REVIEW DIABETES IN THE RENAL TRANSPLANT PATIENT: A PRIMER FOR NEPHROLOGY TRANSPLANT CLINICIANS. Alan Wilkinson, MD* ABSTRACT INTRODUCTION

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1 DIABETES IN THE RENAL TRANSPLANT PATIENT: A PRIMER FOR NEPHROLOGY TRANSPLANT CLINICIANS Alan Wilkinson, MD* ABSTRACT Diabetes mellitus type 2 (DMT2) with onset after transplantation (new-onset diabetes after transplantation [NODAT]) is among the most significant threats to health following kidney transplantation. This article discusses the epidemiology, consequences, diagnosis, and management of NODAT in the renal transplant recipient. The incidence of new-onset diabetes after kidney transplantation ranges from approximately 2% to 25% with current immunosuppressive regimens, but rates as high as 46% were reported with earlier, more diabetogenic regimens. Consequences of NODAT include heightened risk of cardiovascular disease and cardiovascular death, microvascular complications, and reduced graft survival. The etiology of NODAT is not definitively known and is probably multifactorial, involving genetic, biologic, and environmental factors. Many of the risk factors for NODAT are the same as those for DMT2 in the general population. Other risk factors for NODAT are specific to transplantation. For example, specific immunosuppressive drugs used to prevent graft rejection are major contributors to the development of diabetes. NODAT and its deleterious effects can be mitigated through judicious selection of immunosuppressive therapy, maintenance of a healthy body weight, regular physical activity, and pharmacologic and nonpharmacologic control of hypertension and dyslipidemia. Given the contribution of specific immunotherapies to development of NODAT, judicious selection of immunosuppressive therapy is *Professor of Medicine, Director, UCLA Kidney and Kidney/Pancreas Transplantation, University of Californ i a, Los Angeles. A d d ress correspondence: Alan Wilkinson, MD, Pro f e s s o r of Medicine, Dire c t o r, UCLA Kidney and Kidney/Pancre a s Transplantation, UCLA Med-Neph, Box , Suite , 200 Medl Plz, Los Angeles, CA awilkinson@mednet.ucla.edu. one of the most important means of modifying risk of NODAT. Selection of immunosuppressive therapy for the recipient of a kidney transplant entails careful consideration of the benefits of effective immunosuppression and the diabetogenic risks of therapy in the context of patient-specific factors, including immunological, cardiovascular, and metabolic risk profiles. (Adv Stud Med. 2007;7(6): ) INTRODUCTION Improvements in immunosuppressive therapy have reduced the incidence of graft rejection and enhanced patient survival after kidney transplantation. Death with a functioning graft rather than graft rejection is now the most common cause of graft loss. 1 However, the longevity of patients with kidney transplants is still reduced relative to that of the general population. Early mortality among renal transplant recipients is largely attributed to cardiovascular disease and diabetes mellitus type 2 (DMT2), which occur more frequently in renal transplant recipients than in the general population and are among the most significant threats to patients health after kidney transplantation. 2,3 Further advances in long-term outcomes after kidney transplantation depend on effective prevention and control of cardiovascular and metabolic disease. Highly pre valent in Western countries, DMT2 or its p re c u r s o r, prediabetes, is often present before kidney t r a n s p l a n t a t i o n. 4 Howe ve r, kidney transplantation is also frequently complicated by new-onset diabetes ( N O D AT) that is secondary to factors such as use of i m m u n o s u p p re s s i ve therapy to pre vent organ re j e c t i o n. 5 This article discusses the epidemiology, consequences, diagnosis, and management of NODAT in the re n a l transplant recipient. It is also important to stress that the risk of many of the complications of DMT2 are a l ready increased in those with impaired fasting glucose Johns Hopkins Advanced Studies in Medicine 179

2 re l a t i ve to the general population. The overall incidence of transplant-associated hyperglycemia (NODAT and i m p a i red fasting glucose) is extremely high, and the impact of impaired fasting glucose should not be forgotten when managing these patients. DEFINITION Diabetes is a metabolic disease in which defects in insulin action cause the body to process carbohyd r a t e s, lipids, and proteins in an abnormal manner. The 2 prim a ry metabolic abnormalities in DMT2 impaire d insulin secretion and insulin resistance (ie, deficient response of tissues to insulin) cause defective metabolism of carbohydrates, lipids, and amino acids, and re s u l t in hyperglycemia, the cardinal sign of DMT2. 6 T h e metabolic precursor of diabetes is impaired glucose tolerance, which is diagnosed in the presence of impaire d fasting glucose and when postprandial blood glucose l e vels are elevated (ie, mg/dl) but not high enough to meet criteria for diabetes (ie, >200 mg/dl). 7 INCIDENCE The incidence of NODAT in renal transplant recipients varies from study to study, depending on factors such as the study sample, the definition of diabetes, duration of follow-up, and the pattern of use of i m m u n o s u p p re s s i ve therapy. 1, 2, 5 The incidence of NODAT after kidney transplantation ranges from approximately 2% to 25% with current immunosuppressive regimens, but rates as high as 46% were reported with earlier, more diabetogenic regimens. 5 A US Renal Data System study of individuals who received their first kidney transplant in 1996 to 2000 was one of the most comprehensive recent assessments of the incidence of NODAT. It found that the cumulative incidences of NODAT were 9.1%, 16.0%, and 24.0% at 3, 12, and 36 months after transplant, respectively. 8 CONSEQUENCES Consequences of NODAT include a heightened risk of card i ovascular disease and card i ovascular death, m i c rovascular complications, and reduced graft surv i va l. CARDIOVASCULAR CONSEQUENCES Patients with DMT2 are at high risk of card i ova s- cular morbidity and mort a l i t y. Compared with individuals without diabetes, patients with diabetes are 3 to 5 times more likely to develop card i ovascular dise a s e. 9 C a rd i ovascular disease is the most common cause of death in diabetic adults. Eight of 10 deaths among those with diabetes are caused by card i ova s c u- lar disease Patients with DMT2 are significantly m o re likely to experience adverse card i ova s c u l a r e vents, including death, than those without diabetes. In fact, patients with diabetes and no history of card i ovascular disease are at least as likely to experience fatal or nonfatal cardiac events as those without diabetes and a history of myo c a rdial infarc t i o n. 13 Fo r example, in the East-West study conducted in Finland, the incidence of fatal or nonfatal myo c a rd i a l i n f a rction over a 7-year follow-up period was 19% among nondiabetic subjects with a prior myo c a rd i a l i n f a rction and 20% among diabetic subjects with no prior myo c a rdial infarc t i o n. 14 Diabetics with a prior m yo c a rdial infarction we re at extremely high risk of a m yo c a rdial infarction: 45% experienced a fatal or nonfatal myo c a rdial infarction during the 7-year f o l l ow-up period. Because diabetes confers a risk of c a rd i ovascular death equivalent to that of established c a rd i ovascular disease, the National Cholestero l Education Panel designates diabetes as a coro n a ry h e a rt disease risk-equiva l e n t. 15 C o ro n a ry heart disease r i s k - e q u i valents carry a risk of major coro n a ry eve n t s e q u i valent to that of established coro n a ry heart disease. These diabetes-associated cardiovascular risks, dramatic as they are, are magnified in recipients of kidney transplants re l a t i ve to the general population. NODAT, like DMT2 in the general population, is associated with significant risk of cardiovascular disease and cardiovascular death. For example, the presence of diabetes increased the risk of ischemic heart disease by 178% for men and 440% for women among 1124 recipients of kidney transplants followed for 1 year compared with 53% for men and 82% for women in the Framingham Heart Study. 16 In another study that followed 1347 recipients of first kidney transplants for 5 years, ischemic heart disease accounted for 53% of deaths with a functioning graft. 3 Among 55 to 64 year olds with a first kidney transplant, the risk of death from ischemic heart disease versus that in the general population was 6.4 times higher in nondiabetic individuals and 20.8 times higher in diabetic individuals. 180 Vol. 7, No. 6 June 2007

3 MICROVASCULAR COMPLICATIONS Like DMT2 in the general population, NODAT is associated with microvascular complications, the most common of which include nephro p a t h y, neuro p a t h y, re t i n o p a t h y, and infections. 1 In a US Renal Da t a System study of recipients of kidney transplants who had no evidence of pretransplant diabetes, 19% d e veloped NODAT within 3 years of the transplant. 17 Among those with NODAT, 58% had at least 1 diabetic complication, including renal complications (31.3%), neurological complications (16.2%), ketoacidosis (8.1%), and ophthalmic complications (8.3%). REDUCED GRAFT SURVIVAL NODAT can reduce graft survival. In a US Renal Data System study of nearly individuals who received their first kidney transplant in 1996 to 2000, the risk of graft failure was 63% higher in patients who developed NODAT than in patients who did not. 8 Several mechanisms have been proposed to account for diabetes-associated reduction of graft surv i va l. Diabetic nephropathy, diabetes-associated hypertension, and renal effects of changes in immunosuppressive regimens could contribute to impairment of graft function. 1 CAUSES AND RISK FACTORS The etiology of NODAT is not definitively known and is probably multifactorial, involving genetic, biologic, and environmental factors. Many of the risk factors for NODAT are the same as those for DMT2 in the general population. These risk factors are thought to reflect underlying causal factors. Risk factors for DMT2 in the general population include: Obesity or overweight. Individuals with a body mass index of at least 25 kg/m 2 are at risk of DMT2. The growing epidemic of obesity in the United States, where approximately 32% of individuals are obese (defined as a body mass index of at least 30 kg/m 2 ), contributes to the increase in the prevalence of DMT Sedentary lifestyle. Lack of physical activity is an independent risk factor for DMT Ethnicity. The prevalence of diabetes among African Americans, Hispanic Americans, Asian Americans, and Native Americans is greater than that among whites The onset of diabetes also tends to occur earlier among these gro u p s. Epidemiologic data suggest roles of genetic susceptibility and a higher prevalence of risk factors such as visceral obesity as explanations for the higher prevalence of DMT2 among these ethnic groups. The racial groups at highest risk of diabetes are projected to comprise an increasingly larger proportion of the US population over the next 50 years. By 2050, approximately 50% of the US population will be composed of racial groups at high risk of DMT2. Age greater than 45 years. The incidence of DMT2 increases with age, and its peak onset occurs after the age of 50. Although DMT2 is most likely to occur in adults and the elderly, it is increasingly observed in children and adolesc e n t s p a rticularly among ethnic minorities among whom DMT2 has been characterized as an emerging epidemic Family history of diabetes. Those with firstdegree relatives with DMT2 are more likely to develop it than are those whose first-degree relatives do not have DMT Furthermore, the concordance for DMT2 is approximately 60% to 80% in monozygous twins and approximately 30% in dizygous twins, a finding that supports a genetic contribution to diabetes. Impaired glucose tolerance. Recent government figures suggest that up to 16 million Americans who currently do not meet diagnostic criteria for diabetes have impaired glucose tolerance (ie, prediabetes, diagnosed in the presence of impaired fasting glucose and when postprandial blood glucose levels are elevated but not high enough to meet criteria for diabetes) and are at risk for developing DMT Hy p e rt e n s i o n. Patients with hypert e n s i o n ( 140/90 mm Hg in adults) are more likely to have DMT2 than normotensive individuals Dyslipidemia. Patients with dyslipidemia, especially those with low high-density lipoprotein (HDL) cholesterol ( 35 mg/dl in men and 45 mg/dl in women) and high triglyceride levels ( 200 mg/dl) are at increased risk of DMT Waist circumference. Waist circumference is a surrogate measure for visceral obesity Men with waist circumference exceeding 40 inches or women with waist circumference exceeding 35 inches are at risk of DMT2. These criteria, devel- Johns Hopkins Advanced Studies in Medicine 181

4 oped primarily on the basis of data on Caucasians, may not generalize to all ethnic groups. Hepatitis C. Whereas the presence of hepatitis C infection causes a modest increase in the risk of DMT2 in the general population, the risk of NODAT is greatly increased after transplantation, particularly among hepatitis-c positive patients who are immunosuppressed with tacrolimus. 22,23 Other risk factors for NODAT are uncommon in the general population. For example, specific immunos u p p re s s i ve drugs that are used to pre vent graft re j e c t i o n appear to be major contributors to the development of d i a b e t e s. 5, 24 The main immunosuppre s s i ve therapies used in renal transplant re c i p i e n t s c o rt i c o s t e roids, calcineurin inhibitors, mammalian target of rapamyc i n ( m TOR) inhibitors, the immunosuppre s s i ve antimetabolite azathioprine, and the inosine monophosphate dehyd rogenase inhibitor myc o p h e n o- late mofetil differ in their association with N O D AT. 1, 2, 4 C o rt i c o s t e roids and calcineurin inhibitors (ie, tacrolimus, cyclosporine) are associated with N O D AT, whereas azathioprine and myc o p h e n o l a t e mofetil are not. The effect of the mtor inhibitors (eg, s i rolimus, eve rolimus) is not yet well defined. The TO R pathway is important in glucose homeostasis. mto R inhibitors probably affect glucose control, although this mechanism has not yet been well described. The importance of specific immunosuppre s s i ve therapies in influencing the development of NODAT is demonstrated by the finding that the type of immunosuppre s s i o n accounted for 74% of the variability in the incidence of N O D AT in a systematic re v i ew of 19 studies invo l v i n g 3611 renal transplant re c i p i e n t s. 25 Im m u n o s u p p re s s i o n with tacrolimus, high-dose cyclosporine, and cort i c o - s t e roids for organ rejection we re risk factors for deve l- opment of NODAT. Among the calcineurin inhibitors, tacrolimus appears to be more diabetogenic than cyclosporine. In a metaanalysis of 16 randomized studies on the incidence of diabetes in recipients of kidney, live r, or heart transplants, NODAT was re p o rted in 13.4% of patients. 26 Among recipients of kidney transplants, the incidence of n ew-onset diabetes was significantly (P <.00001) higher with tacrolimus (9.8%) than cyclosporine (2.7%). A similar pattern of results was found for recipients of transplants of other organs. In the recently re p o rt e d DIRECT (Diabetes Incidence after Re n a l Transplantation: Neoral C[2] Monitoring Ve r s u s Ta c rolimus) trial (n = 682), NODAT or impaired fasting glucose 6 months after renal transplantation o c c u r red in 26.0% of patients treated with cyc l o s p o r i n e m i c roemulsion compared with 33.6% of patients tre a t- ed with tacrolimus (P =.046). 27 The incidence of biops y - p roven acute rejection, graft loss, or death at 6 months did not differ between treatments (12.8% cyc l o s p o r i n e m i c roemulsion, 9.8% tacrolimus, P =.211). The association between cort i c o s t e roids and calcineurin inhibitors and NODAT is partly explained by the effects of these agents on glucose and insulin re g u l a- tion. Cort i c o s t e roids decrease peripheral glucose utilization, increase hepatic glucose production, and inhibit insulin secre t i o n. 4, 5 Calcineurin inhibitors re d u c e insulin secretion. The calcineurin inhibitor tacro l i m u s also inhibits insulin gene expression and impairs signaling by pancreatic β cells by pre venting phosphory l a t i o n of cyclic adenosine monophosphate response element binding protein, an inducible activator of genes, including those mediating insulin signaling. 5 Some of the risk factors for NODAT are modifiable. Risk can be mitigated through judicious selection of immunosuppre s s i ve therapy, maintenance of a healthy body weight, and pharmacologic and nonpharmacologic control of hypertension and dyslipidemia. Strategies to treat hepatitis C prior to transplantation could also reduce the risk of NODAT. Given the contribution of specific immunotherapies to d e velopment of NODAT, judicious selection of immunosuppressive therapy may be the most important modifiable risk factor. MANAGEMENT The consequences of NODAT can be mitigated by early detection and treatment of diabetes, in addition to judicious choice of immunosuppressive therapies. 24 Table 1 summarizes recently published, internationally endorsed guidelines for the recognition and management of NODAT. General principles for the diagnosis and management of diabetes in the renal transplant recipient are discussed below. DIAGNOSIS Standardized criteria for the diagnosis of NODAT have not been developed. Most authorities recom- 182 Vol. 7, No. 6 June 2007

5 mend using the American Diabetes Association 7 (Table 2) or the World Health Organization 28 standardized diagnostic criteria for DMT2 in diagnosing NODAT. The American Diabetes Association criteria for diagnosis of diabetes include symptoms of diabetes and a casual plasma glucose concentration of at least 200 mg/dl, a fasting plasma glucose concentration of at least 126 mg/dl, or a 2-hour plasma glucose concentration of at least 200 mg/dl during an oral glucose tolerance test (Table 2 ). 7 The American Di a b e t e s Association indicates that presence of any of the 3 criteria can suggest a diagnosis of diabetes and re c o m- mends that a positive finding with respect to one of the criteria be confirmed on a subsequent day by assessing for a second positive finding on any of the 3 criteria. The cut points for fasting plasma glucose and 2-hour postload glucose values on the oral glucose tolerance test were chosen on the basis of studies showing that the risk of microvascular complications of diabetes markedly increases above the designated levels. The concentration of glyc o s y l a t- ed hemoglobin (ie, hemoglobin A 1 c [ H b A 1 c ]) in the c i rculation is pro p o rtional to blood glucose concentrations and reflects glycemic state over the 8 to 12 weeks prior to sampling. HbA 1 c values are often used to measure effects of treatments for diabetes. Howe ve r, they are not currently recommended for use in diagnosis, in part because of lack of nationwide s t a n d a rdization of the HbA 1 c test. In addition, the H b A 1 c is affected by anemia, which is often present in transplant patients. TREATMENT On the basis of data showing that improve d g l ycemic control reduces serious complications of DMT2, management of established DMT2, including NODAT, is guided by the goal of improving glycemic control. Comprehensive diabetes management should Table 1. Guidelines for Recognition and Management of NODAT in Recipients of Organ Tr a n s p l a n t s Pretransplant Management Screen for risk factors Measure blood glucose Counsel patients on the importance of weight control, diet, and exercise Individualize immunosuppressive therapy Post-transplant Management Ongoing monitoring Measure blood glucose and HbA 1c * Management of immunosuppressive therapy Monitoring of patients with new-onset diabetes Treating to target Management of acute hyperglycemia Consider steroid-free or steroid-sparing regimens Reduce exposure to calcineurin inhibitors Encourage self-monitoring of blood glucose Monitor glucose, lipids, and HbA 1c * levels Assess for diabetic complications Follow guidelines outlined by the American Diabetes Association Adopt a treat-to-target approach (Table 3) Intervene immediately to avoid serious consequences for the patient and the graft Administer intensive insulin therapy in the hospital if required Treat dyslipidemia to target (Table 3) Treat hypertension to target (Table 3) *HbA 1c levels should be interpreted cautiously in patients with anemia or kidney impairment, which can interfere with the assay. HbA 1c = hemoglobin A 1c ; NODAT = new-onset diabetes after transplantation. Reprinted with permission from Wilkinson et al. Clin Transplant. 2005;19: Table 2. American Diabetes Association Criteria fo r the Diagnosis of DMT2 Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl. Casual is defined as any time of day without regard to time since the last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. OR Fasting plasma glucose 126 mg/dl. Fasting is defined as no caloric intake for at least 8 hours. OR 2-hour postload glucose 200 mg/dl during an oral glucose tolerance test using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water. DMT2 = diabetes mellitus type 2. Copyright 2007 American Diabetes Association. Reprinted with permission from the American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S42-S47. 7 Johns Hopkins Advanced Studies in Medicine 183

6 also include diagnosis and management of conditions (eg, obesity, hypertension, and dyslipidemia) that can contribute to and/or exacerbate DMT2, in addition to screening for and treatment of common complications, including retinopathy, cardiovascular disease, nephropathy, and neuropathy. 20 The American Diabetes Association put forth specific goals for glycemic control in addition to blood p re s s u re and blood lipids (Table 3). 20 Guidelines for the management of NODAT recommend that patients be treated to these targets in order to re d u c e risk of complications of diabetes. 22 Mo re stringent goals for glycemic control (ie, an HbA 1 c l ower than 6%) may confer additional reductions in risk of complications. Intervention strategies include lifestyle modification (eg, diet and exercise) and pharmacotherapy. Aggressive implementation of a multifactorial treatment approach, including combination drug therapy, may be necessary. 20,29,30 Diet and exercise are core components of management of DMT2. Weight loss in overweight or obese patients can improve insulin sensitivity and glucose utilization, and decrease requirements for insulin therapy or oral hypoglyc e m i c s. Weight loss also may decrease blood pressure and triglyceride levels. Exercise can facilitate weight loss and increase insulin sensitivity by lowering blood glucose and HbA 1 c levels. It can also improve lipid profiles by decreasing triglycerides and total cholesterol and increasing HDL cholesterol. Although diet and exercise are key components of diabetes management, they alone are almost never wholly effective in controlling DMT2 but require supplementation with pharmacotherapy. The pharmacotherapies for DMT2 target the mechanisms underlying insulin resistance and deficient insulin secretion, the 2 primary metabolic defects in DMT2 (Figure). 31 Administered as monotherapy, each of these classes of medication with the exception of the α- glucosidase inhibitors, which are less effective than the other agents confers a 1% to 2% reduction in HbA 1 c levels in controlled clinical comparisons with diet or placebo. 31 Furthermore, the head-to-head trials that have been conducted show comparable effects between medication classes on blood glucose. 31 The use of these medications in patients with NODAT has not been systematically studied; no particular agent appears to be more appropriate for the post-transplant patient than others based on data available to date. Metformin is an effective treatment that can be used in patients with good renal function. It can cause lactic acidosis in patients with renal failure, sepsis, or cardiovascular compromise. 31 Besides improving glycemic control, glucose-moderating interventions can be effective in reducing blood pressure and improving dyslipidemia. However, Table 3. Treatment Goals for Adults with Diabetes Parameter Value Glycemic control HbA 1c <7% Preprandial plasma glucose 90 to 130 mg/dl Postprandial plasma glucose Blood pressure Lipids LDL Triglycerides HDL <180 mg/dl <130/80 mm Hg <100 mg/dl <150 mg/dl >40 mg/dl HbA 1c = hemoglobin A 1c ; HDL = high-density lipoprotein; LDL = lowdensity lipoprotein. Copyright 2007 American Diabetes Association. Reprinted with permission from American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S F i g u re. P h a r m a c o t h e r apies for DMT2:Targeting the Mechanisms Underlying Insulin Resistance and I m p a i red Insulin Secre t i o n DMT2 = diabetes mellitus type 2. Reprinted with permission from Inzucchi. J A M A. 2002;287: Vol. 7, No. 6 June 2007

7 when blood pressure and lipid goals are not achieved with glucose-moderating interventions alone, additional pharmacotherapy may be warranted. Me d i c a t i o n classes often used to treat hypertension in patients with diabetes include angiotensin-conve rting enzyme (AC E ) inhibitors, angiotensin receptor blockers, diuretics, β blockers, and calcium channel blockers. 20 T h e American Diabetes Association recommends that all patients with diabetes and hypertension be treated with an ACE or an angiotensin receptor blocker. 20 When pharmacotherapy is re q u i red to meet lipid targets among patients with a low-density lipopro t e i n (LDL) exceeding 130 mg/dl, the American Di a b e t e s Association recommends the use of a statin. 20 L owe r i n g LDL to less than 100 mg/dl is the first priority of lipid-modulating therapy. To increase HDL and re d u c e t r i g l ycerides, nicotinic acid, fibrates, and niacin may be added. Issues particularly re l e vant for renal transplant recipients include potential drug interaction betwe e n calcineurin inhibitors and statins, both of which are m e t a b o l i zed by cytochrome P450 3A, and potential n e p h ro t oxicity of fibrates except gemfibro z i l. 22 IMMUNOSUPPRESSIVE THERAPY Selection of immunosuppressive therapy for the recipient of a kidney transplant entails careful consideration of the benefits of effective immunosuppression and the diabetogenic risks of therapy in the context of patient-specific factors, including immunological, cardiovascular, and metabolic risk profiles. 1,24 Minimal use of corticosteroids and early tapering of corticosteroid doses should be considered in patients at high risk of or diagnosed with NODAT. Avoidance of calcineurin inhibitors or, in the presence of persistent hyperglycemia, conversion from calcineurin inhibitors to other immunosuppressive therapy, such as mtor inhibitors or mycophenolate mofetil, should also be considered. Because tacrolimus may be more diabetogenic than c yclosporine, conversion from tacrolimus to cyclosporine or an alternative therapy should be cons i d e red in patients with persistent hyperglyc e m i a. Although the impact of conversion from a calcineurin inhibitor to alternative therapy on the incidence and course of NODAT has not been assessed to date, beneficial effects on renal function have been documented in several studies Conversion from tacrolimus to cyclosporine may increase the risk of hypertension and hyperlipidemia. The potential for sirolimus-associated hyperlipidemia and measures for managing it (eg, use of statins) should be considered in choosing the immunosuppressive regimen. In considering conversion of immunosuppressive therapy, the risk of organ rejection should be weighed against potential benefits. The He a rt Sp a re the Nephron Study, which was designed to evaluate the efficacy and safety of replacement of a calcineurin inhibitor with an mtor inhibitor in heart transplant patients receiving a regimen of a calcineurin inhibitor, m ycophenolate mofetil, and cort i c o s t e roids, was recently prematurely stopped because of a higherthan-expected incidence of acute rejection. 35 Although these results in heart transplant patients cannot be generalized to renal transplant patients, the finding illustrates the importance of weighing risks and benefits when considering changes to the immunosuppressive regimen. CONCLUSIONS N O D AT causes significant morbidity and mort a l i- ty in recipients of kidney transplants. Evidence suggests that early detection and aggre s s i ve treatment can prevent diabetes or mitigate its consequences in the re n a l transplant recipients. Judicious selection of immunos u p p re s s i ve therapy tailored to the card i ova s c u l a r, metabolic, and immunological risk profiles of the individual patient is particularly important in this re g a rd. REFERENCES 1. Moore R, Ravindran V, Baboolal K. The burden of new-onset diabetes mellitus after transplantation. Clin Tr a n s p l a n t. 2006;20: Fellström B. Risk factors for and management of post-transplantation cardiovascular disease. BioDrugs. 2001;15: Lindholm A, Albrechtsen D, Frodin L, et al. Ischemic heart disease major cause of death and graft loss after renal transplantation in Scandinavia. Tr a n s p l a n t a t i o n ; 6 0 : Obayashi PAC. Posttransplant diabetes mellitus: cause, impact, and treatment options. Nutr Clin Pract. 2004;19: Duclos A, Flechner LM, Faiman C, et al. Post-transplant diabetes mellitus: risk reduction strategies in the elderly. Drugs Aging. 2006;23: Davis DN, Granner DK. Insulin, oral hypoglycemic agents, and the pharmacology of the endocrine pancreas. In: Hardman JG, Limbird LE, eds. Goodman and Gilman s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001: Johns Hopkins Advanced Studies in Medicine 185

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