Uptal D. Patel

Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Systematic Review: Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers for Treating Essential Hypertension

Context Are angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) more effective for treating essential hypertension? Contribution This systematic review of trials that directly compared ACE inhibitors and ARBs in adults with essential hypertension found good evidence that the agents had similar long-term effects on blood pressure. There were no consistent differential effects for mortality, cardiovascular events, progression to diabetes, left ventricular function, or kidney disease. Cough was more frequent with ACE inhibitors than ARBs. Implication Both ACE inhibitors and ARBs have similar effects on blood pressure and may not have differential effects on other clinical outcomes, although ACE inhibitors do cause cough more often than ARBs. The Editors More than 65 million U.S. adultsapproximately one thirdhave hypertension. In addition to being the leading attributable risk factor for death throughout the world (1), hypertension results in substantial illness due to its effect on several target organs, including the brain, eyes, heart, arteries, and kidneys. Despite the high rate of morbidity and mortality attributable to hypertension, control remains suboptimal (2). In addition to several effective nonpharmacologic interventions, many individuals require antihypertensive medication to lower blood pressure and often require several medications together (2). Among the most common of the many choices in antihypertensive therapy are those aimed at inhibiting the reninangiotensinaldosterone (renin) system. Currently, renin system inhibitors include angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). Although clinicians regard ACE inhibitors and ARBs as effectively equivalent, it is not clear whether this is appropriate. For example, ACE inhibitors do not entirely block production of angiotensin II because of other, unaffected converting enzymes. Also, ACE inhibitors are associated with well-known adverse events not shared by ARBs, including cough (estimated incidence, 5% to 20%) and the possibly related phenomenon of angioedema (estimated incidence, 0.1% to 0.2%) (3). Although both ACE inhibitors and ARBs are highly effective in lowering blood pressure among patients with essential hypertension (4, 5), their comparative effectiveness and the relative advantages and disadvantages of ACE inhibitors versus ARBs are unknown. This review summarizes the evidence on the comparative long-term benefits and harms of ACE inhibitors versus ARBs for treating essential hypertension in adults. The full technical report was commissioned by the Agency for Healthcare Research and Quality (6). Methods We developed and followed a standardized protocol for all steps of the review. Data Sources and Searches We searched MEDLINE (1966 to week 3 of May 2006) and the Cochrane Central Register of Controlled Trials (Issue 2, 2006) for studies published in English after 1988, using terms for drug interventions, hypertension, and study design. We also reviewed bibliographies submitted by pharmaceutical companies to the Scientific Resource Center for the Agency for Healthcare Research and Qualitys Effective Health Care Program, reference lists of relevant review articles, and citations identified by reviewers of the draft report. For the current review, we updated our MEDLINE search to August 2007 to identify new head-to-head trials that reported blood pressure outcomes and major cardiovascular events. Results from the newly identified studies (721) were consistent with the evidence described in the full technical report and are not presented here. Study Selection We included comparative clinical studies of any design (including randomized, controlled trials and nonrandomized, controlled trials; cohort studies; and casecontrol studies) that provided direct comparisons of ACE inhibitors versus ARBs at 12 weeks or more after the initial intervention. In addition to simple comparisons of a single ACE inhibitor versus a single ARB, we included studies with grouped comparisons (such as a specific ARB versus ACE inhibitors or unspecified ARBs versus unspecified ACE inhibitors) and comparisons in which the same drug was administered with an ACE inhibitor versus that drug with an ARB (for example, losartan and hydrochlorothiazide vs. enalapril and hydrochlorothiazide). We excluded studies with comparisons in which the drugs administered with an ACE inhibitor differed from those administered with an ARB (for example, enalapril and manidipine vs. irbesartan and hydrochlorothiazide). We included studies with treatment protocols that permitted the addition of other antihypertensive medications during the trial, provided that the co-intervention protocols were the same in the ACE inhibitor and ARB treatment groups. Outcomes we considered included blood pressure control, adherence, quality of life, several intermediate outcomes, and harms. We excluded studies with fewer than 20 total patients in the ACE inhibitor and ARB treatment groups and focused on studies of adults (18 years of age) with essential hypertension, as defined by the study authors. We also evaluated studies of ARBs versus other (nonACE inhibitor) comparators and ACE inhibitors versus other (non-ARB) comparators, which were to be considered in case too few direct head-to-head trials were identified for outcomes of interest. Appendix 1 contains the details of how we identified and reviewed indirect comparison studies. Data Extraction and Quality, Applicability, and Strength of Evidence Assessments One author extracted data from each study, which were confirmed by another author. Extracted information included study design; interventions; population characteristics; recruitment setting; inclusion and exclusion criteria; numbers of participants screened, eligible, enrolled, and lost to follow-up; and results for each outcome. We used predefined criteria adapted from those developed by the U.S. Preventive Services Task Force (22) and the Centre for Reviews and Dissemination in the United Kingdom (23) to assess the quality of individual studies as good, fair, or poor, and we noted important limitations on internal validity for studies rated as fair or poor. The applicability of individual studies was assessed by noting the most important potential limitations (up to 3) in a studys applicability from among the list described by Rothwell (24), as adapted by the Scientific Resource Center (Appendix 2). Quality and applicability assessments are detailed for individual studies in the evidence tables included in the full report (6). Finally, we assessed the strength of the body of evidence for each key question as high, moderate, low, or very low by using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework (25). Data Synthesis and Analysis Given that many studies did not have the statistical power to determine equivalence for relevant outcomes, we considered pooling (without regard to the specific drug within the ACE inhibitor or ARB class) to overcome a type II error. In evaluating direct comparison studies for potential data synthesis, we primarily considered clinical homogeneity. In general, we considered groups of studies as suitable for quantitative synthesis when we identified at least 4 clinically and relatively similar studies that assessed the same outcome. We used additional and more detailed criteria to determine suitability for pooling of indirect comparisons, as such comparisons are tenuous (Appendix 1). We did not attempt to pool direct and indirect comparison studies in a single analysis, primarily because we did not identify a sufficient number of clinically similar indirect comparison studies to analyze. When we pooled studies, we used the random-effects model for the primary analysis and the fixed-effect model for sensitivity analysis. We stratified analyses by study design, separating randomized, controlled trials from observational studies. We performed all analyses by using Comprehensive Meta-analysis, version 2 (Biostat, Englewood, New Jersey). For count outcomes, we calculated summaries of the relative effect (odds ratios) and absolute effect (risk difference). We chose the Peto method for analyzing data on cough and withdrawals due to adverse events because event rates were low and treatment groups were not substantially imbalanced, conditions under which this method is the least biased and most powerful (26). This method also allows inclusion of studies with zero events in 1 group with no continuity correction. For data on rates of successful monotherapy, we used risk differences because event rates were high, which makes the assumption of a constant odds ratio unreasonable. Role of the Funding Source The Agency for Healthcare Research and Quality formulated the initial study questions and reviewed and commented on planned methods, data analysis, and the draft report. The funding source did not participate in the search of the literature, determination of study eligibility, or evaluation of individual studies. Results Of 1185 citations, 69 reports (61 distinct studies) directly compared ACE inhibitors with ARBs (Figure 1). Forty-seven studies were randomized, controlled trials; 1 was a nonrandomized, controlled trial; 9 were retrospective cohort studies; 2 were prospective cohort studies; 1 was a cross-sectional cohort study; and 1 was a casecontrol study. Table 1 shows the numbers of studies that compared different agents. Enalapril was the most frequently studied ACE inhibitor (24 studies), and losartan the most frequently studied ARB (19 studies). Most studies were relatively short-term; 19 followed patients for 12 weeks, and 21 followed patients between 12 weeks and 6 months. Most studies excluded patients with secondary causes of hypertension, as well as patients with recent acute events, such as myocardial infarction or stroke. Table 2 summarizes the number

Diabetic Kidney Disease: A Report From an ADA Consensus Conference

The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly

Biomarkers Predict Progression of Acute Kidney Injury after Cardiac Surgery

25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.

Contemporary Incidence, Predictors, and Outcomes of Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions: Insights From the NCDR Cath-PCI Registry

Being able to predict whether AKI will progress could improve monitoring and care, guide patient counseling, and assist with enrollment into trials of AKI treatment. Using samples from the Translational Research Investigating Biomarker Endpoints in AKI study (TRIBE-AKI), we evaluated whether kidney injury biomarkers measured at the time of first clinical diagnosis of early AKI after cardiac surgery can forecast AKI severity. Biomarkers included urinary IL-18, urinary albumin to creatinine ratio (ACR), and urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL); each measurement was on the day of AKI diagnosis in 380 patients who developed at least AKI Network (AKIN) stage 1 AKI. The primary end point (progression of AKI defined by worsening AKIN stage) occurred in 45 (11.8%) patients. Using multivariable logistic regression, we determined the risk of AKI progression. After adjustment for clinical predictors, compared with biomarker values in the lowest two quintiles, the highest quintiles of three biomarkers remained associated with AKI progression: IL-18 (odds ratio=3.0, 95% confidence interval=1.3-7.3), ACR (odds ratio=3.4, 95% confidence interval=1.3-9.1), and plasma NGAL (odds ratio=7.7, 95% confidence interval=2.6-22.5). Each biomarker improved risk classification compared with the clinical model alone, with plasma NGAL performing the best (category-free net reclassification improvement of 0.69, P<0.0001). In conclusion, biomarkers measured on the day of AKI diagnosis improve risk stratification and identify patients at higher risk for progression of AKI and worse patient outcomes.

The epidemiology of chronic kidney disease in sub-Saharan Africa: a systematic review and meta-analysis

OBJECTIVES This study sought to examine the contemporary incidence, predictors and outcomes of acute kidney injury in patients undergoing percutaneous coronary interventions. BACKGROUND Acute kidney injury (AKI) is a serious and potentially preventable complication of percutaneous coronary interventions (PCIs) that is associated with adverse outcomes. The contemporary incidence, predictors, and outcomes of AKI are not well defined, and clarifying these can help identify high-risk patients for proactive prevention. METHODS A total of 985,737 consecutive patients underwent PCIs at 1,253 sites participating in the National Cardiovascular Data Registry Cath-PCI registry from June 2009 through June 2011. AKI was defined on the basis of changes in serum creatinine level in the hospital according to the Acute Kidney Injury Network (AKIN) criteria. Using multivariable regression analyses with generalized estimating equations, we identified patient characteristics associated with AKI. RESULTS Overall, 69,658 (7.1%) patients experienced AKI, with 3,005 (0.3%) requiring new dialysis. On multivariable analyses, the factors most strongly associated with development of AKI included ST-segment elevation myocardial infarction (STEMI) presentation (odds ratio [OR]: 2.60; 95% confidence interval [CI]: 2.53 to 2.67), severe chronic kidney disease (OR: 3.59; 95% CI: 3.47 to 3.71), and cardiogenic shock (OR: 2.92; 95% CI: 2.80 to 3.04). The in-hospital mortality rate was 9.7% for patients with AKI and 34% for those requiring dialysis compared with 0.5% for patients without AKI (p < 0.001). After multivariable adjustment, AKI (OR: 7.8; 95% CI: 7.4 to 8.1, p < 0.001) and dialysis (OR: 21.7; 95% CI: 19.6 to 24.1; p < 0.001) remained independent predictors of in-hospital mortality. CONCLUSIONS Approximately 7% of patients undergoing a PCI experience AKI, which is strongly associated with in-hospital mortality. Defining strategies to minimize the risk of AKI in patients undergoing PCI are needed to improve the safety and outcomes of the procedure.

Discussions of the Kidney Disease Trajectory by Elderly Patients and Nephrologists: A Qualitative Study

BACKGROUND Amid rapid urbanisation, the HIV epidemic, and increasing rates of non-communicable diseases, people in sub-Saharan Africa are especially vulnerable to kidney disease. Little is known about the epidemiology of chronic kidney disease (CKD) in sub-Saharan Africa, so we did a systematic review and meta-analysis examining the epidemiology of the disease. METHODS We searched Medline, Embase, and WHO Global Health Library databases for all articles published through March 29, 2012, and searched the reference lists of retrieved articles. We independently reviewed each study for quality. We used the inverse-variance random-effects method for meta-analyses of the medium-quality and high-quality data and explored heterogeneity by comparing CKD burdens across countries, settings (urban or rural), comorbid disorders (hypertension, diabetes, HIV), CKD definitions, and time. FINDINGS Overall, we included 90 studies from 96 sites in the review. Study quality was low, with only 18 (20%) medium-quality studies and three (3%) high-quality studies. We noted moderate heterogeneity between the medium-quality and high-quality studies (n=21; I(2)=47·11%, p<0·0009). Measurement of urine protein was the most common method of determining the presence of kidney disease (62 [69%] studies), but the Cockcroft-Gault formula (22 [24%] studies) and Modification of Diet in Renal Disease formula (17 [19%] studies) were also used. Most of the studies were done in urban settings (83 [93%] studies) and after the year 2000 (57 [63%] studies), and we detected no significant difference in the prevalence of CKD between urban (12·4%, 95% CI 11-14) and rural (16·5%, 13·8-19·6) settings (p=0·474). The overall prevalence of CKD from the 21 medium-quality and high-quality studies was 13·9% (95% CI 12·2-15·7). INTERPRETATION In sub-Saharan Africa, CKD is a substantial health burden with risk factors that include communicable and non-communicable diseases. However, poor data quality limits inferences and draws attention to the need for more information and validated measures of kidney function especially in the context of the growing burden of non-communicable diseases. FUNDING Duke University.

Association of Blood Pressure Increases During Hemodialysis With 2-Year Mortality in Incident Hemodialysis Patients: A Secondary Analysis of the Dialysis Morbidity and Mortality Wave 2 Study

BACKGROUND Elderly patients with advanced kidney disease experience considerable disability, morbidity, and mortality. Little is known about the impact of physician-patient interactions on patient preparation for the illness trajectory. We sought to describe how nephrologists and older patients discuss and understand the prognosis and course of kidney disease leading to renal replacement therapy. METHODS We conducted focus groups and interviews with 11 nephrologists and 29 patients older than 65 years with advanced chronic kidney disease or receiving hemodialysis. Interviews were audiorecorded and transcribed. We used qualitative analytic methods to identify common and recurrent themes related to the primary research question. RESULTS We identified 6 themes that describe how the kidney disease trajectory is discussed and understood: (1) patients are shocked by their diagnosis, (2) patients are uncertain how their disease will progress, (3) patients lack preparation for living with dialysis, (4) nephrologists struggle to explain illness complexity, (5) nephrologists manage a disease over which they have little control, and (6) nephrologists tend to avoid discussions of the future. Patients and nephrologists acknowledged that prognosis discussions are rare. Patients tended to cope with thoughts of the future through avoidance by focusing on their present clinical status. Nephrologists reported uncertainty and concern for evoking negative reactions as barriers to these conversations. CONCLUSIONS Patients and nephrologists face challenges in understanding and preparing for the kidney disease trajectory. Communication interventions that acknowledge the role of patient emotion and address uncertainty may improve how nephrologists discuss disease trajectory with patients and thereby enhance their understanding and preparation for the future.

Performance of kidney injury molecule-1 and liver fatty acid-binding protein and combined biomarkers of AKI after cardiac surgery.

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.

Safety and Efficacy of Drug-Eluting Stents in Older Patients With Chronic Kidney Disease: A Report From the Linked CathPCI Registry–CMS Claims Database

BACKGROUND AND OBJECTIVES AKI is common and novel biomarkers may help provide earlier diagnosis and prognosis of AKI in the postoperative period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a prospective, multicenter cohort study involving 1219 adults and 311 children consecutively enrolled at eight academic medical centers. Performance of two urine biomarkers, kidney injury molecule-1 (KIM-1) and liver fatty acid-binding protein (L-FABP), alone or in combination with other injury biomarkers during the perioperative period was evaluated. AKI was defined as doubling of serum creatinine or need for acute dialysis. RESULTS KIM-1 peaked 2 days after surgery in adults and 1 day after surgery in children, whereas L-FABP peaked within 6 hours after surgery in both age groups. In multivariable analyses, the highest quintile of the first postoperative KIM-1 level was associated with AKI compared with the lowest quintile in adults, whereas the first postoperative L-FABP was not associated with AKI. Both KIM-1 and L-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and IL-18). The highest area under the curves achievable for discrimination for AKI were 0.78 in adults using urine KIM-1 from 6 to 12 hours, urine IL-18 from day 2, and plasma neutrophil gelatinase-associated lipocalin from day 2 and 0.78 in children using urine IL-18 from 0 to 6 hours and urine L-FABP from day 2. CONCLUSIONS Postoperative elevations of KIM-1 associate with AKI and adverse outcmes in adults but were not independent of other AKI biomarkers. A panel of multiple biomarkers provided moderate discrimination for AKI.