The goals of diabetes care for patients with CKD/end-stage renal disease (ESRD) would seem to be similar to the goals of care for diabetic patients in general: control of hyperglycemia and its symptoms, prevention of microvascular and macrovascular complications, maintenance of overall health status and quality of life, and avoidance of hypoglycemia.
Whether glycemic control is beneficial in those with advanced CKD/ESRD, comorbidities, and reduced life expectancy remains unclear at this time. Numerous evidence-based guidelines exist for the general diabetic population, but none has targeted the diabetic CKD/ESRD population.
What is clear is that the pathophysiology of glucose homeostasis in kidney patients is complex, kidney impairment complicates the use of diabetes medications, and hyperglycemia is competing with other determinants of morbidity and mortality in the diabetic ESRD patient.
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While the nephrology community’s recent attention to managing hyperglycemia is appropriate, developing an approach to glycemic management for diabetic kidney patients must start with the basics: (1) finding a way to evaluate glucose control, (2) establishing the target range for glycemic control, and (3) identifying the risks of aggressive glycemic lowering.
Evaluating control
Accurate long-term determination of glycemia is essential to complement daily glucose monitoring, evaluate clinical outcomes, and assess new therapies in diabetes. In the general diabetic population, hemoglobin A1c (HbA1c), which integrates fasting and postprandial glucose levels over the preceding three months, is the standard metric for monitoring glycemic control.
A strong positive relationship exists between HbA1c and mean plasma glucose levels in the general population, with each one percentage point rise in HbA1c reflecting a change of about 35 mg/dL in mean plasma glucose. Guidelines recommend measuring HbA1c twice a year in stable patients who are achieving their glycemic goals and four times a year in those who are not reaching their glycemic goals or whose therapy has changed.
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for diabetic kidney disease acknowledge that data for monitoring glycemia in patients with kidney impairment are severely lacking. In addition, there is growing concern that in the presence of kidney impairment or dialysis, HbA1c does not reliably represent the true glycemic state, correlating poorly with prevailing glycemia and probably underestimating it.
For example, the U.S. Renal Data System (USRDS) report for 2008 noted that the prevalence of patients with HbA1c levels higher than the 7% target was 63% for CKD stages 1 to 2 and fell to 46% in CKD stages 3 to 4. Observational ESRD data suggest a poor correlation with mean glucose levels. In our large national database analysis, the mean HbA1c value was 6.77%, and values were higher than 7.0% in only 35% of patients; the correlation with available random glucose levels was relatively poor.
Two alternatives to HbA1c, glycated albumin and fructosamine, continue to be investigated but remain hampered by poor availability. The mechanism of glycation with albumin is similar to that with hemoglobin and accounts for most of the serum glycated proteins. Because the turnover of serum albumin is shorter (half-life 14-20 days), glycated albumin reflects a shorter glucose exposure. Peacock et al found that ratios of glycated albumin to HbA1c were about 30% higher in hemodialysis (HD) patients, presumably because of lower HbA1c values (Kidney Int. 2008;73:1062-1068).
Inaba and colleagues have attributed this clinical variability to the presence of younger erythrocytes in the blood (the percentage of HbA1c is higher in older cells), a consequence of the shortened RBC life span seen in diabetes and uremia and nearly universal use of erythropoietin (J Am Soc Nephrol. 2007;18:896-903).
While not influenced by dialysis or erythropoietin, the precision of glycated albumin may be limited in states of protein turnover or proteinuria. Inaba et al deemed the accuracy of glycated albumin superior to HbA1c, as did Abe and Matsumoto (Nat Clin Pract Nephrol. 2008;4:482-483). Clinical correlations remain unproven, however, and targets are not established. Fructosamine represents a second general measure of glycated serum proteins and has good correlation with glucose and HbA1c levels.
However, fructosamine reflects glycemia over about one-fourth the span of HbA1c and may be affected by protein levels as well as hyperuricemia. The reliability of this marker in renal failure has not been evaluated.
Target range
Hyperglycemia is the sine qua non of the diabetic state and plays a central role in the development of diabetes complications. In the general diabetic population, any drop in HbA1c level reduces the risk of complications. For several years, the American Diabetes Association (ADA) has acknowledged the limitations of available data regarding the benefits/risks of glycemic control in patients whose diabetic complications are already advanced and suggested that less stringent HbA1c targets might apply to patients with reduced life expectancy.
A broader assessment of the likelihood that a patient’s diabetic microvascular and macrovascular complications will worsen, of the extent of comorbidities, of life expectancy, and of the risks of hypoglycemia is supported by recent American College of Physicians (ACP) guidelines.
ACP guidelines indicate the complexity of setting targets for patients with advanced diabetic kidney disease. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) showed that effective glycemic control in patients with early stages of diabetes mellitus improved outcomes, including microvascular complications and, with less certainty, cardiovascular mortality.
However, outcomes in patients with more advanced diabetes appear to be less responsive. The approach to glycemic targets in diabetic CKD has been further tempered in recent years by clinical trials involving cardiovascular disease and kidney patients.
