Chronic hepatitis C virus (HCV) infection is common

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1 Peritoneal Dialysis International, Vol. 28, pp Printed in Canada. All rights reserved /08 $ Copyright 2008 International Society for Peritoneal Dialysis MORTALITY IN HEPATITIS C-POSITIVE PATIENTS TREATED WITH PERITONEAL DIALYSIS Shu-Ming Wang, 1 Jiung Hsiun Liu, 1 Che-Yi Chou, 1 Chiu-Ching Huang, 1 Chuen-Ming Shih, 2 and Walter Chen 2 Division of Nephrology, 1 Department of Internal Medicine, China Medical University Hospital, Taichung; Division of Nephrology, 2 Department of Internal Medicine, China Medical University Beigang Hospital, Yunlin, Taiwan Objective: The published mortality data for patients with hepatitis C virus (HCV) infection and being treated with peritoneal dialysis (PD) are not available. The aim of this study was to determine the mortality of HCV patients undergoing PD. Methods: We retrospectively reviewed 538 PD patients in our hospital from 1996 to Of these patients, 75 (13.9%) were anti-hcv positive at the beginning of PD. We used Kaplan Meier analysis to compare mortality between patients with and patients without HCV infection. The association between HCV infection and mortality was analyzed using multivariate Cox regression with adjustment for age, gender, residual renal function, and cardiovascular disease. Results: A total of 157 patients (39 HCV positive, 118 HCV negative) died during the 10-year follow-up period. The mortality rate (52%, 39/75) of HCV-positive patients was significantly higher than that of HCV-negative patients (25.5%, 118/463; p < 0.001). Cardiovascular mortality was 57.6% (68/118) among HCV-negative patients and 56.4% (22/39) among HCV-positive patients. Kaplan Meier estimate showed that patients with HCV infection had higher mortality than those without (p < 0.001, log-rank). The result of Cox regression suggested that chronic HCV infection, independent of diabetes, was associated with 10-year mortality. The adjusted hazard ratios (HRs) of HCV infection and diabetes for mortality were (95% CI: , p < 0.001) and (95% CI: , p < 0.001). Conclusion: Our results show that the HCV-positive PD patients had a higher 10-year mortality rate than the HCVnegative PD patients. The association between HCV infection and mortality was independent of diabetes. Cardiovascular Correspondence to: C.Y. Chou, Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Rd. North District, Taichung City 40461, Taiwan. cychou.chou@gmail.com Received 1 May 2007; accepted 21 October mortality, infection, and arrhythmia were the leading causes of death among the PD patients with HCV infection. Perit Dial Int 2008; 28: KEY WORDS: Cardiovascular disease; mortality; hemodialysis; hepatitis C infection; residual renal function. Chronic hepatitis C virus (HCV) infection is common and is associated with increased mortality in hemodialysis (HD) patients (1 3). HCV-related hepatocellular carcinoma and liver cirrhosis may be responsible for the increase in mortality (1). A recent study showed that HCV infection is associated with increased cardiovascular mortality in chronic HD patients (2); however, the prognosis of HCV-positive patients treated with peritoneal dialysis (PD) is unknown. Taiwan is an endemic area of HCV infection, with a 15% of prevalence rate in PD patients (4) and 5% 10% in the general population (5). In our PD program, about 10% of patients are positive for anti-hcv antibody when entering renal replacement therapy. HCV particles can cross the peritoneal membrane and can be detected in the dialysate of PD patients with viremia (6). Screening for HCV antibody in blood donors, implementation of universal precautionary measures, and strict isolation practices may prevent transmission of HCV in chronic HD patients (7). The clinical characteristics of uremic patients with HCV infection may be different from those of the general population. The differences include a periodic lower HCV viral load in HD sessions (8), lower aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and higher hemoglobin and hematocrit levels (2). The lower HCV RNA titers may be explained by an adsorption of HCV by the dialyzer during HD sessions (8). HCV viral load may be lower in patients on PD than in patients treated with HD (9). This 183

2 WANG et al. MARCH 2008 VOL. 28, NO. 2 PDI A total of 157 patients (39 HCV positive, 118 HCV negative) died during the 10-year follow-up period. The mortality rate (52%, 39/75) of HCV-positive patients was significantly higher than that of HCV-negative patients (25.5%, 118/463; p < 0.001). As shown in Figure 1, the Kaplan Meier estimate revealed that patients with HCV infection had higher mortality than those without (p < 0.001, log-rank). The causes of death are listed in Table 1. The incidence of liver cirrhosis was higher in patients with HCV; however, the difference was not statistically significant (p = 0.146). The incidences of the top three causes of death (CVD, infection, and arrhythmia) were not significantly different between patients with and patients without HCV (p = 0.597). Cardiovascular disease was the major cause of death in both HCV-positive and HCV-negative patients. Additionally, the 3 patients in the others category died of suicide, traffic accident, or unknown causes. As shown in Table 2, HCV-positive pastudy was conduced to determine mortality in PD patients with chronic HCV infection. METHODS From 1996 to 2005, we retrospectively reviewed the medical records of 538 PD patients, including 34 on automated PD and 504 on continuous ambulatory PD (CAPD); 42 patients that shifted from HD to PD were excluded. A total of 75 patients were anti-hcv antibody positive, as tested by second- or third-generation enzyme-linked immunosorbent assay (ELISA) on entering the PD program. Time was measured from the date of starting PD to the date of death or the end of the study (December 2005). For patients that were transferred to other dialysis centers, time was measured to the date of transfer. For patients that shifted from PD to HD or kidney transplantation, time was measured to the date of transfer. Cardiovascular disease (CVD) was defined as nonfatal myocardial infarction, fatal coronary disease, coronary bypass surgery or angioplasty, and fatal or nonfatal stroke (10). Diabetes mellitus was defined as a fasting glucose level of 140 mg/dl, non-fasting glucose of 200 mg/dl, or a history of treatment for diabetes (11). Hypertension was defined as blood pressure of at least 140/90 mmhg or the use of antihypertensive medication (12). The baseline biomarkers, including hemoglobin, hematocrit, AST, ALT, blood urea nitrogen (BUN), creatinine, albumin, cholesterol, and triglyceride, were measured at the beginning of PD. Residual renal function (RRF) was calculated from a 24-hour urine collection. The RRF, total Kt/V urea, and normalized protein catabolic rate (npcr) were measured within 3 months after starting PD. Causes of death were classified as CVD, infection, arrhythmia, liver cirrhosis, cancer, and others by the primary care physician. STATISTICAL ANALYSIS Data are presented as mean ± SD or frequency, as appropriate. The association between HCV and mortality was analyzed using Kaplan Meier analysis. The differences in cause of death between patients with and patients without HCV infection were analyzed using chi-square test. The association between HCV and mortality was analyzed using Kaplan Meier analysis. In Kaplan Meier analysis, time was measured from the beginning of PD to the date of death or to the end of the study (December 2005). For patients that transferred, shifted to HD, or underwent kidney transplantation, time was censored and measured to the date of transfer, shift to HD, or kidney transplantation. Possible prognostic 184 factors were analyzed using univariate logistic regression. The prognostic factors with a p value less than 0.05 were further analyzed by multivariate Cox regression with adjustments for age, gender, RRF, and CVD. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated with the use of estimated regression coefficients and their SEs in multivariate Cox regression analysis. A p value less than 0.05 was considered significant. All calculations were carried out using a standard statistical package (SPSS, version 12, SPSS Inc, Chicago, Illinois, USA). RESULTS Figure 1 Kaplan Meier estimate of cumulative survival in patients with chronic hepatitis C virus (HCV) infection treated with peritoneal dialysis.

3 PDI MARCH 2008 VOL. 28, NO. 2 MORTALITY IN PD PATIENTS WITH HCV TABLE 1 Causes [n (%)] of Death in Patients Negative or Positive for Hepatitis C Virus (HCV) HCV( ) (n=118) HCV(+) (n=39) Cardiovascular disease 68 (57.6) 22 (56.4) Infection 29 (24.6) 6 (15.4) Arrhythmia 11 (9.3) 5 (12.8) Liver cirrhosis 3 (2.5) 3 (7.7) Cancer 5 (4.2) 2 (5.1) Others 2 (1.7) 1 (2.6) tients were significantly older and had higher serum AST and ALT levels. Serum albumin levels were significantly lower in patients with HCV than in those without. Serum BUN, creatinine, total Kt/V, and npcr were not significantly different between patients with HCV infection and those without. Twelve percent (9/75) of HCV-positive patients had liver cirrhosis complicated with ascites when entering the PD program. Of those 9 patients, 4 died during follow-up, 1 transferred to HD, and 4 remained on PD. Patients with HCV infection had a higher incidence of hepatitis B virus infection than those without HCV (28.0% vs 9.9%, p < 0.001). The prevalence of CVD was not significantly different between patients with HCV infection and those without (17.3% vs 15.1%). No significant difference in RRF and body mass index, important prognostic factors, was found between patients with and patients without HCV. Because age, RRF, and CVD are important prognostic factors, and because 62.5% of our PD patients were female, age, RRF, gender, and CVD were considered adjusted factors in multivariate Cox TABLE 2 Demographic Data of Entire Study Population Overall (n=538) HCV( ) (n=463) HCV(+) (n=75) Age (years) 59.3± ±15 65±12 a Gender (male/female) 202/ /293 32/43 Duration of peritoneal dialysis (years) 4.2± ± ±3.6 a BMI (kg/m 2 ) 24±4 24±4 24±3 RRF (ml/min/1.73 m 2 ) 5.6± ± ±2.1 HBsAg(+) 67 (12.5) 46 (9.9) 21 (28.0) a HCV(+) 75 (13.9) Cardiovascular disease 83 (15.4) 70 (15.1) 13 (17.3) Underlying disease Chronic glomerulonephritis 202 (37.5) 177 (38.2) 25 (33.3) Diabetes 168 (31.2) 136 (29.4) 32 (42.6) Hypertension 110 (20.4) 99 (21.4) 11 (14.7) Hemoglobin (g/dl) 9.1± ± ±1.5 Hematocrit (%) 27.3± ± ±4.7 AST (IU/L) 28±17 27±16 33±17 a ALT (IU/L) 23±19 22±17 32±23 a BUN (mg/dl) 60±25 60±24 60±28 Creatinine (mg/dl) 10.2± ± ±3.2 Albumin (mg/dl) 3.4± ± ±1 a Cholesterol (mg/dl) 197±53 198±52 178±44 Triglyceride (mg/dl) 212± ± ±121 Total Kt/V 2.1± ±0.5 2±0.6 npcr (g/kg/day) 0.9± ± ±0.4 Peritonitis rate (1 episode/n patient-months) Shifted to hemodialysis 100 (18.6) 90 (19.4) 10 (13.3) Kidney transplantation 24 (4.5) 24 (5.2) 0 (0) RRF = residual renal function measured by a 24-hour collection of urine; HBsAg = hepatitis B virus surface antigen; BMI = body mass index; HCV = hepatitis C virus infection; AST = aspartate aminotransferase; ALT = alanine aminotransferase; BUN = blood urea nitrogen; npcr = normalized protein catabolic rate. a p < 0.05 in independent t-test, Mann Whitney U test, or chi-square test. Values as n (%) unless otherwise stated. 185

4 WANG et al. MARCH 2008 VOL. 28, NO. 2 PDI regression. Possible prognostic factors including hemoglobin, hematocrit, AST, ALT, BUN, creatinine, calcium, phosphate, Kt/V, npcr, and body mass index were screened with univariate Cox regression. In univariate Cox regression, serum albumin, diabetes, and hypertension were significantly associated with mortality (p = 0.005, p = 0.007, and p = 0.05). Therefore, to determine the association between HCV infection and mortality, diabetes, hypertension, and serum albumin levels were included in multivariate Cox regression analysis with adjustments for age, gender, RRF, and CVD (Table 3). The results suggest that chronic HCV infection, independent of diabetes, was associated with 10-year mortality among chronic PD patients (p < 0.001, log-rank). The HRs of HCV infection, diabetes, hypertension, and albumin were (95% CI: , p < 0.001), (95% CI: , p < 0.001), (95% CI: , p = 0.084), and (95% CI: , p = 0.352), respectively. DISCUSSION We found that PD patients with HCV infection had a higher 10-year mortality rate than those patients without in a PD program with a 13.9% prevalence rate of HCV (Figure 1). The association between HCV and mortality was independent of diabetes and CVD, infection, and arrhythmia remained the major causes of death among PD patients with/without HCV infection. The prevalence of HCV in our studies was similar to previous reports (4,13). As the prevalence of HCV in PD patients is significantly lower than that of chronic HD patients, HCV seroconversion during PD treatment is a rare event (14,15). Taiwan is an endemic area of HCV infection: 10% 15% of patients are anti-hcv antibody positive on entering PD. Nevertheless, no study has focused on the prognosis of PD patients with HCV infection. TABLE 3 Adjusted Hazard Ratio (HR) and 95% Confidential Interval (CI) of the Potential Risk Factors in Multivariate Cox Regression Model (Adjusted for Age, Gender, Residual Renal Function, and Cardiovascular Disease) 186 HR 95% CI p Value Diabetes <0.001 HCV infection <0.001 Hypertension Serum albumin HCV = hepatitis C virus. Chronic HCV infection is associated with increased mortality in end-stage renal disease patients treated with HD and transplantation (3,16). The association between chronic HCV infection and mortality may be explained by two factors: First, liver cirrhosis and hepatocellular carcinoma are more prevalent in HCVpositive than in HCV-negative patients (1). Second, HCV infection is associated with increased cardiovascular mortality in patients younger than 65 (2). In our study, we first determined the mortality rate and cause of death in PD patients with HCV infection. As shown in Table 1, patients with HCV infection were not significantly associated with any specific cause of death. The incidence of liver cirrhosis-related mortality was higher in patients with HCV infection than in those without; however, it was not statistically significant. In addition, the lower serum albumin, cholesterol, and triglyceride levels (Table 2) may suggest poor nutrition or inflammatory status in patients with HCV infection. It is possible that patients with HCV infection are associated with higher mortality through the influence of malnutrition. The third-generation ELISA test for anti-hepatitis C antibody test was not available at our hospital until The second-generation ELISA test was associated with a higher false negative rate than the third-generation ELISA test (17). Different genotypes of HCV may influence HCV seropositivity in the second- and thirdgeneration ELISA tests (18). Eight patients with seroconversion of anti-hcv antibody in the change of ELISA tests were excluded from our study because it was difficult to tell if these patients were HCV positive on entering dialysis. In conclusion, chronic hepatitis C infection in endstage renal disease treated with peritoneal dialysis is associated with higher 10-year mortality, independent of diabetes. Cardiovascular death remains the major cause of death in HCV-positive PD patients. More studies are needed to determine optimum treatment of hepatitis C infection among PD patients. REFERENCES 1. Nakayama E, Akiba T, Marumo F, Sato C. Prognosis of antihepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol 2000; 11: Kalantar-Zadeh K, McAllister CJ, Miller LG. Clinical characteristics and mortality in hepatitis C-positive haemodialysis patients: a population based study. Nephrol Dial Transplant 2005; 20: Stehman-Breen CO, Emerson S, Gretch D, Johnson RJ. Risk of death among chronic dialysis patients infected with

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