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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2006.10.042 Byline: Usman Baber, Robert D. Toto, James A. de Lemos Abstract: Although numerous large-scale trials have firmly established the benefits of statins for primary and secondary prevention of coronary artery disease, the role of this class of agents in patients with impaired renal function remains unclear. Author Affiliation: Donald W. Reynolds Cardiovascular Clinical Research Center, and the Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX Article History: Received 6 July 2006; Accepted 28 October 2006

Background: Few studies have examined the association between obesity and markers of kidney injury in a chronic kidney disease population. We hypothesized that obesity is independently associated with proteinuria, a marker of chronic kidney disease progression. Study Design: Observational cross-sectional analysis. Setting & Participants: Post hoc analysis of baseline data for 652 participants in the African American Study of Kidney Disease (AASK). Predictors: Obesity, determined using body mass index (BMI). Measurements & Outcomes: Urine total protein-creatinine ratio and albumin-creatinine ratio measured in 24-hour urine collections. Results: AASK participants had a mean age of 60.2 ± 10.2 years and serum creatinine level of 2.3 ± 1.5 mg/dL; 61.3% were men. Mean BMI was 31.4 ± 7.0 kg/m². Approximately 70% of participants had a daily urine total protein excretion rate <300 mg/d. In linear regression analyses adjusted for sex, each 2-kg/m² increase in BMI was associated with a 6.7% (95% CI, 3.2-10.4) and 9.4% (95% CI, 4.9-14.1) increase in urine total protein-creatinine and urine albumin-creatinine ratios, respectively. In multivariable models adjusting for age, sex, systolic blood pressure, serum glucose level, uric acid level, and creatinine level, each 2-kg/m² increase in BMI was associated with a 3.5% (95% CI, 0.4-6.7) and 5.6% (95% CI, 1.5-9.9) increase in proteinuria and albuminuria, respectively. The interaction between older age and BMI was statistically significant, indicating that this relationship was driven by younger AASK participants. Limitations: May not generalize to other populations; cross-sectional analysis precludes statements regarding causality. Conclusions: BMI is associated independently with urine total protein and albumin excretion in African Americans with hypertensive nephrosclerosis, particularly in younger patients. [ABSTRACT FROM AUTHOR]

Background: Intradialytic increases in blood pressure (BP) can complicate the management of hypertension in hemodialysis (HD) patients. However, the long-term consequences are uncertain. Thus, we sought to determine whether BP increases during HD were associated with greater 2-year mortality in incident HD patients.Study Design: Secondary analysis of a prospective dialysis cohort.Setting& Participants: Incident HD patients in the Dialysis Morbidity and Mortality Wave 2 Study.Predictors: Changes in systolic BP (SBP) during HD (ie, postdialysis SBP -- predialysis SBP), averaged from 3 HD sessions before enrollment.Outcome: Time to 2-year all-cause mortality.Measurements: Cox regression was used to model hazard ratios for mortality associated with changes in SBP during HD while adjusting for demographics, comorbid conditions, interdialytic weight gain, laboratory variables, and antihypertensive agents.Results: Of 1,748 patients, 12.2% showed greater than 10-mm Hg increases in SBP during HD. In adjusted analyses, every 10-mm Hg increase in SBP during HD was associated independently with a 6% increased hazard of death (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.11). When also adjusted for diastolic BP and postdialysis SBP, the adjusted hazard of death associated with increasing SBP during HD remained significant (hazard ratio, 1.12; 95% confidence interval, 1.05 to 1.21 per 10-mm Hg increase in SBP during HD). However, in analyses adjusted for predialysis SBP, there was a significant interaction between change in SBP and predialysis SBP. In analyses stratified by predialysis SBP, trends for increased mortality associated with increasing SBP during dialysis were present in patients with predialysis SBP less than 160 mm Hg. However, this relationship was significant only in patients with predialysis SBP less than 120 mm Hg.Limitations: Secondary analysis with a limited number of baseline BP measurements and limited information about dialysis prescription.Conclusions: Increasing SBP by more than 10 mm Hg during HD occurs in approximately 10% of incident patients, and although increasing SBP during HD was associated with decreased 2-year survival, these findings were limited to patients with predialysis SBP less than 120 mm Hg. [ABSTRACT FROM AUTHOR]

Background: Depressive symptoms, assessed by using self-report scales, are present at a striking rate of 45% in patients with chronic kidney disease (CKD) at dialysis therapy initiation. These scales may emphasize somatic symptoms of anorexia, sleep disturbance, and fatigue, which may coexist with chronic disease symptoms and lead to overestimation of depression diagnosis. No study has validated these scales in patients with CKD before dialysis therapy initiation.Study Design: We conducted a diagnostic test study in participants with CKD to investigate the screening characteristics of 2 depression self-report scales against a gold-standard structured psychiatric interview.Setting& Participants: 272 consecutively recruited outpatients with stages 2 to 5 CKD not treated by dialysis were studied.Index Tests: The Beck Depression Inventory (BDI) and the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR(16)) depression screening scales were administered to all participants.Reference Test: A structured Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based interview, the Mini International Neuropsychiatric Interview, was administered by trained persons blinded to self-report scale scores.Results: 57 of 272 (21%) patients had major depression according to the reference test. The best cutoff scores by means of receiver/responder operating characteristic curves to identify a major depressive episode were 11 for the BDI and 10 for the QIDS-SR(16). Sensitivities were 89% (95% confidence interval [CI], 78 to 96; BDI) and 91% (95% CI, 80 to 97; QIDS-SR(16)), whereas specificities were 88% (95% CI, 83 to 92; BDI) and 88% (95% CI, 83 to 92; QIDS-SR(16)). The positive and negative likelihood ratios for these cutoff scores were 7.6 and 0.1 (BDI) and 7.5 and 0.1 (QIDS-SR(16)).Limitations: Single-center study and a sample not representative of US demographics.Conclusions: We found that a BDI score of 11 or higher was a sensitive and specific cutoff value for identifying a major depressive episode in patients with CKD not on dialysis therapy. Both the BDI and QIDS-SR(16) are effective screening tools. [ABSTRACT FROM AUTHOR]

Background: Depression is prevalent in long-term dialysis patients and is associated with death and hospitalization. Whether depression is present through all chronic kidney disease (CKD) stages or appears after dialysis therapy initiation is not clear. We determined the prevalence of a major depressive episode and other psychiatric illnesses by using a structured gold-standard clinical interview and demographic and clinical variables associated with major depressive episode in patients with CKD.Study Design: Observational cross-sectional study using a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based structured interview administered by trained persons to 272 consecutive participants. Multivariable logistic regression was used to determine demographic and clinical variables associated with major depressive episode.Setting& Participants: Patients with stages 2 to 5 CKD not treated by using dialysis were consecutively approached and enrolled from a Veterans Affairs CKD clinic.Predictors: Demographic and clinical variables.Outcome: Major depressive episode diagnosed by using a structured Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based interview, the Mini International Neuropsychiatric Interview.Results: The cohort had a mean age of 64.5 +/- 12.0 years. Thirty-eight percent were African American, and 55% had diabetes mellitus. Percentages of patients with stages 2, 3, 4, and 5 CKD were 6%, 38%, 41%, and 14%, respectively. Mean hemoglobin level was 12.5 +/- 2.0 g/dL. The prevalence of a major depressive episode was 21% and did not vary significantly among different CKD stages. Variables associated with a major depressive episode were diabetes mellitus, comorbid psychiatric illness, and history of drug or alcohol abuse.Limitations: Single-center study composed of primarily male veterans.Conclusions: One in 5 patients with CKD had a major depressive episode. Patients with CKD should be screened routinely for depression given this high prevalence and the independent association of depression with poor outcomes in patients with end-stage renal disease receiving maintenance dialysis. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a major public health problem in the United States. It is estimated that nearly 20 million Americans have some degree of chronic kidney disease defined as an estimated glomerular filtration rate of less than sixty milliliters per minute or evidence of kidney damage by imaging study, biopsy, biochemical testing or urine tests with an estimated glomerular filtration rate more than sixty milliliters per minute. Hypertension is present in more than 80% of patients with CKD and contributes to progression of kidney disease toward end stage (ESRD) as well as to cardiovascular events such as heart attack and stroke. In fact the risk for cardiovascular death in this patient population is greater than the risk for progression to ESRD. Proteinuria is an important co-morbidity in hypertensives with CKD and increase risk of disease progression and cardiovascular events. Treatment of hypertension is therefore imperative. The National Kidney Foundation clinical practice guidelines recommend a blood pressure goal of <130 mmHg systolic and <80 mmHg diastolic for all CKD patients. Recent post-hoc analyses of the Modification of Diet in Renal Disease study indicate that lower blood pressure may provide long-term kidney protection in patients with nondiabetic kidney disease. Specifically a mean arterial pressure <92 mmHg (e.g. 120/80 mmHg) as compared to 102-107 mmHg (e.g. 140/90 mmHg) is associated with reduced risk for ESRD. In most cases achieving this goal requires both non-pharmacologic and pharmacologic intervention. Dietary sodium restriction to no more than 2 grams daily is important. In addition, moderate alcohol intake, regular exercise, weight loss in those with a body mass index greater than 25 kg/M2 and reduced amount of saturated fat help to reduce blood pressure. The first line pharmacologic intervention should be an angiotensin converting enzyme inhibitor or angiotensin II type 1 receptor blocker in those with diabetes or non-diabetics with more than 200 mg protein/gram creatinine on a random urine sample. For non-diabetics with less than 200 mg protein/gram creatinine on a random urine sample, no specific first-line drug class is recommended. After initial dosing with an ACEi, ARB or other drug, a diuretic should be added to the regimen. Thereafter, beta-blockers, calcium channel blockers, apha blockers and alpha 2 agonists (e.g. clonidine) and finally vasodilators (e.g. minoxidil) should be added to achieve blood pressure goal. Combinations of ACEi and ARB are helpful in reducing proteinuria and may also lower blood pressure further in some some cases. Blood pressure should be monitored closely in hypertensive patients with CKD and both clinic and home blood pressure measurements may help the clinician adjust treatment. [Copyright &y& Elsevier]

Cardiac artery disease and heart failure are major causes for morbidity and mortality in diabetes in general and in those with chronic kidney disease (CKD) in particular. Hypertension and dyslipidemia are more common in diabetes and the prevalence of coronary artery disease in diabetics is two-fold to four-fold higher than in nondiabetics. In those with CKD the incidence of cardiovascular complications is nearly two-fold higher than those without CKD. Recent studies suggest that the pathophysiology of cardiac disease is complex process involving both microvascular and macrovascular disease. In addition, myocardial lipotoxicity may be a novel contributing factor particularly in type 2 diabetics. Compelling evidence from cardiovascular outcomes trials indicates that treatment with drugs that block the renin-angiotensin system are cardioprotective in diabetics with microalbuminuria and early stages of kidney disease. Multiple risk factor intervention aimed at optimal blood pressure control (BP <130/<80 mmHG), lowering LDL cholesterol below 100 mg/dl, lowering triglyceride level to 150 mg/dl, A1C <6.5%, treatment with an ACE inhibitor or an angiotensin II receptor blocker, administration of once daily low-dose aspirin and smoking cessation together reduce cardiovascular morbidity and mortality in type 2 diabetics. Novel studies including diabetics with nephropathy aimed at improving outcomes in diabetics by treatment of anemia and optimal control of dyslipidemia are now underway. These and other clinical trials should provide important new insights into improving the quality of life in diabetics and ultimately preventing cardiac disease. [ABSTRACT FROM AUTHOR]

Studies anemia of chronic kidney disease (CKD). Contribution of anemia to cardiovascular disease in CKD; Role of anemia in CKD progression; Hypothetical mechanisms by which anemia may cause CKD; Treatment goal for anemia in CKD.

Aims: Hypomagnesemia (serum magnesium [Mg] <0.74 mmol/L [<1.8 mg/dL]) is commonly observed in patients with type 2 diabetes (T2D). This study investigated the effect of treatment with dapagliflozin 10 mg on Mg concentrations in patients with T2D.Methods: In this post hoc analysis, we used pooled data from 10 placebo-controlled studies of dapagliflozin over 24 weeks of treatment in patients with T2D. We evaluated the change in Mg in patients receiving dapagliflozin vs. placebo overall, and in subgroups with baseline hypomagnesemia and normal/hypermagnesemia (≥0.74 mmol/L [≥1.8 mg/dL]). We determined the proportion of patients with baseline hypomagnesemia who achieved Mg ≥0.74 mmol/L (≥1.8 mg/dL).Results: A total of 4398 patients with T2D were included. The mean change from baseline to week 24 in Mg was significantly larger with dapagliflozin vs. placebo; difference, 0.06 mmol/L (95% confidence interval [CI]: 0.05, 0.06). The proportion of patients with Mg within the population reference range after 24 weeks of treatment was significantly higher with dapagliflozin vs. placebo; difference, 47.8% (95% CI: 41.4, 53.9). The proportion of patients displaying hypermagnesemia did not increase with dapagliflozin treatment.Conclusions: Treatment with dapagliflozin 10 mg resulted in correction of Mg concentrations in patients with T2D and hypomagnesemia. [ABSTRACT FROM AUTHOR]

Editorial. Comments on the evolution of atherosclerotic renal artery stenosis. Consequences of atherosclerotic narrowing of the renal arteries; Risk factors to ARA disease; Predictors of progression of renal disease.

Proteinuria and hypertensive nephrosclerosis in African Americans. Proteinuria is a known risk factor for both renal disease progression and cardiovascular morbidity and mortality in hypertensive populations. African Americans are among the highest risk groups for development of renal disease in the setting of hypertension and suffer a disproportionate burden of end-stage renal disease attributed to hypertension. Population-based studies indicate that African Americans have higher rates of albuminuria compared to non-African Americans in part due to higher rates of hypertension and diabetes in African Americans as compared to non-Hispanic whites for example. The African American Study of Kidney Disease and Hypertension (AASK) Trial was a prospective long-term clinical trial that examined the effect of aggressive blood pressure lowering versus usual blood pressure lowering in three different classes of antihypertensives on renal outcomes in approximately 1200 African Americans with hypertensive nephrosclerosis. Two thirds of trial participants had <300 mg protein, and one third had ≥300 mg of protein in a 24-hour urine specimen at baseline. Those with >300 mg protein excretion compared to those with <300 mg protein excretion at baseline had more rapid decline in renal function and ESRD events. Moreover, lower levels of proteinuria than previously thought may be important for identifying those at higher risk for kidney disease progression. The AASK cohort study, a follow-up to the trial, is now underway. The longer term follow-up will provide new insights into proteinuria and other risk factors for progression of kidney disease in hypertensive nephrosclerosis. [ABSTRACT FROM AUTHOR]

Pulse pressure is a well established marker of vascular stiffness and is associated with increased mortality in hemodialysis patients. Here we sought to determine if a decrease in pulse pressure during hemodialysis was associated with improved outcomes using data from 438 hemodialysis patients enrolled in the 6-month Crit-Line Intradialytic Monitoring Benefit Study. The relationship between changes in pulse pressure during dialysis (2-week average) and the primary end point of non-access-related hospitalization and death were adjusted for demographics, comorbidities, medications, and laboratory variables. In the analyses that included both pre- and post-dialysis pulse pressure, higher pre-dialysis and lower post-dialysis pulse pressure were associated with a decreased hazard of the primary end point. Further, every 10 mm Hg decrease in pulse pressure during dialysis was associated with a 20% lower hazard of the primary end point. In separate models that included pulse pressure and the change in pulse pressure during dialysis, neither pre- nor post-dialysis pulse pressure were associated with the primary end point, but each 10 mm Hg decrease in pulse pressure during dialysis was associated with about a 20% lower hazard of the primary end point. Our study found that in prevalent dialysis subjects, a decrease in pulse pressure during dialysis was associated with improved outcomes. Further study is needed to identify how to control pulse pressure to improve outcomes. [ABSTRACT FROM AUTHOR]

Thrombotic events while receiving antiplatelet agents (APAs) are more common in subjects with versus without chronic kidney disease (CKD). Data on antiplatelet effects of APA in CKD are scarce and limited by lack of baseline platelet function before APA treatment. We hypothesized subjects with stages 4 to 5 CKD versus no CKD have greater baseline platelet aggregability and respond poorly to aspirin and clopidogrel. In a prospective controlled study, we measured whole blood platelet aggregation (WBPA) in 28 CKD and 16 non-CKD asymptomatic stable outpatients not on APA, frequency-matched for age, gender, obesity, and diabetes mellitus. WBPA was remeasured after 2 weeks of each aspirin and aspirin plus clopidogrel. The primary outcome was percent inhibition of platelet aggregation (IPA) from baseline. The secondary outcome was residual platelet aggregability (RPA; proportion with <50% IPA). Baseline platelet aggregability was similar between groups except adenosine diphosphate-induced WBPA, which was higher in CKD versus non-CKD; median (interquartile range) = 13.5 (9.5 to 16.0) versus 9.0 (6.0 to 12.0) Ω, p = 0.007. CKD versus non-CKD participants had lower clopidogrel-induced IPA, 38% versus 72%, p = 0.04. A greater proportion of CKD versus non-CKD participants had RPA after clopidogrel treatment (56% vs 8.3%, p = 0.01). There were no significant interactions between CKD and the presence of cytochrome P450 2C19 polymorphisms for platelet aggregability in clopidogrel-treated participants. In conclusion, CKD versus non-CKD subjects exhibited similar platelet aggregation at baseline, similar aspirin effects and greater RPA on clopidogrel, which was independent of cytochrome P450 2C19 polymorphisms. [ABSTRACT FROM AUTHOR]

Abstract: Major Depressive Disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3–5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3–5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50mg once daily or matching placebo followed by a dose escalation strategy consisting of 50mg increments at 2week intervals (as tolerated) to a maximum dose of 200mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD. [Copyright &y& Elsevier]

Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy. Background. Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). Anemia is common in diabetics with nephropathy; however, the impact of anemia on progression to ESRD has not been carefully examined. Methods. We studied the relationship between baseline hemoglobin concentration (Hb) and progression of diabetic nephropathy to ESRD in 1513 participants enrolled in Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study and followed for an average of 3.4 years. Multivariate Cox proportional hazards models were used to analyze the relationship between Hb and ESRD, after adjusting for predictors for ESRD. Analyses were performed with Hb stratified by quartile: first quartile <11.3 g/dL, second quartile 11.3 to 12.5 g/dL, third quartile 12.6 to 13.8 g/dL, and fourth quartile ≥13.8 g/dL (reference) and as a continuous variable. Results. Baseline hemoglobin concentration was correlated with subsequent development of ESRD. After adjustment for predictors of ESRD, the hazard ratios for the first, second, and third Hb quartiles were 1.99 (95% CI, 1.34-2.95), 1.61 (95% CI 1.08-2.41), and 1.87 (95% CI 1.25-2.80). With hemoglobin as a continuous variable, the adjusted hazard ratio was 0.90 (95% CI 0.84-0.96, P= 0.0013). The average increase in adjusted relative risk was 11% for each 1 g/dL decrease in hemoglobin concentration. Conclusion. Our data suggest that even mild anemia, Hb <13.8 g/dL increases risk for progression to ESRD. Hemoglobin is an independent risk factor for progression of nephropathy to ESRD in type 2 diabetes. [ABSTRACT FROM AUTHOR]