Preditores de peritonite em pacientes em um programa de diálise peritoneal Predictor factors of peritoneal dialysis-related peritonitis

Introduction: Peritonitis remains a major complication of peritoneal dialysis (PD). Objective: Evaluate peritonitis incidence, etiology and outcome in cronic PD patients. Methods: A retrospective cohort study was carried out on 330 patients (mean age of 53 ± 19 years) who had been treated by PD in a dialysis center in Aracaju/SE, Brazil between January 1st, 2003 and December 31th, 2007. Data of patients with and without peritonitis were compared using Student’s ttest, chi-squared statistic and multiple logistic regression. Results: There were 213 peritonitis among 141 patients (1.51 episode/patient) resulting in a rate of 28.44 patient/episode/ month (0.42 patient/episode/year). Staphylococcus aureus was the most frequent micro-organism isolated (27.8%), followed by Escherichia coli (13.4%) and 32.5% were culture-negative peritonitis. A greater risk of peritonitis was identified at the patients with hypoalbuminemia [relative risk (RR) = 2.0; 95% confidence interval (CI) = 1.21 – 3.43; p < 0,01], < 4 school years (RR = 2.15; CI = 1.09 – 4.24; p = 0.03) and catheter’s exit site infection (RR = 2.63; IC = 1.57 – 4.41; p < 0.01). There were no significant difference among gender, age, family income, diabetes mellitus, type of dialysis treatment, type of catheter and its surgical implant. Conclusions: Hypoalbuminemia, low schooling and catheter’s exit site infection were associated with greater risk to peritonitis. Although peritonitis rate follow international pattern, prophylactic strategies are recommended.


INTRODUCTION
Peritoneal dialysis (PD) is an accepted and widely used form of renal replacement therapy (RRT), peritonitis being its main complication. 1,2ociodemographic 3,4,5 and nutritional 6,7 factors, climatic circumstances, 8 diabetes mellitus, 3,5,6,7 PD modality, 9 and the presence of peritoneal catheter tunnel or exit site infection (PCESI) have been reported as possible risk factors associated with the development of peritonitis. 10,11lthough occurring with an increasing frequency, due to the development of specific programs, 1,2 peritonitis represents one of the major reasons for hospitalization and dialysis technique failure, 10,12,13 and remains as the main cause of death in patients treated with PD. 1,11 Its prevention is, thus, of fundamental importance for a successful dialysis program. 1 This article aimed at assessing the possible predictive factors of peritonitis in patients on a PD program, and at comparing the findings with indicators described in the literature.

METHOD
This was a retrospective study of a cohort of 330 chronic renal patients belonging to the PD program of the Nephrology Clinic of the State of Sergipe (Clinese), in the city of Aracaju.The patients had undergone dialysis therapy for at least 30 uninterrupted days from January 1st, 2003, to December 31st, 2007.
At that dialysis center, the Y connection system PD (Baxter Hospitalar) is used, with implantation of the peritoneal catheter (Tenckhoff, Swan Neck Tenckhoff or Swan Neck Missouri) by use of a trocar or microlaparotomy.Cefalotin is routinely used in surgery as antibiotic prophylaxis and immediately at the beginning of therapy or after break-in, depending on the need for emergency dialysis treatment.At the time, neither antibiotic prophylaxis of peritonitis or of exit site infections was prescribed, nor routine search for Staphylococcus aureus nasal carriers was performed.
Each patient provided the following information: clinical and demographic profile; history of the dialysis treatment; catheter history; infectious complications inherent in treatment; and laboratory tests at the beginning of PD therapy.The patient's age at the beginning of PD was considered for data analysis.Patients on automated peritoneal dialysis (APD) and on continuous ambulatory peritoneal dialysis (CAPD) were not separated into different groups.Peritoneal catheter exit site infection was defined by the presence of purulent secretion, with or without skin erythema in the pericatheter region. 10,14If a certain patient had more than one peritoneal catheter, the catheter present at the time of the peritonitis episode was considered when analyzing that particularity, or the catheter with the longest time of stay, for individuals who did not have that complication.
The peritonitis episodes were assessed regarding their incidence, causative agents, and possible predictive factors related to their development.Diagnosis was confirmed by the simultaneous occurrence of at least two of the following criteria: abdominal pain; cloudy peritoneal effluent; leukocyte count in the dialysate > 100/µL; and positive culture of the peritoneal fluid. 14Peritonitis rate was calculated through the number of episodes as a function of time of exposure to the dialysis technique, according to the recommendations of the International Society for Peritoneal Dialysis (ISPD). 10For determining the predictors of peritonitis, patients were divided into two groups, depending on the presence (141 patients -42.7%) or absence (189 patients -57.3%) of peritonitis, and the first episode of peritonitis was considered.

DATA ANALYSIS
The data obtained were checked and submitted to statistical analysis by using the programs Epi Info 2005, version 3.3.2,and Statistical Package for Social Sciences (SPSS) 16.0 for Windows (SPSS Inc., Chicago, Illinois).The significance level adopted for rejecting the null hypothesis was p < 0.05.
The statistical comparisons between the continuous variables and the calculations of the means were performed by using Student t test.The percentages of the categorical variables (presence or absence of peritonitis) were compared by use of the two-tailed chi-square test.To further explore the individual effects of the predictors involved in the peritonitis episodes, a logistic regression model was built through the analysis of multiple variables (adjusted by the Hosmer-Lemeshow test), including sociodemographic factors and the variables that had p < 0.25 in the non adjusted analysis.

RESULTS
The mean age of the 330 patients studied at the beginning of the dialysis therapy was 53 ± 19 years.Their general characteristics are shown in Table 1.
In those patients, 381 peritoneal catheters were implanted (1.15/patient), and the Tenckhoff type predominated (59.8%).Forty-four patients (11.5%) used more than one catheter during the period.All catheters of the Swan Neck type were implanted through microlaparotomy, and those of the Swan Neck Tenckhoff type, through trocar.Most of those of the Tenckhoff type (95.2%) were implanted through trocar.
Table 2 shows the distribution of the cases of peritonitis as a function of the etiologic agent identified in culture.Gram-positive and Gram-negative microorganisms -55 episodes each -were the most frequent, and Staphylococcus aureus was the commonest agent isolated in the series (54 episodes -25.4%).The negative culture rate was 32.5% (63 cases).Culture was not performed in 19 opportunities (8.9%).
Peritoneal catheter exit site infection was identified in 136 patients (42.1%), 73 of whom (53.7%) later developed peritonitis.In 28 (38.4%) of those peritonitis episodes, Staphylococcus aureus was the causative agent.Peritonitis due to Staphylococcus aureus following PCESI represented 50.9% of the episodes from which that microorganism was isolated.
The following predictors of peritonitis were identified through univariate analysis (Table 3): starting RRT through PD (p = 0.02); serum albumin < 3 g/dL at the beginning of PD (p = 0.03); and presence of PCESI (p < 0.01).The male sex showed statistical tendency towards the development of peritonitis (p = 0.08), while the use of the Swan Neck Tenckhoff catheter provided protection (p < 0.01).
In the analysis with multiple variables (Table 4), the following independent peritonitis predictors were identified: serum albumin < 3 g/dL at the beginning of therapy (p < 0.01); PCESI (p < 0.01); and less than four years of schooling (p = 0.03).Monthly family income ≥ 5 minimum wages (p = 0.06) and beginning RRT through PD (p = 0.06) showed statistical tendency.

DISCUSSION
Peritonitis rates have been decreasing in the past years due to advances in PD techniques. 1,2,15Nevertheless, peritonitis still remains as the major cause of therapeutic failure, in addition to sometimes culminating in patient's death. 1,10,11,13,15n an observation period of five years, 330 patients belonged to the PD program of the dialysis center studied for at least 20 uninterrupted days, 171 of whom (51.8%) began RRT with PD.
On December 31st, 2007, 31.67% of the dialysis patients at that institution were on PD.That percentage was proportionally higher than the North-American (8.8%)16 and national (10.6%) 17 means, similar to the mean in Holland (30%) 18 , and lower than the 74% reported in Mexico, the major user of PD worldwide. 7This reflects our police of impartially presenting the available therapies, allowing patients and their families to freely choose in situations with no contraindication to any method.The fact that 51.8% of the patients had PD as their first dialysis modality emphasizes that observation.The suppressed demand for RRT and the sympathy of the professionals working at the institution for the method can have contributed to the magnitude of the PD program, making Sergipe the State that proportionally has the greatest percentage of patients on that dialysis modality in the country. 17ata have revealed that patients of this study have characteristics similar to those described in other Brazilian series regarding sociodemographic and clinical indicators. 19The percentage of elderly (28.2%) and patients living away from the dialysis center (60.6% live in the countryside or other States) is high, most patients are illiterate or have not completed elementary school (76.7%), and their monthly family income is lower than five minimum wages (87.4%).The lack of access to conservative treatment of most patients has hindered the identification of the underlying disease in 37.5% of the cases and has contributed, along with problems of vascular access to hemodialysis, to the high index of therapy beginning as an emergency indication (83.9%).Table 2 Despite the unfavorable sociodemographic and clinical characteristics, 141 patients (42.7%) had peritonitis, summing up to 213 episodes, and the peritonitis rates are in accordance with the international recommendations and the reports of current series. 6,13,20,21,22ccording to the ISPD, the goal of a dialysis center is peritonitis rates lower than one episode every 18 months (0.67 episode/patient/year).10Fernandes et al., 20 in a large national multicenter study (Brazilian Peritoneal Dialysis Multicenter Study -BRAZPD), have reported a peritonitis rate of one episode every 30 months, while Moraes et al., 22 when describing 25-year cumulative data, have reported one episode every 14.63 months in the city of Curitiba, in the State of Paraná.It is worth emphasizing that, as the latter study relates to a prolonged experience, that rate encompasses all the evolution of PD connections.When analyzing data separately and for five-year intervals, the authors have reported one episode of peritonitis for every 3.38 patients/month from 1980 to 1985, and one episode for every 17.64 patients/month from 2000 to 2005, better representing the results obtained with current connections. 22nalysis of the information about the etiologic agent of peritonitis was partially hindered because culture was not performed in 8.9% of the cases.This may be justified by the fact that 200 patients (60.7%) lived away from the dialysis center, and sometimes their first visit to a health care service and the beginning of the antimicrobial therapy occurred at nonreference hospitals.National authors have reported rates of culture non-performance ranging from 7% to 22.7%. 2,23ost international authors have described Grampositive microorganisms as the major causative agents of peritonitis, Staphylococcus epidermidis being the

Table 4
Predictors of peritoneal dialysis-related peritonitis most frequent. 5,21,24Latin-American authors 4,22 have reported Staphylococcus aureus as the major etiologic agent.In our series, the same proportion of Gram-positive and Gram-negative agents (55 episodes each) was found, Staphylococcus aureus being the most frequently isolated microorganism (27.8%), and Escherichia coli (13.4%) and Klebsiela sp.(9.7%) the most frequently identified Gram-negative microorganisms.Although Barretti et al. 2 and Kavanagh et al. 13 have also reported higher prevalence of Escherichia coli, that distribution varies. 2 The results of that study regarding the prevalence of fungi in positive cultures (2.8%) are similar to those reported by other researchers. 21,22,24he peritoneal fluid cultures of 63 episodes of peritonitis (32.5%) were negative, a value greater than that recommended in the ISPD guidelines (< 20%).10Moraes et al. 22 and Lima et al. 25 have reported negative culture rates of 26% and 33.7%, respectively.
to Barretti et al., 2 a factor that can contribute to a high frequency of negative cultures is the fact that reference laboratories do not comply with some recommendations of the ISPD 10 regarding culture specimen collection and inoculation.Nevertheless, in that series, the rate of cure of peritonitis with negative culture was similar to the rate of cure of episodes caused by Gram-positive agents, 77.8% and 83.6%, respectively, as reported by Mujais. 21As suggested by Fernandes et al., 20 our predominance of Staphylococcus aureus-caused peritonitis can be due to the high rate of negative cultures, which can hide the presence of other microorganisms that prevail in most studies, such as coagulase-negative Staphylococcus.
Sociodemographic variables have been considered as possible risk factors associated with the unfavorable evolution of dialysis patients, more specifically regarding the variations in quality of life scores, peritonitis, and mortality. 2,3,4,5,26,27,28Diabetic nephropathy, advanced age, lower family income, and lower educational level have been associated with worse prognosis in some reports. 3,5,26,27,28In our case series, beginning treatment at advanced age, being diabetic, or having a monthly family income lower than five minimum wages were not associated with the development of peritonitis.However, in accordance with Aslam et al. 3 and Chow et al., 5 low educational level was identified as a risk factor in the analysis through multiple variables.
Hypoalbuminemia, at the beginning of treatment, is associated with a higher chance of developing peritonitis, in accordance with the reports of other authors. 3,5,6Hypoalbuminemia, here defined as albumin < 3.0g/dL, was identified in 36.4% of the patients admitted to the program and in 43.1% of those developing peritonitis, and could have been associated with the low socioeconomic level of the population, as well as with the late referral to a nephrologist.
The benefit of one type of catheter over another has not been conclusively demonstrated by randomized and prospective studies. 10,29,30A comparison of 107 Swan Neck Missouri catheters and 153 Tenckhoff catheters implanted in 236 patients at the same center from December 2000 to June 2005 has shown no differences in survival and prevalence of the major causes of failure.Based on this, from 2007 on, the institution began to adopt the routine use of the Swan Neck Tenckhoff catheter, implanted by a nephrologist through trocar. 31Univariate analysis has shown that the Swan Neck Tenckhoff catheter provided protection against the development of peritonitis, but that was not confirmed after logistic regression.Maybe the still nonrepresentative number of that type of catheter may have hindered the observation of any difference.
Previous catheter tunnel infection and PCESI have shown to be the major independent risk factors for the development of peritonitis, being associated with a 2.6time increase in the occurrence of that complication.The elevated incidence of peritonitis in patients who had previously had PCESI can relate to the fact that, at that time, no antimicrobial agent was used at our institution for the prophylaxis of peritonitis or PCESI.Lima et al. 25 have reported a PCESI-related peritonitis rate of 35.7% at a service where routine prophylaxis with mupirocin is not performed, to avoid the appearance of multiresistant Staphylococcus aureus. 25oreira et al. 32 have shown a significant reduction in the incidence of peritonitis in patients using mupirocin.Takei 33 has reported that the use of mupirocin reduced the colonization by Staphylococcus aureus at catheter exit site and nasal mucosas.Barretti et al. 2 have reported that the daily use of mupirocin at the catheter exit site reduced the peritonitis rate from 1/16.2 episode/ patient/month to 1/24.2 episode/patient/month, and was associated with changes in the epidemiological profile, with a strong reduction in the prevalence of peritonitis caused by Staphylococcus aureus.Piraino et al. 34 have reported an overall reduction in the peritonitis rate with the use of topical gentamicin, mainly due to the reduction in peritonitis caused by Gram-negative agents from 0.52 to 0.34 episode/year.Those authors have also reported a 63% reduction in the risk of infectious complications due to Staphylococcus aureus because of the use of mupirocin.Climatic factors were not assessed in this study, but in the northeastern region of Brazil, the weather is hot and humid during almost the entire year.Szeto et al.8 have shown a higher incidence of catheter infection in countries of hot and humid weather because of the accumulation of sweat and dirt around the catheter exit site.That explanation has also been provided by Stinghen, Barretti, and Pecoits-Filho, 15 who have recommended that maintaining the catheter and the exit site orifice drier can help to reduce the incidence of infections in tropical countries.
The present study has some limitations, such as the fact that the analysis was retrospective and limited to a single center, and, thus, the particularities of the study should be carefully considered before results can be generalized.In addition, measuring serum albumin at the beginning of the PD treatment to infer the patient's nutritional status should be considered with reservation, because that is not a reliable marker and neither serial measurements nor values immediately prior to episodes of peritonitis were considered.Finally, it is worth emphasizing that, when considering a possible association of peritoneal catheter tunnel or exit site infection with the occurrence of peritonitis, no interval between the two events was observed, which does not allow a cause-effect relation to be established.

CONCLUSION
Hypoalbuminemia, low educational level, and catheter exit site infection have shown to be independent predictive factors of peritonitis.
Although the socioeconomic level has been historically considered a contraindication for PD, this was not a limiting factor, because in the study population, even with unfavorable sociodemographic and clinical indicators, the peritonitis rates observed were within the international recommendations.Finally, considering the high penetration of Staphylococcus aureus as an etiological agent, prophylactic strategies in Staphylococcus aureus nasal carriers and for PCESI, as currently recommended by the international guidelines, should be universally applied.
DISTRIBUTION O F THE EPISODES O F PERITONITIS IN PATIENTS O N PERITONEAL DIALYSIS AS A F U N C T I O N O F THE IDENTIFIED E T I O L O G I C A L A G E N T(N = 194)

Table 1
GENERAL CHARACTERISTICS O F THE PATIENTS U N D E R G O I N G PERITONEAL DIALYSIS (N = 330) * The underlying disease was not identifi ed in 124 patients (37.5%). 194)

Table 2 Table 3
STATISTIC U N I V A R I A T E ANALYSIS O F POSSIBLE PREDICTIVE FACTORS O F PERITONITIS IN PATIENTS U N D E R G O I N G PERITONEAL DIALYSIS (N = 330) *Illiterate and literate are included in the educational level up to 4 schooling years; more than 4 schooling years includes complete elementary school level, complete high school, and complete university.

Table 4
STATISTICAL ANALYSIS W I T H MULTIPLE VARIABLES O F POSSIBLE PREDICTIVE FACTORS O F PERITONITIS IN PATIENTS U N D E R G O I N G PERITONEAL DIALYSIS * CI = 95% confi dence interval; ** RRT -renal replacement therapy; *** up to 4 years of schooling includes illiterate and literate; more than 4 years of schooling includes complete elementary school, complete high school, and complete university.