This study attempted to examine the clinical factors associated with SUD in patients undergoing PD. Using a long-term observational cohort, diabetes, K trajectory changes, and mental health and chronic pain were identified as risk factors for these patients. Given that majority of previous studies have focused on few parameters on sudden death in patients undergoing dialysis and rarely report on patients undergoing PD, more demographic data, clinical variables, and comorbidity discrimination were included in this study to examine their associations with SUD in patients undergoing PD. Our findings suggest that a multifaceted approach is potentially beneficial for SUD prevention in patients undergoing PD.
When examining the associations of SUD with demographics and comorbidities, patients with and without SUD were found to have similarities in age, sex, PD modalities, and antihypertensive drug use. Remarkably, patients with SUD had more concordant comorbidities at baseline compared with controls. These include some important cardiac comorbidities, e.g., hypertension, chronic heart failure and atrial fibrillation, diabetes, peripheral vascular disease, and stroke or transient ischemic attack [25]. All these comorbidities were observed in patients undergoing PD with SUD. In addition, majority of these patients demonstrated a prolonged QTc interval in this study. Given that previous studies reported that sudden cardiac death represents a major cause of mortality in patients with end-stage renal disease [1, 9, 11, 26], our results implicated that a planned schedule for cardiac function examination was essential for patients undergoing long-term dialysis.
To date, no studies have reported the association between mental health and chronic pain comorbidities and SUD in patients undergoing PD. We found that patients with SUD had more mental health and chronic pain comorbidities and were more likely to use analgesic drugs, mainly for chronic osteoarticular complaints. Furthermore, by hazard analysis, mental health and chronic pain comorbidities were identified as significant risk factors for SUD in patients undergoing PD. In our cohort, the proportion of patients undergoing PD with SUD who used analgesics was higher than that of controls, i.e., 67.9% and 35.0%, respectively. Analgesic categories included nonsteroidal anti-inflammatory drugs (NSAIDs) and a combination of NSAIDs with weak opioids. NSAIDs have been known to be associated with several adverse effects, including gastrointestinal and cardiac toxicity, blood pressure impairment, and renal toxicity [27]. These adverse effects may be related to fatal consequences [28]. Owing to unwitnessed SUD in some of our subjects, definitive causes of death could not be determined in our cohort. Nevertheless, an accumulating evidence has delivered a warning signaling the association between NSAIDs and fatal events in chronic kidney disease. Thus, we believe that an informative evaluation on the indication for NSAIDs in patients undergoing PD is mandatory to avoid SUD.
Diabetes has also been previously recognized as a risk factor for sudden death in the general population and patients undergoing dialysis especially in Asian population [6, 21, 29–31]. Proposed pathophysiology mechanisms for sudden death in diabetes include microvascular and macrovascular diseases. Among the causes of sudden death, sudden cardiac arrest is known as the primary mechanism [6, 29]. Diabetes triggers various untoward biological effects in the body. Consequently, pathologic changes appear in the organs and account for any observed functional impairment, especially in the heart. In this study, diabetes was a factor for SUD in patients undergoing PD. Our findings are consistent with these studies that showed diabetes led to a higher mortality rate in PD [21]. However, whether diabetic complication control could reduce the incidence of sudden death in diabetic patients undergoing dialysis remains to be elucidated.
Sudden cardiac arrest has been reported as the primary cause of sudden death in patients undergoing dialysis [4, 31]. Uremic milieu predisposes individuals with chronic kidney disease (CKD) to have cardiomyopathy and other vascular diseases [11]. These adverse effects consequently lead to arrhythmias, conduction abnormalities, and sudden cardiac arrest. One study investigated longitudinal changes in cardiac function and structure by echocardiography examinations in patients undergoing PD. The results showed the prevalence of altered cardiac structure and function upon PD initiation [32]. Patients undergoing dialysis are prone to sudden death through prolonged QTc interval or through increased arrhythmogenesis [11]. In this study, we found patients who were undergoing PD and experienced SUD showed longer QTc intervals compared to controls. Thus, patients undergoing dialysis are predisposed to cardiac structure and function abnormalities during the period of renal replacement therapy. Primary and secondary preventions of cardiac arrest could thus reduce SUD in patients undergoing dialysis.
Serum K pattern and its contribution to high cardiac risk has been reported in a large population of patients undergoing PD [33], wherein a U-shaped relationship between time-averaged serum K concentrations and cardiovascular mortality and all-cause mortality was found. The risk for all-cause mortality in cut-off serum K concentrations was < 3.5 mEq/L and ≥ 5.5 mEq/L, respectively [33]. Another smaller study showed that patients undergoing PD with lower time-averaged serum K concentrations and higher standard deviation had higher all-cause and cardiovascular mortality [34]. We found that patients who were undergoing PD and experienced SUD revealed progressively declining serum K concentrations at 3 months before SUD. Serum albumin concentrations also exhibited similar trends. However, synchronized data of ECG and plasma K concentrations were not obtained in our study. In addition, the definitive causes of hypokalemia in patients who were undergoing PD and experienced SUD also could not be obtained in this study. Considering serum K abnormalities, several spectra of cardiovascular diseases could be involved, including conduction defects, heart attack, and sudden cardiac death [35]. We propose that serum albumin and potassium trends in the last months could be a warning signal for SUD in patients undergoing PD.
The present study has notable limitations. First, information on the predictive performance for comorbidity on sudden death in patients undergoing dialysis is lacking. We used concordant and disconcordant variables for death prediction according to previous reports [25]. However, the tool needs to be validated further for consistent discrimination performance. Second, cardiac function and calcification scores were not comprehensively evaluated in this study. Therefore, the true influence of cardiac function on SUD in patients undergoing PD cannot be completely demonstrated in our study. Third, the sample size of SUD is relatively small, and to date, no universally accepted definition of SUD exists. Finally, this study was conducted retrospectively; therefore, anything reported in this study could be a hypothesis and prospective studies need to be conducted in the future.