Association of carotid intima-media thickness with cardiovascular risk factors and patient outcomes in advanced chronic kidney disease: the RRI-CKD study.

BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and an increased risk of adverse cardiovascular disease (CVD) outcomes. The relationships of intima-media thickness (IMT), a measure of subclinical atherosclerosis, with traditional and nontraditional risk factors and with adverse outcomes in CKD patients are not wellestablished. METHODS: IMT, clinical characteristics, cardiovascular risk factors, and clinical outcomes were measured in 198 subjects from the Renal Research Institute (RRI) CKD study, a four-center prospective cohort of patients with estimated glomerular filtration rate (eGFR)≤50 mL/min/1.73 m2 not requiring renal replacement therapy. RESULTS: The patients averaged 61±14 years of age; the mean eGFR was 29±12 mL/min/1.73 m2. Maximum IMT was more closely associated with traditional cardiovascular risk factors, including age, diabetes, dyslipidemia, and systolic blood pressure, than with nontraditional risk factors or with eGFR. Higher values of maximum IMT were also independently associated with clinical CVD and with other markers of subclinical CVD. Maximum IMT≥2.6 mm was predictive of the composite endpoint of CVD events and death (hazard ratio (HR): 5.47 (95% confidence interval (CI): 2.97-10.07, p<0.0001)) but was not related to progression to end-stage renal disease (HR: 1.67 (95% CI: 0.74-3.76, p=0.21)). CONCLUSION: In patients with advanced pre-dialysis CKD, higher maximum IMT was associated with traditional cardiovascular risk factors, CVD, and other markers of subclinical CVD and as an independent predictor of cardiovascular events and death. Additional research is needed to examine the clinical utility of IMT in the risk stratification and clinical management of patients with CKD.

Serum sodium levels and patient outcomes in an ambulatory clinic-based chronic kidney disease cohort.

BACKGROUND: Chronic kidney disease (CKD) patients are prone to both hypo- and hypernatremia. Little has been published on the epidemiology of hypo- and hypernatremia in ambulatory patients with non-dialysis CKD. METHODS: Data collected in two contemporaneous CKD cohort studies, the Renal Research Institute (RRI)-CKD study (n = 834) and the Study of Treatment of Renal Insufficiency: Data and Evaluation (STRIDE) (n = 1,348) were combined and analyzed to study the association between serum sodium (Na(+)) and clinical outcomes. RESULTS: Baseline estimated glomerular filtration rate (eGFR) and Na(+) were 26 ± 11 ml/min/1.73 m(2) and 140.2 ± 3.4 mEq/l, respectively. The prevalence of Na(+) ≤135 mEq/l and ≥144 mEq/l was 6 and 16%, respectively. Higher baseline Na(+) was significantly associated with male sex, older age, systolic blood pressure, BMI, serum albumin, presence of heart failure, and lower eGFR. The risk of end-stage renal disease (ESRD) was marginally significantly higher among patients with Na(+) ≤135 mEq/l, compared with 140< Na(+) <144 mEq/l (referent), in time-dependent models (adjusted hazard ratio, HR = 1.52, p = 0.06). Mortality risk was significantly greater at 135< Na(+) ≤140 mEq/l (adjusted HR = 1.68, p = 0.02) and Na(+) ≥144 mEq/l (adjusted HR = 2.01, p = 0.01). CONCLUSION: CKD patients with Na(+) ≤135 mEq/l were at a higher risk for progression to ESRD, whereas both lower and higher Na(+) levels were associated with a higher risk of mortality. While caring for CKD patients, greater attention to serum sodium levels by clinicians is warranted and could potentially help improve patient outcomes.

Relationship between heart rate variability and pulse wave velocity and their association with patient outcomes in chronic kidney disease.

BACKGROUND: Arterial stiffness and low heart rate variability (HRV) have each been associated with increased cardiovascular risk in a variety of patient populations. We explored the relationship between HRV and pulse wave velocity (PWV measure of arterial stiffness) in patients with chronic kidney disease (CKD prior to ESRD) along with examining their association with the outcomes of cardiovascular disease (CVD), death, and progression to end stage renal disease (ESRD). METHODS: The RRI-CKD Study is a 4-center prospective cohort study of CKD stages 3 - 5 (n = 834). A subset underwent both HRV testing by 24-hour Holter and carotid-femoral PWV (n = 240). Multiple linear regression was used to assess predictors of PWV and Cox regression to investigate the association of HRV and PWV with time to first CVD event or death and ESRD. RESULTS: Although several HRV measures were inversely correlated with PWV, this association was attenuated after adjustment for age and/or diabetes and no longer significant after adjustment for C-reactive protein. Low HRV and high PWV were individually associated with increased risk of the composite endpoint of CVD/death in multivariable analysis. The risk of the composite of CVD/death was highest for patients with both low HRV and high PWV. CONCLUSION: Age, diabetes, and inflammation together explained the inverse association between HRV and PWV. Inflammation may play a role in the pathogenesis of both low HRV and high PWV. The combination of low HRV and high PWV showed the strongest association with a composite CVD outcome. Mechanisms underlying abnormalities in PWV and HRV, and the role of these measures as intermediate outcomes in future trials in CKD patients, merit further study.

Predictors of heart rate variability and its prognostic significance in chronic kidney disease.

BACKGROUND: Heart rate variability (HRV), a noninvasive measure of autonomic dysfunction and a risk factor for cardiovascular disease (CVD), has not been systematically studied in nondialysis chronic kidney disease (CKD). METHODS: HRV was assessed using 24-h Holter monitoring in 305 subjects from the Renal Research Institute-CKD Study, a four-center prospective cohort of CKD (Stages 3-5). Multiple linear regression was used to assess predictors of HRV (both time and frequency domain) and Cox regression used to predict outcomes of CVD, composite of CVD/death and end-stage renal disease (ESRD). RESULTS: A total of 47 CVD, 67 ESRD and 24 death events occurred over a median follow-up of 2.7 years. Lower HRV was significantly associated with older age, female gender, diabetes, higher heart rate, C-reactive protein and phosphorus, lower serum albumin and Stage 5 CKD. Lower HRV (mostly frequency domain) was significantly associated with higher risk of CVD and the composite end point of CVD or death. Significantly, lower HRV (frequency domain) was associated with higher risk of progression to ESRD, although this effect was relatively weaker. CONCLUSIONS: This study draws attention to the importance of HRV as a relatively under recognized predictor of adverse cardiovascular and renal outcomes in patients with nondialysis CKD. Whether interventions that improve HRV will improve these outcomes in this high-risk population deserves further study.

Association between markers of collagen turnover, arterial stiffness and left ventricular hypertrophy in chronic kidney disease (CKD): the Renal Research Institute (RRI)-CKD study.

BACKGROUND: Markers of collagen turnover have not been well studied in the context of cardiovascular disease in patients with chronic kidney disease (CKD). We investigated the associations between serum markers of collagen turnover [N-terminal procollagen type 3 propeptide (PIIINP) and carboxy-terminal telopeptide (C1TP)] and both pulse wave velocity (PWV) and left ventricular mass index (LVMI) in a CKD cohort. METHODS: The study included 242 patients (mean age 60 ± 15 years, 53% males, 80% Caucasian, CKD Stages 3-5) from the Renal Research Institute (RRI)-CKD Study. Serum PIIINP and C1TP levels were analyzed by radioimmunoassay. PWV was obtained by applanation tonometry from carotid and femoral pressure wave contours. LVMI was measured by echocardiography. Statistical analyses included Pearson's correlations and multiple linear regression. RESULTS: Both PIIINP and C1TP values were significantly higher in more advanced stages of CKD (P < 0.05). A positive correlation was demonstrated between PWV and LVMI (r = 0.25, P = 0.0018), persisting after adjustment for potential confounders (partial r = 0.27, P = 0.0009). PIIINP correlated with PWV (r = 0.16, p = 0.029) and LVMI (r = 0.16, P = 0.0018), while C1TP correlated with LVMI (r = 0.18, P = 0.013) but not with PWV (r = 0.12, P = 0.09). In multivariable analysis adjusting for race, diabetes, estimated glomerular filtration rate (eGFR) and renin-angiotensin-aldosterone system inhibitors, only PWV (ß = 0.45, P = 0.0017) but not LVMI (P = 0.09) remained significantly associated with serum PIIINP. CONCLUSIONS: Our results demonstrate the association of PIIINP (but not C1TP), a circulating biomarker of collagen synthesis with arterial stiffness (but not with LVMI) in a CKD cohort, independent of eGFR. This suggests that altered collagen turnover may play a role in the pathogenesis of arterial stiffness in CKD.

Serum potassium and outcomes in CKD: insights from the RRI-CKD cohort study.

BACKGROUND AND OBJECTIVES: The relationship between serum potassium (S(K)) and mortality in chronic kidney disease (CKD) has not been systematically investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined the predictors and mortality association of S(K) in the Renal Research Institute CKD Study cohort, wherein 820 patients with CKD were prospectively followed at four US centers for an average of 2.6 years. Predictors of S(K) were investigated using linear and repeated measures regression models. Associations between S(K) and mortality, the outcomes of ESRD, and cardiovascular events in time-dependent Cox models were examined. RESULTS: The mean age was 60.5 years, 80% were white, 90% had hypertension, 36% had diabetes, the average estimated GFR was 25.4 ml/min per 1.73 m(2), and mean baseline S(K) was 4.6 mmol/L. Higher S(K) was associated with male gender, lower estimated GFR and serum bicarbonate, absence of diuretic and calcium channel blocker use, diabetes, and use of angiotensin-converting enzyme inhibitors and/or statins. A U-shaped relationship between S(K) and mortality was observed, with mortality risk significantly greater at S(K) < or = 4.0 mmol/L compared with 4.0 to 5.5 mmol/L. Risk for ESRD was elevated at S(K) < or = 4 mmol/L in S(K) categorical models. Only the composite of cardiovascular events or death as an outcome was associated with higher S(K) (> or = 5.5). CONCLUSIONS: Although clinical practice usually emphasizes greater attention to elevated S(K) in the setting of CKD, our results suggest that patients who have CKD and low or even low-normal S(K) are at higher risk for dying than those with mild to moderate hyperkalemia.

Dominance of traditional cardiovascular risk factors over renal function in predicting arterial stiffness in subjects with chronic kidney disease.

BACKGROUND: The predictors of arterial stiffness across the spectrum of renal function are unclear. These predictors were investigated across a wide range of estimated glomerular filtration rates (eGFR). METHODS: Carotid-femoral pulse wave velocity (PWV; an index of arterial stiffness) was measured in 264 subjects with chronic kidney disease (CKD) stages 3-5 from three nephrology clinics ('lower GFR group'). PWV was also measured in 149 subjects without previously recognized CKD ('higher GFR group') including n = 26 with eGFR between 30 and 60 ml/min/1.73 m(2) and n = 123 with eGFR between 60 and 100 ml/min/1.73 m(2). The association between PWV and eGFR was investigated using linear regression. RESULTS: The 413 subjects had a mean age of 61.9 years, were 51% male, 28% diabetic and 79% hypertensive. In age-adjusted analyses within the 'lower GFR group', 'higher GFR group' and combined group, PWV correlated with higher systolic blood pressure (SBP), pulse pressure (PP), diabetes mellitus, body mass index (BMI) and resting heart rate (all P < 0.0008). In addition, PWV correlated inversely with eGFR in the 'higher GFR group' (P = 0.03) and combined group (P < 0.0001). In multivariable regression analyses of the combined group (n = 413), PWV was independently predicted by eGFR (P < 0.05). However, eGFR explained at most 4% of the variability in PWV in age-adjusted analyses (compared with 13-15% explained by SBP, PP or diabetes) and <1% of PWV variability in models adjusting for age, SBP, diabetes, heart rate and BMI (P < 0.0001). CONCLUSION: Although eGFR may independently predict PWV, the contribution of GFR per se does not appear to be clinically meaningful when compared with traditional cardiovascular risk factors.

Prevalence and predictors of cardiovascular calcium in chronic kidney disease (from the Prospective Longitudinal RRI-CKD Study).

Although the determinants of cardiovascular calcium have been well described in dialysis patients, the prevalence and predictors in predialysis chronic kidney disease (CKD) are less known. One hundred six patients with CKD from the Renal Research Institute-CKD Study underwent multidetector computed tomography for the assessment of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve. Cardiovascular risk factors and renal function-related parameters (glomerular filtration rate, glomerular filtration rate slope, serum creatinine, serum urea nitrogen, hemoglobin, albumin, calcium, phosphate, and parathyroid hormone) were included in multivariate regression models to predict cardiovascular calcium. Prevalences of calcium deposition at the level of coronary arteries, thoracic aorta, aortic valve, and mitral valve were 69%, 46%, 39%, and 16%, respectively. On multivariate analysis, coronary artery calcium score was predicted by age (p < 0.0001), gender (p = 0.0001), diabetes (p = 0.024), and history of coronary artery disease (p = 0.016), but not by renal function related parameters. Similarly, renal function related parameters were not predictive of aortic or valvular calcium. In conclusion, predialysis CKD is associated with a high prevalence of cardiovascular calcium. The extent of cardiovascular calcium in patients with predialysis CKD is related to some of the traditional risk factors for atherosclerosis but not to indexes of abnormal renal function or progression in renal dysfunction.

Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study.

BACKGROUND: Health-related quality of life (QOL) is an important measure of how disease affects patients' lives. Dialysis patients have decreased QOL relative to healthy controls. Little is known about QOL in patients with chronic kidney disease (CKD) before renal replacement therapy. METHODS: The Medical Outcomes Study Short Form-36 (SF-36), a standard QOL instrument, was used to evaluate 634 patients (mean glomerular filtration rate [GFR], 23.6 +/- 9.6 mL/min/1.73 m2 [0.39 +/- 0.16 mL/s/1.73 m2]) enrolled in a 4-center, prospective, observational study of CKD. SF-36 scores in these patients were compared with those in a prevalent cohort of hemodialysis (HD) patients and healthy controls (both from historical data). QOL data also were analyzed for correlations with GFR and albumin and hemoglobin levels in multivariable analyses. RESULTS: Patients with CKD had higher SF-36 scores than a large cohort of HD patients (P < 0.0001 for 8 scales and 2 summary scales), but lower scores than those reported for the US adult population (P < 0.0001 for 7 of 8 scales and 1 of 2 summary scales). Patients with CKD stage 4 had lower QOL scores than patients with CKD stage 5, although differences were not significant. Hemoglobin level was associated positively with higher mental and physical QOL scores (P < 0.05) in all individual and component scales except Pain. CONCLUSION: SF-36 scores were higher in this CKD cohort compared with HD patients, but lower than in healthy controls. GFR was not significantly associated with QOL. Hemoglobin level predicted both physical and mental domains of the SF-36. Longitudinal studies are needed to define at-risk periods for decreases in QOL during progression of CKD.

Patterns of medication use in the RRI-CKD study: focus on medications with cardiovascular effects.

BACKGROUND: Patients with chronic kidney disease (CKD) stages 2-5 are known to suffer numerous complications and co-morbidities associated with kidney disease. The medication prescription patterns in this population are not well understood. We report on prescription data collected as part of a multicentre longitudinal study in patients with CKD, with a focus on medications with cardiovascular or cardioprotective effects. METHODS: Patients were recruited from four academic nephrology centres in the USA, with patient recruitment from June 2000 to March 2002. Medication data were captured at the time of first enrollment into the study. Individual medications were classified into medication groups, and those with predominant cardioprotective effects or for prevention of progression of kidney disease (e.g. medications for treatment of anaemia, lipid-lowering agents, antihypertensives, statins, etc.) were recorded for analysis. Descriptive statistics were used for medication prescription according to baseline demographics and co-morbidities. Predictors of epoetin and iron use were determined by logistic regression adjusting for age, race, sex, diabetes, glomerular filtration rate (GFR), haemoglobin and serum albumin. RESULTS: Medication data were available for 619 patients with stages 2-5 CKD. Patients were 60.6+/-16.0 years of age, and were prescribed 8+/-4 (range 1-28) medications. Overall, the proportion of patients prescribed different classes of medications included epoetin (20%), intravenous iron (13%), HMG-CoA reductase inhibitors (16%), angiotensin-converting enzyme (ACE) inhibitors (44%), angiotensin receptor blockers (13%), beta-blockers (46%), calcium channel blockers (52%) and aspirin (37%). There was a low use of epoetin (45%) and iron (20%) in patients with anaemia. Only 24% of patients with coronary artery disease were prescribed statins, and ACE inhibitors and angiotensin receptor blockers were used in only 58 and 23% of diabetic patients with proteinuria. Positive predictors of epoetin and iron therapy included white race and diabetes. Higher GFR and higher serum albumin were associated with lower odds of being prescribed epoetin. White race and diabetics were more likely to be prescribed iron. CONCLUSIONS: This study provides an overview of prescription practices in a cohort of CKD patients. Substantial underutilization of certain classes of cardioprotective medications is apparent, and systematic educational efforts in this direction may well prove worthwhile to impact outcomes.

The longitudinal chronic kidney disease study: a prospective cohort study of predialysis renal failure.

Chronic kidney disease (CKD) is a significant public health problem: every year the number of Americans living with CKD and requiring renal replacement therapy increases. In addition, individuals with CKD have substantially increased morbidity and mortality compared to the general population. The Longitudinal Chronic Kidney Dialysis (LCKD) Study is a multicenter, prospective, observational study of patients with moderate to severe CKD that was designed to better describe the course of the disease and the determinants of patient outcomes. Patients with moderate to severe CKD (glomerular filtration rate [GFR] < 60 ml/min/m2) from four academic nephrology clinics were enrolled between 2000 and 2002. Special cardiac and vascular testing has recently commenced as phase II of this study. Areas that have been or are currently being studied include anemia management, health-related quality of life (HRQOL), medication use, and markers of cardiovascular disease. This article describes the LCKD Study in the context of current knowledge of CKD.