US Pharm. 2007;1:HS-3-HS-17.

Tremendous advancements have been made in our understanding of immunology and transplantation in the last 20 years. Kidney transplant patients now benefit from modern immunosuppressive strategies and agents that have greatly reduced the chance of acute cellular rejection of the transplanted organ. Although the incidence of acute cellular rejection is much lower due to better matching techniques and better drugs, long-term kidney survival rates are still marginal at best.1,2

Immunosuppression in renal transplantation (Table 1) typically consists of two phases: induction and maintenance. Induction is utilized in the perioperative time period, when the allograft (transplant, nonself) is at the greatest immunologic risk of rejection. Induction immunosuppression is potent and involves using large, tapering doses of corticosteroids (e.g., methylprednisolone), large doses of calcineurin inhibitors (e.g., cyclosporine, tacrolimus), and in many cases, a polyclonal (e.g., antithymocyte globulin) or monoclonal antibody (e.g., basiliximab, dacl­ izumab, or muromonab-CD3). Maintenance immunosuppression is less intense than induction immunosuppression and is used for the life of the allograft. Conventional maintenance immunosuppression involves a triple-drug combination comprising a calcineurin inhibitor, an antiproliferative agent, such as azathioprine, mycophenolic acid, or sirolimus, and in many cases, a corticosteroid, such as prednisone. However, other combinations have been utilized effectively.2



Corticosteroids exert their immunosuppressive action by reducing cytokine synthesis in T and B lymphocytes and through regulation of numerous cellular receptors that are important in lymphocyte trafficking and communication.

Calcineurin inhibitors inhibit the action of T lymphocytes by negating the action of calcineurin, a phosphatase responsible for several intracellular events that lead to increased synthesis of the proliferative cytokine interleukin-2 (IL-2).

The antiproliferative agents differ from one another by their pharmacodynamics. Azathioprine is a purine analog that acts by interfering with RNA and subsequent protein synthesis. The agent is nonspecific and affects all rapidly dividing cells. Mycophenolic acid is an inhibitor of the enzyme inosine monophospate dehydrogenase, resulting in reduced purine synthesis in T and B lymphocytes. The drug is reported to be more specific for lymphocytes because they rely on de novo synthesis of purine bases, unlike other cells in the body that can utilize salvage pathways for purine synthesis. Sirolimus is a target of rapamycin inhibitor (TOR). By binding to TOR, sirolimus reduces the activity of the S6 ribosome and reduces cellular protein synthesis, leading to cell cycle arrest from the G1-S phase.

IL-2 receptor antagonists are bioengineered antibodies that limit the binding of IL-2 to the CD25 subunit of the IL-2 receptor on T lymphocytes, reducing the intracellular events that ultimately lead to proliferation of the T cell line.

Muromonab-CD3 (OKT3) is a monoclonal antibody preparation that binds to the CD3 receptor on activated T lymphocytes. OKT3 binding to the CD3 receptor causes a conformational change and downregulation of the T cell receptor/CD3 complex, resulting in circulating but inactive T cells.

Antithymocyte globulin polyclonal antibody preparations consist of many different isoforms of immunoglobulin G (IgG) antibodies that bind to numerous cellular receptors on lymphocytes. Binding to various lymphocyte surface receptors results in several pharmacodynamic effects, including inactivation or modulation of receptors, complement-dependent or antibody-directed cellular lysis, and receptor-activated programmed cell death or apoptosis.2

A recent article highlights data compiled from the Scientific Registry of Transplant Recipients for the time period of 1994 to 2003. For cadaveric renal transplant recipients with nonexpanded donor criteria, one- and five-year graft survival rates were reported as 91% and 69%, respectively. In the same time period, recipients of living renal transplants had one- and five-year graft survival rates of 95% and 79%. Factors that contributed to reduced allograft survival included increased cold ischemia time (hours that the kidney is on ice during transport or in storage prior to surgical placement), donor age over 65 years, delayed graft function (need for dialysis during the first week of posttransplantation), second transplant, African-American race, a higher degree of human leukocyte antigen mismatch, and diabetes.1

Cardiovascular Disease (CVD)
CVD accounts for the majority of deaths in renal transplantation. The incidence of CVD has been reported to be as much as four times greater in renal transplant recipients than that seen in the general population.4 Risk factors for CVD in renal transplant patients are similar to, but more extensive than, the general population. Patients with hypertension (HTN), diabetes, renal disease (glomerular filtration rate <60 mL/minute or microalbuminemia), left ventricular hypertrophy, and hyperlipidemia have a higher risk of CVD. Patients who have a family history of premature CVD (men ages <55, women ages <65) or history of acute cellular rejection also have an increased risk. Obesity (body mass index [BMI] ?30 kg/m2), physical inactivity, smoking, immunosuppression, and age (men ages >55, women ages >65) are additional risk factors.3,4 The risk of CVD in kidney transplant recipients can be attributed largely to preexisting CVD, length on dialysis, type of immunosuppressive regimen, HTN, hyperlipidemia, and posttransplant diabetes mellitus (PTDM).2-4

Hypertension
HTN is a significant risk factor for CVD. It has been reported that the risk of CVD doubles with each 20-mmHg increase in systolic blood pressure (SBP) or 10-mmHg increase in diastolic blood pressure (DBP) between the ages of 40 and 70 years. 3 Mange et al.5 retrospectively studied the effect of HTN on renal allograft survival in renal transplant patients. They found that the rate of allograft failure increased by 15% for each 10-mmHg increase of SBP, 27% for every 10-mmHg increase in DBP, and 30% for every 10-mmHg increase in mean arterial pressure.

Calcineurin inhibitors and corticosteroids are the immunosuppressive agents most frequently implicated in posttransplant HTN. There are several hypotheses regarding the mechanism of these unwanted effects on blood pressure. Corticosteroids can induce the retention of sodium in a dose-related fashion via their mineralocorticoid activity and potency. Corticosteroids are also reported to elevate peripheral vascular resistance by increasing vascular sensitivity to circulating catecholamines.6 Cyclosporine (CSA) is believed to induce HTN by enhancing afferent renal artery vasoconstriction, leading to activation of the renin-angiotensin-aldosterone system, increasing sodium retention and sympathetic nervous system discharge. Reduced vasodilatory prostaglandin synthesis and enhanced vascular endothelin production are also reported systemic mechanisms of CSA-induced HTN. Tacrolimus (FK506) shares many of the same mechanisms for calcineurin-associated HTN but does not affect peripheral resistance to the extent that CSA does, and HTN has been found to be less severe in patients taking FK506, compared to CSA. Azathioprine, mycophenolate mofetil, and sirolimus are generally considered to have a neutral effect on blood pressure.2,7

In a two-week crossover study in healthy volunteers, FK506 had little effect on renal hemodynamics and mean arterial pressure, compared to CSA.8 In a follow-up of five-year data from the phase III U.S. Multicenter Trial of tacrolimus versus CSA, significantly more patients who received CSA required treatment with an antihypertensive medication, compared to patients taking tacrolimus (91% vs. 81%; P < .05). All patients received a monoclonal (OKT3) or polyclonal (Atgam) induction regimen and were maintained on azathioprine and prednisone for the duration of the study. These results must be interpreted with caution, since the hypertensive data may have been confounded by better graft function in the patients randomized to FK506 versus CSA (median serum creatinine at five years of 1.7 mg/dL versus 1.4 mg/dL; P =.0014).9

According to recent recommendations for the prevention of posttransplant cardiovascular complications, HTN should be treated as directed by the Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC VII) guidelines for HTN, since long-term outcome data is lacking in renal transplant recipients.4 Transplant recipients should initiate lifestyle changes that help control blood pressure and lower cardiovascular risk (e.g., physical activity, smoking cessation, limiting alcohol consumption, reducing salt intake). If lifestyle changes are not effective, patients should be given drug therapy starting with stage I HTN (SBP >140 mmHg or DBP >90 mmHg) or the prehypertension range (SBP >130 mmHg or DBP > 80 mmHg) if patients have diabetes mellitus or chronic kidney disease. Patients with stage II HTN (SBP >160 mmHg or DBP >100 mmHg) should be initiated on two antihypertensive agents to control their blood pressure. In each case, and unless there is a hypertensive emergency with target organ damage, blood pressure should be reduced gradually to baseline blood pressure and/or goal blood pressure. Compelling indications should be taken into consideration when choosing antihypertensive therapy.3 Data collected from the Collaborative Transplant Study database on long-term graft and patient survival suggest that sustained blood pressure control (SBP <140 mmHg) can significantly increase patient and graft survival based largely on a reduction in CVD.10

Beta blockers and dihydropyridine calcium channel blockers (CCBs) are the most frequently utilized agents in the immediate postrenal transplant phase. If no renal artery stenosis or contraindications exist, angiotensin-converting enzyme inhibitors (ACEIs) are chosen early on by some clinicians with careful monitoring. Many clinicians add these agents to the regimen later on, when the kidney transplant is functioning well and the serum creatinine has stabilized. Clonidine, alpha blockers, and direct vasodilators are frequently used as adjunct therapy or when contraindications exist for CCBs, ACEIs, or beta blockers.2,3,11-13

There is some controversy regarding the treatment of HTN in the early postoperative time period (first 24 to 48 hours). Recipients of cadaveric renal transplants may be prone to allograft renal failure depending on cold ischemia time, immunologic risk, and potential mechanical complications. Some clinicians suggest keeping patients slightly hypertensive immediately after surgery to ensure that the allograft is being adequately perfused.2 Others suggest that increased SBP in the early postoperative phase may increase the risk of acute rejection due to ischemia-reperfusion injury and have advised using antihypertensive agents to keep SBP lower during this critical period.10 Thus, blood pressure control in the immediate postoperative phase should be based on the available data, in combination with clinician experience and extensive patient monitoring.

Dyslipidemia
Hyperlipidemia is a major risk factor for CVD in the renal transplant patient, as seen in a post-hoc analysis of the Assessment of Lescol in Renal Transplantation (ALERT) study, a large trial spanning five years that examined cardiovascular risk factors and the effects of treatment with a hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor or a statin on cardiovascular events in renal transplant patients. It was shown that total cholesterol (TC) and low-density lipoprotein (LDL) were independent risk factors that significantly increased the chances for nonfatal myocardial infarction (MI) (P <.01).14 In transplant patients randomized to 40 mg of fluvastatin and upward titration to 80 mg (65% of treatment group), there was a 35% reduction in the secondary endpoint of combined cardiovascular death and nonfatal MI, compared to the placebo group (P =.005). Cardiovascular mortality alone did not reach significance in ALERT. Since less than 10% of patients studied had a history of CVD, ALERT was largely a primary prevention trial.15

Immunosuppressive agents and regimens can be extremely effective in controlling the immune system and preventing rejection, although they may promote unfavorable cholesterol and triglyceride (TG) metabolism. The antiproliferative agents azathioprine and mycophenolate mofetil have been reported to be lipid-neutral. The calcineurin inhibitors can increase TC, LDL, and TG levels. CSA is much more potent at inducing these changes than tacrolimus. Suggested mechanisms for cyclosporine's effect include interfering with bile acid synthesis and attaching to lipoproteins, altering the body's ability to regulate lipid metabolism at the receptor level. Corticosteroids are also notorious for increasing TC and TG levels-- an effect that may be additive when combined with CSA or sirolimus. Corticosteroids are thought to increase the activity of HMG-CoA and reduce the activity of lipoprotein lipase. Sirolimus can increase TC levels and profoundly increase TG levels through various pathways responsible for enhanced synthesis and reduced metabolism and clearance.16 However, it is not known if these increased values confer increased risk of atherosclerotic CVD, since sirolimus has been successful in preventing vessel proliferation when used in drug-eluting stents placed after angioplasty. Emerging data suggests that systemic exposure to sirolimus does not increase atherosclerotic CVD risk, even if TC and TG levels are high, and systemic exposure to sirolimus may help prevent recurrent coronary in-stent restenosis. 17,18

The National Kidney Foundation (NKF) recently published clinical practice guidelines for managing dyslipidemia in kidney transplant patients.19  These guidelines expand on the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol (NCEP III).20 Differences between the NKF guidelines and NCEP III are summarized in Table 2. The NKF raises kidney transplant recipients to the high-risk NCEP III category of coronary heart disease risk equivalent. The lipid-monitoring (fasting TC, LDL, HDL, and TG) frequency is increased to baseline, after every change in status (e.g., change in immunosuppression, renal function, addition or change in lipid-lowering therapy,), and annually. The following treatment recommendations assume that no contraindications, prior adverse reactions, or drug interactions exist. They recommend statin use in patients with LDL levels greater than 100 mg/dL after a trial of therapeutic lifestyle changes (e.g., weight loss, low-fat diet, exercise) or immediately in patients with LDL levels greater than 130 mg/dL. Patients with isolated, high TG levels (TG > 500 mg/dL) should undergo therapeutic lifestyle changes (TLC) and treatment with a fibrate (gemfibrozil) to prevent pancreatitis, in addition to atherosclerotic CVD. Non-HDL cholesterol (TC-HDL) should be used as a target for lipid lowering in patients with TG levels higher than 200 mg/dL, even if their LDL level is low or normal, because higher levels have been associated with the metabolic syndrome and atherosclerotic CVD. The treatment targets for non-HDL are essentially 30 mg/dL higher than the LDL target ranges set forth in the NCEP III. Thus, CHD risk equivalent patients (kidney transplant patients) should receive drug treatment at non-HDL values higher than 160 mg/dL and at non-HDL values greater than 130 mg/dL after a trial of therapeutic lifestyle changes.


If a statin is prescribed, clinicians must utilize proper monitoring for efficacy and safety with a lipid panel at baseline and every four to six weeks, in addition to liver function tests at baseline, 12 weeks, and semiannually. The most common drug interaction between an immunosuppressive agent and a statin involves CSA. When given concurrently with CSA, statins marginally affect the area under the curve of CSA. CSA can significantly increase the area under the curve of some statins, increasing the risk of myopathy and rhabdomyolysis. Mechanisms thought to be responsible for this interaction include inhibition of cytochrome P-450 3A4 (CYP3A4), competition with biliary elimination, and inhibition of gut transport via p-glycoprotein or the multidrug-resistance-associated protein-2. Due to the correlation of these interactions with statin dosage, it is generally recommended that the maximum dosage of statins be lowered by 50% if used in conjunction with CSA (i.e., 40 mg for atorvastatin, lovastatin, pravastatin, simvastatin, and fluvastatin). Due to ALERT, fluvastatin is the best-studied statin in the renal transplant population with a benign side-effect profile, even when the dose was bumped to 80 mg in a large number of patients. Patients may be at a greater risk for liver disease, myopathy, and rhabdomyolysis when statins are prescribed in conjunction with fibrates or niacin and will require intense monitoring. It is extremely important to remind patients to report any muscle pain/weakness to their transplant physician, especially if the statin is a new medication, if an increase in dosage has been prescribed, if CSA is part of the immunosuppressive regimen, or if a fibrate or niacin is being added to concurrent statin therapy.14,16,19,20

If a patient's TG value does not respond optimally to statin therapy titrated to an acceptable dose for kidney transplant recipients, a fibrate (e.g., gemfibrozil) may be added, provided there are no contraindications, such as liver disease, and there is close monitoring for adverse effects (e.g., liver function test abnormalities, myopathy, gastrointestinal problems). However, the statin/fibrate combination has not been shown to dramatically reduce TG and TC levels, compared to a statin alone. Fibrates can also be utilized for the treatment of isolated, very high TG levels (>500 mg/dL), which is often seen with patients taking sirolimus. Gemfibrozil is the recommended fibrate to use in the renal transplant population because the dose does not need to be adjusted in patients with renal insufficiency/failure. Niacin may be used as a second-line agent in patients who have failed to achieve their treatment goal with optimal dosing of statins and/or fibrate therapy. Niacin has a beneficial effect on all lipid parameters but is associated with many adverse effects. These include hyperglycemia, hyperuricemia, flushing, liver toxicity, gastrointestinal intolerance, and increased risk of myopathy when combined with a statin. Niacin has not been studied extensively in renal transplant patients. Contraindications to niacin include liver disease, gout, and upper gastrointestinal bleeding/ulceration. Bile acid sequestrants like cholestyramine have not been utilized often in renal transplant patients due to gastrointestinal adverse effects, their effect on TG levels, and the potential for binding immunosuppressive and other critical medications in the gut, limiting their absorption.16,19,20

Posttransplant Diabetes Mellitus
Diabetes is frequently diagnosed early after renal transplantation and contributes significantly to CVD. In addition, renal transplant patients with PTDM have lower graft and patient survival rates and less renal function over time, as demonstrated by higher serum creatinine values, compared to renal transplant patients without PTDM.21,22 In a published review of 11,659 first kidney renal transplant recipients with Medicare as their primary form of insurance from 1996 to 2000, PTDM was diagnosed in 9.1%, 16%, and 24% of patients within three, 12, and 36 months of transplantation. Most of the patients studied received a corticosteroid, a calcineurin inhibitor (CSA or FK506), and mycophenolate mofetil.23  Recently, the incidence of PTDM has been reported to be as high as 74% within the year following transplantation.24

Factors that have been shown to significantly increase the likelihood for PTDM include, but are not limited to, immunosuppressive medications (corticosteroids and calcineurin inhibitors), age above 40 years, race (African-American, Hispanic), body weight (BMI > 30 kg/m2), male donor, degree of human leukocyte antigen mismatch, hepatitis C infection, and family history of diabetes.23 Clinicians can help modify or reduce these risk factors by educating patients about weight loss and the effects of a well-rounded diet and benefits of exercise and by using immunosuppressive strategies that lessen the risk of PTDM and impaired glucose tolerance.25

The type of immunosuppression can have a dramatic effect on the incidence of PTDM. Clinicians continue to study methods to reduce the risk of PTDM without increasing the chances for allograft rejection. Corticosteroids have been shown to contribute to glucose intolerance in a dose-dependent and time-dependent manner by reducing peripheral insulin sensitivity and marginally reducing insulin production. There is a large amount of published literature on successfully reducing PTDM by using corticosteroid avoidance, withdrawal, and dosage reduction strategies. By using one of these methods, the risk for allograft rejection and consequences must always be taken into consideration by the transplant physician prior to implementation, and the patient must be intensely monitored. 25,26

The effects of calcineurin inhibitors (CSA and tacrolimus) on PTDM are well described in the literature. A study was recently published as a follow-up report on five-year data from the phase III U.S. Multicenter Trial of Tacrolimus in Kidney Transplantation. Four hundred and twelve patients were randomized to CSA or FK506 dosed to standard trough concentrations at three months (100 to 300 ng/mL for CSA, 5 to 15 ng/mL for FK506), a maintenance regimen consisting of prednisone tapered to 10 mg/day by six months and azathioprine. All patients received OKT3 or Atgam for induction immunosuppression. After one year, 19.9% of patients taking FK506 had PTDM, compared to 4% of patients taking CSA. There was a large degree of reversal in the FK506 arm; 41.2% of patients taking FK506 were able to discontinue insulin after five years, compared to 14% of patients randomized to CSA.9 A recent meta-analysis involving PTDM in transplantation compared CSA to FK506, and the incidence was somewhat lower than reported above (9.8% for FK506, 2.7% for CSA; P <.00001). The authors classified patients as having PTDM when insulin was administered, which may have accounted for the lower numbers.27 CSA is hypothesized to contribute to PTDM by interfering with corticosteroid metabolism, leading to reduced peripheral insulin sensitivity. CSA also inhibits insulin synthesis and secretion from pancreatic beta cells. Tacrolimus shares the same reported mechanism but may be more potent in its ability to inhibit insulin synthesis and secretion. This may be related to differences in pancreatic intracellular CSA and FK506 binding proteins (cyclophylin and FKBP-12). The effects of both calcineurin inhibitors on insulin production and secretion may be dose related, as CSA has been shown to be more diabetogenic in animals with higher CSA blood levels, and FK506-induced PTDM has been correlated with higher trough concentrations in human renal transplant patients.25,26,28   There have been many studies published recently on calcineurin avoidance, withdrawal, and dosage sparing that have reported successful reduction in PTDM incidence rates without increasing the risk of rejection in renal transplantation. Many of these studies employed antibody induction with an IL-2 antagonist or a polyclonal antibody preparation (Thymoglobulin). Sirolimus has been used in many of these studies with some success. The optimal approach remains to be determined.

The diagnosis of PTDM has been refined and standardized by the 2003 International Consensus Guidelines for New-Onset Diabetes after Transplantation (Table 3). This document is based collectively on U.S. and international guidelines for the diagnosis and management of diabetes in the general population; recommendations included the best published literature on PTDM. Unfortunately, PTDM was defined differently in many of the studies published. Some studies defined PTDM by the duration of insulin use, others used impaired fasting glucose and/or oral glucose tolerance testing values, and a few included patient use of oral hypoglycemic medication posttransplantation. This makes it very difficult to examine the impact that various immunosuppressive medications have on the incidence of PTDM across studies. Fasting plasma glucose should be obtained every week immediately following transplantation, three, six, and 12 months, and annually thereafter. Plasma glucose should also be monitored frequently during the immediate posttransplant period, when patients are receiving high doses of corticosteroids and calcineurin inhibitors.21,25


Once PTDM is diagnosed, patients should self-monitor their glucose at home if possible to examine how their plasma glucose level responds to carbohydrate intake, lifestyle alterations (e.g., diet, exercise), and drug therapy. It is recommended that HgbA1c  be obtained every three months with a target value less than 6.5% (normal 4% to 6%) based on data suggesting that tight glycemic control lessens the progression of microvascular and macrovascular complications. Patients should be taught how to recognize complications that may develop secondary to their disease progression (e.g., neuropathy, retinopathy, nephropathy, infection) and should be monitored by their physician annually.25

Prior to initiating drug therapy and depending on the severity of PTDM, transplant physicians may change the immunosuppressive regimen by reducing the corticosteroid dose or withdrawing the steroid altogether if the immunological risk is low. Consideration may also be given to reducing the dose of the calcineurin inhibitor or switching from tacrolimus to CSA or from a calcineurin inhibitor to sirolimus. With tacrolimus, early PTDM is likely to be transient or may be less severe when the dosage is reduced to maintain lower trough blood levels. All of the above must be performed under close supervision of the transplant physician due to the potential for acute rejection. A dietician should be consulted in patients at risk for PTDM to help with optimal dietary lifestyle changes and to help with calorie restriction and weight reduction in patients that require such changes. Patients should be educated on the benefits and importance of exercise, even if this consists of walking for 30 minutes  per day. Education regarding optimal smoking cessation strategies should also be provided.25-30

Surprisingly, there are few large prospective studies on the use of oral hypoglycemic agents and insulin in renal transplant patients. The consensus guidelines recommend an oral hypoglycemic medication as the initial agent of choice, followed by an oral hypoglycemic combination, an oral hypoglycemic agent with insulin, or with insulin alone.25 Patients with very high levels of plasma glucose may require immediate treatment with insulin, especially in the early postoperative period or in situations when patients are acutely ill (e.g., infection, other surgery). When an oral hypoglycemic agent is utilized in renal transplant patients, care must be taken regarding differences between the agents, contraindications, and the available evidence for use in this population based on safety and efficacy (Table 4).


Two recent prospective studies 31,32 were published examining the use of the thiazolidinediones (rosiglitazone and pioglitazone) in the management of PTDM in renal and liver transplant patients. The thiazolidinediones are peroxisome proliferator-activated receptor gamma agonists that reduce insulin resistance in skeletal muscle. Both agents were effective in reducing insulin requirements and lowering HgbA1c to less than 6.5%, often in combination with a sulfonylurea. Patients with congestive heart failure were excluded, and no drug interactions were noted. The most frequent adverse effect reported in the two trials was edema. Despite thiazolidinediones' long onset of action and potential to cause edema, the authors cited the beneficial effects that they have on levels of LDL, HDL, TG, and the vascular endothelium that may make these agents advantageous in the management of PTDM.25

 

Conclusion

Cardiovascular complications in renal transplant patients can be reduced or prevented with optimal pharmacological management and follow-up care. This is a relatively new and exciting area of pharmacotherapy. A substantial amount of data that will impact the way we care for renal transplant patients is continuing to evolve and is becoming even more complex. Pharmacists have an important role in kidney transplantion, as they foster patient compliance through education, are frequently accessible, have the ability to look for prescription and over-the-counter drug interactions, monitor for adverse reactions, serve as a resource for the transplant team physicians and nurses in hospital and ambulatory environments, and have a wide variety of knowledge at their fingertips.

 

References

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24. Sulanc E, Lane JT, et al. New-onset diabetes after kidney transplantation: an application of 2003 international guidelines. Transplantation. 2005;80:945-952.

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