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Glycemic Control and Burnt-Out Diabetes in ESRD Csaba P. Kovesdy,*† Jong C. Park,‡ and Kamyar Kalantar-Zadeh‡§ *Division of Nephrology, Salem Veterans Affairs Medical Center, Salem, Virginia, †Division of Nephrology, University of Virginia, Charlottesville, Virginia, ‡Division of Nephrology and Hypertension, Harold Simmons Center for Chronic Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, and §David Geffen School of Medicine at UCLA, Los Angeles, California ABSTRACT Treatment of early diabetes mellitus, the most common cause of chronic kidney disease (CKD), may prevent or slow the progression of diabetic nephropathy and lower mortality and the incidence of cardiovascular disease in the general diabetic population and in patients with early stages of CKD. It is unclear whether glycemic control in patients with advanced CKD, including those with end-stage renal disease (ESRD) who undergo maintenance dialysis treatment is beneficial. Aside from the uncertain benefits of treatment in ESRD, hypo- glycemic interventions in this population are also complicated by the complex changes in glucose homeostasis related to decreased kidney function and to dialytic therapies, occasion- ally leading to spontaneous resolution of hyperglycemia and normalization of hemoglobin A1c levels, a condition which might be termed ‘‘burnt-out diabetes.’’ Further difficulties in ESRD are posed by the complicated pharmacokinetics of antidiabetic medications and the serious flaws in our available diagnostic tools used for monitoring long-term glycemic control.We review the physiology and pathophysiology of glu- cose homeostasis in advanced CKD and ESRD, the available antidiabetic medications and their specifics related to kidney function, and the diagnostic tools used to monitor the severity of hyperglycemia and the therapeutic effects of available treat- ments, along with their deficiencies in ESRD. We also review the concept of burnt-out diabetes and summarize the findings of studies that examined outcomes related to glycemic control in diabetic ESRD patients, and emphasize areas in need of further research. There are currently�400,000 Americans with chronic kidney disease (CKD) stage 5, a.k.a., end-stage renal disease (ESRD), who are dependent on maintenance hemodialysis (MHD) (�92%) or continuous peritoneal dialysis (CPD) (�8%) for their survival (1). According to US Renal Data System (USRDS) estimates, the number of ESRD patients will surpass one-half million during the 2010s (2). These individuals experience a low quality of life, high hospitalization rates and a 20–25% annual mortality rate, in spite of recent advances in dialysis treatment and technique (1). Approximately two-thirds of all dialysis patients die within 5 years of initiation of dialysis treatment, a 5-year survival worse than that expected in themajority of patients with cancer (3). Almost half of all CPD andMHD patients presum- ably die of CV diseases (1). Diabetes mellitus (DM) is the leading cause of CKD including ESRD in the US and most industrialized nations (1,4). The proportion of incident diabetic dialysis patients in the US has increased from<30% in late 1980s to 50% or higher in 2006 (1). Most studies indicate higher comorbidity and poorer outcomes in diabetic dialysis patients as compared with nondiabetic subjects (5–7), but a large observational study of Medi- care beneficiaries showed that while diabetic patients without CKD have significantly worse survival than their nondiabetic counterparts, among those with CKD the mortality is almost equally high in both diabetic and nondiabetic patients (8). While strict glucose control in patients with normal kidney function and early stages of DM can result in significant clinical benefits including improved cardio- vascular mortality (9,10) and better renal outcomes (11–16), similar interventions in patients with more advanced DM have produced disappointing results, including in some cases worse outcomes in patients who achieved strict glucose control (17–19). As a result a more nuanced view of glycemic control may be emerging, with individual patient characteristics deter- mining what therapeutic targets and treatment regi- mens to be pursued. The issue of long-term outcomes as a function of diabetes control is especially complicated in patients with ESRD in whom there are complex changes affect- ing glucose homeostasis, independent of the usual diabetic pathophysiology. It is currently unclear whether the altered glucose homeostasis in ESRD combined with medical management of DM has any significant bearing Address correspondence to: Csaba P. Kovesdy, MD, Salem VAMC (111D), 1970 Roanoke Blvd., Salem, VA 24153, Tel.: +1-540-982-2463, Fax: +1-540-224-1963, or e-mail: csaba.kovesdy@va.gov. Seminars in Dialysis—Vol 23, No 2 (March–April) 2010 pp. 148–156 DOI: 10.1111/j.1525-139X.2010.00701.x ª 2010 Wiley Periodicals, Inc. IMPROVING OUTCOMES FOR DIABETIC PATIENTS ON DIALYSIS 148 on clinical outcomes of diabetic dialysis patients (20). Indeed, some diabetic ESRDpatients experience sponta- neous improvement in their glycemic control that can occasionally return them to normoglycemia. The occur- rence of such ‘‘burnt-out’’ diabetes in ESRD (21) may necessitate the dissociation of the diagnosis of DM (which includes individuals with blood sugar levels rang- ing from normal to elevated) from that of hyperglyce- mia, which may occur in some diabetic patients, but could also be a de novo ESRD-related phenomenon (22). We review the unique features of DM in ESRD, examine available data on the importance or lack thereof of glycemic control in achieving better survival in this patient population, and examine potential causes and consequences of burnt-out diabetes. We also briefly review ESRD-specific aspects of antidiabetic pharmaceuticals. Glycemic Control in ESRD: The Concept of Burnt-Out Diabetes While diabetes is one of the most important causes of CKD, the gradual decline in kidney function in itself causes significant changes that alter glucose homeostasis in patients with kidney disease (23). Abnormal glycemic control has been described as a complication of advanced CKD (24) independent of underlying diabetic status, as even nondiabetic patients with CKD can dis- play mild fasting hyperglycemia and abnormal glucose tolerance (22). Interestingly enough although, in some patients with establishedDMadecline in insulin require- ments and even spontaneous hypoglycemia can also occur with advancing stages of CKD (22,25). A recent 2-year cohort study of 23,618 diabetic hemodialysis patients showed that 33% of them had A1c levels <6% (26). Although in this cohort higher A1c values were incrementally associated with increased death risk after controlling for demographics and other confounders, low A1c, especially if below 5%, was also associated with poor survival. This nationally representative study shows that approximately one-third of all prevalent dia- betic hemodialysis patients in the United States have a normal to low A1c level despite the fact that they sustained ESRD as a result of diabetic nephropathy (26). The reason for these alterations in glucose homeosta- sis are multifactorial and involve various mechanisms related to both decreased kidney function and dialytic therapies (Table 1) (23). Once GFR declines below 15–20 ml ⁄min, the renal clearance of insulin decreases significantly (22). Concomitantly, hepatic clearance of insulin also declines, likely because of the inhibitory effect of unidentified uremic toxin(s), as the initiation of dialysis seems tomitigate this effect (22). Counterbalanc- ing diminished insulin clearance is lower insulin produc- tion and increased insulin resistance. The exact reason(s) for the diminished insulin secretion is unclear; it may be because of hyperparathyroidism and activated vitamin D deficiency, as insulin secretion appears to improve after the treatment of hyperparathyroidism and after administration of activated vitamin D (27–31). Although activated vitamin D can lower parathyroid hormone (PTH) levels, its effect on insulin secretion is believed to be independent of the PTH lowering effect (31), and may be one of the explanations for the improved outcomes associated with these medications (32,33). The cause of increased insulin resistance in ESRD is also not fully clarified. It may be related to another unspecified uremic toxin possibly acting on the muscle tissue (34–36), as insulin sensitivity is improved with dialysis (37–41). The consequences of insulin resistance and deficiency in ESRD are complex and reach beyond glucose homeostasis, as they are associated with muscle protein breakdown through the ubiqu- itin–proteasome pathway (42,43) via suppression of phosphatidylinositol-3 kinase (44,45), thus contribut- ing to a state of protein-energy wasting which may also play a major role in the higher mortality seen in this population. Decreased kidney function is also associated with deficient renal gluconeogenesis (46), which along with malnutrition, deficient catecholamine release and impaired renal insulin degradation and clearance can contribute to a lower threshold for clinical hypoglycemia (25). Aside from the salutary effects of dialytic therapies on insulin production and sensitivity (37–40), these treatments can complicate the management of diabe- tes by the glucose load provided by both hemo- and peritoneal dialysis. The latter especially can result in significantly higher glucose loads if higher dialysate concentrations are required to achieve ultrafiltration goals. The impact of the often significant glucose load delivered by peritoneal dialysis [which can be as much as 10–30% of total energy intake (47)] is complex. In spite of the added nutritional value of glucose the total nutrient intake of these patients is often below ideal (48), possibly because of a loss of appetite related to continuous glucose absorption (49–51) and the mechanical effects of large filling volumes (in the case of PD) (52). Glucose absorbed during dialysis could at the same time lower patients’ energy TABLE 1. Possible causes of the ‘‘burnt-out diabetes’’ in maintenance dialysis patients (adapted from ref. 21) 1. Decreased renal clearance of insulin 2. Decreased hepatic clearance of insulin 3. Impaired renal insulin degradation 4. Increased insulin half-lifea 5. Decline in renal gluconeogenesis 6. Deficient catecholamine release 7. Other impacts of uremia on glucose homeostasis 8. Diminished food intake because of anorexia, diabetic gastroparesis, etc. 9. Protein-energy wasting (malnutrition–inflammation complex) 10. Loss of body weight and fat mass 11. Comorbid conditions 12. Hypoglycemia during hemodialysis treatments 13. Effects of peritoneal dialysis on glucose metabolism 14. Prescribed medications 15. Imposed dietary restrictions 16. Apparently low A1c because of confounding by uremia or anemia aBecause of conditions other than those under 1 through 3. GLYCEMIC CONTROL IN ESRD 149 expenditure (53), limit amino acid losses and stimu- late insulin secretion (54). The practical significance of the listed changes in glucose homeostasis in ESRD remains unclear. While changes inducing worsening hyperglycemia would result in heightened efforts to better control the blood sugar of such patients, it is less clear what approach has to be taken in the considerable number of dialysis patients whose A1c decreases to levels approaching normalcy (26). It is not entirely clear what distinguishes such patients with normoglycemic or ‘‘burnt-out’’ dia- betes from their counterparts who continue to display hyperglycemia, and studying them may offer further insights into the natural course of diabetes not only in dialysis patients but also in other populations such as those suffering from chronic illnesses (55) or in the elderly, who may experience an altered course of this disease. While in today’s benchmark-driven environ- ment a lower A1c may be perceived as advantageous, we believe that patients with burnt-out diabetes may on the contrary be at higher risk for poor outcomes including mortality. The advantages of a normal blood sugar level likely take a very long time to become mani- fest (56,57), and on the short run these patients may in fact be more prone to develop clinically relevant hypoglycemic episodes. Observational studies in dialy- sis patients indeed suggest that patients with the lowest A1c levels suffer significantly higher mortality rates (26), thus emphasizing the need to relate to burnt-out diabetes as a complication of a disease (ESRD) rather than as a benefit of it. Diagnostic Tests of Glycemic Control in ESRD There have been ongoing questions about what the most reliable marker of long-term glycemic control is in these patients. HbA1c has long been the assay of choice for determining long-term glycemic control among dia- betic dialysis patients. Glycated hemoglobin refers to a series of minor hemoglobin components formed by the adduction of various carbohydrate molecules to hemoglobin. The minor fractions include HbA1a, HbA1b, and HbA1c (58). HbA1c, the largest fraction, is the most consistent index of the prevailing ambient concentration of circu- lating glucose (59). Glycation rate is determined by temperature, pH, hemoglobin concentration, glucose concentration, and length of exposure to glucose. There are various glycated hemoglobin assays avail- able with normal ranges that vary between laborato- ries so that test results may not be directly comparable. HbA1c measurements can be confounded in the ure- mic milieu, by formation of carbamylated hemoglobin (60) or by metabolic acidosis which increase the rate of HbAlc formation (61), but the practical significance of these have been questioned (62,63). Other factors that could affect HbAlc levels in patients on dialysis include a shortened erythrocyte life span, blood transfusion, and accelerated erythropoesis because of routine use of erythropoietin. However, the life span of erythrocyte is close to normal in well dialyzed patients treated with ertythropoesis stimulating agents and routine blood transfusions are rarely needed nowadays. HbA1c was found to underestimate glucose measurements in diabetic patients on hemodialysis because of anemia and use of erythropoietin compared with glycated albumin (64–67); there have been recent suggestions to use a correction factor based on the degree of anemia and the erythropoietin dosage (65). Aside from all the above limitations, HbAlc is still considered to be a reasonable index of glycemic control even in patients with ESRD (68–71). The uses of other marker of long-term glycemic con- trol that are devoid of HbAlc’s drawbacks in dialysis patients have been proposed. Fructosamine is formed by the nonenzymatic reaction between fructose and ammonia or an amine and can form when the carbonyl group of glucose reacts with an amino group of a pro- tein. Therefore, fructosamine is a general measure of glycated serum proteins, 90% of which is represented by glycated albumin (72). Fructosamine level correlates well with measurements of mean blood glucose and HbAlc (73); it has therefore been suggested as an alter- native method for monitoring glycemic control in dia- betes patients. Fructosamine level reflects integrated glycemia during a period of 2–3 weeks compared with 2–3 months for HbAlc (74). Thus, fructosamine may be a better choice in situations when HbA1c cannot be reliably measured. As with HbAlc, fructosamine level may be less reliable in renal failure (69,75), and may not be superior to HbA1c in diabetic patients with ESRD (69,71). High urate levels often seen in patients with CKD may interfere with the fructosamine assay and levels may be falsely low with decreased protein levels such as nephrotic syndrome or liver disease, and also affected by increased protein turnover related to dialysis (20). Use of this marker is further hampered by its lack of availability in routine practice and the lack of established reference levels. Glycated albumin and the percentage of glycated albumin have also received much attention lately as a potentially more accurate measure of glycemic con- trol in diabetic hemodialysis patients. Glycated albu- min was a more accurate measure of glycemic control in two recent studies (64,66). In both of these studies, HbAlc underestimated blood glucose levels in diabetic hemodialysis patients mainly because of erythropoietin use and anemia. In addition to being a significant marker of hyperglycemia in diabetic patients on hemodialysis, higher glycated albumin is also associated with diabetic complications such as increased arterial stiffness (76), peripheral vascular calcification (77), and increased cardiovascular mor- bidity and shortened survival in diabetic patients with ESRD (78,79). It is unclear, however, what therapeu- tic target level of glycated albumin has to be used for glycemic control, and in what stages of CKD its application has to replace or supplement HbAlc. Glycated albumin has limitations in diabetic patients on peritoneal dialysis because of increased albumin turnover, and in nonoliguric patients with significant proteinuria. 150 Kovesdy et al. Antidiabetic Drugs in ESRD The complex pathophysiology of glucose and insulin homeostasis and the imperfect diagnostic and monitor- ing tools available in patient with ESRD make therapy aimed at glycemic control in these patients challenging. Therapeutic interventions are made even more compli- cated by concomitant comorbidities such as sepsis, mal- nutrition, liver disease, and congestive heart failure that could exacerbate hypoglycemia (25), and also by the pharmacokinetic alterations caused by the decrease (or lack) of kidney function. The medications used to treat DMcan be affected in CKDandESRD (Table 2). Insulin Therapy Insulin requirements usually diminish as kidney function declines, but no uniform recipe can be provided for dose adjustment, which has to be individ- ualized. Patients receiving PD are in a unique situation as they can receive insulin by injection into their dialy- sate. One advantage of this approach is that intraperi- toneal delivery of insulin provides a more reliable and more physiologic delivery of insulin when compared with the subcutaneous route. Direct insulin delivery to the liver stimulates endogenous insulin secretion and inhibits hepatic gluconeogenesis and ketogenesis when compared with the subcutaneous route (80), and has been reported to result in better insulin sensitivity (38). Peritoneal insulin delivery can result in fewer hyper- and hypoglycemic episodes and results in smaller diur- nal variation in blood glucose levels (81,82). Potential disadvantages of intraperitoneal insulin delivery include the possibility of an increased incidence of peritonitis (83), lowered plasma HDL levels (84), and rare reports of subcapsular hepatic steatonecrosis (85) and malignant omentum syndrome (86). Controlled clinical trials would be needed to fully describe the net impact of intraperitoneal insulin administration in PD. Oral (and Other) Antidiabetics The number of noninsulin type antidiabetic medica- tions (which are no longer exclusively oral, Table 2) has proliferated in the past decade. These medications depend on renal excretion to various extents; hence they may or may not require adjustments with advanc- ing stages of CKD. Biguanides (metformin) represent a special category in that they have to be withheld in patients with an even modest decline of kidney func- tion (the exact degree of which remains ill-defined), because of the rare but potentially fatal lactic acidosis caused by the accumulation of this drug (87). The other hypoglycemic agents may or may not require dose adjustments, as shown in Table 2. Unfortunately, there is no uniformity in how kidney function is quan- tified