Susan Steigerwalt

Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease.

CONTEXT A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. OBJECTIVE To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. MAIN OUTCOME MEASURES All-cause mortality and end-stage renal disease. RESULTS At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log-transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). CONCLUSION Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease.

Aortic PWV in chronic kidney disease: A CRIC ancillary study

BACKGROUND Aortic pulse wave velocity (PWV) is a measure of arterial stiffness and has proved useful in predicting cardiovascular morbidity and mortality in several populations of patients, including the healthy elderly, hypertensives and those with end-stage renal disease receiving hemodialysis. Little data exist characterizing aortic stiffness in patients with chronic kidney disease (CKD) who are not receiving dialysis, and in particular the effect of reduced kidney function on aortic PWV. METHODS We performed measurements of aortic PWV in a cross-sectional cohort of participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased aortic PWV in CKD. RESULTS PWV measurements were obtained in 2,564 participants. The tertiles of aortic PWV (adjusted for waist circumference) were <7.7 m/s, 7.7-10.2 m/s, and >10.2 m/s with an overall mean (+/- s.d.) value of 9.48 +/- 3.03 m/s (95% confidence interval = 9.35-9.61 m/s). Multivariable regression identified significant independent positive associations of age, blood glucose concentrations, race, waist circumference, mean arterial blood pressure, gender, and presence of diabetes with aortic PWV and a significant negative association with the level of kidney function. CONCLUSIONS The large size of this unique cohort, and the targeted enrollment of CKD participants provides an ideal situation to study the role of reduced kidney function as a determinant of arterial stiffness. Arterial stiffness may be a significant component of the enhanced cardiovascular risk associated with kidney failure.

Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND The purpose of this study is to evaluate serum bicarbonate level as a risk factor for renal outcomes, cardiovascular events, and mortality in patients with chronic kidney disease (CKD). STUDY DESIGN Observational cohort study. SETTING & PARTICIPANTS 3,939 participants with CKD stages 2-4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and December 2008. PREDICTOR Serum bicarbonate level. OUTCOMES Renal outcomes, defined as end-stage renal disease (either initiation of dialysis therapy or kidney transplantation) or 50% reduction in estimated glomerular filtration rate (eGFR); atherosclerotic events (myocardial infarction, stroke, or peripheral arterial disease); congestive heart failure events; and death. MEASUREMENTS Time to event. RESULTS Mean eGFR was 44.8 ± 16.8 (SD) mL/min/1.73 m(2), and median serum bicarbonate level was 24 (IQR, 22-26) mEq/L. During a median follow-up of 3.9 years, 374 participants died, 767 had a renal outcome, 332 experienced an atherosclerotic event, and 391 had a congestive heart failure event. In adjusted analyses, the risk of developing a renal end point was 3% lower per 1-mEq/L increase in serum bicarbonate level (HR, 0.97; 95% CI, 0.94-0.99; P = 0.01). The association was stronger for participants with eGFR >45 mL/min/1.73 m(2) (HR, 0.91; 95% CI, 0.85-0.97; P = 0.004). The risk of heart failure increased by 14% (HR, 1.14; 95% CI, 1.03-1.26; P = 0.02) per 1-mEq/L increase in serum bicarbonate level over 24 mEq/L. Serum bicarbonate level was not associated independently with atherosclerotic events (HR, 0.99; 95% CI, 0.95-1.03; P = 0.6) and all-cause mortality (HR, 0.98; 95% CI, 0.95-1.02; P = 0.3). LIMITATIONS Single measurement of sodium bicarbonate. CONCLUSIONS In a cohort of participants with CKD, low serum bicarbonate level was an independent risk factor for kidney disease progression, particularly for participants with preserved kidney function. The risk of heart failure was higher at the upper extreme of serum bicarbonate levels. There was no association between serum bicarbonate level and all-cause mortality or atherosclerotic events.

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.

Central Pulse Pressure in Chronic Kidney Disease: A Chronic Renal Insufficiency Cohort Ancillary Study

Central pulse pressure (PP) can be noninvasively derived using the radial artery tonometric methods. Knowledge of central pressure profiles has predicted cardiovascular morbidity and mortality in several populations of patients, particularly those with known coronary artery disease and those receiving dialysis. Few data exist characterizing central pressure profiles in patients with mild-moderate chronic kidney disease who are not on dialysis. We measured central PP cross-sectionally in 2531 participants in the Chronic Renal Insufficiency Cohort Study to determine correlates of the magnitude of central PP in the setting of chronic kidney disease. Tertiles of central PP were <36 mm Hg, 36 to 51 mm Hg, and >51 mm Hg with an overall mean (±SD) of 46±19 mm Hg. Multivariable regression identified the following independent correlates of central PP: age, sex, diabetes mellitus, heart rate (negatively correlated), glycosylated hemoglobin, hemoglobin, glucose, and parathyroid hormone parathyroid hormone concentrations. Additional adjustment for brachial mean arterial pressure and brachial PP showed associations for age, sex, diabetes mellitus, weight, and heart rate. Discrete intervals of brachial PP stratification showed substantial overlap within the associated central PP values. The large size of this unique chronic kidney disease cohort provides an ideal situation to study the role of brachial and central pressure measurements in kidney disease progression and cardiovascular disease incidence.

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.

Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort.

BACKGROUND Secondary hyperparathyroidism is a common complication of chronic kidney disease (CKD) that is associated with bone disease, cardiovascular disease and death. Pathophysiological factors that maintain secondary hyperparathyroidism in advanced CKD are well-known, but early mechanisms of the disease that can be targeted for its primary prevention are poorly understood. Diuretics are widely used to control volume status and blood pressure in CKD patients but are also known to have important effects on renal calcium handling, which we hypothesized could alter the risk of secondary hyperparathyroidism. METHODS We examined the relationship of diuretic treatment with urinary calcium excretion, parathyroid hormone (PTH) levels and prevalence of secondary hyperparathyroidism (PTH ≥ 65 pg/mL) in a cross-sectional study of 3616 CKD patients in the Chronic Renal Insufficiency Cohort. RESULTS Compared with no diuretics, treatment with loop diuretics was independently associated with higher adjusted urinary calcium (55.0 versus 39.6 mg/day; P < 0.001), higher adjusted PTH [67.9, 95% confidence interval (CI) 65.2-70.7 pg/mL, versus 52.8, 95% CI 51.1-54.6 pg/mL, P < 0.001] and greater odds of secondary hyperparathyroidism (odds ratio 2.1; 95% CI 1.7-2.6). Thiazide monotherapy was associated with lower calciuria (25.5 versus 39.6 mg/day; P < 0.001) but only modestly lower PTH levels (50.0, 95% CI 47.8-52.3, versus 520.8, 95% CI 51.1-54.6 pg/mL, P = 0.04) compared with no diuretics. However, coadministration of thiazide and loop diuretics was associated with blunted urinary calcium (30.3 versus 55.0 mg/day; P <0.001) and odds of hyperparathyroidism (odds ratio 1.3 versus 2.1; P for interaction = 0.05) compared with loop diuretics alone. CONCLUSIONS Loop diuretic use was associated with greater calciuria, PTH levels and odds of secondary hyperparathyroidism compared to no treatment. These associations were attenuated in patients who were coadministered thiazides. Diuretic choice is a potentially modifiable determinant of secondary hyperparathyroidism in CKD.

Hemodynamic Correlates of Proteinuria in Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Brachial artery measures of BP are associated with increasing degrees of proteinuria. Whether central measures of BP or vascular stiffness are associated with increased risk of proteinuria in patients with chronic kidney disease (CKD) is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Measurements of central and brachial artery BP, and aortic pulse wave velocity (PWV) were performed in a cross-sectional cohort of patients with CKD (n = 2144) from the Chronic Renal Insufficiency Cohort (CRIC) study to determine factors which predict increased risk of proteinuria. Multivariate analysis stratified by diabetes included age, ethnicity, gender, estimated glomerular filtration rate (GFR), waistline, smoking, heart rate, and medications to evaluate the relationship of hemodynamic factors and proteinuria. RESULTS Brachial artery systolic BP (SBP) was important as an explanatory factor for variations in proteinuria among both diabetics (R(2) = 0.40, P < 0.0001) and non diabetics (R(2) = 0.38, P < 0.001). Measures of peripheral pulse pressure (PP), central SBP, and central pulse pressure added little to the explained variation in proteinuria beyond brachial artery SBP, whereas PWV as a measure of vascular stiffness incrementally accounted for a significant portion of variation in proteinuria beyond that explained by brachial artery SBP in diabetics (R(2) = 0.42, P < 0.001) but not non diabetics. CONCLUSIONS Brachial artery SBP and PWV are both associated with variations in proteinuria in patients with CKD.

Aortic pulse pressure is associated with carotid IMT in chronic kidney disease: report from Chronic Renal Insufficiency Cohort.

BACKGROUND Patients with chronic kidney disease (CKD) have a disproportionate risk of cardiovascular disease. This study was designed to assess the association between two noninvasive measures of cardiovascular risk, pulse wave analysis (PWA), and carotid intima-media thickness (IMT), in a cohort of CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. METHODS Three hundred and sixty-seven subjects with CKD enrolled in the CRIC study at the University of Pennsylvania site (mean age 59.9 years, blood pressure 129/74 mm Hg, estimated glomerular filtration rate 48 ml/min/1.73 m2, IMT 0.8 mm) had both carotid IMT and PWA measurements. Carotid ultrasound was also used to determine the presence of plaque. PWA was used to determine augmentation index (AI), amplification ratio (AMPR), aortic pulse pressure (C_PP), and central aortic systolic pressure (C_SP). RESULTS IMT was significantly associated with all PWA-derived measures. However, on multivariable linear regression analysis, only AMPR (regression coefficient -0.072, P = 0.006), C_PP (regression coefficient 0.0025, P < 0.001), and C_SP (regression coefficient 0.0017, P < 0.001) remained significantly associated with IMT. The prevalence of carotid plaque in the cohort was 59%. Of the PWA-derived measures, only C_PP was significantly associated with the presence of carotid plaque (P < 0.001). CONCLUSIONS PWA-derived measures are associated with carotid IMT and plaque in the CKD. Of these measures, C_PP was most associated with carotid IMT and plaque.

Prevalence, Predictors, and Outcomes of Pulmonary Hypertension in CKD

Pulmonary hypertension (PH) is associated with poor outcomes in the dialysis and general populations, but its effect in CKD is unclear. We evaluated the prevalence and predictors of PH measures and their associations with long-term clinical outcomes in patients with nondialysis-dependent CKD. Chronic Renal Insufficiency Cohort (CRIC) Study participants who had Doppler echocardiography performed were considered for inclusion. PH was defined as the presence of estimated pulmonary artery systolic pressure (PASP) >35 mmHg and/or tricuspid regurgitant velocity (TRV) >2.5 m/s. Associations between PH, PASP, and TRV and cardiovascular events, renal events, and all-cause mortality were examined using Cox proportional hazards models. Of 2959 eligible participants, 21% (n=625) had PH, with higher rates among those with lower levels of kidney function. In the multivariate model, older age, anemia, lower left ventricular ejection fraction, and presence of left ventricular hypertrophy were associated with greater odds of having PH. After adjusting for relevant confounding variables, PH was independently associated with higher risk for death (hazard ratio, 1.38; 95% confidence interval, 1.10 to 1.72) and cardiovascular events (hazard ratio, 1.23; 95% confidence interval, 1.00 to 1.52) but not renal events. Similarly, TRV and PASP were associated with death and cardiovascular events but not renal events. In this study of patients with CKD and preserved left ventricular systolic function, we report a high prevalence of PH. PH and higher TRV and PASP (echocardiographic measures of PH) are associated with adverse outcomes in CKD. Future studies may explain the mechanisms that underlie these findings.