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Tian Chen,1 Pamela Brewster,1 Katherine R Tuttle,2 Lance D Dworkin,1 William Henrich,3 Barbara A Greco,4 Michael Steffes,5 Sheldon Tobe,6 Kenneth Jamerson,7 Karol Pencina,8 Joseph M Massaro,8 Ralph B D’Agostino Sr,8 Donald E Cutlip,9 Timothy P Murphy,10 Christopher J Cooper,1 Joseph I Shapiro11 1University of Toledo, Toledo, OH, USA; 2Providence Health Care, University of Washington, Spokane, WA, USA; 3University of Texas Health Science Center, San Antonio, TX, USA; 4Baystate Health, Springfield, MA, USA; 5University of Minnesota, Minneapolis, MN, USA; 6University of Toronto, Toronto, ON, Canada; 7University of Michigan, Ann Arbor, MI, USA; 8Harvard Clinical Research Institute, Boston University, Boston, MA, USA; 9Beth Israel Deaconess Medical Center, Boston, MA, USA; 10Brown University, Providence, RI, USA; 11Marshall University, Huntington, WV, USA Background: Data derived from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study were analyzed in an effort to employ machine learning methods to predict the composite endpoint described in the original study. Methods: We identified 573 CORAL subjects with complete baseline data and the presence or absence of a composite endpoint for the study. These data were subjected to several models including a generalized linear (logistic-linear) model, support vector machine, decision tree, feed-forward neural network, and random forest, in an effort to attempt to predict the composite endpoint. The subjects were arbitrarily divided into training and testing subsets according to an 80%:20% distribution with various seeds. Prediction models were optimized within the CARET package of R. Results: The best performance of the different machine learning techniques was that of the random forest method which yielded a receiver operator curve (ROC) area of 68.1%±4.2% (mean ± SD) on the testing subset with ten different seed values used to separate training and testing subsets. The four most important variables in the random forest method were SBP, serum creatinine, glycosylated hemoglobin, and DBP. Each of these variables was also important in at least some of the other methods. The treatment assignment group was not consistently an important determinant in any of the models. Conclusion: Prediction of a composite cardiovascular outcome was difficult in the CORAL population, even when employing machine learning methods. Assignment to either the stenting or best medical therapy group did not serve as an important predictor of composite outcome. Clinical Trial Registration: ClinicalTrials.gov, NCT00081731 Keywords: chronic kidney disease, cardiovascular disease, glomerular filtration rate, hypertension, ischemic renal disease, renal artery stenosis

Background Early rapid declines of kidney function may occur in patients with atherosclerotic renal artery stenosis with institution of medical therapy. The causes and consequences are not well understood. Methods and Results Patients enrolled in the medical therapy–only arm of the CORAL (Cardiovascular Outcomes With Renal Artery Lesions) study were assessed for a rapid decline (RD) in estimated glomerular filtration rate (eGFR), defined as a ≥30% decrease from baseline to either 3 months, 6 months, or both. In the medical therapy–only cohort, eGFR was available in 359 subjects at all time points, the subjects were followed for a median of 4.72 years, and 66 of 359 (18%) subjects experienced an early RD. Baseline log cystatin C (odds ratio, 1.78 [1.11–2.85]; P=0.02), age (odds ratio, 1.04 [1.00–1.07]; P, See Editorial Beige

Background Multiple randomized clinical trials comparing renal artery stent placement plus medical therapy with medical therapy alone have not shown any benefit of stent placement. However, debate continues whether patients with extreme pressure gradients, stenosis severity, or baseline blood pressure benefit from stent revascularization. Objectives The study sought to test the hypothesis that pressure gradients, stenosis severity, and/or baseline blood pressure affects outcomes after renal artery stent placement. Methods Using data from 947 patients with a history of hypertension or chronic kidney disease from the largest randomized trial of renal artery stent placement, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study, we performed exploratory analyses to determine if subsets of patients experienced better outcomes after stent placement than the overall cohort. We examined baseline stenosis severity, systolic blood pressure, and translesion pressure gradient (peak systolic and mean) and performed interaction tests and Cox proportional hazards analyses for the occurrence of the primary endpoint through all follow-up, to examine the effect of these variables on outcomes by treatment group. Results There were no statistically significant differences in outcomes based on the examined variables nor were there any consistent nonsignificant trends. Conclusions Based on data from the CORAL randomized trial, there is no evidence of a significant treatment effect of the renal artery stent procedure compared with medical therapy alone based on stenosis severity, level of systolic blood pressure elevation, or according to the magnitude of the trans-stenotic pressure gradient. (Benefits of Medical Therapy Plus Stenting for Renal Atherosclerotic Lesions [CORAL]; NCT00081731 )

Purpose To describe the experience and results from the roll-in phase of the Cardiovascular Outcomes with Renal Atherosclerotic Lesions (CORAL) study. Materials and Methods The CORAL roll-in database was used to describe the baseline characteristics of the patients in the roll-in cohort, all of whom underwent renal artery stent placement; to evaluate CORAL site performance; to compare estimates of lesion (stenosis) severity made by site interventionalists with the central CORAL angiographic core laboratory readings; and to report outcomes after renal artery stent placement. During the roll-in phase, 239 patients (mean age, 70.2 y ± 9.0; 49% male) underwent renal artery stent procedures. Angiographic core laboratory analysis of renal arteriograms was done, and participants were followed at 1 month and 9 months. Results Major angiographic complications were identified in 28 (13%) subjects. Kidney function remained unchanged at the short (2–4 weeks) follow-up interval. Improvement in systolic blood pressure with use of distal embolic protection devices (n = 161) did not show any clinical benefit over nonuse of such devices (n = 78) in this small series. At 9 months, there were significantly more endpoints reported by site in subjects with bilateral renal artery stenosis ( P = .01) and prior history of stroke ( P = .03). Conclusions In the roll-in phase of the CORAL study, a significant number of angiographic complications were identified. No effect was seen on estimated glomerular filtration rate after renal artery stent placement, but systolic blood pressure decreased significantly.

Randomized clinical trials have not shown an additional clinical benefit of renal artery stent placement over optimal medical therapy alone. However, studies of renal artery stent placement have not examined the relationship of albuminuria and treatment group outcomes. The CORAL study (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) is a prospective clinical trial of 947 participants with atherosclerotic renal artery stenosis randomized to optimal medical therapy with or without renal artery stent which showed no treatment differences (3(5.8% and 35.1% event rate at mean 43-month follow-up). In a post hoc analysis, the study population was stratified by the median baseline urine albumin/creatinine ratio (n=826) and analyzed for the 5-year incidence of the primary end point (myocardial infarction, hospitalization for congestive heart failure, stroke, renal replacement therapy, progressive renal insufficiency, or cardiovascular disease– or kidney disease–related death), for each component of the primary end point, and overall survival. When baseline urine albumin/creatinine ratio was ≤ median (22.5 mg/g, n=413), renal artery stenting was associated with significantly better event-free survival from the primary composite end point (73% versus 59% at 5 years; P =0.02), cardiovascular disease–related death (93% versus 85%; P ≤ 0.01), progressive renal insufficiency (91% versus 77%; P =0.03), and overall survival (89% versus 76%; P ≤0.01), but not when baseline urine albumin/creatinine ratio was greater than median (n=413). These data suggest that low albuminuria may indicate a potentially large subgroup of those with renal artery stenosis that could experience improved event-free and overall-survival after renal artery stent placement plus optimal medical therapy compared with optimal medical therapy alone. Further research is needed to confirm these preliminary observations. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00081731.

Background and objectives Atherosclerotic renal artery stenosis may cause kidney function loss, but effects of stenting on eGFR and clinical events associated with CKD are uncertain. Our study objectives were to determine effects of stenting on eGFR and predictors of clinical events. Design, setting, participants, & measurements Participants (n=931) in the Cardiovascular Outcomes in Renal Artery Stenosis Trial (from May of 2005 to September of 2012) had >60% atherosclerotic renal artery stenosis and systolic hypertension on two or more antihypertensive drugs and/or stage ≥3 CKD. The intervention was stenting versus no stenting on a background of risk factor management: renin-angiotensin system inhibition, statin, antiplatelet therapy, and smoking cessation education. The effect of stenting on eGFR by the serum creatinine-cystatin C Chronic Kidney Disease Epidemiology Collaboration equation was the prespecified analysis of kidney function. Predictors of eGFR and CKD outcomes (≥30% eGFR loss, ESRD, and death) and cardiovascular disease outcomes (stroke, myocardial infarction, heart failure, and death) controlling for eGFR and albuminuria were also determined. Results eGFR was 59±24 ml/min per 1.73 m2 (mean±SD) at baseline. Over 3 years, eGFR change, assessed by generalized estimating equations, was −1.5±7.0 ml/min per 1.73 m2 per year in the stent group versus −2.3±6.3 ml/min per 1.73 m2 per year in the medical therapy only group (P=0.18). eGFR predictors (multiple variable generalized estimating equations) were age, albuminuria, systolic BP, and diabetes (inverse associations) as well as men, total cholesterol, and HDL cholesterol (positive associations). CKD outcomes events occurred in 19% (175 of 931), and predictors (Cox proportional hazards models) included albuminuria (positive association), systolic BP (positive association), and HDL cholesterol (inverse association). Cardiovascular disease outcomes events occurred in 22% (207 of 931), and predictors included age, albuminuria, total cholesterol, prior cardiovascular disease, and bilateral atherosclerotic renal artery stenosis (positive associations). Conclusions Stenting did not influence eGFR in participants with atherosclerotic renal artery stenosis receiving renin-angiotensin system inhibition–based therapy. Predictors of clinical events were traditional risk factors for CKD and cardiovascular disease.

This review points out the high morbidity and mortality associated with cardiovascular disease in patients with ESRD. Although there have been few randomized controlled trials that have examined this clinical problem in the population of patients with ESRD, there is a growing appreciation of the presentations and consequences of cardiovascular disease in this cohort. The etiology of this disease is multifactorial and the consequences include sudden death, coronary artery disease, and heart failure. The sudden death associated with ESRD has been linked to a progressive cardiac fibrosis that also accompanies left ventricular hypertrophy. Ischemic coronary disease is also common in this population. With regard to new therapy, efforts to control extracellular fluid volume and thereby control blood pressure are important. Two randomized trials have not shown the benefit of lowering low-density lipoprotein cholesterol concentrations in patients with ESRD, but such a strategy is thought to be beneficial in patients with chronic kidney disease. Efforts to optimally control calcium and phosphate concentrations are also beneficial, because vessel calcification remains a major problem for ESRD patients. The increase in vessel calcification leads to an increase in arterial stiffness and an increase in pulse wave velocity, which, in turn, increases cardiovascular morbidity and mortality. Additional recommendations are provided in this review including the use of erythrocyte stimulating agents, the cautious use of beta blockers with patients with a low ejection fraction systolic failure, and drugs that block the renin-angiotensin-alderosterone system.

Intradialytic hypotension continues to play a significant role in the morbidity and in some cases the mortality associated with maintenance hemodialysis. Greater precision in the determination of dry weight using bioimpedance technology and biofeedback systems designed to prevent rapid fluctuations in blood volume have recently been shown to decrease the frequency of this complication. Pharmacologic strategies designed to maintain peripheral vascular resistance in patients with insufficient release of endogenous vasoconstrictors continue to be explored. The sudden development of intradialytic hypotension may respond to specific antagonists to hypotensive mediators.

For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 ± 1.5 vs. 2.4 ± 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal-artery stenosis.

The Centers for Medicare and Medicaid Services (CMS) End-Stage Renal Disease (ESRD) Program has served as a model for health care policy innovation because of several unique features: the program provides dialysis and kidney transplantation services where the alternative to renal replacement therapy

Introduction: Ischemic nephropathy due to atherosclerotic renal artery stenosis (ARAS) is associated with poor event free survival. However, previous studies suggest that stenosis severity has a poor relation to kidney function. We sought to test the interactions of stenosis severity, and revascularization, on kidney function in people with ARAS. Hypothesis: Stenosis severity is associated with poor renal function in people with ARAS. Methods: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) clinical trial is a prospective trial of individuals with atherosclerotic renal-artery stenosis. Patients were followed to a maximum of 8 years. Angiographic images were measured at a single core lab (University of Virginia) using quantitative computer-assisted angiography. Estimated glomerular filtration rate (eGFR) was measured using creatinine and cystatin-C, performed at a single core lab (University of Minnesota), and calculated using the CKD-EPI Creatinine-Cystatin C formula. The analyses are controlled by age and gender. Results: At baseline CKD-EPI eGFR was strongly and negatively correlated with percent stenosis (-0.2472, p Conclusions: Stenosis severity is strongly related to kidney function at the time of presentation in patients with atherosclerotic renal artery stenosis. However, by three years follow-up, this relationship appears to be lost.

Introduction: Stenosis severity and revascularization may have little relation to outcomes in patients with atherosclerotic renal artery stenosis (ARAS). Albuminuria is a direct indicator of glomerular injury and kidney health. The effect of albuminuria on survival in people with ARAS is not well characterized. Hypothesis: Proteinuria predicts clinical events in people with ARAS. Methods: The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) clinical trial is a prospective trial of individuals with ARAS. Patients were followed to a maximum of 8 years. Urine albumin and creatinine were measured at a single core lab and the ratio was log transformed (LUACR). The composite endpoint included: cardiovascular (CV) or renal mortality, myocardial infarction (MI), stroke, chronic heart failure (CHF), progressive renal insufficiency (PRI), and renal replacement therapy (RRT). Utilizing receiver operating characteristic (ROC) curves, we developed 3 cutoff points for the LUACR using three methods: Youden’s, closest to the top-left point and the sample median. In order to verify the cutoff point we randomly divided the sample into a training set and a verification set of equal size. Cross verification was applied and the simulation was repeated 5000 times. The analyses are controlled by age, gender, cystatin-c, and systolic blood pressure. Results: Cross verification shows that Youden’s method gives the highest specificity and accuracy. It yields an optimal cutoff point of LUACR=3.83 (UACR is exp(3.83)=46.06). Subjects with values above this threshold, in the verification sample, had higher rates of the composite event rate (50% vs. 27%), PRI (27% vs. 13%), and CHF (16% vs. 5%), all p Conclusions: Albuminuria powerfully predicts adverse cardiovascular and renal events, including all-cause mortality, in people with ARAS.

People with atherosclerotic renal artery stenosis may benefit from renin-angiotensin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin-receptor blockers, but little is known about the factors associated with their use.The Cardiovascular Outcomes in Renal Atherosclerotic Lesions study (ClinicalTrials.gov identified: NCT00081731) is a prospective, international, multicenter clinical trial that randomly assigned participants with atherosclerotic renal artery stenosis who received optimal medical therapy to stenting versus no stenting from May 2005 through January 2010. At baseline, medication information was available from 853 of 931 randomly assigned participants. Kidney function was measured by serum creatinine-based eGFR at a core laboratory.Before randomization, renin-angiotensin inhibitors were used in 419 (49%) of the 853 participants. Renin-angiotensin inhibitor use was lower in those with CKD (eGFR60 ml/min per 1.73 m(2)) (58% versus 68%; P=0.004) and higher in individuals with diabetes (41% versus 27%; P0.001). Presence of bilateral renal artery stenosis or congestive heart failure was not associated with renin-angiotensin inhibitor use. Although therapy with renin-angiotensin inhibitors varied by study site, differences in rates of use were not related to the characteristics of the site participants. Participants receiving a renin-angiotensin inhibitor had lower systolic BP (mean ± SD, 148 ± 23 versus 152 ± 23 mmHg; P=0.003) and more often had BP at goal (30% versus 22%; P=0.01).Kidney function and diabetes were associated with renin-angiotensin inhibitor use. However, these or other clinical characteristics did not explain variability among study sites. Patients with renal artery stenosis who received renin-angiotensin inhibitor treatment had lower BP and were more likely to be at treatment goal.

Preventing dialysis hypotension: A comparison of usual protective maneuvers.BackgroundIntradialytic hypotension (IH) is a common adverse event. Currently, there are several commonly utilized therapies of IH, but they have not been compared directly in the same group of patients. We performed the present study in order to learn which of these techniques is most effective so that a rational approach to treating IH could then be formulated.MethodsA single-blinded, crossover study design of five different protocols was undertaken in 10 hemodialysis patients with a prior history of IH. Each patient first underwent one week (three dialyses) of standard dialysis (dialysate sodium 138 mEq/L). Then each patient was subjected to one week each (three dialyses) of the four test protocols, performed in random order in a blinded fashion. The specific protocols were as follows: high sodium dialysate, in which the patient was dialyzed using a dialysate sodium of 144 mEq/L; sodium modeling, during which the dialysate sodium declined from 152 to 140 mEq/L in the last half hour of dialysis; one hour of isolated ultrafiltration followed by three hours of isovolemic dialysis; and cool temperature dialysis in which the dialysate was cooled to 35°C.ResultsWeight loss in each of the five protocols was essentially identical, varying between 2.9 and 3 kg. There were significantly fewer hypotensive episodes per treatment in the sodium modeling, high sodium, and cool temperature protocols as compared with the standard protocol (P < 0.05). Ultrafiltration followed by dialysis was associated with a significantly greater number of hypotensive episodes per treatment than any of the three test protocols (P < 0.05). Similarly, the number of nursing interventions required for IH per treatment was significantly greater in the standard dialysis and in the isolated ultrafiltration protocols compared with sodium modeling and cool temperature protocols (P < 0.05). The number of hypotensive signs and symptoms per treatment was also significantly reduced during the sodium modeling and cool temperature protocols compared with the standard protocol (P < 0.004 and P < 0.02, respectively). Again, the isolated ultrafiltration protocol resulted in significantly more hypotensive symptoms and signs than the three test protocols (P < 0.005). Finally, the nadir mean arterial pressures were significantly lower in the standard and isolated ultrafiltration protocols when compared with the three test protocols (P < 0.05). The upright postdialysis blood pressure was best preserved in the sodium modeling and cool temperature protocols compared with the standard and isolated ultrafiltration protocols (P < 0.05).ConclusionThis study supports the use of sodium modeling as a first step in combating IH. Also effective were the use of cool-temperature dialysate and a high-sodium dialysate. All three test protocols were well tolerated. As applied in this study, isolated ultrafiltration followed by isovolemic dialysis was notably less effective in reducing IH.

The necessary exposure of blood to biomembranes during hemodialysis has been viewed by many as an immunogenic challenge leading to an acute phase response. In this study we examined the relationship between hemodialysis-induced immune activation and intradialytic hypotension, using the acute phase reactant serum C-reactive protein (CRP) as a surrogate for immunogenic activation. The maximum percent change in mean arterial pressure (MAP) was found to correlate significantly with CRP (r = 0.67, p < 0.05) in nine consecutive patients with a history of symptomatic hypotension during hemodialysis. In contrast, no correlation was found between CRP and maximum percent change in MAP in eight consecutive hemodialysis patients without intradialytic hypotension. Since interleukin-6 (IL-6) is a major regulator of CRP, the relationship between these two proteins was examined. Plasma IL-6 levels were found to correlate both with CRP (r = 0.67, p < 0.05) and with mean maximum percent change in MAP (r = 0.70, p < 0.05) in hemodialysis patients with a prior history of hypotension. IL-6 levels did not correlate with CRP or blood pressure in the hemodynamically stable patients. The results suggest that immune activation working through IL-6, CRP and other cytokines may play a role in the pathogenesis of hemodialysis hypotension in some patients.

Recent allegations have accused “respected experts” for purportedly promulgating information and opinions to physician-consumers while concealing their conflicts of interest (COIs) and commercial bias.1 The news blitz stemming from these transgressions has led to intense examination of the relationship between physicians and companies that sell medical products and devices. Universities, professional societies, and government agencies uniformly condemn such practice and endorse a variety of methods to reduce the likelihood of commercial influence on activities that are designed to be objective.2,3 In 2008, the American Society of Nephrology (ASN) created a committee to review the Society’s policies and practices regarding its interface with commercial interests. The committee submitted its ensuing report to the ASN Council and published a summary of its final recommendations—which were unanimously approved by council—in this issue of JASN.4 There are four largely separate but contiguous processes whereby commercial interests could influence how physicians provide treatment to patients: conducting research, publishing scientific information, educating practitioners, and developing policy. ASN s educational efforts comprise the majority of the Society’s interactions with commercial interests and, not incidentally, draw the most national attention from the perspective of potential COI and commercial bias. Thus, ASN conducts its major activity squarely in the sights of those who seek to eliminate the possibility of commercial influence in the process of educating practitioners.5 The ASN Committee on Corporate Relations struggled with the meaning and definition of COI. It is widely recognized that everyone has some form of conflict. Although we did not develop a unique definition, we generally agree with the definition proposed by the Institute of Medicine (IOM).6 The practical consequence of this definition is that identifying COI should focus on financial conflicts because they are more objective and better suited to regulatory scrutiny. However, although the committee focused its analysis on financial entanglements, we recognize that professional conflicts should be considered when implementing the proposed recommendations. This emphasis on financial conflicts transforms the focus of bias. We considered one definition of bias as “a conclusion or recommendation based on opinion unsupported by facts.” According to this definition as applied to medicine, almost no recommendation can be totally unbiased. The practical resolution of this matter is to focus on commercial bias, which the committee defines as “an inadequately supported judgment or recommendation about the use of a commercial product.” The committee made no recommendation regarding the highly controversial issue of continuing medical education (CME) funding. However, the sentiment of the committee is more closely aligned with IOM’s recommendations rather than other recommendations directed at eliminating industry support for CME.5,6 The IOM report makes two important points. First, CME is essential to providing high-quality care to patients and, therefore, its importance is increasing. Second, there is no information on the consequences of making a dramatic shift in funding for CME. Making a major change in how CME is funded in the absence of data will have unforeseen consequences.6 The committee generally agrees that any changes should be subject to careful review and testing. The committee strongly endorses the concept that there should be clear separation between the development of the content of educational programs and the generation of financial support. We are impressed with how well ASN has implemented this policy during the past few years. Although virtually everyone can agree that there should be no commercial bias in CME activities, there is surprisingly little understanding of the practical implications of this policy. There are two processes for uncovering potential COI and commercial bias. The first is the process of disclosure. The second is the evaluation of presentations by designated observers and participants. Disclosure is strongly endorsed by all groups. The Accreditation Council for Continuing Medical Education (ACCME) requires disclosure of accredited providers, including ASN. However, what should a speaker disclose? There is wide agreement that a speaker should disclose all financial relationships with commercial entities. In addition, some interPublished online ahead of print. Publication date available at www.jasn.org.

Cardiovascular disease is the single largest cause of mortality in the general population (1) and, as such, it is not surprising that it is also the leading cause of mortality in chronic hemodialysis patients, accounting for nearly half of all deaths in this population in the United States (2). Numerous studies have described the high prevalence of atherosclerotic cardiovascular disease (2,3) and congestive heart failure in the ESRD population (4,5), with these entities accounting for a great majority of cardiovascular mortality in the chronic hemodialysis population.

There is widespread agreement that drug nephrotoxicity plays a major role in the high incidence and prevalence of acute renal failure in both hospitalized and nonhospitalized patients. Recent reviews have suggested that between 5% and 10% of acute renal failure recognized in such patients is caused, at least in part, by drugs [2]. Antibiotics play a major role in these nephrotoxicities, but other drugs are clearly implicated in many cases. The incidence of acute renal failure caused by nephrotoxic agents is particularly notable among the elderly, and there are several reasons for this: (1) there is an age-related decline in glomerular filtration rate in older individuals, and this leads to a decreased clearance of primary drugs or the metabolites of such drugs; (2) there may be a decrease in kidney blood flow and an increase in concentration of some drugs in the cells of medulla; (3) primary differences exist between the elderly and nonelderly and pharmacokinetics of drugs. For example, there may be an increase in free-drug concentration in the elderly in conjunction with hypoalbuminemia, or because of retained metabolites [2]; (4) a decrease in total body water may also alter drug distribution in an adverse way; (5) finally, there may also be a decrease in hepatic metabolism with longer half-lives of some drugs. For example, in a recent study by Dowling et al, individuals with underlying renal disease had a decrease in the maximum cytochrome P450 enzyme activity inducible by rifampin as compared to normal controls [3]. With regard to the fate of individuals who develop acute renal failure caused by nephrotoxicity, several outcomes have been reported. In most cases, the drug

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Fluconazole (FLU) is a widely used antifungal agent. The multiple-dose pharmacokinetics of FLU in renal impairment have not been previously investigated. The following groups were studied: volunteers with creatinine clearances (CLcr, > 50 mL/min) of 107 mL/min, given a loading dose of 400 mg and a daily dose of 200 mg/day for 9 days (Group 1); subjects with CLcr between 21 and 50 mL/min with a mean of 38 mL/min, given a loading dose of 200 mg and a maintenance dose of 100 mg/day for 9 days (Group 2); subjects with CLcr between 11 and 20 mL/min with a mean of 14.8 ml/min, given a loading dose of 100 mg and a maintenance dose of 50 mg/day for 9 days (Group 3); and subjects on hemodialysis (three times per week) receiving a loading dose of 200 mg and then 100 mg after each of four dialysis sessions (Group 4) (N = 10 per group). After the administration of the loading dose on Day 1, the mean area under the curve (AUC) (0-24) measurements were approximately proportional to the dose of FLU and independent of renal function. After 10 days of FLU dosing, the mean renal clearance of FLU decreased as CLcr decreased for Groups 1 to 3, and the Day 10 mean half-lives were inversely related to mean CLcr (36.7 h in Group 1, 84.5 h in Group 2, and 101.9 h in Group 3). The mean AUC (0-24) on Day 10 was similar for Group 1 compared with Group 2, despite a reduction in the maintenance dose by 50%. (ABSTRACT TRUNCATED AT 250 WORDS)

Background— The safety and efficacy of different types of β-blocker therapy in patients with non–dialysis-dependent chronic kidney disease (CKD) and systolic heart failure (HF) are not well described. We assessed whether treatment of systolic HF with carvedilol is efficacious and safe in adults with CKD. Methods and Results— We performed a post hoc analysis of pooled individual patient data (n=4217) from 2 multinational, double-blinded, placebo-controlled, randomized trials, CAPRICORN (Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction Study) and COPERNICUS (Carvedilol Prospective Randomized, Cumulative Survival study). Primary outcome was all-cause mortality. Secondary outcomes included cardiovascular mortality, HF mortality, first HF hospitalization, the composite of cardiovascular mortality or first HF hospitalization, and sudden cardiac death. Non–dialysis-dependent CKD was defined by estimated glomerular filtration rate ≤60 mL/min/1.73 m 2 , using the abbreviated Modification of Diet in Renal Disease equation. CKD was present in 2566 of 4217 (60.8%) of the cohort, 50.4% of whom were randomly assigned to carvedilol therapy. Within the CKD group, treatment with carvedilol decreased the risks of all-cause mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63 to 0.93; P =0.007), cardiovascular mortality (HR, 0.76; 95% CI, 0.62 to 0.94; P =0.011), HF mortality (HR, 0.68; 95% CI, 0.52 to 0.88; P =0.003), first hospitalization for HF (HR, 0.74; 95% CI, 0.61 to 0.88; P =0.0009), and the composite of cardiovascular mortality or HF hospitalization (HR, 0.75; 95% CI, 0.65 to 0.87; P P =0.098). There was no significant interaction between treatment arm and study type. Carvedilol was generally well tolerated by both groups of patients, with an increased relative incidence in transient increase in serum creatinine without need for dialysis and other electrolyte changes in the CKD patients. However, in a sensitivity analysis among HF subjects with estimated glomerular filtration rate 2 (CKD stage 3b), the efficacy of carvedilol was not significantly different from placebo. Conclusions— This analysis suggests that the benefits of carvedilol therapy in patients with systolic left ventricular dysfunction with or without symptoms of HF are consistent even in the presence of mild to moderate CKD. Whether carvedilol therapy is similarly efficacious in HF patients with more advanced kidney disease requires further study.

The renin-angiotensin-aldosterone system is one of the major hormonal systems involved in the long-term regulation of blood pressure. The release of renin is the rate limiting step in the activation of this system. As a result, it is important to understand the factors involved in the regulation of renin release to extend our knowledge of the role of this system in cardiovascular regulation. Extensive research has revealed that renin release may be affected by many local and circulating factors. Rather than review this vast literature, the reader is directed to several recent reviews of this topic [1–5]. This review focuses on the regulation of renin release by local factors that are formed by the endothelial cells of blood vessels and forwards the hypothesis that endothelial factors are important in the control of renin release. Renin is synthesized and released from the juxtaglomerular cells [1, 5]. These cells are modified smooth muscle cells and are located in the media of the afferent arteriole. The endothelial cells which line the lumen of the afferent arteriole are in close anatomical proximity to the juxtaglomerular cells and may release local hormones which alter juxtaglomerular cell function. Specifically, in recent years, it has become apparent that endothelial cells release a number of vasoactive hormones, growth factors and other soluble mediators which may affect juxtaglomerular cells and renin release [6, 7]. Some of these factors include eicosanoids such as PGI 2 and PGE 2 , endothelial derived relaxant factors (EDRF) which may include nitric oxide, endothelial-derived constrictor factors including endothelin, endothelial-derived growth factor, procoagulant factors, tissue plasminogen activator and plasminogen activator inhibitor. Additionally, endothelial cells form a barrier between the blood and the renin secreting cells so circulating hormones must first interact with the endothelial cells before reaching the juxtaglomerular cells. This raises the possibility that the action of circulating hormones on renin release may be mediated by a direct action on the juxtaglomerular cell or through stimulation of an endothelial factor then affects renin release. Furthermore, several endothelial hormones as PGI 2 and EDRF are released in response to stretch or shear stress [8, 9]. These hormones may function as the chemical mediators of the changes in renin release caused by these mechanical forces. Thus, the available information suggests that the endothelium may play a pivotal role in the regulation of renin release. Several of the endothelial-derived hormones with effects on renin are discussed in sequence below.

Heart disease accounts for approximately half of the deaths of patients with ESRD (1–3). In the past 5 yr, there has been increasing recognition of both coronary artery disease (CAD) and left ventricular hypertrophy (LVH) in ESRD patients, as these are the two typical presentations of heart disease in ESRD patients. It is also clear that many patients with chronic kidney disease (CKD) and a GFR of

Previous studies suggested that the non-contrast-enhanced computerized tomography (CT) scan is a highly reliable tool for the diagnosis of analgesic-associated renal disease. However, this issue has not been addressed in the US population. A total of 221 incident patients with ESRD from different regions of the United States underwent a helical CT scan and detailed questioning about drug history. Specific renal anatomic criteria were developed to determine whether a constellation of CT findings (small indented calcified kidneys [SICK]) is linked to analgesic ingestion. For approximating use before the onset of renal disease, only analgesic ingestion at least 9 yr before starting dialysis was considered relevant. Fifteen patients met the criteria for SICK. This represented 7% of the enrolled patients and approximately 1% of the total ESRD population. There was a significant increase in the estimated risk among patients with a history of heavy aspirin ingestion (odds ratio [OR] 7.4 [95% confidence interval (CI) 1.2 to 43] for > or =1 kg lifetime; OR 8.8 [95% CI 1.2 to 66] for > or =0.3 kg/yr). Total analgesic ingestion of > or =0.3 kg/yr also was significantly associated with SICK (OR 8.2; 95% CI 1.5 to 45). These findings were accounted for largely by combination products that contained aspirin and phenacetin (used by three patients with SICK), which are no longer available. In addition, the CT finding of SICK was present only in a minority of heavy analgesic users, yielding a sensitivity of 5 to 26%. Findings of SICK are infrequent in the US ESRD population and do not occur among a sufficient proportion of heavy analgesic users to render the non-contrast-enhanced CT scan a sensitive tool to detect analgesic-associated kidney injury.

In the 15 yr since the Institute of Medicine defined clinical practice guidelines (CPG) as “systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances” (1), there has been an upsurge in their promulgation. The Agency for Healthcare Research and Quality lists more than 2000 active CPG. The factors that have driven the profusion of clinical practice guidelines are essentially the same that have driven a general increase in evidence-based decision-making and the field of outcomes research. Evidence strongly suggests that standardization of medical practice can provide cost-effective care that improves outcomes (2). Despite the seemingly compelling virtue of CPG, they are certainly not a panacea for all of the ills in health care delivery. CPG usually focus on improving the management of one particular disease, often neglecting to provide guidance on the integration of complex medical regimens for patients with multiple comorbid diseases (3,4). When CPG are linked to clinical performance measures, the result can be an increase in auditing and regulation without necessarily improving patient outcomes (5,6). Grading evidence for CPG remains complex, with multiple varying systems and approaches available (7,8). Different conclusions can arise when applying different grading systems to the same body of evidence …

Abnormal regulation of proximal tubule renin mRNA in the Dahl/Rapp salt-sensitive rat.BackgroundThe precise pathogenesis of salt-sensitive hypertension in the Dahl rat is unknown. Abnormalities in renal hemodynamics and NaCl handling have been implicated, and may relate to changes in the activity of the intrarenal renin-angiotensin system.MethodsCirculating, juxtaglomerular and intrarenal (glomerular and proximal tubular) renin were studied in Dahl/Rapp salt-sensitive and salt-resistant rats fed with a normal (0.5%) or high (4%) NaCl diet. Circulating and juxtaglomerular renin were assessed by measurement of plasma renin activity and renin secretory rates. Glomerular and proximal tubular renin mRNA were assessed by microdissection and quantitative competitive RT-PCR.ResultsCirculating and juxtaglomerular renin were suppressed by high dietary NaCl in salt-sensitive rats (plasma renin activity, 0.5%, 10.9 ± 0.7 vs. 4%, 7.9 ± 0.3ng/ml/hr, P < 0.05; renin secretory rate, 0.5% 220 ± 32 vs. 4%, 58 ± 5ng/mg/hr, P < 0.05). Glomerular renin mRNA was also suppressed by the higher salt diet in salt-sensitive animals (0.5%, 411 ± 84 vs. 4%, 67 ± 22 × 103 copies/glomerulus, P < 0.05). In contrast, proximal tubular renin was not suppressed by a high NaCl diet in salt-sensitive animals (0.5%, 13.9 ± 2.7 vs. 4%, 12.1 ± 3.6 × 103 copies/mm tubule, P = NS), but was suppressed in salt-resistant rats (0.5%, 9.5 ± 2.8 vs. 4%, 3.2 ± 1.2 × 103 copies/mm, P < 0.05).ConclusionsFailure to suppress proximal tubular renin in response to high dietary NaCl may result in increased local generation of angiotensin II and enhanced proximal tubular NaCl absorption, and thereby contribute to the generation of salt sensitive hypertension.

While captopril-enhanced renal scintigraphy is acknowledged to be a useful screening technique to detect clinically silent obstructive lesions of the main renal arteries, the presence of significant atherosclerosis of distal, smaller renal vessels as a cause of positive scintigraphy scans has not been reported extensively. In a retrospective 2-year analysis of 31 consecutive captopril-enhanced renal scintigrams, we found a total of 13 studies in 11 patients that were classified as "positive" for renal artery stenosis. Of these 11 patients with positive scintigraphic studies, 4 patients underwent 5 renal arteriography procedures; only 1 of these renal arteriograms showed significant stenosis of the main renal artery. In the other 4 cases, an angiographic pattern of diffuse intrarenal distal arterial disease correlated with scintigram lateralization. Angiography was also performed in 4 patients with negative captopril renal scintiscans. In each of these cases the arteriogram was also negative for significant renal artery stenosis, and only 1 patient had diffuse bilateral intrarenal arterial disease. We conclude that distal renal arterial narrowing should be considered in the differential diagnosis of lateralized renal scintigrams. A negative renal scintigraphic study may be more reliable for excluding significant main renal artery obstructive disease.

Abstract Recent studies have documented the presence of a complete renin-angiotensin system in the proximal tubule of the kidney; however, little is known about the regulation of renin in this proximal tubular system. Therefore, we performed the present studies to learn whether the behavior of the renin system in cultured proximal tubule is similar to that of the juxtaglomerular renin system. Basal renin secretion from rabbit proximal tubular cells in primary culture was low and not affected by isoproterenol (10 −5 mol/L), diltiazem (10 −5 mol/L), or a zero-calcium bath (0 nmol/L). Only the calcium ionophore A23187 (10 −4 mol/L) significantly reduced renin secretion in these cells (from 2.44±0.37 to 1.14±0.08 ng angiotensin I/mg protein per hour, P P 1 nuclease protection assay. Densitometry analysis of renin mRNA and either GAPDH mRNA (rat) or α-actin (rabbit) showed no significant alterations in renin mRNA abundance. In summary, these results confirm the presence of renin mRNA in cultured proximal tubular cells and suggest that a low-level, constitutive secretion of renin occurs in this system that is decreased by A23187. Moreover, the results also suggest that proximal tubular renin is regulated, albeit differently from the juxtaglomerular renin system. Finally, short-term increments in proximal tubular renin occur without a change in renin mRNA.

Mucormycoses is a fungus which increasingly has been reported as a cause of opportunistic infection during the last 40 years. This infection is most commonly associated with underlying predisposing conditions, particularly diabetic ketoacidosis, hematologic and other malignancies, steroid therapy, broad-spectrum antibiotic therapy, or various acquired and hereditary immunodeficient disease states. The present report is that of a previously healthy patient with acute renal failure secondary to a postviral rhabdomyolysis syndrome, who received corticosteroids and developed unsuspected and undiagnosed systemic mucormycosis. Autopsy revealed that he died as a consequence of a massive pulmonary hemorrhage due to disseminated invasive mucormycosis, involving both the lungs and kidneys. A review of the literature reporting disseminated mucormycosis in association with renal failure is provided. Mucormycosis should be considered in immunocompromised patients with renal failure and fevers of unknown origin so that early diagnosis and prompt surgical and medical therapy may be instituted.

Angiotensinogen, angiotensin-converting enzyme, and renin constitute the components of the renin-angiotensin system. The mammalian renal proximal tubule contains angiotensinogen, angiotensin-converting enzyme, and angiotensin receptors. Previous immunohistochemical studies describing the presence of renin in the proximal tubule could not distinguish synthesized renin from renin trapped from the glomerular filtrate. In the present study, we examined the presence of renin activity and mRNA in rabbit proximal tubule cells in primary culture and renin mRNA in microdissected proximal tubules. Renin activity was present in lysates of proximal tubule cells in primary culture. Cellular renin content in cultured proximal tubule cells was increased by incubation with 10(-5) M isoproterenol and 10(-5) M forskolin by 150 and 110%, respectively. In addition, renin transcripts were detected in poly(A)+ RNA from cultured proximal tubule cells by RNA blots under high stringency conditions. In microdissected tubules from normal rats, renin mRNA was not detectable with reverse transcription and polymerase chain reaction. However, in tubules from rats administered the angiotensinogen-converting-enzyme inhibitor, enalapril, renin was easily detected in the S2 segment of the proximal tubule. We postulate the existence of a local renin-angiotensin system that enables the proximal tubule to generate angiotensin II, thereby providing an autocrine system that could locally modulate NaHCO3 and NaCl absorption.

Context Cardiac troponin T (cTnT) and C-reactive protein (CRP) are prognostic markers in acute coronary syndromes. However, for patients with end-stage renal disease (ESRD) the ability of combinations of these markers to predict outcomes, and their association with cardiac pathology, are unclear. Objective To investigate the association between levels of cTnT and CRP and longterm risk of cardiac pathology and death in patients with ESRD. Design, Setting, and Participants A prospective cohort study initiated February through June 1998 and enrolling 224 patients with ESRD from 5 hemodialysis centers in the Houston-Galveston region of Texas. Levels of cTnT and CRP were analyzed at study entry in patients without ischemic symptoms. MainOutcomeMeasures All-causemortalityduringameanfollow-upof827(range, 29-1327) days. Secondary outcomes in predefined substudies were coronary artery disease (CAD), decreased (40%) left ventricular ejection fraction (LVEF), and presence of left ventricular hypertrophy (LVH). Results One hundred seventeen (52%) patients died during follow-up. For levels of cTnT and CRP, progressively higher levels predicted increased risk of death compared with the lowest quartile (for cTnT quartile 2: unadjusted hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.2-4.1; quartile 3: HR, 2.7; 95% CI, 1.5-4.9; quartile 4: HR, 3.0; 95% CI, 1.6-5.3. For CRP quartile 2: HR, 0.9; 95% CI, 0.5-1.6; quartile 3: HR, 1.8; 95% CI, 1.1-3.1; quartile 4: HR, 1.8; 95% CI, 1.1-3.2). Both cTnT and CRP remained independent predictors of death after adjusting for a number of potential confounders. The combination of cTnT and CRP results provided prognostic information when patients were divided into groups at or above and below the biomarker medians (high cTnT/high CRP levels vs low cTnT/low CRP levels for risk of death: HR, 2.5; 95% CI, 1.5-4.0). Elevated levels of cTnT, but not CRP, were strongly associated with diffuse CAD (n=67; 0%, 25%, 50%, and 62% prevalence of multivessel CAD across progressive cTnT quartiles, P.001). An LVEF of 40% or less was identified in 4 (9%), 3 (8%), 10 (27%), and 7 (19%) of patients across cTnT quartiles (P=.07). No trend for cTnT levels was found among patients with LVH (P=.45); similarly, no trend for CRP was found among patients with LVH (P=.65) or an LVEF of 40% or less (P=.75). Conclusions Among stable patients with ESRD, increasing levels of cTnT and CRP are associated with increased risk of death. Furthermore, higher levels of cTnT may identify patients with severe angiographic coronary disease.

Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure. The factors that regulate sodium and potassium excretion in patients with chronic renal failure have not been fully clarified. The role of aldosterone in the control of sodium and potassium excretion was therefore examined in eight normokalemic patients with chronic renal failure (mean creatinine clearance, 14.3 ml/min). With a normal sodium intake (120 to 151 mEq/24 hr), plasma aldosterone levels were above normal in five of the eight patients and in five of six patients with a creatinine clearance of less than 15 ml/min. Aldosterone levels were further increased in all eight patients by assumption of an upright posture (from a mean of 523 to 1,454 pg/ml, P < 0.01). When seven of the patients were placed on a low sodium diet (10 to 20 mEq/24 hr), mean plasma aldosterone levels increased from 587 to 2,393 pg/ml; (P < 0.02). The low sodium diet was also associated with a fall in mean body of 2.1 kg and a decrease in plasma sodium concentration from 140 to 131 mEq/liter (P < 0.005) in all patients. To further define the physiologic role of the high aldosterone levels, we administered the aldosterone antagonist, spironolactone (300 mg/24 hr), to the patients while they were on a normal sodium diet. The administration of spironolactone was associated with a significant natriuresis, as mean sodium excretion increased from 142 to 173 mEq/24 hr (P < 0.02) and mean body wt decreased by 1.4 kg (P < 0.02). With the administration of spironolactone, the mean potassium excretion decreased from 47 to 41 mEq/24 hr (P < 0.05) as plasma potassium rose from 4.6 to 5.4 mEq/liter (P < 0.01). We conclude that (1) many normokalemic patients with advanced renal failure (creatinine clearance < 15 ml/min) are in a state of hyper-aldosteronism, (2) nevertheless, the secretion of aldosterone in these patients can be stimulated further by posture and volume depletion, and (3) aldosterone plays a physiologic role not only in the maintenance of serum potassium concentration but also as an antinatriuretic force in advanced chronic renal failure.

Effects of angiotensin II on plasma antidiuretic hormone and renal water excretion. The effects of intravenous (i.v.) and intracarotid (IC) angiotensin II (AII) infusion on systemic and renal hemodynamics, renal water excretion, and plasma antidiuretic hormone (ADH) levels were examined in six conscious dogs under water loaded and hydropenic conditions. In the first group of seven studies, AII in a mean dose of 12.7 ng/kg/min was administered i.v. to water loaded dogs. The infusion induced a significant increase in mean arterial pressure (MAP, 99 to 118mm Hg, P < 0.001), and significant reductions in both glomerular filtration rate (GFR, 67 to 57 ml/min, P < 0.05) and para-aminohippurate clearance (CPAH, 280 to 212 ml/min, P < 0.005) occurred. Despite this decrement in renal hemodynamics, urine remained maximally dilute (Uosm, 58 to 61 mOsm/kg H2O, NS). Furthermore, plasma ADH was suppressed maximally after water load and did not increase after i.v. AII infusion. The IC infusion of AII (mean dose 5.8 ng/kg/min) produced similar changes in hemodynamics; plasma ADH remained undetectable. When AII was administered i.v. to hydropenic animals (mean dose 8.3 ng/kg/min), MAP again increased (86 to 111mm Hg, P < 0.001) as GFR (81.3 to 68.6 ml/min, NS) and CPAH (291 to 223 ml/min, P < 0.05) declined modestly. In these animals, Uosm decreased significantly (1429 to 1114 mOsm/kg H20, P < 0.005) and plasma ADH did not change significantly (1.66 to 1.88 pg/ml, NS). When IC AII (4 ng/kg/min) was repeated in hydropenic dogs pretreated with indomethacin, neither Usom (1787 to 1664 mOsm/kg H2O, NS) nor plasma ADH were altered. In summary, these results provide no evidence for an effect of AII to alter water excretion or plasma ADH either in the presence or absence of prostaglandin inhibition.

High sodium bicarbonate and acetate hemodialysis: Double-blind crossover comparison of hemodynamic and ventilatory effects. The superiority of bicarbonate dialysis (Bi HD) over acetate dialysis (Ac HD) using a high sodium dialysate has not been established to our knowledge. We compared Bi HD to Ac HD over 6 weeks each in ten stable patients using a double-blind crossover design and a dialysate sodium concentration of 140 mEq/liter. The dialyzer, delivery system, and disalysate constituents were identical except for the substitution of Bi or Ac. Interdialytic weight gain, pre- and post-HD blood pressures, and heart rates were also comparable in the two protocols. Beginning of the week pre-HD serum Bi was greater during Bi HD than Ac HD (19.1 ± 0.9 vs. 15.1 ± 0.8 mEq/liter, P < 0.001); post-HD Bi values were also higher during Bi HD. Similarly, pre-HD pH was also greater with Bi HD (7.40 ± 0.012 vs. 7.35 ± 0.001 U, P < 0.01). The number of adverse symptoms and signs were similar during each protocol (2.0 ± 0.65 for Bi HD vs. 2.5 ± 0.5 for Ac HD episodes/patient/6 weeks, NS). However, fewer therapeutic interventions were required during the Bi HD protocol (1.5 ± 0.43 vs. 3.1 ± 0.6 treatments/patient/6 weeks, P < 0.02). The ventilatory effects of the two dialysates were evaluated at the end of the 6-week course in seven of the ten patients and revealed comparable declines in carbon dioxide excretion, minute ventilation, and arterial oxygen tension. In summary, these results demonstrate strikingly similar hemodynamic and ventilatory responses with the two dialysates when a higher osmolality dialysate is used. However, Bi HD was associated with a significant reduction in the number of therapeutic interventions required, and also resulted in a greater pre-HD pH and bicarbonate concentration.Hémodialyse avec des concentrations élevées de bicarbonate ou d'acétate de sodium: Une comparaison croisée en double insu des effets hemodynamiques et ventilatoires. La supériorité de la dialyse avec du bicarbonate (Bi HD) sur la dialyse avec de l'acétate (Ac HD) en utilisant un dialysat riche en sodium n'a pas été établie, à notre connaissance. Nous avons comparé la Bi HD à l'Ac HD pendant 6 semaines chacune avec dix malades stables en utilisant un protocole croisé en double insu, et une concentration de sodium dans le dialysat de 140 mEq/litre. Le dialyseur, le système d'apport, et les constituants du dialysat étaient identiques exceptés en ce qui concerne la substitution de Bi ou Ac. La prise de poids interdialytique, les pressions artérielles pré- et post-HD, et les rythmes cardiaques étaient également comparables dans les deux protocoles. Au début de la semaine avant HD, le Bi sérique était plus élevé durant Bi HD que pendant Ac HD (19.1 ± 0.9 contre 15.1 ± 0.8 mEq/litre, P < 0.001); les valeurs de Bi post-HD étaient aussi plus élevées pendant Bi HD. De la même manière, le pH pré-HD était également plus élevé avec Bi HD (7.40 ± 0.012 contre 7.35 ± 0.001 U, P < 0.01). Le nombre de symptomes et de signes d'intolérance était identique pendant chaque protocole (2.0 ± 0.65 pour Bi HD contre 2.5 ± 0.5 pour Ac HD épisodes/malade/6 semaines, NS). Cependant moins d'interventions thérapeutiques ont été nécessaires pendant le protocole Bi HD (1.5 ± 0.43 contre 3.1 ± 0.6 traitements/malade/6 semaines, P < 0.02). Les effets ventilatoires des deux dialysats ont été étudiés à la fin de la période de 6 semaines chez sept des dix malades et cela a révélé des diminutions comparables de l'excrétion de dioxyde de carbone, de la ventilation par minute, et de la tension artérielle d'oxygène. En résumé, ces résultats démontrent des réponses hémodynamiques et ventilatoires à l'évidence identiques avec les deux dialysats quand une plus forte osmolalité du dialysat est utilisée. Cependant, Bi HD était associé avec réduction significative du nombre d'interventions thérapeutiques nécessaires, et a également été à l'origine d'un bicarbonate et d'un pH pré-HD plus élevés.

Role of osmolality in blood pressure stability after dialysis and ultrafiltration. To clarify the mechanisms involved in the stability of blood pressure during ultrafiltration (UF) alone versus regular dialysis, this study systematically examined the importance of changes in serum potassium, osmolality, and plasma norepinephrine during several dialysis maneuvers. Six stable, normotensive chronic dialysis patients were subjected to a uniform 2 to 3% decrease in body weight during the 2 hours of each dialysis maneuver. Supine to upright mean blood pressure (MBP) decreased (90 to 75 mm Hg, P < 0.05), and three patients became symptomatic after weight loss during regular dialysis, but orthostatic blood pressure was stable (89 to 86 mm Hg, NS) and the patients were asymptomatic after UF and weight loss. Isokalemic regular dialysis did not afford hemodynamic stability, as orthostatic MBP declined (85 to 56 mm Hg, P < 0.02), and four of the patients again were symptomatic after standing. A continuous hypertonic mannitol (25%) infusion during the 2-hour dialysis, however, kept osmolality from decreasing and was associated with a stable orthostatic MBP (89 to 83 mm Hg, NS). A continuous infusion of isotonic mannitol (5%) given in a volume five times that of the hypertonic mannitol failed to prevent orthostatic hypotension (89 to 60 mm Hg, P < 0.005). Plasma norepinephrine concentrations were high in these patients and increased only modestly after weight loss. These results implicate constant plasma osmolality as a critical protective factor of blood pressure during UF and further demonstrate that changes in blood pressure may be dissociated from changes in both serum potassium and plasma norepinephrine concentration.Rôle de l'osmolalité dans la stabilité de la pression artérielle après dialyse et ultrafiltration. Afin de clarifier les mécanismes impliqués dans la stabilité de la pression artérielle au cours de l'ultrafiltration (UF) seule par comparaison avec la dialyse habituelle ce travail évalue systématiquement l'importance des modifications de la kaliémie, de l'osmolalité et de la norépinéphrine plasmatique au cours de plusieurs tactiques de dialyse. Six sujets stables, normotendus, en hémodialyse chronique ont subi une diminution de poids corporel de 2 à 3% au cours des 2 heures de chaque tactique de dialyse. La pression artérielle moyenne a diminué de la position couchée à la position debout (de 90 à 75 mm Hg, P < 0,05) et trois patients sont devenus symptomatiques après la perte de poids au cours de la dialyse habituelle. Par contre la pression artérielle orthostatique a été stable (89 à 86 mm Hg, NS) et les malades ont été asymptomatiques après UF. La dialyse habituelle isokaliémique n'a pas déterminé de stabilité hémodynamique, la pression artérielle moyenne orthostatique a diminué (85 à 56 mm Hg, P < 0,02) et quatre malades ont été à nouveau symptomatiques quand ils se sont levés. Cependant quand une perfusion continue de mannitol hypertonique (25%) pendant les deux heures de la dialyse a empêché la baisse de l'osmolalité la pression artérielle moyenne orthostatique a été stable (89 à 83 mm Hg, NS). Une perfusion continue de mannitol isotonique (5%) apportant un volume cinq fois celui du mannitol hypertonique n'a pas empêché l'hypotention orthostatique (89 à 60 mm Hg, P < 0,005). Les concentrations plasmatiques de norépinéphrine étaient élevées chez ces malades et n'ont que peu augmenté après la perte de poids. Ces résultats impliquent qu'une osmolalité plasmatique constante est un facteur protecteur critique pour la pression artérielle au cours de UF et ils démontrent, de plus, que les modifications de la pression artérielle peuvent être dissociées des modifications du potassium plasmatique et de la concentration de norépinéphrine.

Prior studies of the effect of hemodialysis on left ventricular function have not distinguished between the removal of uremic toxins and the change in cardiac filling volume. To separate these effects, left ventricular function was examined by serial echocardiography in five stable hemodialysis patients before and after three different dialysis procedures: (a) hemodialysis with volume Loss, (b) ultrafiltration (volume loss only), and (c) hemodialysis without volume loss. The patients were similarly studied under control conditions and after increased (5 degrees of head-down tilt for 90 min) and decreased (lower body negative pressure) cardiac filling volume. After hemodialysis with volume loss, end-diastolic volume (EDV) decreased from 167 to 128 ml (P less than 0.001) and end-systolic volume (ESV) decreased from 97 to 51 ml (P less than 0.001) without a change in stroke volume (SV). Ejection fraction increased from 42 to 52% (P less than 0.001) and mean velocity of circumferential fiber shortening (VCF) increased from 0.61 to 1.04 circumferences (circ)/s (P less than 0.001). After ultrafiltration, EDV decreased from 167 ml to 124 ml (P less than 0.001) and SV from 73 ml to 39 ml (P less than 0.001), without significant changes in ESV or VCF. In contrast to the maneuvers in which volume loss occurred, after hemodialysis without volume loss ESV decreased from 95 to 66 ml (P less than 0.001) and SV increased from 74 ml to 97 ml (P less than 0.001) without changes in EDV. EF increased from 44 to 59% (P less than 0.001) and VCF increased from 0.64 to 1.26 circ/s (P less than 0.001). Ventricular function curves plotted from data obtained under conditions of altered cardiac filling volume before and after the three dialysis maneuvers demonstrate that ultrafiltration produced a pure Frank-Starling effect, while hemodialysis with or without volume loss produced a shift in the ventricular function curves, which demonstrated an increase in the contractile state of the left ventricle. The changes in left ventricular function produced by regular hemodialysis are the combined effects of a decrease in EDV and an increase in the contractile state of the left ventricle.

Although clinical studies suggest that chronic hypercapnic acidosis may be associated with renal sodium retention, little information is available on the effect of acute hypercapnic acidosis on renal sodium excretion. We, therefore, increased PCO2 from 23 to 74 mm Hg in anesthetized dogs and observed a marked antinatriuresis as absolute sodium excretion (235 to 60 muEq/min, P less than 0.001) and fractional excretion of sodium (4.0 to 1.2 %, P less than 0.02) decreased significantly. This decrease in sodium excretion occurred independent of consistent changes in renal perfusion pressure, PO2, glomerular filtration rate, renal blood flow, extraction of P-aminohippuric acid, and filtration fraction. The antinatriuretic response to acute hypercapnic acidosis could be attenuated significantly by surgical renal denervation, intrarenal phenoxybenzamine, and by intrarenal infusion of 1-sarcosine,8-glycine angiotensin II. Administration of 10 mg/kg indomethacin enhanced the antinatriuretic response to hypercapnic acidosis in denervated kidneys. These results suggest that renal alpha-adrenergic nerves and the renal angiotensin system result in an antinatriuretic effect during acute hypercapnic acidosis. Renal prostaglandins or related substances may serve to attenuate this antinatriuretic response.

The importance of renal perfusion pressure (RPP), the sympathetic beta adrenergic nervous system and renal prostaglandins (PG) on renin release during a uniform 15-17% reduction in blood pressure by hemorrhage (HH) was studied systematically in anesthetized dogs. All groups of animals had similar decrements in systemic and renal hemodynamics with HH. In control dogs (n = 7), both plasma renin activity (PRA, 4.1-9.0 ng angiotensin I/ml per h, P < 0.05) and renin secretory rate (RSR, 26-228 ng/ml per h·min, P < 0.005) increased significantly with HH. This increase in renin release during HH was not abolished by any single maneuver alone including beta adrenergic blockade with d,l-propranolol (n = 6), renal PG inhibition with indomethacin (n = 7), or control of RPP (n = 6). However, when beta adrenergic blockade was combined with control of RPP (n = 7) during HH, neither PRA (1.9-2.7 ng/ml per h, NS) nor RSR (16-53 ng/ml per h·min, NS) increased significantly. Similarly, a combination of beta adrenergic blockade and PG inhibition (n = 6) also abolished the increase in PRA (1.5-1.4 ng/ml per h, NS) and RSR (14-55 ng/ml per h·min, NS) during HH despite significant decreases in sodium excretion. Finally, a combination of PG inhibition and RPP control was associated with significant increases in PRA and RSR during HH. These results support a multifactorial mechanism in renin release during HH and implicate both the beta adrenergic receptors, renal baroreceptors, and possibly the macula densa as constituting the primary pathways of renin release during HH of this magnitude. Because either constant RPP or PG inhibition blunted renin release during HH in the setting of beta adrenergic blockade, the present results strongly suggest that the renal baroreceptor, and probably the macula densa mechanism are PG mediated.

A case of acute bacterial endocarditis is presented in which gallbladder infarction and areas of hepatic infarction were documented. Selective angiography showed findings consistent with emboli to the gallbladder and hepatic circulations.

The effects of hypotensive hemorrhage (HH) on renal hemodynamics and plasma renin activity (PRA) during prostaglandin (PG) synthesis inhibition were examined in three groups of dogs. In each group of animals arterial blood pressure was lowered by a 30% decrement. In the first group of eight control animals, HH was not associated with a significant change in glomerular filtration rate (GFR, 42-36 ml/min, NS); renal blood flow (RBF) declined significantly, from 234 to 171 ml/min, P < 0.05. In the second group of eight animals, pretreated with RO 20-5720 (RO, 2 mg/kg), a competitive inhibitor of PG synthesis, HH was associated with a significant fall in GFR (43-17 ml/min, P < 0.001) and RBF (195-89 ml/min, P < 0.001). In the third group of eight animals, pretreatment with indomethacin (IN, 10 mg/kg), a chemically dissimilar PG inhibitor, HH was also associated with a significant fall in GFR (38-8 ml/min, P < 0.001) and RBF (150-30 ml/min, P < 0.001). Renal denervation attenuated this renal ischemic effect of HH in the presence of PG inhibition. In the RO group, GFR (34 vs. 17 ml/min, P < 0.005) and RBF (145 vs. 89 ml/min, P < 0.025) were significantly greater in denervated vs. innervated kidneys during HH. Similarly, in animals treated with IN, a significantly higher GFR (28 vs. 8 ml/min, P < 0.005) and RBF (101 vs. 30 ml/min, P < 0.005) occurred in denervated as compared to innervated kidneys during HH. With HH, the increase in PRA in the control group (3.34-11.68 ng/ml per h, P < 0.005) was no different than that observed in the RO group (4.96-18.9 ng/ml per h, P < 0.001) or IN group (4.71-17.8 ng/ml per h, P < 0.001). In summary, the present results indicate that renal PG significantly attenuate the effect of HH to decrease GFR and RBF. Furthermore, renal denervation exerts a protective effect against the enhanced renal ischemic effects which occur in the presence of PG inhibition during HH. Finally, PG inhibition does not alter the effect of HH to cause an increase in PRA.

The relationship between circulating catecholamines and prostaglandins and the independent contribution of circulating catecholamines to renal vasoconstriction during hemorrhage is unknown. The renal hemodynamic effects of a 30% decrease in blood pressure by hemorrhage were therefore studied in three groups of anesthetized dogs which had undergone prior bilateral renal denervation. A constant unilateral infusion of the catecholamine antagonist phenoxybenzamine (POB, 0.2 micrograms/kg per min) into the renal artery during hemorrhage was also performed. In the control (C) dogs (n = 6), hemorrhage was not associated with significant changes in glomerular filtration rate (GFR) or renal blood flow (RBF) in either POB-infused and denervated or noninfused, denervated kidneys. In the second group of dogs (n = 8), pretreated with the prostaglandin inhibitor indomethacin (IN, 10 mg/kg, iv), POB-infused and denervated kidneys had a significantly higher GFR (30 vs. 23 ml/min, P less than 0.05) and RBF (180 vs. 130 ml/min, P less than 0.0-5) than contralateral denervated kidneys during the hemorrhage period. Similar results were observed in the third group of dogs (n = 6) pretreated with the chemically dissimilar prostaglandin inhibitor meclofenemate (M). Circulating plasma catecholamines increased to a similar degree in C (116 to 530 pg/ml, P less than 0.005), IN (116 to 488 pg/ml, P less than 0.005), and M (75 to 315 pg/ml, P less than 0.01) groups; the major part of this increase was due to an increase in plasma norepinephrine (NE). These results indicate that, in this model of hemorrhage, plasma NE exerts a moderate but significant renal vasoconstrictor effect which is unmasked by prostaglandin inhibition.

Competitive effects of hypokalemia and volume depletion on plasma renin activity, aldosterone and catecholamine concentrations in hemodialysis patients. The effects of isokalemic and hypokalemic ultrafiltration dialysis on plasma renin activity (PRA), aldosterone (ALDO) and plasma catecholamine (CA) concentrations were investigated in eight patients with end-stage renal failure. Plasma sodium concentration was kept constant during each hemodialysis, but plasma potassium decreased (4.8 to 3.4 mEq/liter, P < 0.001) only in the hypokalemic dialysis group. The falls in mean body weight (-1.77 vs. -1.66 kg) and mean blood pressure (125 to 109 vs. 126 to 108 mm Hg) were similar in the isokalemic and hypokalemic dialysis patient groups. PRA increased during dialysis both in the isokalemic (4.55 to 8.85 ng/ml/hr, P < 0.02) and hypokalemic (2.18 to 3.19 ng/ml/hr, P < 0.01) groups. These changes in body wt, blood pressure, and PRA were not significantly different in the isokalemic and hypokalemic dialyses. There were, however, important differences between the isokalemic and hypokalemic groups. While the mean ALDO increased (105 to 198 pg/ml, P < 0.05) during the isokalemic dialyses, ALDO actually fell significantly during the hypokalemic dialyses (120 to 36.8 pg/ml, P < 0.005). Prior to dialysis, CA's were increased significantly above normal values in both dialysis groups. With dialysis, CA's did not change significantly in the isokalemic group and actually fell in the hypokalemic group (1.27 to .93 ng/ml, P < 0.02). In spite of decreased body wt and blood pressure in both groups, heart rate increased only during the isokalemic dialysis. These results demonstrate a dominant effect of a fall in plasma potassium concentration to suppress ALDO, despite a concomitant fall in blood pressure and body wt and a rise in PRA. The elevated CA concentrations in these patients may possibly interact with sodium balance and contribute to the hypertension in these patients. The fall in CA's and absence of tachycardia during hypokalemic dialysis raises the possibility that a fall in plasma potassium concentration may cause or unmask autonomic insufficiency in these chronic renal failure patients who are predisposed to this disorder.Effets compétitifs de l'hypokaliémie et de la diminution du volume sur l'activité rénine et les concentrations plasmatiques d'aldostérone et de catécholamines chez les malades en hémodialyse. Les effets de la dialyse par ultrafiltration isokaliémique et hypokaliémique sur l'activité rénine plasmatique (PRA), l'aldostérone (ALDO) et les catécholamines (CA) plasmatiques ont été étudiés chez huit malades au stade terminal de l'insuffisance rénale. La concentration plasmatique de sodium a été maintenue constante au cours de toutes les hémodialyses mais le potassium plasmatique n'a diminué(4,8 à 3,4 mEq/litre, P < 0,001) que dans le groupe soumis à une dialyse hypokaliémique. Les diminutions moyennes du poids corporel (-1,77 vs. - 1,66 kg) et de la pression artérielle moyenne (125 à 109 vs. 126 à 108 mm Hg) ont été semblables dans les deux groupes. PRA a augmenté au cours de la dialyse aussi bien dans le groupe isokaliémique (4,55 à 8,85 ng/ml/hr, P < 0,02) que dans le groupe hypokaliémique (2,18 à 3,19 ng/ml/hr, P < 0,01). Ces modifications du poids corporel, de la pression artérielle et de PRA ne sont pas significativement différentes dans les deux groupes. Des différences importantes, cependant, sont apparues entre les deux groupes. Alors que l'ALDO moyenne augmente (105 à 198 pg/ml, P < 0,05) au cours de la dialyse isokaliémique, elle chute significativement au cours de la dialyse hypokaliémique (120 à 36,8 ng/ml, P < 0,005). Avant la dialyse les CA sont significativement supérieures aux valeurs normales dans les deux groupes. Avec la dialyse les CA ne sont pas significativement modifiées dans le groupe isokaliémique et chutent dans le groupe hypokaliémique (1,27 à 0,93 ng/ml, P < 0,02). Malgré la diminution du poids corporel et de la pression artérielle dans les deux groupes, la fréquence cardiaque n'augmente qu'au cours de la dialyse isokaliémique. En conclusion, ces résultats obtenus chez des malades soumis à l'hémodialyse démontrent l'effet d'une diminution du potassium plasmatique dans le sens de la suppression de l'ALDO,effet prédominant malgré la diminution de la pression artérielle et du poids corporel et l'augmentation de PRA concomitants. L'augmentation des CA, chez ces malades, a peut-être une interaction avec le bilan du sodium et contribue à l'hypertension. La diminution des CA et l'absence de tachycardie au cours de la dialyse hypokaliémique soulève l'hypothèse qu'une chute de la concentration de potassium plasmatique puisse déterminer ou démasquer une insuffisance du système rerveux autonome chez ces malades atteints d'insuffisance rénale chronique, malades dont on sait qu'ils sont exposés à de tels désordres.

Effects of cooler temperature dialysate on hemodynamic stability in “problem” dialysis patients. Symptomatic hypotension is a common and disabling complication of hemodialysis treatments. The incidence of symptomatic hypotensive episodes is particularly high in patients who have normal or low blood pressure at the initiation of dialysis and in patients who have large interdialytic weight gains. The aim of this study was to determine whether cooling the dialysate temperature from 37°C to 35°C improved tolerance to dialysis in a group of 12 of these “problem” patients. A double-blinded protocol was performed in six hypotension-prone and six large weight gainers who were subjected to two identical hemodialyses except for the dialysate temperature of 37°C or 35°C. Changes in biochemical parameters and weight were comparable during the two maneuvers. Recumbent blood pressure declined significantly (P < 0.01) during 37°C dialysis but not 35°C dialysis; blood pressure was significantly lower at 1, 2, and 3 hours of 37°C dialysis compared to 35°C dialysis (P < 0.05). Further, both supine and upright blood pressure was significantly lower following 37°C dialysis (P < 0.02). This lower blood pressure was present in both subgroups of patients. All 18 episodes of symptomatic hypotension noted during the study occurred during 37°C dialysis. A significantly greater increase in peripheral vascular resistance (calf blood flow was measured directly by venous occlusion plethysmography) occurred upon exposure to the 35°C dialysate in both subgroups of patients (P < 0.01); supine and upright post-dialysis plasma norepinephrine values were also significantly greater (P < 0.001) after 35° dialysis. Thus, 35°C dialysate significantly improves the hemodynamic tolerance to hemodialysis in hypotension-prone and large weight gainer patient groups and also reduces the incidence of symptomatic hypotension. This improvement is partly the result of a greater increase in peripheral vascular resistance, possibly mediated via the efferent sympathetic nervous system.

To elucidate the mechanisms responsible for systemic and renal hemodynamic changes in early endotoxemia, the roles of prostaglandins (PG) and renal nerves were investigated. Endotoxin (E, 3 micrograms/kg i.v.) was given to two groups of anesthetized dogs that had undergone unilateral renal denervation: Group I (n = 9) E only; Group II (n = 11) E + indomethacin (10 mg/kg i.v.) or meclofenamate (5 mg/kg i.v.). A third group of dogs (Group III, n = 5) received indomethacin (10 mg/kg i.v.) only. 1 h after E group I dogs, mean arterial pressure (MAP) decreased from 126 to 94 mm Hg (P less than 0.001), and prostacyclin (6-keto-Fl alpha metabolite, PGI2) increased (from 0.64 to 2.08 ng/ml, P less than 0.005). Glomerular filtration rate (GFR) and renal blood flow (RBF) declined comparably both in innervated and denervated kidneys. In marked contrast, group II dogs had a stable MAP (136-144 mm Hg, NS) and no increase in PGI2 levels. Plasma renin activity (0.7-2.5 ng/ml per h, P less than 0.005) increased, and renin secretion was greater in innervated compared with denervated kidneys (255 vs. 74 U/min, P less than 0.01) in these PG-inhibited dogs. In addition, denervated kidneys in group II dogs had a greater GFR (42 vs. 34 ml/min, P less than 0.01) and RFB (241 vs. 182 ml/min, P less than 0.01) than innervated kidneys after E. Group III animals had no significant changes in systemic or renal hemodynamics, plasma renin activity or PGI2 during the study. These results suggest that PGI2 mediates the systemic hypotension of early endotoxemia in the PG-intact animal. Moreover, PG inhibition uncovers an important effect of E to increase efferent renal nerve activity with a consequent decline in GFR and RBF independent of changes in MAP. Finally, the results demonstrate that renal nerves are important stimuli to renin secretion in early endotoxemia via pathways that are PG-independent.

Acetate and bicarbonate hemodialysis in patients with and without autonomic dysfunction. To test the contribution of bicarbonate (Bi) to hemodynamic stability during hemodialysis (HD), we compared the effects of ultrafiltration dialysis with bicarbonate and with acetate under conditions of high-sodium (141 mEq/liter) and low-sodium (130 mEq/liter) dialysate concentrations in 12 stable HD patients. Group 1 was patients (N = 5) who had normal findings on autonomic testing; group 2, patients (N = 7) who had abnormal findings on autonomic testing. All patients and staff were unaware of which dialysate was being used. During the high-sodium dialysate studies, changes in mean blood pressure (MBP), cardiac output (CO), and orthostatic tolerance to standing after HD were similar in both groups of patients with both acetate and bicarbonate dialysate. When the studies were repeated under low-sodium dialysate conditions, several differences emerged between acetate and bicarbonate HD. In group 1, the frequency of adverse symptoms upon standing after HD were reduced with bicarbonate (P < 0.05). In group 2, bicarbonate HD prevented a significant decrease in orthostatic MBP after HD. These results suggest that bicarbonate affords no greater hemodynamic stability than does acetate if a dialysate sodium of 141 mEq/liter is used. With lower sodium dialysate, bicarbonate appears to provide a modest improvement in decreasing orthostatic symptoms and signs in patients with and without autonomic insufficiency.Hémodialyse à l'acétate et au bicarbonate chez des malades avec ou sans dysfonctionnement autonome. Afin de tester la contribution des bicarbonates (Bi) à la stabilité hémodynamique au cours de l'hémodialyse (HD), nous avons comparé les effets hémodynamiques d'une dialyse avec ultrafiltration avec BiHD ou HD avec acétate (Ac) pour des dialysats riches (141 mEq/litre) ou pauvres (130 mEq/litre) en sodium chez 12 malades HD stables. Les malades du groupe 1 (N = 5) avaient une fonction autonome intacte, alors que ceux du groupe 2 (N = 7) avaient des tests autonomes anormaux. Aucun des malades, ni le personnel n'étaient au courant du dialysat utilisé. Pendant les études avec un dialysat riche en sodium, les modifications de la pression artérielle moyenne (MBP), du débit cardiaque (CO) et de la tolérance orthostatique à la station debout après HD étaient identiques dans les deux groupes de malades, avec dialysat Ac ou Bi. Quand ces études ont été répétées avec un dialysat pauvre en sodium, plusieurs différences sont apparues entre Ac et BiHD. Chez les malades du groupe 1, la fréquence des symptômes indésirables à la station debout après HD était réduite avec BiHD (P < 0,05). Chez les malades du groupe 2, BiHD prévenait une diminution significative de MBP orthostatique après HD. Ces résultats suggèrent que BiHD ne procure pas une plus grande stabilité hémodynamique qu'AcHD si un sodium dans le dialysat de 141 mEq/liter est employé. Avec un dialysat plus pauvre en sodium, BiHD semble apporter une amélioration modeste en diminuant les symptômes orthostatiques et les manifestations chez les malades avec ou sans insuffisance autonome.

Renal hemodynamic effects of therapeutic plasma levels of sulindac sulfide during hemorrhage. There is continued debate over any renalsparing effects of sulindac (S): such a property would be of benefit and be unique among nonsteroidal anti-inflammatory drugs (NSAIDS). S undergoes a distinct metabolism whereby the active drug (sulindac sulfide (SS)) does not appear in the urine. Accordingly, we tested the effect of a plasma concentration of SS in the therapeutic range on renal blood flow (RBF), glomerular filtration rate (GFR), and renal prostaglandin (PG) concentrations during sudden renal ischemic stress. The ischemic stress was produced by a 15 to 20% reduction in arterial pressure by arterial hemorrhage (H) in four separate groups of anesthetized dogs: control, SS (0.4 mg/kg i.v. bolus followed by 0.03 mg/kg/min constant infusion), indomethacin (I, 10 mg/kg), and benoxaprofen (B, 75 mg/kg). A plasma concentration of 3.69 µg/ml of SS was achieved by the infusion, and no SS appeared in the urine. H reduced GFR (by 46%) and RBF (by 38%) in control dogs; in SS-treated dogs, a 60% decline in GFR and a 73% decrease in RGF occurred. These decreases in renal hemodynamics in the SS group during H were significantly greater than in the control group. Further, these decrements in GFR and RBF were similar to those observed in the I- and B-treated dogs. Finally, SS reduced baseline arterial and renal PG concentrations, and prevented any increase in renal PG release during H. Thus, we conclude that a concentration of SS in the therapeutic range, which does not appear in the urine, is capable of enhancing the decline in GFR and RBF during a sudden ischemic stress such as H.