New-Onset Diabetes in Peritoneal Dialysis Patients – Which Predictors Really Matter?

Worldwide, it is estimated that over 200,000 individuals with end-stage renal disease are treated with maintenance peritoneal dialysis (PD) (1). Although the total number of patients per million population treated with PD has continuously increased over the past 2 decades, the first years of the 21st century saw a declining proportional use of PD in developed countries (1). However, at least in the United States, this downward trend in proportional use has recently reversed, and recent years have seen a surge in adoption of PD among patients with end-stage renal disease, in part due to changes in reimbursement (2). In parallel, most contemporary comparative effectiveness studies published from around the world over the past decade comparing mortality among patients undergoing maintenance hemodialysis with that for patients treated with PD have either found no significant association between dialysis modality use and mortality risk, or lower risk for death for patients undergoing PD (3–5). Patients treated with PD avoid exposure to tunneled central venous catheters, do not experience treatment-related myocardial stunning, and likely have better preservation of residual kidney function compared with patients undergoing maintenance hemodialysis (6,7). Despite these putative advantages of PD relative to hemodialysis, PD-specific potential risk factors for adverse outcomes also exist. Most notably, PD entails either intermittent or continuous exposure of the peritoneal cavity to large volumes of dialysate containing 1 of 3 osmotically active agents: glucose, icodextrin, or amino acids. Because icodextrin or amino acid-containing solutions are designed to be used for only a single exchange during a 24-hour period, the vast majority of dialysate used for PD worldwide contains glucose. Use of PD thus results in significant obligatory systemic carbohydrate absorption which varies from 50 – 150 g of glucose daily depending on the specifics of the PD regimen, as well as on each patient’s peritoneal membrane solute transfer rate. For patients with pre-existing diabetes mellitus, higher PD-solution glucose concentration has been associated in clinical trials with worsened glycemic control as measured by either glycosylated hemoglobin or serum fructosamine (8,9). Of note, participants in these clinical trials were followed for a maximum of 12 months, and over that duration of follow-up, improved glycemic control did not translate into improvements in cardiac function, fat-free mass, or health-related quality of life. Indeed, although observational studies have suggested an increased risk for morbidity and mortality in diabetic PD patients with poor glycemic control, no randomized trial published to date has shown a beneficial impact of improved glycemic control or reduced glucose exposure on clinically meaningful patient outcomes (10). In contrast to such data regarding diabetic PD patients, very little is known about which patientor treatment-related factors predict the development of new-onset diabetes mellitus or impaired glucose tolerance following initiation of PD in patients without pre-existing diabetes mellitus. There are several possible mechanisms which might explain the development of new-onset diabetes or elevated fasting glucose in patients with end-stage renal disease, and these include weight gain with amelioration of uremic anorexia and protein-energy wasting, changes in insulin resistance with loss of residual kidney function, and unmasking of previously undiagnosed diabetes. Inflammation is a clearly established risk factor for impaired glucose tolerance (11), and PD patients are known to have a high burden of both systemic and intraperitoneal inflammation (12). Additionally, for patients undergoing PD, obligatory carbohydrate absorption with PD solutions has been considered to be an additional potential risk. However, 2 recent studies from Taiwan have compared the risk of new-onset diabetes mellitus among incident hemodialysis and PD patients and have found either an equivalent or lower risk among patients starting PD (13,14). Beyond this comparison with hemodialysis, however, there remains a substantial gap in understanding regarding risk factors and predictors of new-onset diabetes for patients initiating PD therapy. It is within this context that Dong and colleagues report, in this issue of Peritoneal Dialysis International, their findings from a prospective cohort study investigating baseline and time-varying predictors of new-onset diabetes or impaired glucose tolerance in incident PD patients at a single center in China (15). Baseline information on demographics and coexisting illnesses was collected immediately prior to PD catheter placement. Laboratory measurements, blood pressure, dialysis regimen, and dietary parameters were recorded within the first 3 months after initiation of PD, and subsequent values were averaged for each 6-month period of follow-up. Laboratory measurements included markers of systemic inflammation, including C-reactive protein. Twenty-four-hour glucose absorption via dialysate was calculated for each patient at least every 3 months, with subsequent calculation of dialysate energy absorption. Patients also completed multi-day food diaries to allow calculation of time-varying dietary carbohydrate intake. Perhaps most importantly, the authors used a rigorous definition of a composite outcome of new-onset diabetes or impaired glucose tolerance endorsed by the American Diabetes Association, which included a true fasting plasma glucose or an oral glucose tolerance test (16). Fasting plasma glucose values were measured after a 10-hour period in which the