Although diabetes is the most common cause of end-stage renal disease (ESRD) worldwide, accounting for 44.2% of ESRD patients in the US Renal Data System in 2005,1 data are scarce on how diabetes should best be treated in patients in ESRD.
We do know that blood glucose levels need to be well controlled in these patients. Several observational studies and one nonrandomized interventional study2–10 showed that higher levels of hemoglobin A1c were associated with higher death rates in patients with diabetes and chronic kidney disease after adjusting for markers of inflammation and malnutrition.
However, ESRD significantly alters glycemic control, the results of hemoglobin A1c testing, and the excretion of antidiabetic medications. The various and opposing effects of ESRD and dialysis can make blood glucose levels fluctuate widely, placing patients at risk of hypoglycemia—and presenting a challenge for nephrologists and internists.
In this review, we summarize the available evidence and make practical recommendations for managing diabetes in patients on hemodialysis.
GLUCOSE LEVELS MAY FLUCTUATE WIDELY
In ESRD, both uremia and dialysis can complicate glycemic control by affecting the secretion, clearance, and peripheral tissue sensitivity of insulin.
Several factors, including uremic toxins, may increase insulin resistance in ESRD, leading to a blunted ability to suppress hepatic gluconeogenesis and regulate peripheral glucose utilization. In type 2 diabetes without kidney disease, insulin resistance leads to increased insulin secretion. This does not occur in ESRD because of concomitant metabolic acidosis, deficiency of 1,25 dihydroxyvitamin D, and secondary hyperparathyroidism.11,12 Hemodialysis further alters insulin secretion, clearance, and resistance as the result of periodic improvement in uremia, acidosis, and phosphate handling.
The dextrose concentration in the dialysate can also affect glucose control. In general, dialysates with lower dextrose concentrations are used and may be associated with hypoglycemia. Conversely, dialysates with higher dextrose concentrations are occasionally used in peritoneal dialysis to increase ultrafiltration, but this can lead to hyperglycemia.10,13
Thus, ESRD and hemodialysis exert opposing forces on insulin secretion, action, and metabolism, often creating unpredictable serum glucose values. For example, one would think that a patient who has insulin resistance would need more supplemental insulin; however, the reduced renal gluconeogenesis and insulin clearance seen in ESRD may result in variable net effects in different patients. In addition, ESRD and hemodialysis alter the pharmacokinetics of diabetic medications. Together, all of these factors contribute to wide fluctuations in glucose levels and increase the risk of hypoglycemic events.
HEMOGLOBIN A1c MAY BE FALSELY HIGH
Self-monitoring of blood glucose plus serial hemoglobin A1c measurements are the standard of care in diabetic patients without renal failure.
However, in diabetic patients with ESRD, elevated blood urea nitrogen causes formation of carbamylated hemoglobin, which is indistinguishable from glycosylated hemoglobin by electrical-charge-based assays and can cause the hemoglobin A1c measurement to be falsely elevated. Other factors such as the shorter red life span of red blood cells, iron deficiency, recent transfusion, and use of erythropoietin-stimulating agents may also cause underestimation of glucose control.14
Despite these limitations, the hemoglobin A1c level is considered a reasonable measure of glycemic control in ESRD. Glycated fructosamine and albumin are other measures of glycemic control with some advantages over hemoglobin A1c in dialysis patients. However, they are not readily available and can be affected by conditions that alter protein metabolism, including ESRD.15–18
Self-monitoring of blood glucose and continuous glucose monitoring systems provide real-time assessments of glycemic control, but both have limitations. Self-monitoring is subject to errors from poor technique, problems with the meters and strips, and lower sensitivity in measuring low blood glucose levels. Continuous monitoring is expensive and is less reliable at lower glucose concentrations, and thus it needs to be used in conjunction with other measures of glucose control. For these reasons, continuous glucose monitoring is not yet widely used.
The guidelines of the 2005 National Kidney Foundation Kidney Disease Outcomes Quality Initiative did not clearly establish a target hemoglobin A1c level for patients with diabetes and ESRD, but levels of 6% to 7% appear to be safe. The target fasting plasma glucose level should be lower than 140 mg/dL, and the target postprandial glucose level should be lower than 200 mg/dL.19