Tariq Shafi

Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study.

BACKGROUND Residual kidney function (RKF) is associated with improved survival in peritoneal dialysis patients, but its role in hemodialysis patients is less well known. Urine output may provide an estimate of RKF. The aim of our study is to determine the association of urine output with mortality, quality of life (QOL), and inflammation in incident hemodialysis patients. STUDY DESIGN Nationally representative prospective cohort study. SETTING & PARTICIPANTS 734 incident hemodialysis participants treated in 81 clinics; enrollment, 1995-1998; follow-up until December 2004. PREDICTOR Urine output, defined as producing at least 250 mL (1 cup) of urine daily, ascertained using questionnaires at baseline and year 1. OUTCOMES & MEASUREMENTS Primary outcomes were all-cause and cardiovascular mortality, analyzed using Cox regression adjusted for demographic, clinical, and treatment characteristics. Secondary outcomes were QOL, inflammation (C-reactive protein and interleukin 6 levels), and erythropoietin (EPO) requirements. RESULTS 617 of 734 (84%) participants reported urine output at baseline, and 163 of 579 (28%), at year 1. Baseline urine output was not associated with survival. Urine output at year 1, indicating preserved RKF, was independently associated with lower all-cause mortality (HR, 0.70; 95% CI, 0.52-0.93; P = 0.02) and a trend toward lower cardiovascular mortality (HR, 0.69; 95% CI, 0.45-1.05; P = 0.09). Participants with urine output at baseline reported better QOL and had lower C-reactive protein (P = 0.02) and interleukin 6 (P = 0.03) levels. Importantly, EPO dose was 12,000 U/wk lower in those with urine output at year 1 compared with those without (P = 0.001). LIMITATIONS Urine volume was measured in only a subset of patients (42%), but agreed with self-report (P < 0.001). CONCLUSIONS RKF in hemodialysis patients is associated with better survival and QOL, lower inflammation, and significantly less EPO use. RKF should be monitored routinely in hemodialysis patients. The development of methods to assess and preserve RKF is important and may improve dialysis care.

Changes in Serum Potassium Mediate Thiazide-Induced Diabetes

Thiazides, recommended as first-line antihypertensive therapy, are associated with an increased risk of diabetes. Thiazides also lower serum potassium. To determine whether thiazide-induced diabetes is mediated by changes in potassium, we analyzed data from 3790 nondiabetic participants in the Systolic Hypertension in Elderly Program, a randomized clinical trial of isolated systolic hypertension in individuals aged ≥60 years treated with chlorthalidone or placebo. Incident diabetes was defined by self-report, antidiabetic medication use, fasting glucose ≥126 mg/dL, or random glucose ≥200 mg/dL. The mediating variable was change in serum potassium during year 1. Of the 459 incident cases of diabetes during follow-up, 42% occurred during year 1. In year 1, the unadjusted incidence rates of diabetes per 100 person-years were 6.1 and 3.0 in the chlorthalidone and placebo groups, respectively. In year 1, the adjusted diabetes risk (hazard ratio) with chlorthalidone was 2.07 (95% CI: 1.51 to 2.83; P<0.001). After adjustment for change in serum potassium, the risk was significantly reduced (hazard ratio: 1.54; 95% CI: 1.09 to 2.17; P=0.01); the extent of risk attenuation (41%; 95% CI: 34% to 49%) was consistent with a mediating effect. Each 0.5-mEq/L decrease in serum potassium was independently associated with a 45% higher adjusted diabetes risk (95% CI: 24% to 70%; P<0.001). After year 1, chlorthalidone use was not associated with increased diabetes risk. In conclusion, thiazide-induced diabetes occurs early after initiating treatment and appears to be mediated by changes in serum potassium. Potassium supplementation might prevent thiazide-induced diabetes. This hypothesis can and should be tested in a randomized trial.

Novel Markers of Kidney Function as Predictors of ESRD, Cardiovascular Disease, and Mortality in the General Population

BACKGROUND Cystatin C level predicts mortality more strongly than serum creatinine level. It is unknown whether this advantage extends to other outcomes, such as kidney failure, or whether other novel renal filtration markers share this advantage in predicting outcomes. STUDY DESIGN Observational cohort study. SETTING & PARTICIPANTS 9,988 participants in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based study in 4 US communities, followed for approximately 10 years. PREDICTORS Serum creatinine-based estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR(CKD-EPI)) and cystatin C, β-trace protein (BTP), and β(2)-microglobulin (B2M) levels. OUTCOMES Mortality, coronary heart disease, heart failure, and kidney failure. RESULTS Higher cystatin C and B2M concentrations were associated more strongly with mortality (n = 1,425) than BTP level and all were associated more strongly than eGFR(CKD-EPI) (adjusted HR for the upper 6.7 percentile compared with the lowest quintile: 1.6 [95% CI, 1.3-1.9] for eGFR(CKD-EPI), 2.9 [95% CI, 2.3-3.6] for cystatin C level, 1.9 [95% CI, 1.5-2.4] for BTP level, and 3.0 [95% CI, 2.4-3.8] for B2M level). Similar patterns were observed for coronary heart disease (n = 1,279), heart failure (n = 803), and kidney failure (n = 130). The addition of cystatin C, BTP, and B2M levels to models including eGFR(CKD-EPI) and all covariates, including urinary albumin-creatinine ratio, significantly improved risk prediction for all outcomes (P < 0.001). LIMITATIONS No direct measurement of GFR. CONCLUSIONS B2M and, to a lesser extent, BTP levels share cystatin Cs advantage over eGFR(CKD-EPI) in predicting outcomes, including kidney failure. These additional markers may be helpful in improving estimation of risk associated with decreased kidney function beyond current estimates based on eGFR(CKD-EPI).

Determinants of Blood Pressure Response to Quinapril in Black and White Hypertensive Patients. The Quinapril Titration Interval Management Evaluation Trial

Race has been considered an important factor in determining blood pressure response to treatment and selection of antihypertensive drug therapy. Data collected during a clinical trial that evaluated rapidity of medication up-titration with blood pressure response to monotherapy with the angiotensin-converting enzyme (ACE) inhibitor quinapril were used to characterize response in 533 black and 2046 white participants. Our objectives were to examine the influence of race and other factors on blood pressure response and to assess the degree to which nonrace factors account for apparent racial differences in response. Average systolic and diastolic blood pressure responses (baseline minus follow-up) to treatment were assessed with treatment groups combined. Crude systolic and diastolic blood pressure responses averaged 4.7 and 2.4 mm Hg less, respectively, in black compared with white participants; however, the response distributions largely overlapped. In multivariate linear regression models adjusted for study design variables and measured participant characteristics, the racial difference in systolic response was reduced by 51% to 2.3 mm Hg, and diastolic response by 21% to 1.9 mm Hg. In these models, participant characteristics, including age, gender, body size, and pretreatment blood pressure severity, significantly predicted either attenuated or enhanced blood pressure response to treatment. Our findings demonstrate that a large source of variability of blood pressure response to treatment is within, not between, racial groups, and that factors that vary at the level of the individual contribute to apparent racial differences in response to treatment.

Prevention of hypertension and its complications: Theoretical basis and guidelines for treatment

Hypertension is a nutritional-hygienic disease. Long-term caloric intake in excess of energy expenditures, chronic supraphysiological intake of dietary sodium, excessive alcohol consumption, and psychosocial stressors all contribute to the development of hypertension throughout the world. Elevated BP, particularly systolic BP, has been linked to multiple adverse clinical outcomes including stroke, heart failure, myocardial infarction, renal insufficiency/failure, peripheral vascular disease, retinopathy, dementia, and premature mortality. These undesirable clinical outcomes are typically, although not invariably, preceded by pressure-related target-organ injury such as left ventricular hypertrophy, renal insufficiency and proteinuria. The relation of BP and CKD and, in turn, the prevention of CKD or forestalling its progression by hypertension treatment, will be the focus of this manuscript. In hypertensive persons with reduced kidney function and/or proteinuria, lowering BP with multidrug therapy that is inclusive of pharmacologic modulators of the renin-angiotensin-aldosterone-kinin system is an effective strategy to forestall the progressive loss of kidney function. The totality of data support low therapeutic BP targets for persons with proteinuria >1 g/d. Nevertheless, in persons with CKD, even those with proteinuria below the dipstick positive level (approximately 300 mg/d or urine protein to creatinine ratio of 0.22), aggressive BP control also may be warranted because of the high risk of nonrenal cardiovascular disease. Multiple antihypertensive drugs will be required in the vast majority of patients with diabetes and/or reduced kidney function to attain BP goal. Renin-angiotensin system (RAS) modulator therapy is indicated among persons with diabetes mellitus and CKD. Available data support the use of angiotensin receptor blockers in persons with type 2 diabetes and overt nephropathy for preservation of kidney function. Among persons with type I diabetes with or without overt nephropathy, type 2 diabetes without overt nephropathy and in nondiabetic CKD, the available clinical data support the use of angiotensin-converting enzyme inhibitors as the RAS modulator of choice. Low therapeutic target BP levels <130/80 mmHg in persons with type 2 diabetes mellitus also appear warranted based on available data mostly for reducing the risk of nonrenal cardiovascular disease and overall mortality.

Serum and dietary potassium and risk of incident type 2 diabetes mellitus: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND Serum potassium levels affect insulin secretion by pancreatic β-cells, and hypokalemia associated with diuretic use has been associated with dysglycemia. We hypothesized that adults with lower serum potassium levels and lower dietary potassium intake are at higher risk for incident diabetes mellitus (DM), independent of diuretic use. METHODS We analyzed data from 12 209 participants from the Atherosclerosis Risk in Communities (ARIC) Study, an ongoing prospective cohort study, beginning in 1986, with 9 years of in-person follow-up and 17 years of telephone follow-up. Using multivariate Cox proportional hazard models, we estimated the hazard ratio (HR) of incident DM associated with baseline serum potassium levels. RESULTS During 9 years of in-person follow-up, 1475 participants developed incident DM. In multivariate analyses, we found an inverse association between serum potassium and risk of incident DM. Compared with those with a high-normal serum potassium level (5.0-5.5 mEq/L), adults with serum potassium levels lower than 4.0 mEq/L, 4.0 to lower than 4.5 mEq/L, and 4.5 to lower than 5.0 mEq/L had an adjusted HR (95% confidence interval [CI]) of incident DM of 1.64 (95% CI, 1.29-2.08), 1.64 (95% CI, 1.34-2.01), and 1.39 (95% CI, 1.14-1.71), respectively. An increased risk persisted during an additional 8 years of telephone follow-up based on self-report with HRs of 1.2 to 1.3 for those with a serum potassium level lower than 5.0 mEq/L. Dietary potassium intake was significantly associated with risk of incident DM in unadjusted models but not in multivariate models. CONCLUSIONS Serum potassium level is an independent predictor of incident DM in this cohort. Further study is needed to determine if modification of serum potassium could reduce the subsequent risk of DM.

Serum Fructosamine and Glycated Albumin and Risk of Mortality and Clinical Outcomes in Hemodialysis Patients

OBJECTIVE Assays for serum total glycated proteins (fructosamine) and the more specific glycated albumin may be useful indicators of hyperglycemia in dialysis patients, either as substitutes or adjuncts to standard markers such as hemoglobin A1c, as they are not affected by erythrocyte turnover. However, their relationship with long-term outcomes in dialysis patients is not well described. RESEARCH DESIGN AND METHODS We measured fructosamine and glycated albumin in baseline samples from 503 incident hemodialysis participants of a national prospective cohort study, with enrollment from 1995–1998 and median follow-up of 3.5 years. Outcomes were all-cause and cardiovascular disease (CVD) mortality and morbidity (first CVD event and first sepsis hospitalization) analyzed using Cox regression adjusted for demographic and clinical characteristics, and comorbidities. RESULTS Mean age was 58 years, 64% were white, 54% were male, and 57% had diabetes. There were 354 deaths (159 from CVD), 302 CVD events, and 118 sepsis hospitalizations over follow-up. Both fructosamine and glycated albumin were associated with all-cause mortality; adjusted HR per doubling of the biomarker was 1.96 (95% CI 1.38–2.79) for fructosamine and 1.40 (1.09–1.80) for glycated albumin. Both markers were also associated with CVD mortality [fructosamine 2.13 (1.28–3.54); glycated albumin 1.55 (1.09–2.21)]. Higher values of both markers were associated with trends toward a higher risk of hospitalization with sepsis [fructosamine 1.75 (1.01–3.02); glycated albumin 1.39 (0.94–2.06)]. CONCLUSIONS Serum fructosamine and glycated albumin are risk factors for mortality and morbidity in hemodialysis patients.

GFR Estimation Using β-Trace Protein and β2-Microglobulin in CKD

BACKGROUND β-Trace protein (BTP) and β2-microglobulin (B2M) are novel glomerular filtration markers that have stronger associations with adverse outcomes than creatinine. Comparisons of BTP and B2M to creatinine and cystatin C are limited by the absence of rigorously developed glomerular filtration rate (GFR) estimating equations for the novel markers. STUDY DESIGN Study of diagnostic test accuracy. SETTING & PARTICIPANTS Pooled database of 3 populations with chronic kidney disease (CKD) with mean measured GFR of 48 mL/min/1.73 m2 (N=3,551; MDRD [Modification of Diet in Renal Disease] Study, AASK [African American Study of Kidney Disease and Hypertension], and CRIC [Chronic Renal Insufficiency Cohort] Study). INDEX TESTS GFR estimated using creatinine, cystatin C, BTP, or B2M level. REFERENCE TEST GFR measured as the urinary clearance of iothalamate. RESULTS For BTP and B2M, coefficients for age, sex, and race were smaller than for creatinine and were similar or smaller than for cystatin C. For B2M, coefficients for sex, age, and race were smaller than for creatinine and were similar (age and race) or smaller (sex) than for cystatin C. The final equations with BTP (BTP, age, and sex) or B2M (B2M alone) were less accurate than either the CKD-EPI (CKD Epidemiology Collaboration) creatinine or cystatin C equations. The combined BTP-B2M equation (BTP and B2M alone) had similar accuracy to the CKD-EPI creatinine or cystatin C equation. The average of the BTP-B2M equation and the CKD-EPI creatinine-cystatin C equation was not more accurate than the CKD-EPI creatinine-cystatin C equation. LIMITATIONS No external validation population, study population was restricted to CKD, few participants older than 65 years, or nonblack nonwhite race. CONCLUSIONS BTP and B2M are less influenced by age, sex, and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates than the CKD-EPI creatinine and cystatin C equations. The CKD-EPI BTP and B2M equation provides a methodological advance for their study as filtration markers and in their associations with risk and adverse outcomes, but further study is required before clinical use.

Association of Intradialytic Blood Pressure Variability With Increased All-Cause and Cardiovascular Mortality in Patients Treated With Long-term Hemodialysis

BACKGROUND Blood pressure is known to fluctuate widely during hemodialysis; however, little is known about the association between intradialytic blood pressure variability and outcomes. STUDY DESIGN Retrospective observational cohort. SETTING & PARTICIPANTS A random sample of 6,393 adult, thrice-weekly, in-center, maintenance hemodialysis patients dialyzing at 1,026 dialysis units within a single large dialysis organization. PREDICTOR Intradialytic systolic blood pressure (SBP) variability. This was calculated using a mixed linear effects model. Peridialytic SBP phenomena were defined as starting SBP (regression intercept), systematic change in SBP over the course of dialysis (2 regression slopes), and random intradialytic SBP variability (absolute regression residual). OUTCOMES All-cause and cardiovascular mortality. MEASUREMENTS SBPs (n = 631,922) measured during hemodialysis treatments (n = 78,961) during the first 30 days in the study. Outcome data were obtained from the dialysis unit electronic medical record and were considered beginning on day 31. RESULTS High (ie, greater than the median) versus low SBP variability was associated with greater risk of all-cause mortality (adjusted HR, 1.26; 95% CI, 1.08-1.47). The association between high SBP variability and cardiovascular mortality was even more potent (adjusted HR, 1.32; 95% CI, 1.01-1.72). A dose-response trend was observed across quartiles of SBP variability for both all-cause (P = 0.001) and cardiovascular (P = 0.04) mortality. LIMITATIONS Inclusion of patients from a single large dialysis organization, over-representation of African Americans and patients with diabetes and heart failure, and lack of standardized SBP measurements. CONCLUSIONS Greater intradialytic SBP variability is associated independently with increased all-cause and cardiovascular mortality. Further prospective studies are needed to confirm findings and identify means of reducing SBP variability to facilitate randomized study.

Intravenous Iron Exposure and Mortality in Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Clinical trials assessing effects of larger cumulative iron exposure with outcomes are lacking, and observational studies have been limited by assessment of short-term exposure only and/or failure to assess cause-specific mortality. The associations between short- and long-term iron exposure on all-cause and cause-specific mortality were examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study included 14,078 United States patients on dialysis initiating dialysis between 2003 and 2008. Intravenous iron dose accumulations over 1-, 3-, and 6-month rolling windows were related to all-cause, cardiovascular, and infection-related mortality in Cox proportional hazards models that used marginal structural modeling to control for time-dependent confounding. RESULTS Patients in the 1-month model cohort (n=14,078) were followed a median of 19 months, during which there were 27.6% all-cause deaths, 13.5% cardiovascular deaths, and 3% infection-related deaths. A reduced risk of all-cause mortality with receipt of >150-350 (hazard ratio, 0.78; 95% confidence interval, 0.64 to 0.95) or >350 mg (hazard ratio, 0.79; 95% confidence interval, 0.62 to 0.99) intravenous iron compared with >0-150 mg over 1 month was observed. There was no relation of 1-month intravenous iron dose with cardiovascular or infection-related mortality and no relation of 3- or 6-month cumulative intravenous iron dose with all-cause or cardiovascular mortality. There was a nonstatistically significant increase in infection-related mortality with receipt of >1050 mg intravenous iron in 3 months (hazard ratio, 1.69; 95% confidence interval, 0.87 to 3.28) and >2100 mg in 6 months (hazard ratio, 1.59; 95% confidence interval, 0.73 to 3.46). CONCLUSIONS Among patients on incident dialysis, receipt of ≤ 1050 mg intravenous iron in 3 months or 2100 mg in 6 months was not associated with all-cause, cardiovascular, or infection-related mortality. However, nonstatistically significant findings suggested the possibility of infection-related mortality with receipt of >1050 mg in 3 months or >2100 mg in 6 months. Randomized clinical trials are needed to assess the safety of exposure to greater cumulative intravenous iron doses.