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Association between reduced left ventricular ejection fraction and peritoneal dialysis related peritonitis: a single center retrospective cohort study in Japan – Scientific Reports

This study included patients aged ≥ 20 years who began PD as renal replacement therapy between January 1997 and December 2017 at Narita Memorial Hospital. Ultrasound echocardiography (UCG) was routinely performed within one month of PD initiation. Among 252 patients, 24 (9.5%) were excluded because of missing UCG data and clinically relevant information, and 228 patients with PD (90.5%) were finally included in the analysis (Fig. 1).

Figure 1
figure 1

Flow diagram showing patient selection.

Ethics

The study protocol was approved by the Ethics Committee of the Narita Memorial Hospital (Approval Number 29-12-01). The study was conducted in accordance with Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects enacted by the Ministry of Health, Labour and Welfare of Japan [https://www.mhlw.go.jp/content/001077424.pdf]. Due to the retrospective nature of the study, the need for patients’ informed consent was waived by the Ethics Committee of the Narita Memorial Hospital.

Measurements

The design of the present study has been described in detail in a previous report25. Briefly, baseline characteristics at the start of PD included age, sex, body mass index (BMI), previous atherothrombotic events (coronary heart disease, heart failure, stroke, aortic aneurism and/or peripheral vascular disease requiring intervention or hospital admission), comorbidities (hypertension and diabetes mellitus), cause of kidney disease (diabetic nephropathy, glomerulonephritis, and renal sclerosis), laboratory data (hemoglobin, serum albumin, serum potassium, C-reactive protein, brain natriuretic peptide (BNP) level, and estimated glomerular filtration rate [eGFR], estimated using the equation recently generated by the Japanese Society of Nephrology: eGFR [mL/min/1.73 m2] = 194 × Scr−1.094 × Age−0.287 × 0.739 [if female]26), urine volume (mL/day), peritoneal transport characteristics (dialysate/plasma ratio of creatinine at 240 min during peritoneal equilibration test), daily peritoneal ultrafiltration rate (calculated as the difference between the volume of total dialysate infused and volume drained over 24 h), domestic pets, smoking, constipation (defined as a state of using laxatives), and usage of PPI or H2RA, as previously reported27, cardiothoracic ratio on chest X-ray, and findings of ultrasonic echocardiography. Furthermore, the follow-up data on BMI and urine volume (mL/day) were collected every 12 months.

PD-related peritonitis was diagnosed when at least two of the following conditions were met: (1) abdominal pain and/or cloudy dialysis effluent, which are clinical features of peritonitis; (2) dialysis effluent white cell count > 100/µL or > 0.1 × 109/L (after a dwell time of at least 2 h), with > 50% polymorphonuclear leukocytes; (3) positive dialysis effluent culture5.

The anonymized data set is shown in Table S1.

Echocardiography

Ultrasonic echocardiography was performed according to the American Society of Echocardiography recommendations. LVEF was measured using the modified Sympson method28. We stratified the patients into two LVEF groups, i.e., reduced LVEF group (LVEF < 50%), and preserved LVEF group (LVEF ≥ 50%), as reported previously29,30. LV mass was calculated using the formula recommended by the American Society of Echocardiography28, and indexed based on the body surface area. The diameters of the inferior vena cava (IVC) were measured at approximately 3 cm before merging with the right atrium at end expiration (IVC max) and at inspiration with sniffing (IVC min)31. The collapsibility of the IVC (IVCC) was calculated as IVCmax minus IVCmin divided by IVCmax.

Exposure and outcomes

The primary exposure of interest was LVEF at baseline and the first episode of peritonitis from any cause was the primary outcome of interest. Patients were followed up until the first episode of peritonitis, or censoring events such as loss to follow-up, death (cardiovascular disease, malignancy, infection, and others), PD withdrawal, or end of the follow-up for this study, whichever happened earlier.

Furthermore, we classified peritonitis into “enteric” and “non-enteric” peritonitis corresponding to previous reports32,33. Specifically, we defined enteric peritonitis as being caused by enteric organisms such as enteric bacilli (Escherichia, Klebsiella, Serratia, Proteus, etc.) and enterococcus (Enterococcus faecalis, Enterococcus faecium, etc.)34. We defined other peritonitis cases as non-enteric peritonitis. Incident enteric and non-enteric peritonitis were defined as secondary outcomes.

Additionally, outcomes including PD withdrawal and its causes (PD-related peritonitis, inadequate solute clearance, impairment of activities of daily living, fluid overload, and kidney transplantation) were obtained.

Statistics

Differences in clinical characteristics and outcomes according to the LVEF groups (reduced LVEF (< 50%) and preserved LVEF (≥ 50%)) were compared using the Wilcoxon rank-sum test or Fisher’s exact test.

To identify predictors independently associated with the outcome, we examined potential confounding factors that have previously been reported as clinically important risks for PD-related peritonitis occurrence5 by using unadjusted and time-dependent multivariable-adjusted Cox proportional hazard (CPH) regression models. The models were adjusted for the following potential confounders: baseline data, including age (years), sex, diabetes mellitus, constipation, serum albumin (g/dL), serum potassium (mEq/L), use of PPI, daily ultrafiltration rate (mL), reduced LVEF (< 50%); and follow-up data, including BMI and urine volume (mL/day) at every 12 months.

Furthermore, we employed a stratified analysis to account for each potential confounder, including age, sex, constipation, use of PPI, diabetes mellitus, serum albumin, serum potassium, BMI, urine output, and daily ultrafiltration rate, with reduced LVEF as the exposure of interest. We constructed a forest plot to demonstrate the hazard ratio (HR) for the development of enteric peritonitis in each stratum.

To elucidate the dose-dependent association between LVEF and incidence of peritonitis, restricted cubic spline functions with three knots placed at the 10th, 50th, and 90th percentiles of LVEF were used. Furthermore, we conducted a similar analysis after classifying patients into the enteric and non-enteric peritonitis groups.

The proportional hazard assumption for covariates was tested using scaled Schoenfeld residuals. The cumulative probability for the occurrence of the first episode of peritonitis from any cause, enteric and non-enteric, was calculated using the Kaplan–Meier method and log-rank test.

Continuous variables are expressed as the medians and interquartile ranges, while categorical variables are expressed as numbers and proportions. Significance was set at P < 0.05. Statistical analyses were conducted using the Stata software (version 15.0; StataCorp LP, College Station, TX, USA) and JMP software version 14.0.0 (SAS Institute, Cary, NC, USA).