The impact of peritoneal dialysis-related peritonitis on mortality in peritoneal dialysis patients

This was a retrospective cohort study. Incident PD patients at the PD centre of The First Affiliated Hospital, Sun Yat-sen University, from 1 January 2006 to 31 December 2011 were included. Patients who were 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, were excluded. Tenckhoff catheters were placed using a sterile surgical technique and conventional PD solutions (Dianeal 1.5%, 2.5% or 4.25% dextrose; Baxter Healthcare, Guangzhou, China), and Y-sets and twin-bag systems were utilized in over 98% of the PD patients. Patients and their caregivers underwent a standard training program after catheterization. The study protocol was consistent with the ethical principles of the Helsinki Declaration and was approved by the Ethics Committee of The First Affiliated Hospital, Sun Yat-sen University. All participants were asked for permission to use their medical data for a non-commercial study, and written informed consent was obtained from them at the initiation of PD follow-up.

Demographic data, including age, sex, causes of ESRD, and comorbidity conditions, were collected at the time of PD initiation. A history of cardiovascular disease (CVD), which included cerebrovascular disease, ischemic heart disease, congestive heart failure, and peripheral vascular disease, was also reviewed. The baseline laboratory data were obtained during the first 1–3 months after initiating PD. All of the patients were followed up until death, or administrative censoring (including renal transplantation, switching to hemodialysis, transfer to another PD centre, loss to follow-up, and withdrawal of treatment), or the end of the study follow-up period (31 December 2013). Therefore, deaths while on PD treatment were considered as mortality in this study. The primary outcome was all-cause mortality. Secondary outcomes were infection-related mortality and cardiovascular (CV) mortality.

PD-related peritonitis was diagnosed based on at least two of the following criteria [3]: (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. CV death was defined as death due to ischemic heart disease, arrhythmias, sudden cardiac death, congestive heart failure, other heart disease, or cerebrovascular events [12, 13]. Death related to peritonitis was defined as death of a patient with active peritonitis, or admitted with peritonitis or within 2 weeks of a peritonitis episode [3]. When discussing the causes of deaths, the PD team, which consists of three nephrologists in our PD centre, reviewed the details of the individual medical records. Regarding inherent difficulties in assigning cause of death to infection or cardiovascular events, we tended to assign the death to the primary reason for hospitalization when the two coexisted.

A total of 1473 patients received PD therapy in our PD centre between 1 January 2006 and 31 December 2011. Patients who were younger than 18 years (n = 17), dropped out of PD within 90 days (n = 72), transferred from permanent hemodialysis (n = 54), and had a history of renal transplantation (n = 9) were excluded. A total of 1321 patients were ultimately included in the study (Fig. 1). The mean age of the entire cohort was 48.1 ± 15.3 years; 58.7% were male, 23.5% had DM, and 36.3% had a history of CVD. The demographic characteristics and clinical data of patients in the two cohorts are shown in Table 1.

During the median of 34 (IQR: 21–48) months of follow-up, 372 (28.2%) patients experienced episodes of peritonitis. Among them, 234 (62.9%) had one episode of peritonitis, 72 (19.4%) had two episodes, and 66 (5.5%) had three episodes or more (Table 2). The peritonitis rate was 0.16 per patient-year (95% confidence interval [CI] 0.14–0.18). Figure 2 shows the distribution of patients who experienced peritonitis by dialysis duration. 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. As estimated by Kaplan–Meier survival analysis, the cumulative risk of experiencing peritonitis events and all-cause mortality increased in concert with the extension of PD duration (Fig. 3).

By the end of the follow-up period, 261 (19.8%) of the 1321 patients had died, 111 (8.4%) were transferred to hemodialysis, 218 (16.5%) received renal transplantation, and 611 (46.3%) remained on PD (Table 2). The mortality rate of the patients was 0.07 per patient-year (95% CI: 0.06–0.08). A total of 147 (56.3%) patients died due to cardiovascular disease while 46 (17.6%) died of infectious disease, of which 19 (41.3%) were peritonitis-related. The etiological details of all-cause deaths and infection-related deaths in the cohort are shown in Fig. 1 and Table 3, respectively. Similarly, the risks for peritonitis and death both increased as the PD duration extended (Fig. 2).

As shown in Table 4, peritonitis was associated with an increased risk of all-cause mortality, infection-related mortality, and CV mortality in the study population. After adjustment for age, sex, DM, history of CVD, 24-h urine output, hemoglobin, serum phosphorus, and serum albumin, peritonitis was independently associated with a higher risk of all-cause mortality (hazard ratio [HR] = 1.95, 95% CI: 1.46–2.60, p < 0.001), infection-related mortality (HR = 4.94, 95% CI: 2.47–9.86, p < 0.001), and CV mortality (HR = 1.90, 95% CI: 1.28–2.81, p < 0.001).

For age was also independently associated with all-cause, infection-related, and CV mortality, we further examined the interaction effects between age and peritonitis on mortality. However, no statistically significant interaction effects were apparent (Additional file 1: Table S4).

The negative impacts of peritonitis on mortality changed by the follow-up period (Fig. 4). The adjusted HR of peritonitis for all-cause and infection-related mortality was 0.80 (95% CI: 0.46-1.38) and 1.06 (95% CI: 0.26-4.32) for patients within 2 years of PD initiation, respectively, gradually increasing to 1.74 (95% CI: 1.28-2.36) and 4.44 (95% CI: 2.14-9.22) after 5 years of PD treatment, the HRs sustained thereafter (for detailed data see Additional file 1: Table S5).

Based on the results shown in Fig. 4, we further conducted a stratified analysis by the follow-up time period in the Cox regression model. For patients within 2 years of PD, the adjusted HR of peritonitis for all-cause and infection-related mortality was 0.80 (95% CI: 0.46–1.38) and 1.06 (95% CI: 0.26–4.32), respectively, while it was much higher in patients on dialysis longer than 2 years, with an adjusted HR of 3.98 (95% CI: 2.70–5.86) and 9.33 (95% CI: 3.56–24.47), respectively. The interaction test also demonstrated that the relationship between peritonitis and follow-up period for all-cause and infection-related mortality was statistically significant (Table 5).

In this cohort study covering 1321 incident PD patients, we demonstrated that peritonitis was independently associated with higher risk of all-cause mortality, infection-related mortality, and CV mortality. Further analysis showed that the impacts of peritonitis on mortality were more significant in patients with longer PD duration.

Controversial conclusions were made in previous studies regarding the impact of peritonitis on mortality in PD patients. Fried et al. found that an increased peritonitis rate was an independent risk factor for overall mortality in 516 adult PD patients in a single centre in Pittsburgh [4]. Boudville et al., using a case-crossover design, demonstrated that there was an approximately 6-fold increase in the odds of peritonitis in the 30 days before death compared with the 30-day window 6 months before death [7]. However, in a retrospective study of 565 PD patients in Spain, the peritonitis rate was not significantly associated with all-cause mortality after adjustment for potential confounders [5]. Moreover, Hsieh et al. reported recently that patients with a history of peritonitis episodes had a lower risk of all-cause mortality in a Kaplan–Meier analysis and multivariate Cox regression in a Taiwan population with a peritonitis rate of 0.196 episodes per patient-year [9]. These controversial conclusions may be attributed to the difficulty in evaluating the impact of peritonitis on mortality. First, at present there is no standard definition of peritonitis-related mortality. Second, the indirect long-term effects of peritonitis on mortality, which would be mediated by the inflammation state [16‐18], poor nutritional status [17], and/or peritoneal membrane change after peritonitis events [19], may be obscure and difficult to define. Moreover, our preliminary exploration found that when a peritonitis event as a conventional binary covariate was entered into the time-dependent Cox regression model, the proportional hazards assumption was violated (Additional file 1: Table S1), suggesting that peritonitis event was a time-dependent covariate for mortality, which has rarely been considered in the statistical methods of most of the previous studies.

In observational studies, treatment is often time dependent. The time from the beginning of follow-up to treatment initiation, with no study event occurs, is known as immortal time in epidemiological studies, and mishandling immortal time can lead to an overestimated treatment effect, sometimes even draw an inverse conclusion [14]. Similar to the treatment, peritonitis is also time dependent. The time from the beginning of follow-up to the time of peritonitis onset should be treated as another kind of immortal time, which being properly handled will be extremely important when assessing the impacts of peritonitis on outcomes. Referring to the suggestions by the authors of the published article above [14], considering the treatment as time-varying variable in the COX regression model would be a prior choice for controlling the immortal time bias. Therefore, with peritonitis parameterizing as a time-dependent variable, we used the Cox regression models to assess the effects of peritonitis on mortality, and demonstrated that peritonitis was independently associated with a higher risk of mortality in our cohort of PD patients.

It is not difficult to understand the negative impact of peritonitis on mortality in PD patients. First, severe and/or persistent peritonitis may lead to serious complications such as intestinal obstruction, intestinal perforation and sepsis, which can directly cause death. Therefore, such severe and/or persistent peritonitis may be readily related to the cause of a PD patient’s mortality. Second, the indirect long-term effects of peritonitis on mortality, as already mentioned [16‐19], have been emphasized in recent years. Moreover, patients who are prone to experience an episode of peritonitis may also be likely to experience other infections, as they may share similar risk factors. For example, lower serum albumin, which was verified as a remarkable risk factor for peritonitis episodes in PD patients [20‐22], was also demonstrated to be an independent risk factor for pneumonia in our centre’s previous work [23]. As also shown in this study, patients with peritonitis episodes had a significantly higher risk for infection-related mortality, although peritonitis events only accounted for 41.3% of the direct causes of infection-related deaths.

We also found that the negative effects of peritonitis on mortality increased among patients with longer PD follow-up times. Previous studies have reported that the first episodes of peritonitis had better outcomes than subsequent ones, and that a longer duration of PD was associated with worse clinical outcomes of peritonitis [5, 10, 11, 24], which may partially support our findings. In the study conducted by Xu et al., among patients with subsequent peritonitis episodes, those with longer PD duration had a significantly higher drop-out (defined as death or transferring to hemodialysis) rate than those with shorter duration (30.6% vs. 9.7%) [11]. In addition, Krishnan et al. have reported a higher non-resolution rate (24.4% vs. 16.5%) of peritonitis in patients on PD for more than 2.4 years than those on PD for less than 2.4 years [25]. In comparison with these studies, our findings did not directly demonstrate that PD duration affected the impact of peritonitis on mortality, but did indicate that the risk for mortality increased in patients with longer PD duration who experienced a peritonitis event. The mechanisms of this phenomenon remain unclear. On the one hand, the impaired host defence due to the long-term exposure of the conventional glucose dialysate and malnutrition [26‐29] may be the main contributor to the poor outcomes in long-term PD patients when exposed to an episode of peritonitis, although this notion needs to be clarified. On the other hand, a longer duration of PD may also be associated with chronic inflammation [30‐32] and cardiovascular calcification [33, 34], which are risk factors for overall and CV mortality in PD patients. In addition, ESRD patients on dialysis for a number of years were associated with higher levels of alkaline phosphatase [35, 36], which is traditionally a marker of high-turnover bone disease in ESRD patients but was recently found to be an independent predictor of adverse outcomes of peritonitis in PD patients [35].