Is a Single Time Point C-Reactive Protein Predictive of Outcome in Peritoneal Dialysis Patients?

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1 J Am Soc Nephrol 14: , 2003 Is a Single Time Point C-Reactive Protein Predictive of Outcome in Peritoneal Dialysis Patients? ANGELA YEE-MOON WANG,* JEAN WOO, CHRISTOPHER WAI-KEI LAM, MEI WANG,* MANDY MAN-MEI SEA, SIU-FAI LUI,* PHILIP KAM-TAO LI,* and JOHN SANDERSON* *Department of Medicine and Therapeutics, Center for Nutritional Studies, and Department of Chemical Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong. Abstract. C-reactive protein is the prototype marker of inflammation and has been shown to predict mortality in hemodialysis patients. However, it remains uncertain as to whether a single C-reactive protein level has similar prognostic significance in peritoneal dialysis patients. A single high-sensitivity C-reactive protein (hs-crp) level was measured in 246 continuous ambulatory peritoneal dialysis patients without active infections at study baseline together with indices of dialysis adequacy, echocardiographic parameters (left ventricular mass index, left ventricular dimensions, and ejection fraction), nutrition markers (serum albumin, dietary intake, and subjective global assessment) and biochemical parameters (hemoglobin, lipids, calcium, and phosphate). The cohort was then followed-up prospectively for a median of 24 mo (range, 2 to 34 mo), and outcomes were studied in relation to these parameters. Fifty-nine patients died (36 from cardiovascular causes) during the follow-up period. The median hs-crp level was 2.84 mg/l (range, 0.20 to mg/l). Patients were stratified into tertiles according to baseline hs-crp, namely those with hs-crp 1.26 mg/l, 1.27 to 5.54 mg/l, and 5.55 mg/l. Those with higher hs-crp were significantly older (P 0.001), had greater body mass index (P 0.001), higher prevalence of coronary artery disease (P 0.003), and greater left ventricular mass index (P 0.001). One-year overall mortality was 3.9% (lower) versus 8.8% (middle) versus 21.3% (upper tertile) (P ). Cardiovascular death rate was 2.7% (lower) versus 5.2% (middle) versus 16.2% (upper tertile) (P ). Multivariable Cox regression analysis showed that every 1 mg/l increase in hs-crp was independently predictive of higher all-cause mortality (hazard ratio [HR], 1.02; 95% CI, 1.01 to 1.04; P 0.002) and cardiovascular mortality (HR, 1.03; 95% CI, 1.01 to 1.05; P 0.001) in peritoneal dialysis patients. Other significant predictors for all-cause mortality included age (HR, 1.07; 95% CI, 1.04 to 1.10), gender (HR, 0.49; 95% CI, 0.27 to 0.90), atherosclerotic vascular disease (HR, 2.65; 95% CI, 1.46 to 4.80), left ventricular mass index (HR, 1.01; 95% CI, 1.00 to 1.01) and residual GFR (HR, 0.53; 95% CI, 0.38 to 0.75). Age (HR, 1.06; 95% CI, 1.02 to 1.10), history of heart failure (HR, 3.31; 95% CI, 1.36 to 8.08), atherosclerotic vascular disease (HR, 3.20; 95% CI, 1.43 to 7.13), and residual GFR (HR, 0.57; 95% CI, 0.38 to 0.86) were also independently predictive of cardiovascular mortality. In conclusion, a single, random hs-crp level has significant and independent prognostic value in PD patients. Elevated plasma C-reactive protein (CRP) level, the prototypic marker of inflammation, has been shown to be strongly predictive of an increased risk of future myocardial infarction and predicts mortality in apparently healthy people (1 3) as well as in patients with established coronary artery disease (4 6). On the other hand, increased CRP is also frequently observed in chronic renal failure patients (7 11) and is associated with atherosclerosis (11). Whether CRP is simply a marker of atherosclerosis or is causally related to the development of Received November 29, Accepted March 14, Correspondence to Dr. Angela Yee-Moon Wang, Department of Medicine & Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, N.T. Hong Kong. Phone: ; Fax: ; E- mail: awang@cuhk.edu.hk / Journal of the American Society of Nephrology Copyright 2003 by the American Society of Nephrology DOI: /01.ASN B3 atherosclerosis remains an open question. However, prospective cohort studies showed that CRP is one of the important predictors for mortality in hemodialysis patients (7 8,12). What is more intriguing is that a single determination of CRP is predictive of all-cause mortality and cardiovascular death even after a follow-up period of 4 yr in patients on hemodialysis treatment (12), although there is also a study showing that the predictive value of CRP is not independent of nutritional and cardiovascular risk factors (13). On the other hand, very few studies examined the role of CRP in predicting outcome of peritoneal dialysis (PD) patients, and the results were inconclusive. One study showed that CRP is associated with increased mortality independent of cardiovascular disease (14). Another study showed that CRP is predictive of nonfatal myocardial infarction but not all-cause mortality (15). Although the negative finding may be partly explained by the small sample size, there is recent data to suggest that CRP is increased in a significant proportion of PD patients without any obvious cause and in approximately one

2 1872 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 third of these patients with raised CRP without an apparent cause, the repeat levels become normal in 40% over the next few months (16). Moreover, CRP level was noted to fall with time on PD and was significantly lower in PD compared with hemodialysis patients (17). Hence the question as to whether a single CRP level has prognostic significance in PD patients remains unanswered. In this study, we hypothesized that a C-reactive protein level at a single time point predicts all-cause mortality and cardiovascular mortality in a prevalent cohort of PD patients. Our study differs from previous studies in PD patients in that not only do we take into account of inflammatory parameters but also clinical, cardiovascular, echocardiographic, dialysis, nutritional, and biochemical factors other well-known predictors for mortality in PD patients. Materials and Methods Study Population The prospective study was carried out at the dialysis unit in the Prince of Wales Hospital in Hong Kong in September Altogether 246 continuous ambulatory peritoneal dialysis (CAPD) patients who had been on dialysis treatment for at least 3 mo were recruited into the study over a period of 20 mo. Our study cohort represented 91% of the total number of patients on PD treatment at our unit. All patients are of Chinese origin. The remaining 9% of patients were excluded from the study because of underlying malignancy, chronic liver disease, systemic lupus erythematosus, chronic rheumatic heart disease, congenital heart disease, or because they received PD treatment for less than 3 mo or were on automated PD. The study protocol was approved by the Human Research Ethics Committee of the Chinese University of Hong Kong. Informed consent was obtained from all study participants. At study baseline, demographic and clinical parameters, cardiovascular and echocardiographic parameters, nutritional indices, biochemical and inflammatory parameters as well as indices of dialysis adequacy were assessed. Clinical and Demographic Parameters Clinical and demographic data, including the duration on CAPD at study entry, underlying cause of renal failure, smoking history, presence of diabetes, ischemic heart disease, history of heart failure, cerebrovascular disease and peripheral vascular disease, history of exit site infection and peritonitis within 1 yr before study entry were recorded at study baseline. Clinical atherosclerotic vascular disease was defined as the presence of ischemic heart disease and history of angina, previous myocardial infarction, coronary artery bypass surgery or stenting, cerebrovascular event, transient ischemic attack, or peripheral vascular disease with or without amputation. Use of erythropoietin as well as the number and type of antihypertensive medication at study baseline were recorded. These include the use of calcium channel blocker, angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), and beta-blocker. Use of HMG- CoA-reductase inhibitor and aspirin were also recorded. Biochemical and Inflammatory Parameters Twenty milliliters of fasting venous blood was collected at the time of nutrition assessment, which was also the time of study entry for measurement of high-sensitivity C-reactive protein (hs-crp), fibrinogen, parathyroid hormone (PTH), total, HDL- and LDL-cholesterol, triglyceride, urea, creatinine, calcium, phosphate, and hemoglobin. hs-crp was measured using the Tina-quant CRP (Latex) ultrasensitive assay (Roche Diagnostics GmbH, Mannheim, Germany). The coefficient of variation of the hs-crp assay was 4.7% and 1.6% at concentrations of 4.3 mg/l and 2.0 mg/l, respectively. Fibrinogen was measured by a prothrombin time-derived and turbidimetric clot detection method using the ACL Futura (Instrumentation Laboratory). Serum albumin was measured by the bromcresol purple method. PTH was measured by the chemiluminescence immunoassay on the Immunlite analyzer (Diagnostic Products Corp, Los Angeles, CA). Total cholesterol and triglyceride were measured by the Hitachi 911 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). HDL-cholesterol was measured by the precipitation of Apo B containing lipoproteins with phosphotungstate, whereas LDL-cholesterol was calculated using the Friedwald formula. Serum urea, creatinine, calcium, and phosphate were measured by dye-binding methods on the Dimension AR automatic analyzer (Du Pont Co, Wilmington, DE). Hemoglobin was measured in the standard hematology laboratory. Echocardiographic Parameters Two-dimensional echocardiography was performed with a GE- VingMed System 5 echocardiographic machine (GE-VingMed Sound AB, Horten, Norway) with a 3.3-mHz multiphase array probe in subjects lying in the left decubitus position by a single experienced cardiologist blinded to all clinical details of patients. All echocardiographic data were recorded according to the guidelines of the American Society of Echocardiography (18 19). Left ventricular mass (LVM) was corrected by the body surface area and expressed as LVM index, an index reflecting the severity of LVH. LVH was defined as LVM index 131 g/m 2 in men and 100 g/m 2 in women in accordance with Framingham criteria (20). Systolic and diastolic BP was measured at the time of echocardiography after resting for 15 min. Nutrition Indices Subjective global assessment (SGA) was used to evaluate the overall protein-energy nutritional status (21 22). The SGA includes six subjective assessments; three are based on the patient s history of weight loss, presence of anorexia, and vomiting, and three are based on the physician s grading of muscle wasting, presence of edema, and loss of subcutaneous fat. Although edema is not a useful index of malnutrition (22), its presence or absence has to be taken into account when assessing changes in body weight. On the basis of these assessments, each patient was graded a score that reflected the nutrition status: 1, normal nutrition; 2, mild malnutrition; 3, moderate malnutrition; and 4, severe malnutrition (22). A 7-d dietary survey questionnaire that has previously been validated in the Chinese population was administered in all study patients to estimate the average daily dietary protein and energy intake. Details and validation of the questionnaire was described elsewhere (23). Dietary protein and energy intake was normalized for dry weight (measured by a weighing scale with abdomen drained dry of peritoneal dialysis fluid). Body mass index was calculated by dividing dry weight (in kilograms) by the square of the height (in meters). Both the SGA and dietary survey questionnaire were performed by experienced research staff blinded to all clinical, biochemical, dialysis, and echocardiographic data of patients. Dialysis Adequacy Patients were asked to bring back 24-h urine and dialysate on the morning of nutrition assessment for measurement of urea and creat-

3 J Am Soc Nephrol 14: , 2003 Single Time Point C-Reactive Protein and PD Outcomes 1873 inine concentration. Adequacy of dialysis was determined by measuring total weekly urea clearance (Kt/V) and creatinine clearance (CrCl) using standard methods (24). Weekly CrCl was normalized to 1.73 m 2 of body surface area. Contribution of urea clearance by peritoneal dialysis was estimated separately. Residual GFR was calculated as an average of the 24-h urine urea and creatinine clearance (25). Dialysate creatinine concentration was corrected for interference by glucose according to the reference formula determined in our laboratory (26). Total body water (V) was derived from Watson formula (27). The dialysate/plasma creatinine ratio (D/P Cr ) was calculated from the concentrations of creatinine in the 24 h dialysate and the plasma (28). Study Outcome All patients were then followed up prospectively after all the baseline assessments. No patient was lost to follow-up. Patients who underwent kidney transplant or transferred to hemodialysis were censored at the time of transfer to alternative renal replacement therapy. If a patient died within 3 mo of transfer to hemodialysis, then he or she was not censored as the early mortality was considered to reflect the health status during the period of failing CAPD treatment. During the period of follow-up, all deaths were accurately recorded with the exact cause of death provided by the attending physician who had no knowledge of the echocardiography results. In the case of death out of hospital, family members were interviewed by telephone to ascertain the circumstances surrounding death. The clinical outcomes evaluated were all-cause mortality and cardiovascular mortality. Cardiovascular mortality included death associated with a definite myocardial ischemic event, heart failure, cerebrovascular accident, arrhythmia, or peripheral vascular accident, all of which defined according to standard clinical criteria and sudden death, which was defined as unexpected natural death within 1 h from the symptom onset and without any prior condition that would appear fatal (29,30). Statistical Analyses Statistical analyses were performed using SPSS software, version 10.0 (SPSS, Inc., Chicago, IL). Continuous data are expressed as mean SD or median (interquartile range [IQR]), and categorical data are expressed as percentages. Patients were stratified into tertiles according to the single hs-crp level at study baseline. Comparisons of characteristics of patients across the different tertiles were performed using the one-way ANOVA for mean data, Kruskal-Wallis test for median data, and 2 test for categorical data. Factors predictive of all-cause mortality and cardiovascular mortality were further determined with multivariable Cox regression analysis. Any variables with difference between tertiles of hs-crp found at P 0.20 were considered as potential confounders and were adjusted for in the Cox regression analysis (31). A backward elimination procedure was performed with P 0.05 to remove to identify independent predictors for all-cause mortality and cardiovascular mortality in PD patients. Survival curves were generated according to the Kaplan-Meier method. Differences in the survival curves among the three tertiles were compared by the log-rank test. A P-value of less than 0.05 was considered statistically significant. Results Patient Characteristics The baseline characteristics of the study cohort are shown in Tables 1 and 2. There were altogether 128 men and 118 women. The mean age was yr. The study cohort was dialyzed for a mean duration of 38 mo (range, 4 to 151 mo) at the time of study entry. Ninety-five patients (39%) had no residual renal function. Forty percent of our patients were prescribed erythropoietin. Antihypertensive medications including beta-blockers, ACE inhibitors/arb, and calcium channel blockers were used in 52%, 25%, and 62% of patients, respectively. Fourteen percent of patients were treated with HMG Co-A reductase inhibitors, and 6% took aspirin. The distribution of hs-crp of our study cohort taken at the time of study entry was shown in Figure 1. The median (IQR) hs-crp level was 2.84 mg/l (0.92 to 9.10 mg/l). hs-crp level was below 5 mg/l in 64% of patients, between 5 and 10 mg/l in 12%, between 10 and 15 mg/l in 7%, and over 15 mg/l in 17% of patients. Comparisons among Patients of the Different Tertiles of hs-crp Comparisons among patients of the different tertiles of hs- CRP level, namely those with hs-crp 1.26 mg/l (lower tertile), between 1.26 and 5.56 mg/l (middle tertile), and 5.56 mg/l (upper tertile) are shown in Tables 1 and 2. A significant increase in age (P 0.001), body weight (P 0.041), and body mass index (P 0.001) was observed across the three tertiles of increasing hs-crp. More patients in the upper tertile had ischemic heart disease (P 0.003). Thirtyseven percent of patients in the lower versus 45% in the middle and 50% in the upper tertile had exit site infections (P 0.215), and 29% of patients in the lower versus 39% in the middle and 31% in the upper tertile were complicated with peritonitis within 1 yr before study entry (P 0.350). A significant decrease in diastolic BP was observed across the three tertiles (P 0.018). The left ventricular mass index (P 0.001), left ventricular end-diastolic diameter (P 0.001), ejection fraction (P 0.002), and fractional shortening (P 0.001) showed significant increase across the three tertiles of increasing hs-crp. Patients in the upper tertile had the lowest residual GFR (P 0.018) but received the highest average daily PD exchanges (P 0.028). A significant decrease in dietary energy (P 0.001) and protein intake (P 0.003), as well as serum albumin (P 0.005), was observed across the three tertiles of increasing hs-crp. According to SGA, a trend toward greater prevalence of moderate and severe malnutrition was observed in the upper tertile though not reaching statistical significance. Biochemical parameters including fibrinogen and triglyceride increased significantly while HDL- and LDL-cholesterol decreased significantly across the three tertiles of increasing hs-crp (Table 2). Calcium, phosphate, and PTH did not differ significantly among the three tertiles. Thirty-eight percent of patients (lower tertile) versus 38% (middle tertile) versus 45% (upper) were prescribed erythropoietin (P 0.544). Beta-blocker was used in 56% versus 44% versus 57% of patients in the lower versus middle versus upper tertiles, respectively (P 0.164). Slightly more frequent use of ACE inhibitor or ARB was observed in the upper (33%) than lower (20%) and middle tertiles (22%) (P 0.106). Use of calcium channel blocker (66% versus 61% versus 59%; P 0.617), HMG Co-A reductase inhibitor (11% versus 15% versus 16%; P 0.642) and aspirin (5% versus 4% versus 9%; P

4 1874 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 1. Comparison of baseline demographic, clinical, and cardiovascular characteristics of study patients stratified according to tertiles of high-sensitivity C-reactive protein a Total (n 246) High Sensitivity C-Reactive Protein in Tertiles Lower Middle Upper P c Demographic and clinical parameters age (yr) male gender (%) CAPD (mo) body weight (kg) body height (m) body mass index (kg/m 2 ) smoking history (%) nonsmoker ex-smoker current smoker renal diagnosis (%) chronic glomerulonephritis diabetic nephropathy hypertensive nephrosclerosis others Comorbidity diabetes (%) ischemic heart disease (%) previous heart failure (%) atherosclerotic vascular disease (%) Cardiovascular parameters systolic BP (mmhg) diastolic BP (mmhg) total number of antihypertensives (%) LV mass index (g/m 2 ) LV end-diastolic diameter (cm) LV ejection fraction (%) LV fractional shortening (%) a Plus-minus values are means SD. CAPD, continuous ambulatory peritoneal dialysis; LV, left ventricular. Percentages may not add up to 100 due to rounding off of decimal places. c Comparison among the three tertiles ) did not differ significantly across the three tertiles. Twenty-one percent of patients with versus 12% of patients without atherosclerotic complications were treated with statin (P 0.061). Among patients with atherosclerotic complications, hs-crp was not significantly different for those treated (5.9 mg/l [1.2 to 13.3 mg/l]) and not treated with statin (5.4 mg/l [1.4 to 22.3 mg/l]; P 0.83). Patient Survival and Causes of Death in Relation to hs-crp Our study cohort was followed-up for a median duration of 24 mo (range, 2 to 34 mo) after all the baseline assessments including hs-crp. During this period of follow-up, there were 59 deaths (24%). Twenty-three patients (9.3%) were transferred to long-term hemodialysis, and 19 patients (7.7%) received a kidney transplant. More men (30%) than women (18%) died during the period of follow-up. On the other hand, more women (12%) than men (7%) were transferred to longterm hemodialysis. The causes of death of our study cohort were shown in Table 3. The main cause of death was cardiovascular disease in 36 patients (61%), followed by infections in 15 patients (25%); 19 of the 36 patients (53%) had sudden cardiac death. Patients in the upper tertile had the shortest follow-up duration, yet they had the highest mortality (41.5%) compared with patients in the lower and middle tertiles (11% and 19.5%, respectively; P 0.001). Death from cardiovascular causes was 7.3%, 9.8%, and 26.8% for patients in the lower, middle, and upper tertiles, respectively. Noncardiovas-

5 J Am Soc Nephrol 14: , 2003 Single Time Point C-Reactive Protein and PD Outcomes 1875 Table 2. Comparison of baseline biochemical, dialysis, and nutritional indices of study patients stratified according to tertiles of high-sensitivity C-reactive protein a Total (n 246) High-Sensitivity C-Reactive Protein in Tertiles Lower Middle Upper P c Biochemical parameters hemoglobin (g/dl) fibrinogen (g/l) total cholesterol (mmol/l) HDL-cholesterol (mmol/l) LDL-cholesterol (mmol/l) triglyceride (mmol/l) Dialysis parameters weekly total urea clearance weekly PD urea clearance creatinine clearance (L/wk per m 2 ) residual GFR b (ml/min per 1.73 m 2 ) 0.61 (0 to 1.94) 0.75 (0.03 to 2.04) 0.74 (0 to 2.09) 0 (0 to 1.59) dialysate-to-plasma creatinine ratio daily PD exchanges (L) Nutritional parameters subjective global assessment, n (%) normal mild moderate/severe dietary protein intake (g/kg per day) dietary energy intake (kcal/kg per day) albumin (g/l) a Plus-minus values are means SD. HDL, high-density lipoprotein; LDL, low-density lipoprotein; PD, peritoneal dialysis; GFR, glomerular filtration rate. Percentages may not add up to 100 due to rounding off of decimal places. b Expressed as median (interquartile range). c Comparison among three tertiles. Figure 1. Frequency distribution of high sensitivity C-reactive protein (hs-crp) in Chinese continuous ambulatory peritoneal dialysis (PD) patients. cular deaths were 3.7%, 9.8% and, 14.6% for patients in the lower, middle, and upper tertiles, respectively (P 0.001). The overall 1-yr survival was 79% for patients in the upper tertile compared with 91% for patients in the middle tertile (P ) and 96% for patients in the lower tertile (P ; Figure 2A). The survival rate was not significantly different for patients in the lower and middle tertiles. Cardiovascular death rate at 1 yr was 16% for patients in the upper tertile compared with 5% for patients in the middle tertile (P ) and 3% for patients in the lower tertile (P ; Figure 2B). Patients in the upper tertile had a 4.7-fold increased risk (95% CI, 2.23 to 9.73; P 0.001) for all-cause mortality and a 4.9-fold higher risk (95% CI, 2.00 to 12.01; P 0.001) for cardiovascular mortality than those in the lower tertile. Patients in the middle tertile showed no significant increase in the risk for all-cause (P 0.232) and cardiovascular mortality (P 0.785) than those in the lower tertile. Multivariable Cox regression analysis was used to determine the independent effects of a single random hs-crp in predicting all-cause and cardiovascular mortality and included terms for age, gender, duration of dialysis, body mass index, positive smoking history, diabetic nephropathy, atherosclerotic vascular disease, history of heart failure, left ventricular mass index, left ventricular end-diastolic diameter, ejection fraction, fractional shortening, diastolic BP, weekly total and peritoneal dialysis Kt/V, residual GFR, hemoglobin, fibrinogen, choles-

6 1876 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 3. Clinical outcome of patients according to the hs-crp level at study baseline a Total (n 246) Lower (n 82) hs-crp in Tertiles Middle (n 82) Upper (n 82) P Follow-up time from hs-crp measurement (mo) Outcome, n (%) died on peritoneal dialysis 59 (24.0) 9 (11.0) 16 (19.5) 34 (41.5) alive on peritoneal dialysis 145 (58.9) 59 (72.0) 55 (67.1) 31 (37.8) transfered to hemodialysis 23 (9.3) 4 (4.9) 6 (7.3) 13 (15.9) transplanted 19 (7.7) 10 (12.2) 5 (6.1) 4 (4.9) Causes of death, n (%) cardiovascular causes 36 (14.6) 6 (7.3) 8 (9.8) 22 (26.8) myocardial infarction 4 (1.6) 1 (1.2) 0 (0) 3 (8.8) cerebrovascular 9 (3.7) 2 (2.4) 2 (2.4) 5 (6.1) sudden death 19 (7.7) 3 (3.7) 6 (7.3) 10 (12.2) peripheral vascular 4 (1.6) 0 (0) 0 (0) 4 (4.8) disease, arrhythmia, or heart failure non-cardiovascular causes 23 (9.3) 3 (3.7) 8 (9.8) 12 (14.6) unresolved peritonitis 4 (1.6) 0 (0) 1 (1.2) 3 (3.7) other infections or sepsis 11 (4.5) 1 (1.2) 5 (6.1) 5 (6.1) other miscellaneous causes 8 (3.2) 2 (2.4) 2 (2.4) 4 (4.9) a hs-crp, high-sensitivity C-reactive protein. b Percentages may not add up to 100 due to rounding off of decimal places. terol, triglyceride, and serum albumin. Every 1 mg/l increase in hs-crp was independently predictive of a 2% increase in all-cause mortality (95% CI, 1.01 to 1.04; P 0.002) and a 3% increase in cardiovascular mortality (95% CI, 1.01 to 1.05; P 0.001) in PD patients. Other significant and independent predictors for mortality included age, male gender, presence of atherosclerotic vascular disease, history of heart failure, left ventricular mass index, and residual GFR (Table 4). Correlation analysis showed a small but significant correlation between hs-crp with residual GFR (r 0.16; P 0.011) and duration of dialysis (r 0.147; P 0.018), suggesting residual GFR and duration of dialysis may have confounding influence on the association between CRP and mortality, although statistical analysis showed no significant colinear relationships between hs-crp and GFR as well as between hs-crp and duration of dialysis. To determine whether there is nonlinear association between CRP and mortality, a quadratic term, namely square of CRP, is fitted to the final model in Table 4. However, the quadratic term is not significant in the model predicting all-cause mortality (P 0.369) as well as in the model predicting cardiovascular mortality (P 0.604). This suggests that imposing a nonlinear term does not provide additional predictive power to the models in Table 4. Discussion This study shows that a considerable proportion (36%) of the Chinese PD patients exhibited evidence of an activated acute phase response as denoted by a hs-crp level 5 mg/l. The prevalence of inflammation was considered much lower when compared with the white dialysis cohorts, in whom the prevalence was estimated to be at least 50 to 60% (32). Another study in the Asian population reported that only 12% of the PD patients had CRP 8 mg/l (14). This may reflect difference in inflammatory response or genetic susceptibility to develop inflammation between Asian and white populations and will require further investigation. Our results demonstrate the usefulness of a single random CRP in predicting all-cause and cardiovascular mortality, independent of other cardiovascular, echocardiographic, dialysis, biochemical, and nutritional parameters in PD patients. This is in keeping with studies in both the general and hemodialysis populations as well as very recent study in patients initiating PD showing that a single time point measurement of CRP is predictive of overall mortality and cardiovascular death even after prolonged period of follow-up (12,33 34). Our results however differed from those reported by Owen and Lowrie (13) in hemodialysis patients and by Herzig et al. (15) in PD patients that failed to show a significant relationship between CRP and risk of death on multivariate analysis. Both these studies showed that the depletion of body proteins and not inflammation is a more important contributor to mortality risk in dialysis patients. The study by Owen and Lowrie was however limited in that it only had 6 mo of follow-up and that by Herzig included only 50 patients. The difference in sample size, follow-up

7 J Am Soc Nephrol 14: , 2003 Single Time Point C-Reactive Protein and PD Outcomes 1877 Figure 2. Kaplan-Meier analysis of (A) overall survival and (B) cardiovascular event-free survival in relation to tertiles of high sensitivity C-reactive protein (hs-crp). duration, and the extent of adjustment for confounding covariates may well explain the disparity between our findings and these studies. The finding that a single, cross-sectional measurement of a plasma protein with such a short half-life (19 h) carries significant long-term prognostic information is intriguing, as some studies demonstrated marked variations of CRP levels in individual patients (16,35). On the other hand, others reported relative stability of CRP as shown by the high concordance for CRP levels measured at baseline and 6 mo later (15,17,36). Recent study showed that a persistently elevated CRP for more than 6 mo is largely related to the presence of ischemic heart disease or other atherosclerotic complications (37). This is in keeping with our current finding of higher prevalence of ischemic heart disease and atherosclerotic complications as well as increased cardiovascular mortality among patients of the upper tertile. The clinical outcomes of patients in the middle tertile were not significantly different from the lower tertile. This is in contrast to study in cardiac patients (4 6) and general population (3,33) showing that even high normal CRP levels are associated with adverse prognosis. The exact reason for this difference is not clear, but it may be partly related to the study power. Our study only had 83 patients in each tertile and may not be adequately powered to detect difference in outcome between high normal and low normal CRP. The other explanation may relate to the numerous cardiovascular risk factors uniquely operating in renal failure patients namely, calcium phosphate parameters, anemia, hypoalbuminemia, dialysis adequacy, and volume status other than inflammation and traditional Framingham risk factors. These different factors are well known to affect clinical outcomes of renal failure patients and may influence the association of CRP with survival. A novel finding was that patients in the upper tertile had the greatest left ventricular mass index and left ventricular enddiastolic diameter as well as the lowest ejection fraction and fractional shortening. They were also dialyzed for the longest duration, had the lowest residual GFR, and were the most malnourished according to nutrition assessments. It is therefore intriguing to find that these patients, on the contrary, had the highest body weight and BMI. We hypothesized that these patients were also volume overloaded. This may explain why they had the highest BMI despite being more malnourished and had the worst cardiac status. Indeed, previous study demonstrated immune activation in patients with fluid overload (38). Increased extracellular fluid volume was shown to cause hypoalbuminemia (39) and was linked to hypertension, progressive LV hypertrophy, and dilatation in PD patients (40 41). Increased extracellular fluid removal reduced dry weight, improved BP control, and increased serum albumin in PD patients (42). Whether CRP is elevated in volume overload state and is in turn associated with more LV hypertrophy and dilatation or CRP is simply a marker of the degree of LV hypertrophy and dilatation in PD patients requires further investigation. The small association between body height and CRP may be due to more female patients in the upper tertile and is unlikely to be of real clinical significance. Hypoalbuminemia (43), hyperfibrinogenemia, hypercholesterolemia, and hypertriglyceridemia (44 46) were important cardiovascular risk factors and predictors of mortality in dialysis patients. In this study, serum albumin, fibrinogen, HDL and LDL-cholesterol, and triglyceride were significantly associated with CRP but lost their significance in predicting mortality and cardiovascular death on multivariate analysis. This is consistent with the study by Zimmerman et al. (7) and suggests that, other than being cardiovascular risk factors, serum albumin, fibrinogen, cholesterol, and triglyceride behave like markers of acute phase response though not as powerful as CRP in predicting outcome of PD patients. The cause of lower LDL in patients with higher CRP is not clear but may be related to more frequent use of statins. Patients with higher hs-crp were older and may be explained by higher prevalence of vascular complications with increasing age. The association between CRP and residual renal function was well described in previous study (47). CRP was positively associated with the time on dialysis. Although being adjusted for in the multivariate analysis, the time on dialysis may well have a confounding effect on the association between CRP and mortality as with time on dialysis, there is decline of residual GFR, increasing LV hypertrophy, higher prevalence of atherosclerotic complications, more malnutrition, and inflammation in PD patients.

8 1878 Journal of the American Society of Nephrology J Am Soc Nephrol 14: , 2003 Table 4. Cox regression analysis showing important predictors for mortality in CAPD patients after a median follow-up of 24 mo a All-Cause Mortality (n 59) Cardiovascular Mortality (n 36) Unit Increase Hazard Ratio (95% CI) P Unit Increase Hazard Ratio (95% CI) P hs-crp 1 mg/l 1.02 (1.01 to 1.04) mg/l 1.03 (1.01 to 1.05) Age 1 yr 1.07 (1.04 to 1.10) yr 1.06 (1.02 to 1.10) Gender Female 0.49 (0.27 to 0.90) 0.02 Atherosclerotic vascular disease 2.65 (1.46 to 4.80) (1.43 to 7.13) Left ventricular mass index 1 g/m (1.00 to 1.01) History of heart failure 3.31 (1.36 to 8.08) Residual GFR 1 ml/min per 1.73 m (0.38 to 0.75) ml/min per 1.73 m (0.38 to 0.86) a CAPD, continuous ambulatory peritoneal dialysis; CI, confidence interval. In summary, this study clearly confirms the significance of a single random hs-crp in predicting all-cause mortality and cardiovascular mortality in PD patients. Our results indicate that determination of CRP by a high-sensitive assay should be considered in all PD patients without active infections in order for risk stratification. Whether lowering CRP level will improve outcome of these patients requires further determination. Acknowledgments This study was supported by the Hong Kong Health Services Research Fund and the Bristol Myers Squibb Unrestricted Nutrition Grant Program. We express sincere gratitude to Mr. Lam Peggo Kwok Wai from the Center of Clinical Trials and Epidemiological Research for providing statistical support for the study, Mr. Chan Joseph Fat Yiu for performing the hs-crp assay, and Miss Law Man Ching and Miss Wong Esther for collecting data for this study. References 1. Ridker PM, Glynn RJ, Hennekens CH: C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. 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