Overhydration and low serum prealbumin predict peritoneal dialysis-related peritonitis in continuous ambulatory peritoneal dialysis patients

Abstract

Background: In this study, we focused on the role of overhydration (OH) and low serum prealbumin concentration in predicting 3-year peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients.

Methods: We measured serum prealbumin concentration and OH by body composition monitor on 278 CAPD patients (159 males and 119 females) with mean age of 46 years and the median peritoneal dialysis (PD) duration of 21 months. PD-related peritonitis was collected for 3 years.

Results: After the 3-year follow-up, 44 patients diagnosed PD-related peritonitis (15.8%). Low education, serum albumin, prealbumin, high CRP-hs and OH were independent risk factors for predicting peritonitis during 36 months in CAPD patients. Based on the ROC curve model and Kaplan–Meier analysis, we realized that patients with low prealbumin and high OH were the independent predictors of 3-year peritonitis in CAPD patients (Prealbumin: AUC = 0.838, cut-off value = 32.5 mg/dL, Se= 90.9%, Sp = 32.9%; OH: AUC = 0.851, cut-off value = 1.33 L, Se = 79.5%, Sp = 85.5%; and Log-rank test p < 0.001, respectively).

Conclusion: Overhydration and low serum prealbumin level were the independent predictors of PD-related peritonitis in CAPD patients.

Background

Peritoneal dialysis (PD) is a renal replacement therapy based on infusing a sterile solution into the peritoneal cavity through a catheter and provides for the removal of solutes and water using the peritoneal membrane as the exchange surface [1-3]. Infusion and drainage of the solution into the peritoneal cavity can be performed in two ways: manually (continuous ambulatory PD) or machine-assisted PD (automated PD) [1, 2]

     Peritonitis is a common serious complication of peritoneal dialysis that results in considerable morbidity, mortality, and health care costs [4-6]. Depending on the underlying causative organism, PD-related peritonitis is complicated by relapse in 3%-20% (14% overall), catheter removal in 10%-88% (22% overall), permanent HD transfer in 9%-74% (18% overall) of cases [7, 8]. After a single episode of peritonitis, the risks of death due to infection, cardiovascular disease are markedly increased in the first month and continue to remain significantly elevated for up to 6 months afterward [9]. There are many risk factors of peritonitis in PD patients including low education, malnutrition, insufficient dialysis, catheter-related peritonitis…[10-12].

    PD is the second most common method of renal replacement therapy after maintenance hemodialysis (HD) in Viet Nam. Similar to other countries in the world, peritonitis always happens and many patients have to switch to maintenance hemodialysis. Overhydration (OH) complicates frequently the clinical course of PD patients and keeps a controversial association with the risk of peritoneal infection [13, 14]. Beside, prealbumin (transthyretin) is a hepatic secretory protein used to assess malnutrition in PD patients, had a prognostic value of peritonitis and mortality in PD patients [15, 16]. Up to now, there is no research in Vietnam on peritonitis, excess fluid, as well as the role of excess fluid, nutritional factors in the prognosis of peritonitis in continuous ambulatory PD patients. With the above reasons, we conducted this study to determine the frequency of peritonitis as well as predictive value PD related peritonitis of assess OH and low serum prealbumin in peritoneal dialysis patients in Viet Nam.

Methods

Study design and setting

     There were 426 patients on continuous ambulatory peritoneal dialysis (PD duration >2 months) who joined in our study at the Department of Nephrology, Cho Ray Hospital, Ho Chi Minh City, Viet Nam, as of February 2014 to February 2017 (36 months). Of these, patients younger than 18 years, dropped out from PD within 90 days, or on long-term hemodialysis or had chronic renal transplant failure before initiating PD or acute illness, significant infection, malignancy, hepatitis virus infection, and peritonitis before collecting data for the study were excluded. The remaining patients, 278 PD patients, were provided informed consent before participation in our study. This study was approved by the ethics review committee of the hospital. The enrolled patients were treated with stable, continuous ambulatory peritoneal dialysis (CAPD), using conventional PD solutions (Dianeal 1.5%, 2.5% or 4.25% dextrose; Baxter Healthcare), and Y-sets and twin-bag systems were utilized in over 100% of the PD patients. All our patients and their caregivers underwent a standard training program. 4 h dialysate-to-plasma ratio of creatinine (D/Pcr) was measured by a standard peritoneal equilibration test (PET). PET was categorized 4 levels (H: High; HA: High-Average; LA: Low-Average; L: Low) basing on PET, that developed and described by Twardowski in 1987 [17]. Based on education, patients with elementary and junior secondary education are defined as low education.

Follow-up and outcomes

     Demographic data, including age, sex, and comorbidity conditions were collected at the time of study initiation. Residual kidney function, kind of peritoneal membrane, Kt/V, creatinine clearance (CCr) were calculated and collected at the time of study initiation, too. PD-related peritonitis was diagnosed and noted for 3 continuous follow-up years.

     PD-related peritonitis was diagnosed based on at least two of the following criteria [18]: (1) abdominal pain or cloudiness of PD effluent; (2) white blood cell count in PD effluent >100/μL with >50% polymorphonuclear leukocytes; and (3) a positive culture from PD effluent.

    Serum prealbumin concentration was measured using a quantitative electrochemiluminescence method (ECLIA) at the time of enrolment. OH was measured using a body composition monitor (BCM, Fresenius).

Statistical analyses

 All normally distributed and continuous data are represented as mean ± standard deviation and were analyzed using the Student’s t-test, one-way analysis of variance, and post-hoc Bonferroni comparison. All the non-normally distributed data are represented as median (25 percentile-75 percentile) and were analyzed using the Mann–Whitney U test and Kruskal–Wallis test. Categorical data are presented as the frequency with percentage and were analyzed using the chi-squared test. Multivariate logistic regression analysis was performed to identify the predictor of peritonitis (using backward selection procedure). Receiver operating characteristic (ROC) curves with the area under the curve (AUC) was calculated to predict the peritonitis from patients after three years' follow-up. Peritonitis prognosis were assessed using the Kaplan–Meier analysis and evaluated by the log-rank test. Statistical analysis was performed using the Statistical Package for Social Science (SPSS) version 20.0 (Chicago, IL, USA). A p-value <0.05 was considered significant.

Results

Table 1 showed the basic demographics of all study subjects. In our study, the mean age of the entire cohort was 48.61 ± 13.63 years, in which 57.2% of patients were male, 16.9% of patients had diabetic mellitus (DM), the median duration of PD was 21 months, 22.7% of patients had low education, 71.9% of patients had lost residual kidney function, 95.3% of patients had anemia, and 15.8% of patients had peritonitis during 3-year follow-up with the ratio of positive bacteria was 27.3% (12/44 patients).

     As the results in Table 2, in peritonitis patients, the average age was older, the ratio of low education and DM were higher, the average OH and CRP-hs level were higher, and serum average albumin and prealbumin concentration were lower significantly than those of non-peritonitis group, p< 0.001.

    There are many independent factors associated significantly with peritonitis, including low education, CRP-hs, albumin, prealbumin, and OH based on the results of multivariate logistic regression analysis with p< 0.05 (Table 3).

     Based on the results of ROC curve analysis in Figure 1, there were many factors prediction of the peritonitis, in which prealbumin level and OH had strong value (Prealbumin: AUC = 0.838, cut-off value = 32.5 mg/dL, Se= 90.9%, Sp = 32.9%; OH: AUC = 0.851, cut-off value = 1.33 L, Se = 79.5%, Sp = 85.5%).

    The Kaplan-Meier analysis in Figure 2 showed that patients in the high OH (OH ≥ 1.33 L: blue line) exhibited a significantly higher peritonitis rate compared to that with lower OH (OH < 1.33 L: violet line) (Log-rank test, p< 0.001).

    Oppositely, as the results of Kaplan-Meier analysis in Figure 3, patients in the lower prealbumin level (Serum prealbumin ≤ 32.5 mg/dL: blue line) exhibited a significantly higher peritonitis rate compared to that with higher serum prealbumin level (Serum prealbumin > 32.5 mg/dL: violet line) (Log-rank test, p< 0.001).

Discussion

Prevalence peritonitis

     To determine PD-related peritonitis in the end-stage kidney disease patients undergoing CAPD, we excluded patients who had previous peritonitis, follow up for 3 years, the ratio of peritonitis in our study was 15.8% (Table 1). There were some reports about the prevalence of PD-related peritonitis. Ye H. et al [5] conducted a study with 1321 PD patients following-up 5 years, the ratio of peritonitis was 28.16% (372/1321 patients), in which in the first year of PD initiation, 169 (13%) patients had experienced episodes of peritonitis, and the proportion of patients with peritonitis fluctuated from 8% to 13% in the subsequent years. Gadola L. et al. [19] surveyed the rate of peritonitis in 222 PD patients following-up 6 years, the result showed 95 patients suffered 1 or more episodes of peritonitis (42.79%). In children, the ratio of peritonitis was 25.45% in Ponce’s study with 7 years follow-up (125 first episodes of peritonitis in 491 children PD patients) [21]. The ratio of peritonitis in our study was lower than others because our time of follow-up was shorter than other studies. There was 27.3% patient with positive bacteria culture in our study, that similar to other study results [5, 20].

      In Viet Nam, peritoneal dialysis is concentrated only in 2 big cities, Ha Noi and Ho Chi Minh City. When recommending chronic kidney replacement therapy, most patients choose maintenance hemodialysis. Only about 20% of patients choose peritoneal dialysis because they do not have time to go to hemodialysis centers. When comparing groups of patients with peritonitis and non-peritonitis, we found some patient characteristics related to peritonitis. In peritonitis patients, the average age was older, the ratio of low education and DM were significantly higher than those of non-peritonitis group, p< 0.001 (Table 2). It remains controversial whether older PD patients have a substantially increased risk of peritonitis than their younger counterparts. More recently, retrospective studies found that older age (more than 65 years) was the only identified risk factor associated with peritonitis [21, 22]. It seems highly probable that touch contamination and bowel dysfunction are important underlying causes of peritonitis episodes in older PD patients [23]. Diabetic mellitus and low education were risk factors of PD-related peritonitis in previous studies [23-25]. As diabetes mellitus is regarded as a risk factor for infections in general, it seems to be reasonable to consider it also as a risk factor for peritonitis in PD patients [25]. In the study, we found the relationship between peritonitis and overhydration (Table 2,3). The result of our study was similar to others [13, 14]. The association between OH and peritonitis maybe by enteric germs [14]. This seems to be reasonable, by a trend toward an association between baseline levels of C-reactive protein and the PD-related peritonitis (Table 2,3).  

      The relationship between peritonitis and malnutrition was also expressed in our study (Table 2,3). The average level of serum albumin and prealbumin in peritonitis patients was lower significantly than the non-peritonitis group, p< 0,001. Peritoneal dialysis itself might lead to protein-energy wasting as continuous glucose absorption from peritoneal dialysis solutions, abdominal fullness induced by the dialysate. The result is a decrease in serum albumin and prealbumin concentration in patients with peritoneal dialysis [26]. Dong J et al. also confirmed that protein leakage predicts risk for peritonitis in patients on peritoneal dialysis, and this association remained even adjustment for systemic inflammation estimated by serum albumin, CRP, and IL-6 [27]. 

Factors predict peritonitis

     In this study, we found that there are many independent factors related to peritonitis in CAPD patients, of which prealbumin and OH are closely related, p< 0.001 (Table 3). We also found that OH and serum prealbumin are the independent predictors of peritonitis compared to other factors such as hemoglobin, serum albumin, and CRP-hs (AUC of prealbumin was 0.838; of OH was 0.851, p< 0.001), (Figure 1). Predictive value for peritonitis of serum prealbumin, OH is also evident when we followed-up 3 years CAPD patients by Kaplan–Meier analysis (Figure 2,3). There are some previous reports about predictive factors of PD-related peritonitis in CAPD patients [19, 21, 22]. Gadola L. et al. [19] confirmed that multidisciplinary peritoneal educational program improved peritonitis rates, independently of other risk factors. Okayama M. et al found aging is an important risk factor for peritoneal dialysis-associated peritonitis [21]. In particular, Kerschbaum J et al. [25] reviewed 415 studies writing risk factors for peritonitis in PD patients. From those studies, the author found that the risk of peritonitis is divided into two groups: nonmodifiable and modifiable risk factors. Nonmodifiable risk factors consist of ethnicity, old age, female, cardiovascular comorbidities, DM, underlying renal disease as lupus, lose of residual renal function... Modifiable risk factors are malnutrition, overweight, smoking, comedication as immunosuppression, depression, low socioeconomic status… In summary, plenty of risk factors for PD-related peritonitis have been identified in studies of acceptable methodological quality. Overhydration is common among PD patients and related cardiovascular risk and death [28-30]. Prealbumin levels were an independent and sensitive predictor for mortality in incident PD patients, showing a good correlation with nutritional and inflammatory markers [16, 31]. Association between OH and the risk of peritoneal infection by enteric germs was reported in Carvalho Fiel D’s study [14]. It has been suggested that persistent oedema of the intestinal wall may favour microbial and bacterial endotoxin transmigration, in some cases leading to systemic infections including peritonitis [14]. Serum Albumin and prealbumin are the measures to evaluate the nutritional status of chronic patients in general, patients with peritoneal dialysis in particular. Decreased albumin and prealbumin concentrations associated with peritonitis in peritoneal dialysis patients have been mentioned by several authors [25-27]. It might be hypothesized that hypoalbuminemia, as a result of malnutrition, inflammatory response, or of uremia itself, may lead to a higher susceptibility to infection [25]. Thus, both OH and serum prealbumin are modifiable risk factors for PD-related peritonitis, which have predictive value for peritonitis in CAPD patients. This result once again confirms the role of OH and serum prealbumin in predicting outcomes of CAPD patients.   From this result, good control of OH and serum prealbumin is needed to reduce the rate of peritonitis in CAPD patients.

Although our results showed that overhydration and low serum prealbumin level were the independent predictors of PD-related peritonitis in CAPD patients, this study still had some limitations. Firstly, various studies had shown that there were many factors associated to peritonitis in PD patients including both modifiable and non-modifiable factors. However, in this study, we still did not have the specific measures to eliminate the influence of these factors. Secondly, we were unable to obtain complete data from all patients during the 3-year follow-up. Therefore, in this study, we could only evaluate OH and prealbumin baseline values at the beginning of the study.

Conclusion

     In conclusion, overhydration and low serum prealbumin levels were the independent predictors of PD-related peritonitis in CAPD patients.

Abbreviations

OH: overhydration

CAPD: continuous ambulatory peritoneal dialysis

PD: peritoneal dialysis

CCr: creatinine clearance

ROC: Receiver operating characteristic

DM: diabetic mellitus

AUC: Area Under the Curve

Declarations

Ethics approval and consent to participate

     This study was approved by the Ethical Committee of Vietnam Military Medical University (No. 1238/QĐ-HVQY).

Consent for publication

Informed consent was obtained from all the participants and authors.

Human and animal rights

     Animals did not participate in this research. All human research procedures were followed the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2008.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

     The authors declare that they have no competing interests.

Funding

We did not receive any funding to conduct this research.

Authors' contributions

-    Research idea and study design: QĐBQ, TPNH

-     Data acquisition: LND, DNH

-     Data analysis/interpretation: MPV

-     Statistical analysis: TND

-     Supervision or mentorship: TTV, QĐ, TLV

All authors have read and approved the manuscript

Acknowledgments

     In this study, we had been strongly supported by clinical application funding of our local hospital and university to complete our research.

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Tables

Table 1. Baseline demographic and laboratory characteristics of patients 

PD: Peritoneal Dialysis; BMI: Body Mass Index; OH: Overhydration; RKF: Residual Kidney Function; PET: Peritoneal Equilibration Test; H: High; HA: High-Average; LA: Low-Average; L: Low; WBC: White Blood Cell; hs-CRP: high sensitive C Reactive Protein.

Table 2. Comparison of demographic and laboratory characteristics of peritonitis and non-peritonitis group

PD: Peritoneal Dialysis; BMI: Body Mass Index; OH: Overhydration; PET: Peritoneal Equilibration Test; H: High; HA: High-Average; LA: Low-Average; L: Low; WBC: White Blood Cell; hs-CRP: high sensitive C Reactive Protein.

Table 3. Multivariate logistic regression analysis between peritonitis and clinical variables in studied patients

PD: Peritoneal Dialysis; hs-CRP: high sensitive C Reactive Protein; OH: Overhydration