HOW TO IDENTIFY AND MANAGE DIABETES MELLITUS AFTER RENAL TRANSPLANTATION

INTRODUCTIONPatients with chronic kidney disease are at increased risk ofpremature cardiovascular disease and death. This risk reducesafter renal transplantation although the prevalence of cardio-

vascular disease remains elevated above that of the generalpopulation and cardiovascular disease is the most commoncause of death in this population (Foley et al. 1998). Impairedglucose tolerance and the development of new-onset diabetesmellitus (DM) after renal transplantation (NODAT) are recog-nised complications and both conditions have serious conse-quences in terms of renal and patient outcomes (Montori et al. 2002; Wilkinson et al. 2005; Cosio et al. 2008). There isa clear association between both impaired glucose toleranceand NODAT and reduced patient survival and evidence of sig-nificantly diminished transplant function and survival(Gonzalez-Posada et al. 2004; Kuo et al. 2010; Wiesbauer et al. 2010). Impaired glucose tolerance and NODAT are alsorisk factors for cardiovascular disease post-renal transplanta-tion (Cosio et al. 2005).

To limit the impact of NODAT, it is crucial that at-risk individu-als are identified early, ideally pre-transplant and modifiablerisk factors for NODAT addressed to optimise both patient andrenal outcomes. This is particularly important in the current climate where the numbers of older patients (who are alreadyat increased risk of traditional impaired glucose tolerance andDM) developing established renal failure and considering kidney transplant as a renal replacement therapy option areincreasing (Byrne et al. 2010). Where prevention fails, it isimperative that impaired glucose tolerance and NODAT arediagnosed and managed promptly. Impaired glucose toleranceis in itself a risk factor for the development of NODAT(Wilkinson et al. 2005).

125Journal of Renal Care 2012 © 2012 European Dialysis and Transplant Nurses Association/European Renal Care Association

Stevens K.K., Patel R.K., Jardine A.G. (2012). How to identify and manage diabetes mellitus after renal transplantation. Journalof Renal Care 38(Suppl. 1), 125-137.

SUMMARYNew-onset diabetes after transplantation (NODAT) has serious consequences for the patient in terms of overall survival, graftfunction and graft survival. The incidence of NODAT and impaired glucose tolerance has probably been underestimated previ-ously because of lack of a universal diagnostic definition. Many risk factors have been identified, a proportion of which aremodifiable. Early identification of those who are at high risk of NODAT and strategies to reduce risk will help to reduce themorbidity and mortality resulting from this condition. Where prevention is not possible, stringent management strategies areessential. Although, this article focuses on NODAT in the renal transplant recipient and considers the scale of the problem,impact on patient and transplant survival, determinants and risk factors for, and the management of, impaired glucose toler-ance and NODAT, much of it will also be applicable to other types of solid organ transplantation.

KEY WORDS Diabetes mellitus • NODAT • Renal transplantation • Survival

Kathryn K. Stevens, BSc, MB, ChB, MRCP, Rajan K. Patel, MB, ChB, PhD, MRCP, Alan G. Jardine, MB, ChB, MD, FRCPRenal Research Group, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow,Scotland, UK

HOW TO IDENTIFY AND MANAGE DIABETES MELLITUS AFTER RENAL TRANSPLANTATION

BIODATA

AAllaann JJaarrddiinnee is a Professor of RenalMedicine in Glasgow. His research interestsare in the cardiovascular complications ofrenal disease and transplantation, rangingfrom laboratory based studies on cardiacand vascular function, to international,multicentre trials.

KKaattee SStteevveennss is a Clinical ResearchFellow in Glasgow. Her research focuseson the role of phosphate as a cardiovascu-lar risk factor and, in particular, on its effects on vascular and endothelialfunction through laboratory based andclinical studies.

CORRESPONDENCEKate StevensRenal Research Group,Institute of Cardiovascular and Medical Sciences,University of Glasgow,Glasgow, G12 8TA, UKTel.: �44 141 330 2409Fax: �44 141 330 [email protected]

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DEFINITION OF IMPAIRED GLUCOSE TOLERANCE AND NODATWilkinson et al. published guidelines for the treatment andmanagement of NODAT in 2003 which recommended that thediagnosis of impaired glucose tolerance and NODAT be basedupon the World Health Organisation (WHO) definition of tra-ditional impaired glucose tolerance and DM (Wilkinson et al.2005; WHO 2006) (Figure 1). These definitions use fastingplasma glucose and ‘a two-hour’ plasma glucose measured aspart of an oral glucose tolerance test. For fasting plasma glu-cose, a glucose sample is tested after an eight-hour fast andfor ‘a two-hour’ plasma glucose, a 75 g glucose load is con-sumed and plasma glucose is measured two hours later.

Patients with fasting plasma glucose �7.0 mmol/l (126mg/dl)or a two-hour plasma glucose of �11.1mmol/l (200 mg/dl)meet the diagnostic criteria for DM. Fasting plasma glucose�6.1 mmol/l (110 mg/dl) is considered an impaired fasting glucose which is a risk factor for the development of impairedglucose tolerance and DM. Impaired glucose tolerance isdefined as FPG �7mmol/l and a 2-hour plasma glucose of�7.8mmol/l (140 mg/dl) and �11.1 mmol/l (200 mg/dl). TheAmerican Diabetes Association suggested in 2003 that the definition of impaired fasting plasma glucose should be loweredto include those with fasting plasma glucose of �5.6 mmol/l(110 mg/dl) (Report of Expert Committee 2003). However, aftercareful review, the WHO felt this should not be adopted

Figure 1: World Health Organisation, definition of impaired glucose tolerance and diabetes mellitus.

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because although it would significantly increase the prevalenceof impaired fasting plasma glucose, there is no evidence, cur-rently, that it would offer any benefit in terms of either progres-sion to DM or reduction in adverse outcomes (WHO 2006).

An oral glucose tolerance test is often not performed becauseit is considered be inconvenient and expensive. However, several studies show that reliance solely upon fasting plasmaglucose as a means of diagnosis of new onset DM will result inan approximately 30% of cases being missed (Report of ExpertCommittee 1997; DECODE Study Group 1998; WHO 2006).

SCALE OF THE PROBLEMNODAT has been a recognised complication of renal transplan-tation since first described in 1964 (Starzl et al. 1964). UntilWilkinson et al. published their guidelines in 2003, there wasno standard definition for diagnosis and this made it exception-ally difficult to determine the precise incidence and prevalenceof both NODAT and impaired glucose tolerance in the renaltransplant population. In addition, the choice of immunosup-pressive therapy in predisposed individuals can affect the risk ofNODAT and impaired glucose tolerance and thus potentiallyclouds true incidence estimates (Vincenti et al. 2007).

Montori et al. (2002) performed a meta-analysis of 19 studiesand found that the incidence of NODAT after solid organtransplant ranged from 2% to 50%. Often an oral glucose tol-erance test was not used as part of diagnostic criteria and asmentioned previously this might result in an underestimationof the incidence of impaired glucose tolerance and NODAT. Inour own centre, Joss et al. performed a retrospective analysisof 787 renal transplant recipients and found the overall inci-dence of NODAT to be 7% and that incidence increased withadvancing age (Joss et al. 2007).

NODAT definition: two non- fasting plasma glucose levels of�11.1 mmol/l or the use of any oral anti-diabetic agent.

In 388 renal transplant recipients of predominately South EastAsian origin, Bee et al. reported a cumulative incidence ofNODAT of 15.8%, 22.8% and 24.5% at one, three and fiveyears post-transplantation (Bee et al. 2011). Fasting and non-fasting plasma glucose samples were used in diagnosis but oralglucose tolerance test was not routinely performed. Kasiske et al. (2003) showed incidences in a predominantly CaucasianAmerican renal transplant population to be 9.1%, 16% and

24% at 3, 12 and 36 months post-transplant. NODAT wasidentified using Medicare Claims data (where diagnosis ofNODAT is made with fasting plasma glucose, non-fastingplasma glucose or both).

Although, it may be difficult to quantify accurately the fullextent of the problem of NODAT and impaired glucose toler-ance post-renal transplantation, it is likely to be underestimatedrather than overestimated. Regardless, if a patient developseither of these conditions, they are at increased risk of death,graft dysfunction, graft loss and premature cardiovascular dis-ease. All of which result in a large socioeconomic burden.

IMPACT ON PATIENT AND GRAFT SURVIVAL

PATIENT SURVIVALSeveral studies have demonstrated a link between developingNODAT and reduced patient survival. In 11,659 recipients of afirst renal transplant between 1996 and 2000, Kasiske et al.showed that those with NODAT had an 87% increase in mortality from any cause and a 47% increase in mortality fromcardiovascular disease (Kasiske et al. 2003). In 2001, Revanuret al. showed that in 939 patients, over 10 years of follow-up,51% of patients with NODAT died compared with 25% with-out. The relative risk of death in patients �55 years was signif-icantly higher in those who developed NODAT (2.54, p �

0.001) (Revanur et al. 2001). In almost 2,000 renal transplantrecipients, Cosio et al. identified an 80% increase risk of deathin those with NODAT (Cosio et al. 2008).

The increase in mortality is partially explained by an increase ininfection as a result of hyperglycaemia (Kasiske et al. 2003).However, cardiovascular disease is the leading cause of deathin chronic kidney disease including post-transplantation (Foleyet al. 1998). In 2002, Matas et al. demonstrated that cardio-vascular disease explained up to 47.6% of deaths in renaltransplant recipients (Matas et al. 2002). Subsequent studieshave confirmed that cardiovascular disease is the major causeof death in renal transplant recipients (Meier-Kriesche et al.2003; Boerner et al. 2011). NODAT has been shown to beassociated with a three-fold increase in the risk of major car-diovascular events (HR: 3.27 CI 1.22–8.8, p � 0.019) and itincreases the risk of myocardial infarction within the first threeyears post-transplantation by 60% (p � 0.0001) (Lentine et al.2005; Hjelmesaeth et al. 2006). In addition, in almost 30,000recipients of a first renal transplant between 1995 and 2002,

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the development of NODAT was associated with a 41%increased risk of death with a functioning transplant (CI1.25–1.59, p � 0.001) (Cole et al. 2008). Thus, prevention,early detection and management of NODAT are key to reduc-ing the mortality of renal transplant recipients.

GRAFT SURVIVALMultiple studies have demonstrated an association betweenNODAT and reduced graft survival (Rakel & Karelis 2001;Revanur et al. 2001; Matas et al. 2002; Cole et al. 2008; Mataset al. 2008). Kasiske et al. linked NODAT with a 63% increasein graft failure (1.46–1.84, p � 0.0001) (Revanur et al. 2001;Cole et al. 2008). Cole et al. (2008) found the risk of graft fail-ure to be increased by 24% (1.14–1.35, p � 0.0001).However, when censored for death, NODAT was not linkedwith increased graft loss. Similarly, in transplant patients whodid not experience acute rejection, rates of graft loss were verysimilar for the first nine years post-transplant in patients withand without NODAT (Matas et al. 2008). At nine years, thosewith NODAT experienced increased rates of graft loss com-pared to those without NODAT, this is most likely because ofthe delay between the onset of DM and complications andsupports the belief that differences in graft survival might atleast in part be attributable to cardiovascular deaths despite afunctioning graft (Cole et al. 2008; Duckworth et al. 2009).

There is also evidence to suggest that transplant function,assessed by serum creatinine level is poorer in those withNODAT compared with those without (Miles et al. 1998).

Acute rejection and NODAT are both independently associatedwith graft loss and the proportion of patients who experienceacute rejection and develop NODAT have the worst outcomeof all (Cole et al. 2008; Matas et al. 2008). Immunosuppressiveregimens are discussed in next section but steroid usage isassociated with NODAT and thus the balance between the pre-vention of both acute rejection and NODAT poses a challenge,as clinicians must minimise the risk of acute rejection whilst try-ing to prevent the development of NODAT.

RISK FACTORS FOR NODATSeveral risk factors for NODAT in the transplant population aresimilar to those of traditional DM in the general populationincluding age, ethnicity, genetic factors, obesity and the pres-ence of hepatitis C virus. Several other factors, unique to therenal transplant population have been identified as risk factors

including the type of immunosuppressive regimen. Figure 2summarises the known risk factors for the development ofNODAT and impaired glucose tolerance.

GENERAL RISK FACTORS

AGEOlder transplant recipients are at increased risk of developingNODAT with recipients �45 years displaying a 2.2-foldincrease in the risk of developing NODAT (Cosio et al. 2001).

ETHNICITYPatients of Caucasian origin are at lowest risk of NODAT. Thoseof Hispanic or African American origin are at highest risk.Incidence rates between races are difficult to determine accu-rately but Kasiske et al. report a 68% and 35% increase in thedevelopment of NODAT in the African American and Hispanicraces, respectively (Kasiske et al. 2003).

GENETIC FACTORSSeveral genetic polymorphisms are associated with the devel-opment of traditional DM and a positive family history of tra-ditional DM has been shown to be a risk factor for the devel-opment of NODAT in renal transplant recipients (Sumrani et al.1991; Rakel & Karelis 2001). It seems probable therefore thatthe genetic polymorphisms associated with traditional DM arealso associated with NODAT and the development of NODAT isdependent upon both genetic susceptibility and environmentalfactors.

OBESITYHeavier weight pre-transplant is associated with increased riskof NODAT in several studies with Cole et al. demonstrating thatbody mass index (BMI) of �30 kg/m2 may increase the risk ofdeveloping NODAT by as much as 76% (CI 1.6–1.94) withinthe first year post-transplant (Joss et al. 2007; Cole et al.2008). It is well documented that patient weight gain post-transplantation can be attributed in part to the use of steroidcontaining immunosuppressive regimens and to an improve-ment in overall well being and subsequent nutritional status.Cosio et al. showed that for every 10 kg gained post-transplantin patients with a starting weight of �60 kgs, the risk ofNODAT increased by a factor of 1.4 (Cosio et al. 2001). In addi-tion, the distribution of body fat is important; male type cen-tral adiposity has a much higher association with insulin resist-ance than female type adipose distribution around the hips.

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Waist:hip ratio may be of more value then traditional BMImeasures in assessment (Davidson et al. 2003).

IMPAIRED GLUCOSE TOLERANCEPre-transplant impaired glucose tolerance is in itself a risk fac-tor for the development of NODAT (Kasiske et al. 2003). Aswith traditional DM, steps can be taken to reduce the likeli-hood of progression to diabetes including weight loss anddietary modification (Cruz-Munoz et al. 2011). However,although it seems probable, it is not known if this improvespatient or transplant outcomes.

HEPATITIS C VIRUSThere is an increased incidence of traditional DM in patientswho are hepatitis C positive and this risk translates to the trans-plant population (Mehta et al. 2001). The mechanism isunclear but may relate to increased insulin resistance(Kawaguchi et al. 2011). Renal transplant recipients who are

hepatitis C positive may have up to a four-fold increase in riskof developing NODAT but this risk can be lowered by as muchas 60% with pre-transplant treatment with interferon (Kamaret al. 2003; Fabrizi et al. 2005; Arase et al. 2009).

RENAL ‘UNIQUE’ RISK FACTORS

IMMUNOSUPPRESSIVE REGIMEN—CORTICOSTEROIDSCorticosteroids promote glucose intolerance by increasinginsulin resistance and reducing insulin sensitivity. The effectsseem to be dose related with a 5% increase in the risk of devel-oping NODAT for every 0.01 mg/kg increase in prednisolonedose (Hjelmesaeth et al. 1997). Pulsed high dose steroid foracute rejection is also a risk factor for NODAT (Vesco et al.1996). Reducing steroid dose has been shown to improve glu-cose intolerance with a 1 mg reduction in prednisolone doseleading to a 0.12-mmol/l reduction in two-hour plasma glu-cose as part of an oral glucose tolerance (Hjelmesaeth et al.

Figure 2: Risk factors for impaired glucose tolerance and new-onset diabetes after renal transplantation.

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2001). However, this improvement may not be sustained withpatients developing impaired glucose tolerance or NODATagain at a later stage. Studies have looked at steroid free regi-mens in an attempt to further reduce the incidence of impairedglucose tolerance and NODAT. The results are mixed and theuse of steroid free regimens or steroid withdrawal is controver-sial. A Cochrane review of 30 randomised controlled trials ofsteroid avoidance or withdrawal showed lower rates of NODATrequiring treatment in patients concomitantly on ciclosporinbased regimens. Acute rejection occurred more frequently inthe steroid avoidance and withdrawal patients (Pascual et al.2009). Midvedt et al. (2004) demonstrate improved insulinsensitivity with lowered prednisolone doses to 5 mg/day butfailed to demonstrate any further improvement with completewithdrawal of steroids.

IMMUNOSUPPRESSIVE REGIMEN—CALCINEURIN INHIBITORSBoth tacrolimus and ciclosporin have been shown to be dia-betogenic. The mechanism is not certain but is likely to involveone or more of impaired insulin release through FKBP12 bind-ing, islet cell toxicity and increased insulin resistance (Rakel &Karelis 2001). Tacrolimus is more likely to result in the develop-ment of NODAT than ciclosporin (Rakel & Karelis 2001; Kasiskeet al. 2003; Webster et al. 2005; Cole et al. 2008). Kasiske et al. (2003) report a 70% higher incidence of NODAT post-transplant in patients treated with tacrolimus compared tociclosporin. However, tacrolimus reduces the incidence ofacute rejection. A meta-analysis in the British Medical Journal(BMJ) concluded that acute rejection could be prevented in 12patients with the caveat that an extra 5 patients will develop‘insulin dependent NODAT’ if 100 renal transplant recipientswere treated with tacrolimus instead of ciclosporin for the firstyear post-transplant. The risk of diabetes increased with highertacrolimus concentrations (Webster et al. 2005). In a studycomparing steroid withdrawal in living donor transplantation,7.8% of recipients receiving tacrolimus and mycophenolatemofetil (MMF) developed NODAT by one year post-transplantcompared to 0% in those receiving ciclosporin and MMF (Kim et al. 2004).

IMMUNOSUPPRESSIVE REGIMEN—SIROLIMUSThere have been few studies on sirolimus and results are con-flicting. Sirolimus may potentially increase the risk of NODATbecause it is known to increase insulin resistance and is toxicto pancreatic � cells (Rakel & Karelis 2001). Similarly, studies ofazathioprine and MMF are conflicting and often confounded

by the presence or absence of specific calcineurin inhibitors andor corticosteroids (Rakel & Karelis 2001; Kasiske et al. 2003;Cole et al. 2008). At present, there is no firm evidence to sug-gest that either drug promotes the development of NODAT.

Inevitably, all immunosuppressive regimens include one ormore of corticosteroids, which promote insulin resistance andweight gain and calcineurin inhibitors or sirolimus, which bindto FKBP12 and reduce insulin secretion. Thus, reducing therisk of NODAT whilst minimising the risk of acute rejection isa fine balance.

IMMUNOSUPPRESSIVE REGIMEN—NEWER AGENTSBelatacept is a co-stimulation blocker, which selectivelyinhibits T-cell activation. In both the BENEFIT and BENEFIT-EXT studies, in comparison to ciclosporin based regimens,belatacept resulted in improved cardiovascular and metabolicoutcomes including fewer cases of NODAT. In a pooled analy-sis from both studies of 873 patients, the incidence ofNODAT was doubled in the ciclosporin group compared withthe belatacept group (Vanrenterghem et al. 2011). It isunknown yet whether the improvements in metabolic andcardiovascular profiles translate to improved patient andgraft outcomes and there was a higher incidence of earlyacute rejection and post-transplant lymphoproliferative disor-der with belatacept based regimens. Further work is neededbefore belatacept could become part of a standard immuno-suppressive regimen.

Basiliximab is often used as an induction agent; it is a mon-oclonal antibody against the CD25 receptor and suppressesregulatory T cells. Studies have shown that patients treatedwith basiliximab may have an increased incidence ofNODAT, impaired fasting plasma glucose and impaired glu-cose tolerance, despite lower doses of calcineurin inhibitorand corticosteroid (Rakel & Karelis 2001). This might be secondary to toxic effects on pancreatic � cells but themechanism is unknown.

ADDITIONAL RISK FACTORSHigher plasma glucose levels as early as 24 hours after trans-plant are linked with increased development of NODAT (Cosioet al. 2005; Joss et al. 2007). Cosio et al. showed that inpatients with elevated plasma glucose levels within the firstweek after transplant, at one year, 33% had impaired glucosetolerance and 13% had NODAT (Cosio et al. 2005).

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Both asymptomatic Cytomegalovirus (CMV) infection and CMVdisease have been linked with an increased risk of NODAT.CMV may impair insulin secretion and through a pro-inflam-matory response may promote pancreatic �-cell dysfunction(Rakel & Karelis 2001; Hjelmesaeth et al. 2005).

An underlying diagnosis of polycystic kidney disease has beenassociated with an increased risk of NODAT. De Mattos et al.compared recipients of a first renal transplant recipient withand without an underlying diagnosis of polycystic kidney dis-ease and found that there was a three-fold increase risk of thedevelopment of NODAT in patients with polycystic kidney dis-ease (de Mattos et al. 2005). The mechanism is unclear butmay relate to impaired insulin resistance (Rakel & Karelis 2001).

A primary renal diagnosis of interstitial nephritis poses anincreased risk of NODAT whereas an underlying diagnosis ofglomerulonephritis seems to be associated with a lower risk.Higher numbers of HLA mismatches are also linked with anincreased risk of NODAT (Kasiske et al. 2003; Cole et al. 2008).Education to degree level seems to reduce the risk of NODAT(Kasiske et al. 2003).

Some studies found gender to be predictive of risk of NODAT;in some, females were at increased risk, in others it was maleswho were more at risk (Kasiske et al. 2003; Gonzalez-Posadaet al. 2004; Cosio et al. 2005). Other studies have shown nodifference between the sexes (Joss et al. 2007).

MANAGEMENT OF IMPAIRED GLUCOSE TOLERANCEAND NODATUntil 2003, there was a paucity of guidance on the diagnosisand management of impaired glucose tolerance and NODAT. Ina bid to establish a universal definition, diagnostic and manage-ment strategy, the International Consensus Guidelines onNODAT were published and then updated in 2004 (Davidson et al. 2003; Wilkinson et al. 2005). The main aims of a universaldiagnostic and management strategy as set out by the guide-lines are to raise awareness, promote early recognition andimplement prompt and standardised management strategies toattenuate the risk of each individual transplant recipient devel-oping impaired glucose tolerance and or NODAT and experienc-ing the consequences of these post-transplant complications.

Table 1 summarises the pre-transplant measures recom-mended by the guidelines. Pre-transplant, individuals should

be screened for risk factors particularly those, which are mod-ifiable (obesity, impaired glucose tolerance). All patients shouldhave the fasting plasma glucose and an oral glucose tolerancetest regardless of the result of the fasting plasma glucose.Standard cardiovascular and metabolic measures should bemade as part of screening including smoking status, bloodpressure and a full lipid profile to include triglycerides and cho-lesterol levels. All patients should be counselled about weightcontrol, diet and exercise regardless of plasma glucose levels.In the case of impaired glucose tolerance or impaired fastingplasma glucose this is imperative and such patients must bereferred to dietetic services.

The importance of lifestyle modification in the prevention ofNODAT must not be underestimated. Although most trialshave been carried out in the general population, there is nodoubt that lifestyle modification is applicable as a core compo-nent of both the management and prevention of NODAT inthe transplant population. The diabetes prevention pro-gramme demonstrated that in overweight adults withimpaired glucose tolerance, achieving and maintaining a mod-est weight loss with a structured diet and exercise plan canreduce the risk of developing DM by 58% and the benefit

Personal history

Cardiovascular

Glucose history

Smoking status

Family history

Cardiovascular

Traditional DM/NODAT

Body mass index

FPG and OFTT

Blood pressure

Cholesterol and triglycerides

Lifestyle advice/dietician

Weight control

Dietary advice

Exercise

Tailored immunosuppressive refimen

Establish risk

Consider rapid reduction of corticosteroids

Consider use of ciclosporin rather than Tacrolimus

Table 1: Pre-transplant recommendations for diabetic risk profiling.

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maintained long-term (Tuomilehto et al. 2001; Knowler et al.2009). Weight loss goals must be realistic and achievable forexample an initial weight loss of up to 10% of total bodyweight; a patient centred approach to education has beenlinked with success. In terms of diet specifics, increased fibreconsumption (15 g per 1000 kcal), increased consumption offruit and vegetables and whole grains (from baseline) andreduced saturated fat to less than 10% of energy consumptionhave been shown to have health benefits in preventing thedevelopment of diabetes (Tuomilehto et al. 2001).

There is also some evidence that consumption of fish oilsmight be of benefit. There is a reasonable body of evidencesupporting a role in reducing dislipidaemia particularly ele-vated triglycerides. The evidence pertaining to effects on bloodpressure, endothelial function and glycaemic control is lessclear-cut. It seems that the consumption of fish in moderatequantities, 1–2 portions per week, has cardioprotective effectsin those with type 2 diabetes and may reduce the incidence ofdeveloping diabetes in the general population (Rudkowska2010). Excessive consumption (more than five portions perweek) may have deleterious effects. Although, there is apaucity of studies in the transplant population, it is reasonableto recommend that these patients consume fish or a fish oilsupplement as part of a healthy diet.

In those with established DM regular exercise (The AmericanHeart Association recommend 30 minutes 5 times per week)has been shown to reduce cardiovascular risk and improve gly-caemic control (Marwick et al. 2009).

Additional risk factor modification might include the use ofdrugs to block the renin–angiotensin system. There is no directdata to support their use in the renal transplant population.However, there are clearly documented benefits in terms ofcardioprotective, anti-proteinuric and blood pressure loweringeffects in other populations with diabetes (Ram 2011). In addi-tion, in a meta-analysis of trials in patients with congestive car-diac failure, there was a clear reduction in the incidence of dia-betes in those taking either an angiotensin-converting enzymeinhibitor or an angiotensin receptor blocker compared withplacebo, diuretic, beta blocker or amlodipine (Scheen 2004).These drugs should be introduced cautiously in patients withrisk factors (impaired glucose tolerance, NODAT, hypertension,proteinuria, cardiovascular disease) and with careful monitor-ing of renal function. In addition, patients receiving live donor

renal transplants are more likely to experience delayed graftfunction if taking drugs to block the renin angiotensin systemat the time of transplant and this needs to be considered(Stevens et al. 2010).

Before transplantation, consideration should be given to thetype of immunosuppressive regimen to be used. This should beindividualised and should take account of cardiovascular anddiabetic risk profile. To minimise risk, rapid reduction in corti-costeroid and the use of ciclosporin rather than tacrolimus maybe considered in high-risk individuals or in those with problem-atic glycaemic control with the caveat that this switch hasyielded mixed results. Steroid sparing or avoidance regimesmust be tailored to each patient. In a study of more than20,000 patients from the United States Renal data System,Johnston et al. demonstrated that those on an immunosup-pressive regimen involving both sirolimus and a calcineurininhibitor (either ciclosporin or tacrolimus) were at highest riskof developing NODAT. Furthermore, there was evidence thatsirolimus increased the risk of NODAT independently of theeffects of tacrolimus (Johnston et al. 2008). In patients at mod-erate or high risk of NODAT, sirolimus in combination with acalcineurin inhibitor should be avoided, mycophenolatemofetil and azathioprine have not been shown to have dia-betogenic effects; Kasiske et al. showed that the combinationof mycophenolate with tacrolimus might reduce the pro-dia-betic effects of tacrolimus, perhaps because lower doses oftacrolimus can then be used (Kasiske et al. (2003).

Post-transplant monitoring should take place as outlined inFigure 3. Close monitoring is essential. If NODAT is detected,stringent management is needed (Figure 4). Patient education,self monitoring and screening for diabetic complications forman important part of management. Micro-albuminuria may beuseful but it has not been validated in the transplant popula-tion. Regular sampling will allow for detection of increased lev-els, which are likely to be of significance.

HbA1c percentage is widely used to monitor long-term gly-caemic control in all patients with DM. However, recent evi-dence suggests that lowering HbA1c levels below 6% mayincrease mortality. A large trial (ACCORD) was stopped earlybecause patients in the intensive treatment arm (target HbA1c

of �6%) had increased mortality (Gerstein et al. 2008). Thereason for the higher number of deaths was not clear but itcasts shadows on the safety of low HbA11cc levels. Similarly,

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although another large trial (ADVANCE) achieved HbA1c levelsof 6.3% in the intensive treatment group compared with 7%in the standard treatment group, there was no improvementseen in the number of cardiovascular events (Patel et al. 2008).It is not clear to what extent these findings can be applied torenal transplant recipients who have pre-existing or new onsetdiabetes but it does raise serious concerns about advocatinglow levels of HbA1c. In additiion, in a randomised control trialof glycaemic control in renal transplant recipients with type 1diabetes, the risk of severe hypoglycaemia was far greater inthose in the intensive glucose control arm (Barbosa et al.1994). Thus, an appropriate target HbA1c in kidney transplant

recipients should be approximately 6.5–7% and probably notlower although this should be individualised depending uponhypoglycaemic risk.

The choice of agent should be based upon the guidelines for tra-ditional type 2 diabetes. In the UK, NICE or SIGN guidelinesshould be followed (NICE guidelines 2011; SIGN guidelines2011). Elsewhere, The American Diabetic Association guidelinesmight be followed (American Diabetic Association 2011). A‘treat to target’ approach is advised where each patient withnewly diagnosed NODAT has an individualised target plasmaglucose level and treatment should be geared towards that level.

Figure 3: Monitoring of plasma glucose post-transplantation.

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In addition to lifestyle therapy, initially an oral agent monother-apy should be considered. The choice will vary depending uponan individual (Wilkinson et al. 2005). Metformin is the anti-gly-caemic agent of choice for ‘traditional’ type 2 DM and confersa variety of benefits including improvement in the metabolicsyndrome and cardiovascular protection. It does not promoteweight gain and is an effective anti-glycaemic therapy.However, it is not clear if these benefits translate to the trans-plant population because of a paucity of randomised controlledtrials. Concerns have been raised about the possibility ofnephrotoxicity and increased incidence of lactic acidosis withreduced renal function; there is a linear relationship betweenlevels of metformin and renal function. At present, there is notevidence to deny metformin to transplant recipients particularlyif renal function is ‘normal’ (eGFR � 60 ml/min). It could beused with caution at eGFR of 30–60 ml/min and until furtherstudies are undertaken should only be used in conjunction witha diabetologist and based on an individuals particular circum-stances at an eGFR �30 ml/min (Sharif 2011). If glycaemic con-trol is not achieved with monotherapy, a combination might betried and if targets are not achieved within two to four months,

insulin should be introduced either as a monotherapy or incombination with an oral anti-hypoglycaemic (Wilkinson et al.2005). Diabetologists should be involved particularly if hyper-glycaemia persists or is difficult to control.

It is worth noting that sulfonylureas (e.g. gliclazide) increaseciclosporin levels and so levels must be monitored closely andthe ciclosporin dose adjusted accordingly (KDIGO 2009). Thereis no data in the transplant population but in those onhaemodialysis, rosiglitazone increased all-cause mortality, car-diovascular mortality and non-fatal myocardial infarction androsiglitazone has been suspended from use in Europe (Ramirezet al. 2009). Pioglitazone, a similar drug should only be usedwith extreme caution in renal transplant recipients and onlyunder the guidance of a diabetologist.

Therapies, which improve pancreatic islet function, are currently being studied in NODAT. The DP4 inhibitor drugs(e.g. sitagliptin, vildagliptin) do not promote weight gain,unlike the sulfonylureas and they work by enhancing both�- and �-cell responsiveness to increased blood glucose. Data

Figure 4: Management of NODAT.

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in animals suggests a protective effect on pancreatic cell func-tion even after stress with immunosuppression. Therefore,these drugs are very attractive therapies for the managementof NODAT. In the non-transplant population, vildagliptin isused to treat type 2 diabetes as monotherapy or in combina-tion with metformin or a sulfonylurea (Doupis & Veves 2008).It has been shown to be safe in patients with moderatelyimpaired kidney function. In a study, which has yet to report,Haldinger et al. are looking at the safety and efficacy ofvildagliptin monotherapy in renal transplant recipients withNODAT (Haidinger et al. 2010).

Concomitant measures to lower cardiovascular risk should beundertaken including smoking cessation with referral to localspecialist services. Evidence suggests that at least in the short-term, patients are more likely to stop smoking if they have reg-ular contact and support by smoking cessation services (Aveyard& Bauld 2011). Cardiovascular risk should be assessed regularlyand hypertension and dyslipidaemia should be treated promptly.The use of statin therapy remains controversial in late CKD (stage5) but the SHARP study demonstrates that statins are safe andthe ALERT study showed that there was non-significant benefitof statin therapy in transplant recipients (Holdaas et al. 2003;

Baigent et al. 2011). Therefore, in the absence of an effectivealternative, statins should be used in combination with dietaryadvice to achieve target cholesterol levels.

CONCLUSIONImpaired glucose tolerance and NODAT are serious conse-quences of renal transplantation with resultant detrimentaleffects on mortality, morbidity, transplant function and out-come and also present a significant socioeconomic burden. Auniversal definition, screening and management strategyshould allow clinicians to establish those at risk, minimise thatrisk and instigate prompt management.

AUTHORS’ CONTRIBUTIONSKS researched and wrote the article. RP and AJ read and editedthe draft version.

CONFLICT OF INTERESTKS received an educational grant from Amgen and Shire. RPdeclares no conflicts of interest. AJ is a member of trial steer-ing, data monitoring and endpoints committees, and advisoryboards for Novartis, AstraZeneca, Astellas, Roche, Merck,Sharp and Dohme and Genzyme.

REFERENCES

American Diabetic Association (2011). http://professional.diabetes.org/CPR_Search.aspx. (accessed on 11 September 2011).

Arase Y., Suzuki F., Suzuki Y. et al. (2009). Sustained virologicalresponse reduces incidence of onset of type 2 diabetes in chronichepatitis C. Hepatology 4499, 3, 739-744.

Aveyard P. & Bauld L. (2011). Incentives for promoting smoking cessa-tion: What we still do not know. Cochrane Database Syst Rev 8,ED000027.

Baigent C., Landray M.J., Reith C. et al. (2011). The effects of loweringLDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection):A randomised placebo-controlled trial. Lancet 337777, 9784, 2181-2192.

Barbosa J., Steffes M.W., Sutherland D.E. et al. (1994). Effect ofglycemic control on early diabetic renal lesions. A 5-year random-ized controlled clinical trial of insulin-dependent diabetic kidneytransplant recipients. JAMA 227722, 8, 600-606.

Bee Y.M., Tan H.C., Tay T.L. et al. (2011). Incidence and risk factors fordevelopment of new-onset diabetes after kidney transplantation.Ann Acad Med Singapore 4400, 4, 160-168.

Boerner B.P., Shivaswamy V., Desouza C.V. et al. (2011). Diabetes andcardiovascular disease following kidney transplantation. CurrDiabetes Rev 77, 4, 221-234.

Byrne C., Ford D., Gilg J. et al. (2010). UK Renal Registry 12th AnnualReport (December 2009): Chapter 3: UK ESRD incident rates in2008: National and centre-specific analyses. Nephron Clin Pract111155,, Supplement 1, c9-39.

Cole E.H., Johnston O., Rose C.L. et al. (2008). Impact of acute rejec-tion and new-onset diabetes on long-term transplant graft andpatient survival. Clin J Am Soc Nephrol 33, 3, 814-821.

Cosio F.G., Hickson L.J., Griffin M.D. et al. (2008). Patient survival andcardiovascular risk after kidney transplantation: The challenge ofdiabetes. Am J Transplant 88, 3, 593-599.

Cosio F.G., Kudva Y., van d V., Larson T.S. et al. (2005). New onsethyperglycemia and diabetes are associated with increased cardio-vascular risk after kidney transplantation. Kidney Int 6677, 6, 2415-2421.

Cosio F.G., Pesavento T.E., Osei K. et al. (2001). Post-transplant dia-betes mellitus: Increasing incidence in renal allograft recipientstransplanted in recent years. Kidney Int 5599, 2, 732-737.

Cruz-Munoz N., Messiah S.E., Arheart K.L. et al. (2011). Bariatric sur-gery significantly decreases the prevalence of type 2 diabetes mel-litus and pre-diabetes among morbidly obese multiethnic adults:Long-term results. J Am Coll Surg 221122, 4, 505-511.

Davidson J., Wilkinson A., Dantal J. et al. (2003). New-onset diabetesafter transplantation: 2003 International consensus guidelines.

jorc_282.qxd 2/2/12 10:48 AM Page 135


Stevens et al.


Proceedings of an international expert panel meeting. Barcelona,Spain, Transplantation; 7755, 10 Supplement, SS3-24.

DECODE Study Group on behalf of the European DiabetesEpidemiology Study Group (1998). Will new diagnostic criteriafor diabetes mellitus change phenotype of patients with dia-betes? Reanalysis of European epidemiological data. BMJ 331177,7155, 371-375.

de Mattos A.M., Olyaei A.J., Prather J.C. et al. (2005). Autosomal-dominant polycystic kidney disease as a risk factor for diabetesmellitus following renal transplantation. Kidney Int 6677, 2, 714-720.

Doupis J. & Veves A. (2008). DPP4 inhibitors: A new approach in dia-betes treatment. Adv Ther 2255, 7, 627-643.

Duckworth W., Abraira C., Moritz T. et al. (2009). Glucose control andvascular complications in veterans with type 2 diabetes. N Engl JMed 336600, 2, 129-139.

Fabrizi F., Martin P., Dixit V. et al. (2005). Post-transplant diabetes mel-litus and HCV seropositive status after renal transplantation:Meta-analysis of clinical studies. Am J Transplant 55, 10, 2433-2440.

Foley R.N., Parfrey P.S. & Sarnak M.J. (1998). Epidemiology of cardio-vascular disease in chronic renal disease. J Am Soc Nephrol. 99, 12(Supplement), S16-S23.

Gerstein H.C., Miller M.E., Byington R.P. et al. (2008). Effects of inten-sive glucose lowering in type 2 diabetes. N Engl J Med 335588, 24,2545-2559.

Gonzalez-Posada J.M., Hernandez D., Bayes G.B. et al. (2004). Impactof diabetes mellitus on kidney transplant recipients in Spain.Nephrol Dial Transplant 1199, Supplement 3, iii57-iii61.

Haidinger M., Werzowa J., Voigt H.C. et al. (2010). A randomized,placebo-controlled, double-blind, prospective trial to evaluate theeffect of vildagliptin in new-onset diabetes mellitus after kidneytransplantation. Trials 1111, 91.

Hjelmesaeth J., Hartmann A., Leivestad T. et al. (2006). The impact ofearly-diagnosed new-onset post-transplantation diabetes mellituson survival and major cardiac events. Kidney Int. 6699,, 3, 588-595.

Hjelmesaeth J., Muller F., Jenssen T. et al. (2005). Is there a linkbetween cytomegalovirus infection and new-onset posttransplan-tation diabetes mellitus? Potential mechanisms of virus inducedbeta-cell damage. Nephrol Dial Transplant 2200, 11, 2311-2315.

Hjelmesaeth J., Hartmann A., Kofstad J. et al. (2001). Tapering offprednisolone and cyclosporin the first year after renal transplan-tation: The effect on glucose tolerance. Nephrol Dial Transplant1166, 4, 829-835.

Hjelmesaeth J., Hartmann A., Kofstad J. et al. (1997). Glucose intoler-ance after renal transplantation depends upon prednisolone doseand recipient age. Transplantation 6644, 7, 979-983.

Holdaas H., Fellstrom B., Jardine A.G. et al. (2003). Effect of fluvastatinon cardiac outcomes in renal transplant recipients: A multicentre,randomised, placebo-controlled trial. Lancet 336611, 9374, 2024-2031.

Johnston O., Rose C.L., Webster A.C. et al. (2008). Sirolimus is associ-ated with new-onset diabetes in kidney transplant recipients. JAm Soc Nephrol 1199, 7, 1411-1418.

Joss N., Staatz C.E., Thomson A.H. et al. (2007). Predictors of newonset diabetes after renal transplantation. Clin Transplant 2211, 1,136-143.

Kamar N., Toupance O., Buchler M. et al. (2003). Evidence that clear-ance of hepatitis C virus RNA after alpha-interferon therapy indialysis patients is sustained after renal transplantation. J Am SocNephrol 1144, 8, 2092-2098.

Kasiske B.L., Snyder J.J., Gilbertson D. et al. (2003). Diabetes mellitusafter kidney transplantation in the United States. Am J Transplant33, 2, 178-185.

Kawaguchi T., Taniguchi E., Itou M. et al. (2011). Sakata M, Sumie S,Sata M. Insulin resistance and chronic liver disease. World JHepatol 33, 5, 99-107.

KDIGO (2009). Clinical practice guideline for the care of kidney trans-plant recipients. Am J Transplant 99 (Suppl 3), S1-155.

Kim S.J., Lee K.W., Lee D.S. et al. (2004). Randomized trial oftacrolimus versus cyclosporine in steroid withdrawal in livingdonor renal transplant recipients. Transplant Proc 3366,, 7, 2098-2100.

Knowler W.C., Fowler S.E., Hamman R.F. et al. (2009). 10-year follow-upof diabetes incidence and weight loss in the Diabetes PreventionProgram Outcomes Study. Lancet 337744,, 9702, 1677-1686.

Kuo H.T., Sampaio M.S., Vincenti F. et al. (2010). Associations of pre-transplant diabetes mellitus, new-onset diabetes after transplant,and acute rejection with transplant outcomes: An analysis of theOrgan Procurement and Transplant Network/United Network forOrgan Sharing (OPTN/UNOS) database. Am J Kidney Dis 5566,, 6,1127-1139.

Lentine K.L., Brennan D.C., Schnitzler M.A. (2005). Incidence and pre-dictors of myocardial infarction after kidney transplantation. J AmSoc Nephrol. 1166,, 2, 496-506.

Marwick T.H., Hordern M.D., Miller T. et al. (2009). Exercise training fortype 2 diabetes mellitus: Impact on cardiovascular risk: A scientificstatement from the American Heart Association. Circulation 111199,,25, 3244-3262.

Matas A.J., Humar A., Gillingham K.J. et al. (2002). Five preventablecauses of kidney graft loss in the 1990s: A single-center analysis.Kidney Int 6622,, 2, 704-714.

Matas A.J., Gillingham K.J., Humar A. et al. (2008). Posttransplant dia-betes mellitus and acute rejection: Impact on kidney transplantoutcome. Transplantation 2008; 8855,, 3, 338-343.

Mehta S.H., Brancati F.L., Sulkowski M.S. et al. (2001). Prevalence oftype 2 diabetes mellitus among persons with hepatitis C virusinfection in the United States. Hepatology 3333,, 6, 1554.

Meier-Kriesche H.U., Baliga R. & Kaplan B. (2003). Decreased renalfunction is a strong risk factor for cardiovascular death after renaltransplantation. Transplantation 2003; 7755,, 8, 1291-1295.

Midtvedt K, Hjelmesaeth J., Hartmann A. et al. (2004). Insulin resistance after renal transplantation: The effect of steroid dosereduction and withdrawal. J Am Soc Nephrol 1155,, 12, 3233-3239.

Miles A.M., Sumrani N., Horowitz R. et al. (1998). Diabetes mellitusafter renal transplantation: As deleterious as non-transplant-asso-ciated diabetes? Transplantation 6655,, 3, 380-384.

jorc_282.qxd 2/2/12 10:48 AM Page 136




Montori V.M., Basu A., Erwin P.J. et al. (2002). Posttransplantation dia-betes: A systematic review of the literature. Diabetes Care 2255,, 3,583-592.

NICE guidelines. (2011). http://www.nice.org.uk/cg66. (accessed on11 September 2011).

Pascual J., Zamora J., Galeano C. et al. (2009). Steroid avoidance orwithdrawal for kidney transplant recipients. Cochrane DatabaseSyst Rev (1), CD005632.

Patel A., MacMahon S, Chalmers J. et al. (2008). Intensive blood glu-cose control and vascular outcomes in patients with type 2 dia-betes. N Engl J Med 335588,, 24, 2560-2572.

Rakel A. & Karelis A.D. (2001). New-onset diabetes after transplanta-tion: Risk factors and clinical impact. Diabetes Metab 2011; 3377,,1, 1-14.

Ram C.V. (2011). Reappraisal of role of angiotensin receptor blockersin cardiovascular protection. Vasc Health Risk Manag 77, 315-319.

Ramirez S.P., Albert J.M., Blayney M.J. et al. (2009). Rosiglitazone isassociated with mortality in chronic hemodialysis patients. J AmSoc Nephrol 2200,, 5, 1094-1101.

Report of the Expert Committee (1997). Report on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2200,, 7, 1183-1197.

Report of the expert committee (2003). Report on the diagnosis andclassification of diabetes mellitus. Diabetes Care 2003; 2266(Supplement 1), S5-20.

Revanur V.K., Jardine A.G., Kingsmore D.B. et al. (2001). Influence ofdiabetes mellitus on patient and graft survival in recipients of kid-ney transplantation. Clin Transplant 1155, 89-94.

Rudkowska I. (2010). Fish oils for cardiovascular disease: Impact ondiabetes. Maturitas 6677,, 1, 25-28.

Scheen A.J. (2004). Renin-angiotensin system inhibition prevents type2 diabetes mellitus. Part 1. A meta-analysis of randomised clinicaltrials. Diabetes Metab 3300,, 6, 487-496.

Sharif A. (2011). Should Metformin Be Our Antiglycemic Agent ofChoice Post-transplantation? Am J Transplant 1111,, 7, 1376-1381.

SIGN guidelines (2011). www.sign.ac.uk/guidelines/fulltext/116/index.html. (accessed on 11 September 2011).

Starzl T.E., Marchioro T.L., Rifkind D. et al. (1964), Factors in successfulrenal transplantation. Surgery 1964; 56, 296-318.transplanta-tion. Clin Transplant 1155,, 2, 89-94.

Stevens K.K., Patel R.K., Clancy M. et al. (2010). Angiotensin blockadeis associated with early graft dysfunction after live donor renaltransplantation. Transplantation 8899,, 6, 707-709.

Sumrani N., Delaney V., Ding Z. et al. (1991). Posttransplant diabetesmellitus in cyclosporine-treated renal transplant recipients.Transplant Proc 1991; 23, 1 (Pt 2), 1249-1250.

Tuomilehto J., Lindstrom J., Eriksson J.G. et al. (2001). Prevention of type2 diabetes mellitus by changes in lifestyle among subjects withimpaired glucose tolerance. N Engl J Med 334444,, 18, 1343-1350.

Vanrenterghem Y., Bresnahan B., Campistol J. et al. (2011). Belatacept-based regimens are associated with improved cardiovascular andmetabolic risk factors compared with cyclosporine in kidney trans-plant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation9911,, 9, 976-983.

Vesco L., Busson M., Bedrossian J. et al. (1996). Diabetes mellitus afterrenal transplantation: Characteristics, outcome, and risk factors.Transplantation 6611,, 10, 1475-1478.

Vincenti F., Friman S., Scheuermann E. et al. (2007). Results of an inter-national, randomized trial comparing glucose metabolism disor-ders and outcome with cyclosporine versus tacrolimus. Am JTransplant 77 ,, 6, 1506-1514.

Webster A.C., Woodroffe R.C., Taylor R.S. et al. (2005). Tacrolimusversus ciclosporin as primary immunosuppression for kidneytransplant recipients: Meta-analysis and meta-regression ofrandomised trial data. BMJ 333311,, 7520, 810.

Wiesbauer F., Heinze G., Regele H. et al. (2010). Glucose control isassociated with patient survival in diabetic patients after renaltransplantation. Transplantation 8899,, 5, 612-619.

Wilkinson A., Davidson J., Dotta F. et al. (2005). Guidelines for thetreatment and management of new-onset diabetes after trans-plantation. Clin Transplant 1199,, 3, 291-298.

World Health Organisation (2006). Establishing consensus criteria forthe diagnosis of: http://www.who.int/diabetes/publications/Definition%20and%20diagnosis%20of%20diabetes_new.pdf.(accessed on 19 July 2011).

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