin system (RAS). These findings may have implications for the interpretation of creatinine-based indices in patients with diabetes.
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Acute administration of diclofenac, but possibly not long term low dose aspirin, causes detrimental renal effects in heart failure patients treated with ACE-inhibitors.
Juhlin, T, Björkman, S, Gunnarsson, B, Fyge, A, Roth, B, Höglund, P
European journal of heart failure. 2004;(7):909-16
Abstract
BACKGROUND Non-steroidal anti-inflammatory drugs (NSAID) or high doses of aspirin (acetylsalicylic acid) can exert detrimental effects on renal function and counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with congestive heart failure. AIMS The objective of our study was to evaluate the renal effects of low dose aspirin and the NSAID diclofenac in patients with congestive heart failure treated with ACE-inhibitors. METHODS Ten patients on their individually titrated dose of ACE-inhibitors and low dose aspirin (< or =125 mg daily) with stable congestive heart failure from coronary artery disease, entered an open investigation while on low dose aspirin, which was then discontinued. After one week wash-out they received an oral dose of 50 mg diclofenac potassium or placebo in a double-blind cross-over fashion with a one week wash-out period between treatments. RESULTS Diclofenac caused significant (P<0.05) decreases in GFR, urine flow, osmolality clearance, and excretion rates of sodium and potassium compared to placebo and aspirin. At t(max) for diclofenac or corresponding time for placebo diclofenac caused 40 (11-59)% (geometric mean and 95% confidence limits) reduction in GFR compared to placebo and 36 (5.4-56)% reduction to low-dose aspirin. No significant changes between low dose aspirin and placebo were found. CONCLUSION Acute administration of diclofenac, but not long term low dose aspirin, has profound impact on renal function in patients with heart failure treated with ACE-inhibitors and may cause worsened heart failure.
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Preventing microalbuminuria in type 2 diabetes.
Ruggenenti, P, Fassi, A, Ilieva, AP, Bruno, S, Iliev, IP, Brusegan, V, Rubis, N, Gherardi, G, Arnoldi, F, Ganeva, M, et al
The New England journal of medicine. 2004;(19):1941-51
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BACKGROUND The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion. METHODS We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits). RESULTS The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups. CONCLUSIONS In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.
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Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.
Anavekar, NS, McMurray, JJ, Velazquez, EJ, Solomon, SD, Kober, L, Rouleau, JL, White, HD, Nordlander, R, Maggioni, A, Dickstein, K, et al
The New England journal of medicine. 2004;(13):1285-95
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BACKGROUND The presence of coexisting conditions has a substantial effect on the outcome of acute myocardial infarction. Renal failure is associated with one of the highest risks, but the influence of milder degrees of renal impairment is less well defined. METHODS As part of the Valsartan in Acute Myocardial Infarction Trial (VALIANT), we identified 14,527 patients with acute myocardial infarction complicated by clinical or radiologic signs of heart failure, left ventricular dysfunction, or both, and a documented serum creatinine measurement. Patients were randomly assigned to receive captopril, valsartan, or both. The glomerular filtration rate (GFR) was estimated by means of the four-component Modification of Diet in Renal Disease equation, and the patients were grouped according to their estimated GFR. We used a 70-candidate variable model to adjust and compare overall mortality and composite cardiovascular events among four GFR groups. RESULTS The distribution of estimated GFR was wide and normally shaped, with a mean (+/-SD) value of 70+/-21 ml per minute per 1.73 m2 of body-surface area. The prevalence of coexisting risk factors, prior cardiovascular disease, and a Killip class of more than I was greatest among patients with a reduced estimated GFR (less than 45.0 ml per minute per 1.73 m2), and the use of aspirin, beta-blockers, statins, or coronary-revascularization procedures was lowest in this group. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, congestive heart failure, stroke, or resuscitation after cardiac arrest increased with declining estimated GFRs. Although the rate of renal events increased with declining estimated GFRs, the adverse outcomes were predominantly cardiovascular. Below 81.0 ml per minute per 1.73 m2, each reduction of the estimated GFR by 10 units was associated with a hazard ratio for death and nonfatal cardiovascular outcomes of 1.10 (95 percent confidence interval, 1.08 to 1.12), which was independent of the treatment assignment. CONCLUSIONS Even mild renal disease, as assessed by the estimated GFR, should be considered a major risk factor for cardiovascular complications after a myocardial infarction.
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Recruitment of African Americans with chronic renal insufficiency into a multicenter clinical trial: the african american study of kidney disease and hypertension.
Phillips, RA, Faulkner, M, Gassman, J, Jaen, L, Kusek, JW, Norris, K, Ojo, A
Journal of clinical hypertension (Greenwich, Conn.). 2004;(8):430-6
Abstract
In patients with hypertensive nephrosclerosis, the African American Study of Kidney Disease and Hypertension (AASK) demonstrated the superiority of angiotensin-converting enzyme inhibitor therapy in blunting progression of renal disease compared with a b blocker and a dihydropyridine calcium channel blocker. In addition, the study found that a blood pressure treatment strategy that resulted in an achieved blood pressure of 128/78 mm Hg (low blood pressure goal) was no more effective in slowing the progression of renal disease than a strategy that resulted in a blood pressure of 141/85 mm Hg (usual blood pressure goal). AASK, which enrolled only African Americans with mild to moderate chronic renal insufficiency, also provided an opportunity to evaluate recruitment methods in minority populations. Eighty-three percent of patients were recruited through screening in clinical practice. To randomize 635 patients, 558,295 charts were reviewed (approximately 879 charts per randomized patient). More than half of the randomized patients (n=635 or 58%) were found by chart review. Sixty percent of women with creatinine levels considered within the normal range had at least mild chronic renal insufficiency. Screening in clinical practice was the most effective strategy to recruit participants with mild to moderate chronic renal insufficiency and hypertension into the clinical trial. This technique may also be an effective approach in trials of other essentially asymptomatic conditions.
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The JNC 7 approach compared to conventional treatment in diabetic patients with hypertension: a double-blind trial of initial monotherapy vs. combination therapy.
Fox, JC, Leight, K, Sutradhar, SC, Demopoulos, LA, Gleim, GW, Lewin, AJ, Bakris, GL
Journal of clinical hypertension (Greenwich, Conn.). 2004;(8):437-42; quiz 443-4
Abstract
The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg. A randomized, double-blind trial force titrated initial combination therapy utilizing an angiotensin receptor blocker (ARB) combination (losartan/hydrochlorothiazide [LOS/HCTZ]) compared with an angiotensin-converting enzyme (ACE) inhibitor (ramipril), for 8 weeks, and tested the hypothesis that combination therapy is more likely to achieve goal BP vs. monotherapy. At 4 weeks, 30.5% of LOS/HCTZ and 14.4% of ramipril recipients achieved goal diastolic BP (p<0.001). More participants achieved goal systolic BP in the ARB/HCTZ group at 4 weeks (29.8% vs. 14.4%; p<0.001). At 4 weeks, mean diastolic BP had decreased 10.2+/-7.4 mm Hg in the LOS/HCTZ group compared with 6.4+/-6.8 mm Hg in the ramipril group (p<0.001), and systolic BP had fallen 15.4+/-13.1 mm Hg in the ARB/HCTZ compared with 9.2+/-10.2 mm Hg in the ACE-inhibitor group (p<0.001). Significant differences favoring the combination were also noted at 8 weeks. Drug-related adverse experiences were 10.3% for the combination compared with 12.7% for the monotherapy group. Initial combination therapy with an ARB/HCTZ was more effective than ACE-inhibitor monotherapy in achieving BP goals in participants with diabetes with no significant differences in the incidence of adverse experiences. These observations confirm other studies of combination therapies, such as b blocker/diuretic, ACE inhibitor/diuretic, or ACE inhibitor/calcium channel blocker. The use of two medications will achieve goal BP in more patients than monotherapy. This observation is important in treatment of high-risk patients with diabetes.