Arnold Alper

Childhood Uric Acid Predicts Adult Blood Pressure: The Bogalusa Heart Study

Uric acid has been proposed as an important risk factor in the development of primary hypertension in humans. However, limited information is available linking childhood uric acid levels and blood pressure levels in adulthood. This study examined 334 whites and 243 blacks enrolled in the Bogalusa Heart Study as children aged 5 to 17 years and as adults aged 18 to 35 years. The average follow-up period was 12 years. Childhood uric acid was significantly correlated with childhood and adult blood pressure, both systolic and diastolic. In a multivariate regression analysis, adjusting for age, sex, race, childhood body mass index, childhood uric acid levels, and change in levels of uric acid were significant predictors of adult diastolic blood pressure, whereas change in uric acid was a significant predictor of adult systolic blood pressures. In conclusion, elevated childhood serum uric acid levels are associated with increased blood pressure beginning in childhood and higher blood pressure levels that persist into adulthood, in males and females, whites and blacks, suggesting that early elevations in serum uric acid levels may play a key role in the development of human hypertension.

Blood Pressure and Risk of All-Cause Mortality in Advanced Chronic Kidney Disease and Hemodialysis The Chronic Renal Insufficiency Cohort Study

Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease, before starting hemodialysis. We determined the association between SBP and mortality at advanced chronic kidney disease and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort participants with advanced chronic kidney disease followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants (1) had an estimated glomerular filtration rate <30 mL/min/1.73 m2 (n=1705), (2) initiated hemodialysis and had dialysis-unit SBP measures (n=403), and (3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a Chronic Renal Insufficiency Cohort study visit (n=326). Cox models were adjusted for demographics, cardiovascular risk factors, and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced chronic kidney disease, there was no association between SBP and mortality (hazard ratio, 1.02 [95% confidence interval, 0.98–1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (hazard ratio, 1.26 [95% confidence interval, 1.14–1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP, which may merit more consideration as a target for clinical management and in interventional trials.

Sodium excretion and the risk of cardiovascular disease in patients with chronic kidney disease

IMPORTANCE Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared with the general population. Prior studies have produced contradictory results on the association of dietary sodium intake with risk of CVD, and this relationship has not been investigated in patients with CKD. OBJECTIVE To evaluate the association between urinary sodium excretion and clinical CVD events among patients with CKD. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients with CKD from 7 locations in the United States enrolled in the Chronic Renal Insufficiency Cohort Study and followed up from May 2003 to March 2013. EXPOSURES The cumulative mean of urinary sodium excretion from three 24-hour urinary measurements and calibrated to sex-specific mean 24-hour urinary creatinine excretion. MAIN OUTCOMES AND MEASURES A composite of CVD events defined as congestive heart failure, stroke, or myocardial infarction. Events were reported every 6 months and confirmed by medical record adjudication. RESULTS Among 3757 participants (mean age, 58 years; 45% women), 804 composite CVD events (575 heart failure, 305 myocardial infarction, and 148 stroke) occurred during a median 6.8 years of follow-up. From lowest (<2894 mg/24 hours) to highest (≥4548 mg/24 hours) quartile of calibrated sodium excretion, 174, 159, 198, and 273 composite CVD events occurred, and the cumulative incidence was 18.4%, 16.5%, 20.6%, and 29.8% at median follow-up. In addition, the cumulative incidence of CVD events in the highest quartile of calibrated sodium excretion compared with the lowest was 23.2% vs 13.3% for heart failure, 10.9% vs 7.8% for myocardial infarction, and 6.4% vs 2.7% for stroke at median follow-up. Hazard ratios of the highest quartile compared with the lowest quartile were 1.36 (95% CI, 1.09-1.70; P = .007) for composite CVD events, 1.34 (95% CI, 1.03-1.74; P = .03) for heart failure, and 1.81 (95% CI, 1.08-3.02; P = .02) for stroke after multivariable adjustment. Restricted cubic spline analyses of the association between sodium excretion and composite CVD provided no evidence of a nonlinear association (P = .11) and indicated a significant linear association (P < .001). CONCLUSIONS AND RELEVANCE Among patients with CKD, higher urinary sodium excretion was associated with increased risk of CVD.

Relation of Serum Lipids and Lipoproteins with Progression of CKD: The CRIC Study

BACKGROUND AND OBJECTIVES Hyperlipidemia is common in patients with CKD. The objective of this study was to evaluate whether measures of plasma lipids and lipoproteins predict progression of kidney disease in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Prospective cohort study in adults (n=3939) with CKD aged 21-74 years recruited between 2003 and 2008 and followed for a median of 4.1 years. At baseline, total cholesterol, triglycerides, very-low-density lipoprotein cholesterol (VLDL-C), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), apoA-I , apoB, and lipoprotein(a) [Lp(a)] were measured. The outcomes were composite end point of ESRD or 50% decline in eGFR from baseline (rate of change of GFR). RESULTS Mean age of the study population was 58.2 years, and the mean GFR was 44.9 ml/min per 1.73 m(2); 48% of patients had diabetes. None of the lipid or lipoprotein measures was independently associated with risk of the composite end point or rate of change in GFR. However, there were significant (P=0.01) interactions by level of proteinuria. In participants with proteinuria<0.2 g/d, 1-SD higher LDL-C was associated with a 26% lower risk of the renal end point (hazard ratio [HR], 0.74; 95% confidence interval [95% CI], 0.59 to 0.92; P=0.01), and 1-SD higher total cholesterol was associated with a 23% lower risk of the renal end point (HR, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In participants with proteinuria>0.2 g/d, neither LDL-C (HR, 0.98; 95% CI, 0.98 to 1.05) nor total cholesterol levels were associated with renal outcomes. Treatment with statins was reported in 55% of patients and was differential across lipid categories. CONCLUSIONS In this large cohort of patients with CKD, total cholesterol, triglycerides, VLDL-C, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) were not independently associated with progression of kidney disease. There was an inverse relationship between LDL-C and total cholesterol levels and kidney disease outcomes in patients with low levels of proteinuria.

Increased urinary excretion of angiotensinogen is associated with risk of chronic kidney disease

BACKGROUND The effect of intrarenal renin-angiotensin system (RAS) activity on risk of chronic kidney disease (CKD) has not been well studied in human subjects. METHODS We investigated the association between urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, and risk of CKD in 201 patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) or presence of albuminuria ( ≥ 30 mg/24 h). RESULTS Compared to controls, median urinary angiotensinogen excretion (45.4 versus 7.4 μg/24 h, P < 0.0001) and angiotensinogen-to-creatinine ratio (26.3 versus 4.4 μg/g, P < 0.0001) were significantly higher in patients with CKD. Log-transformed urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were inversely correlated with eGFR (r = -0.59 and -0.57, both P < 0.0001) and positively correlated with log-transformed urinary albumin excretion (r = 0.89 and 0.87, both P < 0.0001). After adjusting for multiple covariables, including the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diuretics and statins, the odds ratios (95% confidence interval) for CKD comparing the highest tertile to the lowest two tertiles of urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were 6.70 (3.43, 13.1; P < 0.0001) and 6.45 (3.34, 12.4; P < 0.0001), respectively. CONCLUSIONS These data indicate the intrarenal RAS may play an important role in the etiology of CKD, and urinary angiotensinogen may be a useful clinical biomarker for the identification of patients at a high risk for CKD.

Association of Serum Intact Parathyroid Hormone with Lower Estimated Glomerular Filtration Rate

BACKGROUND AND OBJECTIVES The prevalence of mineral metabolism abnormalities is almost universal in stage 5 chronic kidney disease (CKD), but the presence of abnormalities in milder CKD is not well characterized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data on adults > or =20 yr of age from the National Health and Nutrition Examination Survey 2003-2004 (N = 3949) were analyzed to determine the association between moderate declines in estimated GFR (eGFR), calculated using the Modfication of Diet in Renal Disease formula, and serum intact parathyroid hormone (iPTH) > or = 70 pg/ml. RESULTS The geometric mean iPTH level was 39.3 pg/ml. The age-standardized prevalence of elevated iPTH was 8.2%, 19.3%, and 38.3% for participants with eGFR > or = 60, 45 to 59, and 30 to 44 ml/min/1.73 m(2), respectively (P-trend < 0.001). After adjustment for age; race/ethnicity; sex; menopausal status; education; income; cigarette smoking; alcohol consumption; body mass index; hypertension; diabetes mellitus; vitamin D supplement use; total calorie and calcium intake; and serum calcium, phosphorus, and 25-hydroxyvitamin D levels-and compared with their counterparts with an eGFR > or = 60 ml/min/1.73 m(2)-the prevalence ratios of elevated iPTH were 2.30 and 4.69 for participants with an eGFR of 45 to 59 and 30 to 44 ml/min/1.73 m(2), respectively (P-trend < 0.001). Serum phosphorus > or = 4.2 mg/dl and 25-hydroxyvitamin D < 17.6 ng/ml were more common at lower eGFR levels. No association was present between lower eGFR and serum calcium < 9.4 mg/dl. CONCLUSIONS This study indicates that elevated iPTH levels are common among patients with moderate CKD.

Masked Hypertension and Elevated Nighttime Blood Pressure in CKD: Prevalence and Association with Target Organ Damage

BACKGROUND AND OBJECTIVES Masked hypertension and elevated nighttime BP are associated with increased risk of hypertensive target organ damage and adverse cardiovascular and renal outcomes in patients with normal kidney function. The significance of masked hypertension for these risks in patients with CKD is less well defined. The objective of this study was to evaluate the association between masked hypertension and kidney function and markers of cardiovascular target organ damage, and to determine whether this relationship was consistent among those with and without elevated nighttime BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional study. We performed 24-hour ambulatory BP in 1492 men and women with CKD enrolled in the Chronic Renal Insufficiency Cohort Study. We categorized participants into controlled BP, white-coat, masked, and sustained hypertension on the basis of clinic and 24-hour ambulatory BP. We obtained echocardiograms and measured pulse wave velocity in 1278 and 1394 participants, respectively. RESULTS The percentages of participants with controlled BP, white-coat, masked, and sustained hypertension were 49.3%, 4.1%, 27.8%, and 18.8%, respectively. Compared with controlled BP, masked hypertension independently associated with low eGFR (-3.2 ml/min per 1.73 m(2); 95% confidence interval, -5.5 to -0.9), higher proteinuria (+0.9 unit higher in log2 urine protein; 95% confidence interval, 0.7 to 1.1), and higher left ventricular mass index (+2.52 g/m(2.7); 95% confidence interval, 0.9 to 4.1), and pulse wave velocity (+0.92 m/s; 95% confidence interval, 0.5 to 1.3). Participants with masked hypertension had lower eGFR only in the presence of elevated nighttime BP (-3.6 ml/min per 1.73 m(2); 95% confidence interval, -6.1 to -1.1; versus -1.4 ml/min per 1.73 m(2); 95% confidence interval, -6.9 to 4.0, among those with nighttime BP <120/70 mmHg; P value for interaction with nighttime systolic BP 0.002). CONCLUSIONS Masked hypertension is common in patients with CKD and associated with lower eGFR, proteinuria, and cardiovascular target organ damage. In patients with CKD, ambulatory BP characterizes the relationship between BP and target organ damage better than BP measured in the clinic alone.

Performance of estimated glomerular filtration rate prediction equations in preeclamptic patients

Accurate estimation of the glomerular filtration rate (GFR) in patients with preeclampsia requires the collection of a 24-hour urine and can have important therapeutic and diagnostic implications. This procedure is often difficult or impossible to accomplish in this patient group. In this study, the Cockcroft-Gault, the Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were evaluated for their accuracy in determining GFR in the setting of preeclampsia. The estimated GFRs calculated from the above formulas were compared with the creatinine clearance values obtained from a 24-hour urine collections in 543 preeclamptic patients recruited from several large hospitals. Additionally, a set of new equations, preeclampsia GFR (PGFR), based on ethnicity, was created. The Cockcroft-Gault, MDRD, and CKD-EPI formulas were inaccurate in predicting GFR and both were significantly less accurate than PGFR. The latter formula provided an estimated GFR that was much closer to the creatinine clearance. Current GFR estimation equations based on serum creatinine values in nonpregnant patients are not reliable measures of renal function in patients with preeclampsia. The use of a new formula (PGFR) is recommended.

Interferon-alpha-induced focal segmental glomerulosclerosis in chronic myelogenous leukemia: A case report and review of the literature

Chronic myelogenous leukemia (CML), hepatitis C, and interferon alpha (IFN&agr;) have all been associated with renal dysfunction. In this paper we present a patient with the diagnosis of nephrotic syndrome and a known history of hepatitis C who received IFN&agr; therapy for newly diagnosed CML. The renal biopsy showed focal segmental glomerulosclerosis, which has only been previously reported in two cases of CML treated with IFN&agr;. There have also been two cases of patients with hepatitis C associated with focal segmental glomerulosclerosis. Despite the underlying hepatitis C, this case represents renal abnormalities consistent with IFN&agr; therapy for CML.

Psychosocial Status of Hemodialysis Patients One Year After Hurricane Katrina

Background:Hemodialysis patients experience a high degree of psychosocial impairment. Methods:The psychosocial status of hemodialysis patients after Hurricane Katrina was evaluated using the Hurricane Coping Self-Efficacy (HCSE) measure, the Short Form-12 Health Survey (physical component summary [PCS] and mental component summary [MCS]), and the Center for Epidemiologic Studies Short Depression Scale (CES-D). These scales were administered to 391 hemodialysis patients (86% participation rate), 7 to 14 months after Hurricane Katrina. Results:The mean score (standard deviation) was 36.2 (9.6) for the HCSE scale, 37.1 (10.9) and 46.7 (12.7) for the PCS and MCS, respectively, and 10.0 (6.5) on the CES-D. Symptoms of depression (CES-D scores ≥10) were present in 45.5% of patients. After age, race, and gender adjustment, evacuating less than 2 days before Hurricane Katrina making landfall and more fear of dying were associated with less favorable scores on the HCSE, MCS, and CES-D scales. Patients placed in a shelter and with a longer displacement had significantly lower MCS scores and more depressive symptoms. More depressive symptoms were observed among patients hospitalized in the month after the storm. Those who evacuated to a hotel, with more fear of dying and who were hospitalized in the month after Hurricane Katrina had lower scores on the PCS. Conclusions:Impaired psychosocial status was common among dialysis patients surviving Hurricane Katrina and associated with reduced coping. These data demonstrate the need for screening and management of psychosocial issues in hemodialysis patients after disasters.