Glycemic Control in PD

Introduction  

Diabetes Mellitus (DM) is a potent cardiovascular risk factor in the general population as well as in those undergoing maintenance dialysis (1–5). Glycemic control, as measured by glycosylated hemoglobin (A1c) is a predictor of cardiovascular complications, including myocardial infarctions and hospitalizations for coronary artery disease (6,7). Clinical trials have shown that tight glycemic control decreases the risk of developing retinopathy, nephropathy, and neuropathy in the general population. However, there are limited studies that have investigated the impact of glycemic control in diabetic patients especially on peritoneal dialysis (PD) (8–10). Nonetheless, it has been shown that diabetes mellitus (DM) is a significant cause of kidney failure (11). Expert groups have recommended that diabetic dialysis patients should follow the American Diabetes Association guidelines; however, there is no consistent evidence to support these recommendations for patients with end-stage renal disease (ESRD), and the data for patients treated with peritoneal dialysis (PD) are even more limited (11–13). 

Measures of glycemic control in PD patients 

Current parameters used to assess glycemic control in diabetic patients include, but are not limited to, blood or capillary plasma glucose, glycated hemoglobin (HbA1c) and glycated albumin (14,15). Hemoglobin A1c (HbA1c) is the standard measure for glucose monitoring in patients without kidney impairment. According to NKF-KDOQI guidelines, currently recommended HbA1c targets in the setting of CKD are no different from those for the general diabetic population; that is, <7.0%, although the seminal glycemic control trials in type 1 and type 2 diabetes have excluded patients with significantly decreased kidney function (11). There are several issues unique to the dialysis population that mandates a separate examination of the glycemic control on outcomes in this population. Chronic kidney disease is associated with insulin resistance and, in advanced kidney disease, decreased insulin degradation (16). Moreover, it is difficult to accurately assess glycemic control in the ESRD population due to alterations in insulin metabolism and changes in red blood cell survival that lead to competing effects on measurements of glycemic control (16,17). 

Importance of glycemic control 

Duong et al. examined mortality and its predictability in 2,798 diabetic peritoneal dialysis patients by measuring HbA1c levels (9). They determined that poor glycemic control was associated with higher mortality in peritoneal dialysis patients, and that moderate to severe hyperglycemia was associated with a higher death risk. Data from Yoo and colleagues support these results (10). Peritoneal dialysis can result in a large amount of glucose absorption from the dialysate; therefore, strict glycemic control may be difficult in PD patients (22,23). Concerning peritoneal dialysis associated infections, poor glycemic control has not been established as a specific risk factor; however, it is known to increase the risk of infections in the general DM population (24). Recurrent peritonitis and inflammatory processes can increase peritoneal transport rates and cause rapid absorption of glucose from the peritoneal cavity which may, in turn, cause deterioration of glycemic control (25). This could lead to reduced ultrafiltration, requiring administration of increasingly hypertonic peritoneal dialysis solutions and, consequently, the perpetuation of hyperglycemia. It is suggested that glycemic control, measured by HbA1c, is not associated with preservation of residual renal function in diabetic peritoneal dialysis patients, at least in the first year on PD as reported in a study by Sung et al (26). However, this study included only 89 patients and was not sufficiently powered to detect a difference. Based on the currently available evidence from clinical studies, it is not known if better glycemic control preserves residual function (20). Regular and frequent monitoring of blood glucose, frequent and effective adjustment of therapy, and early diagnosis and treatment of concurrent conditions are essential. 

Recommendations for glycemic control in PD 

The KDOQI guidelines recommend that hyperglycemia be managed in diabetic patients regardless of kidney function status (11). Intensive treatment of hyperglycemia can help to prevent or delay kidney disease (11). The KDOQI workgroup suggests maintaining pre–prandial capillary glucose levels within 90-130 mg/dL (5.0-7.2 mmol/L), with postprandial sugars below 180 mg/dL (10 mmol/L) and an HbA1c of approximately 7%, which is consistent with the American Diabetes Association (ADA) guidelines (14). The ADA also recommends that blood sugar monitoring be conducted at least three times per day, before meals and at bedtime.  

When compared to diabetic hemodialysis patients, diabetic peritoneal dialysis patients demonstrated better outcomes in a study by Lin et al. (27). However, Vonesh et al. showed that peritoneal dialysis was favored in younger diabetic patients while hemodialysis was favored in older diabetic patients (28). These studies demonstrate that any given dialysis therapy is not necessarily recommended over another and must be tailored to each individual patient. In order to achieve osmotic removal of retained fluid, peritoneal dialysis fluids contain supraphysiological concentrations of glucose. Time coupled with progressive loss of diuresis from the failing kidneys results in the average glucose concentration of the peritoneal dialysis prescription being increased. The potential for this glucose load to cause problems such as obesity, hyperlipidemia, potential worsening of insulin resistance, and blood glucose level fluctuations has led to the production of biocompatible alternatives PD solutions (29).  

Biocompatible solutions have been shown to alleviate undesirable local and/or systemic effects while providing necessary therapy (30,31). Some biocompatible PD solutions use a glucose polymer, or amino acids as the alternative osmotic agent instead of glucose, thus preventing or minimizing glucose absorption during treatment (32,33). Two randomized clinical studies with at least 1 year of follow-up using a polyglucose-based PD solution in diabetic patients showed significant improvements in glycemic control and reduced insulin requirements (34,35). However, no effect on survival or mortality was found in several randomized controlled trials (36,37). 

Glycemic control through pharmaceutical intervention is a part of therapy in diabetic peritoneal dialysis patients (25,38–47). Doses and regimens tend to vary and should be adjusted based on frequent monitoring by the physician, with the aim of achieving target goals of glycemic control. The presence of insulin resistance is a prevalent metabolic feature in chronic kidney disease (CKD) and it should be considered when evaluating therapy (48). The clinical impacts of insulin resistance in this setting are numerous, including endothelial dysfunction, increased cardiovascular mortality, muscle wasting, and possibly initiation and progression of CKD (49).  Regarding intraperitoneal (IP) versus subcutaneous (SC) insulin administration, a meta-analysis of three studies found that glycemic control, as determined by HbA1c in diabetic CAPD patients, was comparable or better with IP versus SC insulin ; however, the dose required was more than two-fold higher in the IP treatment (45).  

Overall, therapy for glycemic control in peritoneal dialysis patients should be individualized according to patient preference, compliance, peritoneal transport status, and coexisting co-morbid conditions. 

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