It has been reported that increased peritoneal transport

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1 Peritoneal Dialysis International, Vol. 20, pp Printed in Canada. All rights reserved /00 $ Copyright 2000 International Society for Peritoneal Dialysis PERITONEAL TRANSPORT CHARACTERISTICS, COMORBID DISEASES AND SURVIVAL IN CAPD PATIENTS Sung Hee Chung, 1 Won Suk Chu, Hyun Ah Lee, Yong Hwa Kim, In Sang Lee, Bengt Lindholm, 1 and Hi Bahl Lee Hyonam Kidney Laboratory, Soon Chun Hyang University, Seoul, Korea; Divisions of Baxter Novum and Renal Medicine, 1 Department of Clinical Science, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden Correspondence to: H.B. Lee, Hyonam Kidney Laboratory, Soon Chun Hyang University Hospital, 657 Hannamdong, Yongsan-ku, Seoul Korea. hblee@korea.com Received 15 February 2000; accepted 26 April Objective: To evaluate the influence of initial peritoneal transport rate, serum albumin concentration, and comorbid diseases on continuous ambulatory peritoneal dialysis (CAPD) patient survival. Design: A prospective single-center study with a longterm follow-up. Patients: A total of 213 consecutive CAPD patients, who underwent a peritoneal equilibration test (PET) at a mean of 7 days (range 3 30 days) after beginning CAPD, were included in this study. One hundred twenty patients were male, 116 patients had comorbid diseases, and mean age was 49.5 years (range years). Methods: A modified PET was performed using 4.25% glucose dialysis solution. Based on the dialysate-to-plasma creatinine concentration ratio at 4 hours dwell ( Cr, 0.62 ± 0.14), patients were divided into high (H), highaverage (HA), low-average (LA), or low (L) transporters. Results: Of 213 patients, 16.9% were classified as H transporters, 30.5% as HA, 36.6% as LA, and 16.0% as L transporters. The H transporter group had a higher proportion of men, higher proportion of patients with comorbid diseases, lower initial serum albumin concentration, lower glucose, and lower drained volume. The initial Cr correlated with initial serum albumin (r = 0.35, p < 0.001). The patients with comorbid diseases had lower initial serum albumin and higher initial Cr. On Kaplan Meier analysis, 2-year patient survival of group H was significantly lower compared to the other groups combined (57.1% vs 79.5%, p = 0.009). On Cox proportional hazards analysis, age, comorbid diseases, initial serum albumin concentration, and initial Cr were found to be independent risk factors for mortality. However, in the patients without comorbid diseases, patient survival was not different between group H and the other transport groups combined (p > 0.05), and only age was found to be an independent risk factor for mortality. Conclusion: These data suggest that a high peritoneal transport rate at initial PET is associated with high mortality, and that this is in part due to an increased prevalence of comorbid disease in H transporters. These H transporters with comorbid diseases represent a subset of patients with an especially poor prognosis. In patients without comorbid diseases, high transport status or low serum albumin concentration was not an independent risk factor for mortality. KEY WORDS: Peritoneal transport rate; comorbid diseases; serum albumin; mortality. It has been reported that increased peritoneal transport rate is associated with lower patient survival (1 4). The CANUSA study showed that high solute transport predicts increased technique failure or death (1). Wang et al. found that peritoneal transport category was a strong predictor of mortality, and that patient survival was significantly lower in the high transporters compared with the other groups (3). However, the reason for this is still uncertain. A possible explanation may be that high transporters have a lower drained volume and, consequently, decreased small solute removal, leading to inadequate fluid balance, inadequate dialysis, and malnutrition (3,5). On the other hand, high peritoneal transport rate is associated with low serum albumin concentration, whether it is obtained at the start of peritoneal dialysis (PD) (1,6) or during the entire duration of dialysis (6 8). Although serum albumin is an index of nutritional status, its concentration is affected by many nonnutritional factors, such as capillary permeability (9), inflammation, and infection (10,11), and reflects the presence of a comorbid disease (12,13). Moreover, it has been suggested that high peritoneal transport rate and low serum albumin concentration are the common consequence of an underlying comorbidity that may be the real cause of the adverse outcome (14). Recently, Heimbürger et al. (15) reported that a high peritoneal transport rate from an early peritoneal equilibration test (PET) is related to inflammation, cardiovascular disease, and mortality. 541

2 CHUNG et al. SEPTEMBER 2000 VOL. 20, NO. 5 PDI Davies et al. (16) found that the predictive value of small solute clearance and peritoneal solute transport in continuous ambulatory peritoneal dialysis (CAPD) patients is dependent on the type of comorbidity present. Therefore, we performed the present study to evaluate the relationship between initial peritoneal transport rate, serum albumin concentration, and comorbid diseases, and to determine the influence of these factors on CAPD patient survival. PATIENTS AND METHODS PATIENT POPULATION AND STUDY DESIGN A total of 228 consecutive patients who started CAPD at Soon Chun Hyang University Hospital, Seoul, Korea, between July 1989 and August 1999 were enrolled in the study. Fifteen patients, who either had been treated for less than 3 months on CAPD or had their initial assessment after 1 month of CAPD, were excluded from the study. The remaining 213 patients underwent PET at a mean of 7 days after beginning CAPD (range 3 30 days). One hundred twenty patients were male, 86 were diabetics (15 patients with type I and 71 with type II diabetes), 38 had cardiovascular disease (CVD), 24 respiratory disease, and 10 hepatic disease. Of 86 diabetic patients, 21 had CVD, 13 had respiratory disease, and 3 had hepatic disease. Their mean age was 49.5 years (range years). PERITONEAL EQUILIBRATION TEST (PET) The PET was performed as described by Twardowski et al. (17) but modified by using 4.25% glucose concentration. Briefly, a standard 4-hour dwell with a 2-L dialysis fluid (first exchange of the day) was performed. Glucose interferes with the Jaffe reagent for creatinine each milligram percent of glucose overestimates creatinine concentration by mg/dL in our laboratory. The creatinine values in the dialysate were corrected for glucose interference before further calculations. The dialysateto-plasma creatinine concentration ratio at 4-hours of dwell ( Cr) was used to classify the patients as high (H), high-average (HA), low-average (LA), or low (L) transporters according to Twardowski et al. (17). The mean ± 1 SD of Cr was 0.62 ± BIOCHEMICAL MEASUREMENTS Serum albumin concentration was determined by bromcresol green method. Concentrations of creatinine (Jaffe method) and glucose (glucose oxidase method) were measured in dialysate and blood samples immediately after the samples were taken. COMORBID DISEASES The following categories of comorbid diseases were recognized. For the criteria of comorbid diseases, we used the classification of initial comorbidity proposed by Kaplan et al. (18). Cardiovascular disease was defined as previous history of congestive heart failure, myocardial infarction, angina, peripheral vascular disease, or cerebrovascular disease. Respiratory disease included recent active tuberculosis, chronic lung disease, or recurrent asthmatic attacks. Hepatic disease was defined as chronic liver disease proved on biopsy or by persistently elevated serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase. Diabetes mellitus included both type I and type II. STATISTICAL ANALYSES Analysis of variance (ANOVA) was used to compare the difference in clinical characteristics between different transporter groups. Chi-square test or Fisher s exact test was used to compare the nominal variables between different transport groups. Mantel Haenszel chi-square test was also used to see the trend in distribution. Spearman s rank correlation was used to determine the correlation between peritoneal transport rate and serum albumin concentration. Comparison of serum albumin and Cr in the subgroups was made using the t-test and the Kruskal Wallis test. Actuarial survival rates were determined by the Kaplan Meier method. A log-rank was used to compare the different survival curves. Cox proportional hazards model was used to identify factors determining patient mortality. Data are presented as mean ± SD. A difference was considered significant when the p value was less than RESULTS CLINICAL CHARACTERISTICS Of 213 patients, 16.9% were H transporters, 30.5% HA transporters, 36.6% LA transporters, and 16.0% L transporters. The clinical characteristics of the four transport groups are shown in Table 1. There were significant differences in gender, comorbid diseases, initial serum albumin, glucose, and the volume drained in 4 hours. The H transporters had a higher proportion of men, more comorbid diseases, lower initial serum albumin, lower glucose, and lower drained volume. The H transporters had a significantly higher proportion of CVD and hepatic disease, but not diabetes or respiratory disease. 542

3 PDI SEPTEMBER 2000 VOL. 20, NO. 5 PERITONEAL MEMBRANE TRANSPORT AND PATIENT SURVIVAL DISTRIBUTION OF COMORBID DISEASES ACCORDING TO GENDER Distribution of comorbid diseases according to gender is shown in Table 2. Male patients had significantly more comorbid diseases overall and more diabetes and hepatic disease compared to females. RELATIONSHIP BETWEEN INITIAL SERUM ALBUMIN, INITIAL Cr, AND COMORBID DISEASES Initial serum albumin was inversely related with initial Cr (r = 0.35, p < ). Comparisons of initial serum albumin and initial Cr between patients with and without comorbid diseases are shown in Figures 1 and 2. Patients with comorbid diseases (group 2) had lower initial serum albumin concentration and higher initial Cr compared to patients without comorbid diseases (group 1). The initial serum albumin was 3.2 ± 0.6 g/dl and 3.7 ± 0.7 g/dl for group 2 and group 1, respectively (p < 0.001) (Figure 1). The initial Cr was 0.65 ± 0.15 and 0.60 ± 0.13 for group 2 and group 1, respectively (p = 0.006) (Figure 2). CLINICAL OUTCOME AND SURVIVAL On 31 August 1999, 20 patients were still on CAPD, 65 had died, 103 had transferred to hemodialysis, 13 had undergone kidney transplantation, 11 had transferred to other units, and 1 patient had withdrawn from treatment. Of the 65 patients who died, 17/36 (47.2%) were in the H group, 21/65 (32.3%) in the HA group, 20/78 (25.6%) in the LA group, and 7/34 (20.6%) in the L group. Seventeen of the 65 patients who died had no comorbid diseases. Of the 103 patients who transferred to hemodialysis, 17/36 (47.2%) were in the H group and 86/177 (48.6%) were in the other groups; the difference was not significant (p = 0.91). Patient survival rates are shown in Figures 3 and 4. The patient survival rates between the H and LA (p = 0.02), H and L (p = 0.02), and H and the other groups TABLE 1 Clinical Characteristics of Four Transport Groups at Initiation of CAPD H H A LA L (n=36) (n=65) (n=78) (n=34) p Value Age (years) 51.1± ± ± ±14.5 N S Male gender (n) 29 (80.6%) 39 (60.0%) 34 (43.6%) 18 (52.9%) <0.05 Comorbid diseases a (n) 25 (69.4%) 40 (61.5%) 36 (46.1%) 15 (44.1%) <0.05 Diabetes b (n) 15 (41.7%) 30 (46.2%) 29 (37.2%) 12 (35.3%) N S CVD (n) 10 (27.8%) 13 (20.0%) 10 (12.8%) 5 (14.7%) <0.05 Respiratory (n) 8 (22.2%) 5 (7.7%) 6 (7.7%) 5 (14.7%) N S Hepatic (n) 6 (16.7%) 3 (4.6%) 1 (1.3%) 0 (0%) <0.005 Serum albumin (g/dl) 3.2± ± ± ±0.9 < Cr 0.84± ± ± ±0.07 < glucose 0.24± ± ± ±0.09 < Drained volume at 4 hours (ml) 2731± ± ± ±201 < H = high transporter; HA = high-average transporter; LA = low-average transporter; L = low transporter; CVD = cardiovascular disease; Cr = dialysate-to-plasma creatinine concentration ratio at 4 hours of dwell; glucose = concentration ratio of dialysate glucose at 4 hours and at 0 dwell time. a History of CVD, respiratory disease, hepatic disease, and presence of diabetes mellitus before starting CAPD. b Combination of type I and type II. TABLE 2 Distribution of Comorbid Diseases According to Gender Male Female (n=120) (n=93) p Value Comorbid diseases (n) 77 (64.2%) 39 (42.0%) <0.005 Diabetes (n) 57 (47.5%) 29 (31.2%) <0.05 Cardiovascular disease (n) 25 (20.8%) 13 (14.0%) N S Respiratory disease (n) 15 (12.5%) 9 (9.7%) N S Hepatic disease (n) 10 (8.3%) 0 (0%) <

4 CHUNG et al. SEPTEMBER 2000 VOL. 20, NO. 5 PDI Figure 1 Patients with comorbid diseases (group 2) had lower serum albumin compared to patients without comorbid diseases (group 1) (3.2 ± 0.6 g/dl vs 3.7 ± 0.7 g/dl, p < 0.001). Figure 3 Probability of patient survival according to peritoneal membrane transport status in all 213 patients is shown. The 2-year patient survival was 57.1% for the high transporter group and 79.5% for all other transport groups combined (p = 0.009). Figure 2 Patients with comorbid diseases (group 2) had higher Cr compared to patients without comorbid diseases (group 1) (0.65 ± 0.15 vs 0.60 ± 0.13, p = 0.006). combined (p < 0.05) were significantly different (Figure 3). The 2-year patient survival was significantly lower in the H group compared to the other groups combined (57.1% and 79.5%, p = 0.009). However, when we excluded the patients with comorbid diseases from the analysis, the difference in patient survival rates between the groups was not statistically significant (p > 0.05) (Figure 4). The 2-year patient survival rate was 72.7% for the H group and 90.6% for the other groups, respectively (p = 0.10). PREDICTORS OF PATIENT SURVIVAL Predictors of survival in the 213 patients are shown in Table 3. On Cox proportional hazards analysis, age, comorbid diseases, initial serum albumin concentration, and initial Cr were found to be independent risk factors for mortality. Among comorbid diseases, CVD and respiratory disease, but not hepatic disease or diabetes mellitus, were predictors of Figure 4 Probability of patient survival according to peritoneal membrane transport status in 97 patients without comorbid diseases is shown. The 2-year patient survival was 72.7% for the high transporter group and 90.6% for all the other transport groups combined, but the difference was not statistically significant (p = 0.10). patient survival (Table 4). However, in the patients without comorbid diseases, only age was found to be an independent risk factor for mortality (Table 5). DISCUSSION The present study shows that CAPD patients who were high transporters at the start of CAPD had more comorbid diseases, a higher proportion of males, lower initial serum albumin, lower drained volumes, and higher mortality. However, in the patients without comorbid diseases, patient survival was not different and was not affected by increased peritoneal transport rate. Although factors contributing to the high peritoneal transport rate at the beginning of CAPD have 544

5 PDI SEPTEMBER 2000 VOL. 20, NO. 5 PERITONEAL MEMBRANE TRANSPORT AND PATIENT SURVIVAL TABLE 3 Risk Factors for Mortality in All 213 Patients (Multivariate Analysis; Cox Proportional Hazards Analysis) Relative risk Variable χ 2 (95% CI) p Value Age (per year) < ( ) Serum albumin (per g/l) ( ) Comorbid diseases ( ) Cr (per 0.1 unit) ( ) CI = confidence interval. TABLE 4 Risk Factors for Mortality in Comorbid Diseases (Cox Proportional Hazards Analysis) Relative risk Variable χ 2 (95% CI) p Value Cardiovascular disease ( ) Respiratory disease ( ) Hepatic disease ( ) Diabetes mellitus ( ) CI = confidence interval. TABLE 5 Risk Factors for Mortality in 97 Patients Without Comorbid Diseases (Cox Proportional Hazards Analysis) Relative risk Variable χ 2 (95% CI) p Value Age (per year) < ( ) Serum albumin (per g/l) ( ) Cr (per 0.1) ( ) CI = confidence interval. not been clearly established, we found that high peritoneal transport rate was related to comorbid diseases. It is generally accepted that peritoneal transport rate depends on both effective peritoneal surface area and permeability, and that peritoneal permeability is affected by peritoneal blood circulation (19). Furthermore, many of the mediators produced in the inflammatory process can affect microvascular permeability and vascular tone (20). Thus, our finding of a significant relation between peritoneal transport rate and comorbid diseases suggests that comorbid diseases may affect microcirculation, and may also affect peritoneal transport characteristics at the start of CAPD. The CANUSA study showed that a greater proportion of patients had diabetes mellitus with higher peritoneal membrane transport rate, according to PET at 1 month after initiation of dialysis (1). Heimbürger et al. reported that initial D/P Cr was significantly higher in patients with CVD (15). In the present study, high transporters had more CVD and hepatic disease compared to the other groups. Although small in number, the higher proportion of hepatic disease in the high transporters in this study is an interesting finding since there have been observations that an increase in the peritoneal surface area related to portal hypertension may increase solute transport. In a study of 5 CAPD patients with liver cirrhosis, Bajo et al. observed increased peritoneal mass transfer coefficients for urea and creatinine in patients at the start of CAPD (21). In a cross-sectional study, Dadone et al. showed that patients with chronic hepatic disease had an increased transport of small solutes compared to patients without chronic hepatic disease (22). Yoon et al. found that patients with liver cirrhosis and ascites had an increased solute transport rate by PET performed at 10 days after starting CAPD (23). The significantly higher proportion of men in the high transporter group is also consistent with previous studies (1,24). In a study of 60 CAPD patients, Ates et al. reported that D/P Cr was strongly correlated with male gender (24). The CANUSA study showed a significantly increased proportion of men with increased transport rate (1). The cause of this effect is not clear. However, our finding of significantly more comorbid diseases in male patients leads us to speculate that the effect of comorbid diseases on the peritoneal transport rate may explain the relation between men and high transport rate. In addition to comorbid diseases, our study reveals that initial serum albumin concentration is significantly correlated with initial peritoneal transport rate, a finding consistent with previous reports. The CANUSA study showed that increased transport rate was associated with low serum albumin but not with other initial nutritional parameters such as subjective global assessment, percent lean body mass, or normalized protein catabolic rate (1). Heimbürger et al. found that initial D/P Cr was negatively correlated with initial serum albumin and positively correlated with low hyaluronan (15). Acute and chronic infections and inflammation are present in a large proportion of predialysis patients (25), and serum albumin is generally accepted as an indicator of inflammation (26). 545

6 CHUNG et al. SEPTEMBER 2000 VOL. 20, NO. 5 PDI Although many previous reports have shown that patient survival is significantly worse in the high transporters (1 4), it is controversial whether increased peritoneal transport rate predicts patient survival independently. Both the CANUSA study (1) and the Stoke PD study (2) reported that the peritoneal membrane transport rate predicted patient survival independently. However, Wang et al. (3) found that high mortality rate with increased peritoneal permeability was related to impaired fluid and small solute removal in high transporters. Fluid overload is often present in PD patients (27 29), and CVD is the most common cause of mortality (30). Blake suggested that the most likely mechanism underlying the high mortality in high transporters is the effect on cardiovascular status, which is further impaired by fluid overload (14). The present study shows that high peritoneal transport rate has a significant impact on patient survival. However, it did not affect patient survival in patients without comorbid diseases. Indeed, in the present study, high transporters had lower dialysate drained volume, and CVD and respiratory disease were predictors of mortality. Therefore, it is likely that high peritoneal transport rate is in some way associated with an increased risk of death due to comorbid diseases. In contrast to several reports (31 33), the presence of diabetes mellitus did not predict mortality in our study. Cueto Manzano and Correa Rotter showed that diabetes mellitus was significantly more frequent in high transporters, and was the most important risk factor for mortality while on CAPD (31). In the present study, however, we found no significant difference in the proportion of diabetics among different transport groups. In addition, our previous study showed no difference in peritoneal clearances of urea and creatinine, drained protein concentrations, or fractional glucose absorption between diabetic and nondiabetic patients (34). Of our 86 diabetic patients, 21 had CVD, 13 had respiratory disease, and 3 had hepatic disease. Some diabetic patients had more than one comorbid disease. Thus, it is this high rate of comorbid diseases in diabetes that explains why diabetes per se is not an independent risk factor for mortality, while CVD and respiratory disease are. Although it is generally accepted that serum albumin concentration at the commencement of CAPD is an independent predictor of survival (35 37), in the present study, serum albumin did not predict survival in patients without comorbid diseases. Struijk et al. suggested that serum albumin is a predictor of survival but that it mainly reflects the presence of a systemic disease, which is the most important risk factor for patient survival (13). Mallick et al. suggested that serum albumin might simply be a marker of the adverse effects of coexisting illness on survival (38). In the present study also, serum albumin was strongly correlated with comorbid diseases, and this may be the reason for serum albumin not being an independent predictor of survival in patients without comorbid diseases. In conclusion, our data suggest that a high peritoneal transport rate at the initial PET is associated with high mortality, and that this is in part due to an increased prevalence of comorbid diseases in high transporters. These high transporters with comorbid diseases represent a subset of patients with especially poor prognosis. REFERENCES 1. Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR, Oreopoulos DG, Pagé D. Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. The Canada-USA (CANUSA) Peritoneal Dialysis Study Group. 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