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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.

A 54-year-old woman with type 2 diabetes presents for care. Her creatinine level has increased from 1.1 mg per deciliter (97 μmol per liter) 4 years ago to 3.1 mg per deciliter (274 μmol per liter) at the most recent measurement (estimated glomerular filtration rate, 26 ml per minute per 1.73 m2 of body-surface area). Her urinary protein excretion is 2.8 g per 24 hours. Her blood pressure is 155/90 mm Hg, and the glycated hemoglobin level is 7.6 mg per deciliter. Her current medications include an oral hypoglycemic agent, an angiotensin-converting–enzyme inhibitor, a statin, and a thiazide diuretic. How should her case be managed?

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.

Summary Cardiac performance during hemodialysis is dependent on preexisting conditions (i.e., coronary artery disease, myocardial hypertrophy, LV compliance, anemia, hypertension, etc.) and the hemodynamic alterations caused by the dialysis procedure itself (osmotic shifts, ionized calcium changes, etc.). Clinical hemodynamic investigations of cardiac performance during uremia have been hampered by the difficulty in isolating individual parameters of ventricular function. Myocardial reserve in dialysis patients is often reduced because of antecedent ischemic disease, hypertension, and the presence of autonomic dysfunction in many patients. Rapid volume losses or gains are likely to be less well tolerated with resultant hypotensive syndromes or pulmonary edema as the result. The controlled volume loss achievable with newer dialysis machines, the use of higher dialysate sodium concentrations, and the wider availability of erythropoietin may improve the tolerance to the procedure for many patients.

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 goal of risk stratification of CVD inpatients with CKD is to lead to effective and early intervention and to prevent the adverse outcomes associated with this complex multisystem disease that is characteristic of growing number of patients with CKD in the general population and of patients receiving dialysis therapy or kidney transplantation. By 2030, there will be 2.24 million patients with ESRD in the United States, and approximately 1.3 million of these cases of ESRD will be caused by diabetes mellitus. Thus, CVD in this high-risk population presents a challenge for the nephrology and the cardiology community.

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

Toxic nephropathy is an important cause of reversible renal injury if detected early. Renal damage can be due to several different mechanisms affecting different segments of the nephron, renal microvasculature or interstitium. Clinical signs may not be apparent in the early stages and assessment of renal function should include thorough evaluation of glomerular filtration rate, proximal and distal tubular function. A kidney biopsy may be indicated to establish the cause and effect relationship. The presence of comorbid conditions such as older age, diabetes mellitus, hypertension and congestive heart failure have a significant influence on the patient's ability to recover from the toxic effects. A significant degree of drug-induced renal toxicity is only acceptable if the causative agent is used for the curative treatment of an underlying disease but not if the aim is the palliative or supportive therapy. The decision to reduce the dose or to stop the toxic agent must be based on the ultimate goal of therapy and the patient's baseline health status.

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.

Caring for the urban renal patient can be a challenge to providers for many reasons. Although racial and socioeconomic factors have an impact on the health of this population, one must also consider the effect of the urban environment on the ill, especially those with renal disease. This article reviews the state of health among the poor and nonwhite minorities, who tend to inhabit the urban regions of this country, and then highlights the unique characteristics of those with renal disease. The impact of the Medicare end-stage renal disease (ESRD) program and center-specific quality of care on the outcome of the urban patient with ESRD is explored.

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.

Coexisting diabetes and hypertension can set off a vicious cycle of increasing renal damage and rising blood pressure. Early treatment—before blood pressure reaches levels traditionally considered hypertensive—can preserve renal function. Late treatment typically requires multiple drugs and may not effectively control blood pressure and arrest progression of renal disease.

Although it is anticipated that most patients with renal insufficiency will progress towards end-stage renal disease (ESRD) there have been few population-based studies to validate this assumption. We examined serial creatinines from 3,874 anonymous patients at an urban VA medical center who had a baseline creatinine of 1.4 mg/dl or greater to estimate the frequency of deterioration in renal function (DRF). DRF was defined as the first Cr (1stCr) value being lower than the last Cr (LCr) for each patient. The median follow-up was 48.3 ± 0.5 months with 18 ± 0.5 creatinine values per patient. The median 1stCr was 1.6 ± 0.1 mg/dl with 32.2% of the patients having a 1stCr greater than or equal to 1.7 mg/dl. In the study group, 1,723 (44.4%) had DRF including 1,089 (41.4%) of those patients with a 1stCr of 1.4–1.7 mg/dl. However, 45 (36.6%) of those with a 1stCr value 3.0–5.0 mg/dl did not have DRF, the percent with stable creatinine in this group did not vary with length of follow-up. Over the study period, 299 (7.7%) of all the patients had a creatinine rise to 7.0 mg/dl, with 104 (4%) of those with a 1stCr of 1.4–1.7 mg/dl reaching this endpoint. Conclusion: A majority, but not all, patients with renal insufficiency lose renal function over time and those with even mild hypercreatinemia are at risk for deterioration in renal function. Hypercreatinemia, however, does not accurately discriminate between those renal insufficiency patients who are stable versus those at high risk for ESRD.

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.

Drugs that block the renin-angiotensin system have multiple mechanisms of action that may be beneficial in stabilizing or delaying progression of renal disease. The most important of these actions is the simultaneous control of both systemic and glomerular capillary hypertension. Angiotensin-converting enzyme (ACE) inhibitors are a class of drugs that have proven antihypertensive and antiproteinuric effects, with a demonstrated ability to delay progression of renal disease in conjunction with the ability to reduce systemic blood pressure. The mechanism of action for these drugs remains poorly described, but depends in part on an ability to reduce plasma angiotensin II levels and increase plasma bradykinin levels. Angiotensin II receptor subtype 1 (AT1) blockers differ in their mechanism of action from the ACE inhibitors. These drugs primarily block the binding of angiotensin II to its type 1 site. In so blocking the type 1 binding site, however, greater levels of circulating angiotensin II result, and the resultant biologic activity of angiotensin II or its metabolites such as angiotensin(1-7) and angiotensin(3-8) may be more directed to other angiotensin-binding sites. AT1 blockers have similar antihypertensive and antiproteinuric effects to those of ACE inhibitors and they may prove to be as useful as ACE inhibitors in delaying progression of renal disease. Because ACE inhibitors and AT1 blockers inhibit the renin-angiotensin system by different mechanisms, there is a possibility that combining them in clinical practice may prove efficacious for lowering blood pressure and for providing target organ protection.

Renal artery stenosis is a common disorder and is an established cause of hypertension and renal insufficiency. Although treatment with renal artery stents has been shown to improve blood pressure and renal function for some patients, the patient population most likely to benefit is unknown. The current study was designed to determine which factors are predictive of improved blood pressure and renal function when patients with renal artery stenosis are treated with renal artery angioplasty and stent placement.In a prospective evaluation 127 consecutively enrolled patients with renal artery stenosis in 171 vessels were treated with angioplasty and intravascular stents. Blood pressure and serum creatinine concentration were measured before stent placement and during the follow-up period.The mean length of the follow-up period was 15 +/- 14 months. Mean systolic blood pressure improved among patients with hypertension (from 177 +/- 26 mm Hg before stent placement to 151 +/- 24 mm Hg 6 months after stent placement (P.001). The greatest improvement occurred among those with the highest baseline systolic blood pressure. This beneficial effect on blood pressure was sustained for 3 years. Sex, age, diastolic blood pressure, number of vessels into which stents were placed, serum creatinine concentration, presence of bilateral disease, race, and severity of stenosis were not predictive of improved blood pressure. Mean creatinine concentration was not significantly changed for the group as a whole. A significant decrease in serum creatinine concentration occurred among 43% of patients with baseline renal insufficiency. None of the examined variables was predictive of improvement.Renal artery angioplasty and stent placement produced a significantly greater reduction in systolic blood pressure among patients with the highest baseline systolic blood pressure. Other examined variables were not predictive of a significant improvement in blood pressure. No examined variable was predictive of improved renal function. We concluded that management of renal artery stenosis with renal artery angioplasty and stent placement is most likely to result in significant improvement in systolic blood pressure among patients with the highest baseline systolic blood pressure.

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.

Although the cause may be inadequate blood flow or a toxic insult to the renal tubules--or a combination thereof--iatrogenesis often underlies acute renal failure. Awareness of the procedures and treatments most likely to precipitate renal failure can help physicians to prevent the condition, or at least to detect it at the earliest opportunity.

This brief review discusses the problem of atherosclerotic renal artery obstruction in the elderly. This disorder is common in the elderly; the overall incidence is estimated to be 10%. The disorder presents with new onset hypertension, a loss of control of BP or a decline in renal function in some patients. In others, the obstruction may be unmasked by the use of angiotensin converting enzyme inhibitors or angiotensin receptor blocker agents. The current approach to the diagnosis of renal artery obstruction is discussed as are the indications for invasive procedures. Careful patient selection for any invasive procedures is particularly important in the elderly since this population has a propensity to higher morbidity.

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

Angiotensin II is thought to play a role in the renal adaptations to reduced renal mass, but earlier work has shown that plasma renin activity (PRA) does not increase in this setting. To examine this paradox, we studied the effect of uninephrectomy (UNX) on circulating, juxtaglomerular, glomerular, and proximal tubular (PT) renin. PRA was unchanged 2 wk following UNX and fell slightly at 6 wk. Single kidney renin secretory capacity and cortical renin mRNA, reflecting juxtaglomerular renin, were unchanged at 2 and 6 wk. With quantitative competitive reverse transcription-polymerase chain reaction, renin mRNA in microdissected glomeruli and PT were dramatically increased 2 wk post-UNIX (for glomeruli: sham, 1.2 +/- 0.3, vs. UNX, 8.8 +/- 1.9 x 10(5) copies/glomerulus; for PT: sham, 4.6 +/- 0.9, vs. UNX, 17.7 +/- 5.1 x 10(3) copies/mm). By 6 wk, glomerular renin was unchanged, and PT renin mRNA was markedly suppressed (for glomeruli; sham, 2.9 +/- 1.2, vs. UNX, 4.2 +/- 1.1 x 10(5) copies/glomerulus; for PT: sham, 7.5 +/- 2.1, vs. UNX, 1.0 +/- 0.3 x 10(3) copies/mm). These results demonstrate differential regulation of the circulating, juxtaglomerular, glomerular, and PT renin systems. Early activation of glomerular and PT renin may result in increased local generation of angiotensin II and thereby affect renal structural and functional adaptations following UNX.

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The intrinsic ability of the kidney to regulate renal blood flow and glomerular filtration rate (GFR) over a wide range of perfusion pressures has fascinated physiologists for decades. These adaptive responses to physiologic and pathologic alterations in renal perfusion, known collectively as renal autoregulation, serve to maintain renal excretory function in settings of decreased renal blood flow, such as in states of volume depletion, hypotension, or reduced cardiac output. Another important and unique setting of renal hypoperfusion is that of renal arterial occlusive disease due to a fixed stenosis, a situation that typically presents with a chronic, gradual, and eventually critical reduction of perfusion. This physiologic stress depends on renal autoregulation to maintain GFR, but the ongoing global renal hypoperfusion appears to eventually produce chronic ischemic injury to the renal parenchyma through mechanisms that are not clearly understood. This latter prospect is clearly a threat to the viability of the kidney and appears to be an important cause of chronic and often irreversible kidney disease. An understanding of the limits, mechanisms, and the pharmacologic manipulation of renal autoregulation is important in this setting because the disordered physiology is silent. Likewise, an understanding of the pathophysiology of chronic ischemic injury is important in designing effective clinical strategies to treat this disorder.

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)

The glomerulus has several components of the renin-angiotensin system (RAS). The purpose of this study was to evaluate the ability of glomeruli isolated from adult Wistar-Kyoto rats to produce angiotensin II (ANG II). When isolated glomeruli were incubated in Krebs buffer, the peak concentration of immunoreactive angiotensin (ANG) in the incubation medium, representing simultaneous production and degradation, occurred after 15 min of incubation (3.98 +/- 0.34 pg.mg protein-1.15 min-1, of which 18% was ANG II. When 125I-labeled ANG II was incubated with isolated glomeruli, the half-life of ANG II was 6.06 min. Hence, we estimated ANG II production at 3.77 +/- 0.21 pg.mg protein-1.15 min-1. When angiotensinogen-rich serum was added to the incubation medium, ANG concentration at 15 min increased by 500-fold (1,978 +/- 44 pg.mg protein-1.15 min-1, P < 0.001). ANG concentration in the glomerular incubate responded to perturbations known to alter systemic RAS. Enalaprilat, chymostatin, propranolol, and renin antiserum decreased ANG concentration in glomerular incubate, whereas salt depletion increased this (P < 0.05). We conclude that the rat glomerulus can generate ANG II independent of neural, hormonal, or vascular control.

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.

Emerging evidence suggests the endothelium produces several substances capable of locally regulating organ blood flow. Vasoactive prostaglandins, endothelium-derived relaxing factor, and endothelin are examples of these vasoactive substances. Abnormalities of endothelial function may contribute to the pathogenesis of disease in several circumstances, including hypertension, diabetes, and septicemia. Evidence for the endothelium as a regulator of regional perfusion and several of the endothelium-derived substances and their potential role in disease are reviewed.