Prevalence of Dysglycemia Among Kidney Transplant Recipients

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Abstract

Background

Diabetes mellitus is the commonest cause of end stage renal disease worldwide. There is an increased incidence of DM in the third world country and Kenya being one of them. Evidence has showed that kidney transplantation is the best treatment for ESKD. It improves health related quality of life and prevents complications of kidney failure. Higher incidence of dysglycemia among kidney transplant recipients (KTR) has been documented. This makes them more susceptible to fatal cardiovascular events. Prevention, early detection and treatment of the dysglycemia in KTR have beneficial effects.

Objectives of the study:

Our primary objective was to determine the prevalence of dysglycemia (pre transplant DM, NODAT, IFG, IGT) among kidney transplant recipients (KTRs) at Kenyatta National Hospital (KNH). Secondary objectives were to determined quality of glycemic control in the known diabetic patients and to describe the clinical characteristics of the KTRs with dysglycemia.

Methods

We did across-sectional, descriptive hospital based at the transplant clinic at the renal unit of Kenyatta National Hospital. All adult (age 18 and above) KTRs, who agree to participate were included with a minimum targeted sample of 103. Study questionnaire was filled after a signed written consent was obtained thereafter patients’ weight, height and waist circumference were measured by PI and later blood samples were taken for HbA1c percent for the diabetic patients, and fasting blood sugar and OGTT for the rest to determine presence of dysglycemia. Data was managed in Microsoft Access 2013 database. Study population was described using their socio demographic and clinical characteristics. Statistical analysis was done using SPSS version 21.0. The prevalence of dysglycemia was analyzed and presented as a percentage of all KTRs and a 95% confidence interval (CI) of the prevalence was presented. T test method was used for comparison for continuous data and chi-square test for categorical data. Multivariate analysis was performed to investigate independent association between patient characteristics and dysglycemia.

 

Results

Between September 2016 and May 2017, 105 kidney transplant recipients were recruited in the study and we found a prevalence of 13.3% for new onset diabetes after transplantation, 14.29% for impaired glucose tolerance and 6.67% for impaired fasting glucose. The prevalence of pre transplant DM was 23.81%. Important risk factors noted at univariate analysis were female gender, longer duration post transplantation, BMI more that 25kg/m2, higher waist hip ratios and family history of diabetes. More than half of the diabetes KTRs had poor glycemic control (56%) with a mean HbA1c of 9.62±2.03.

Conclusion

We found a high prevalence of dysglycemia in our set up and also poor glycemic control in KTRs with diabetes mellitus. This calls for screening programs on KTRs who previously were non diabetic and intensive risk stratification to optimize graft survival.

1.0 INTRODUCTION

Dysglycemic states which encompasses overt diabetes, impaired fasting glucose and abnormal glucose tolerance. Dysglycemia is a common phenomenon in renal transplant recipients. There is a variability in the natural history of IFG and OGT but approximately 25 percent develop diabetes in three to five years (1).

Diabetes mellitus is the commonest cause of end stage renal disease worldwide and third after chronic glomerulonephritis and hypertension in Kenya (2). Kidney transplantation has been proven to improve the health related quality of life and also reduces cardiovascular disease effect by removing the kidney failure adverse effects (3) but also in the other hand there is an increased risk of cardiovascular events in the group of patients with dysglycemia as compared with other kidney transplant recipients (4).

Renal transplantation science has been developing with improved survival rates due to enhancement in treatment with immunosuppressive or antirejection drugs. In Kenya, there has been an accelerated program: interlife® which is a private public partnership between KNH and Norvatis pharma since year 2010. This has made the numbers of KTRs increase exponentially.

Diabetes mellitus is an important risk after renal transplantation and it has been implicated to be a cause of increased mortality due to cardiovascular events (5), deleterious effects on allograft survival (6) and high incidence of infection rates (7). The diagnosis of DM in KTRs is per the International consensus guidelines meeting which is in line with the WHO/ADA guidelines (8).

Several factors have been associated with the impairment of glucose metabolism, for example, the use of certain immunosuppressive medications. Glucocorticoid is a backbone drug in many immunosuppressive regimens but causes DM by increasing insulin resistance (9). Calcinuerin inhibitors include tacrolimus with more effects than its counterpart cyclosporine cause DM by affecting insulin secretion (10). Other risks factors include increasing age, family history of DM, pre transplant impaired glucose, overweight and obesity, ethnicity and lifestyle changes such as smoking and alcohol intake (11).

Early identification and intensive treatment of the abnormal sugar levels have beneficial outcomes in overall patients’ survival (12). Adjustment of antirejection (13), lifestyle changes (14) and intensive early treatment (15) are some of the management plans of NODAT.  The usual antidiabetic medications are used with a stepwise approach with an aim of achieving good glycemic targets, reduced side effects and favorable costs.

2.0 LITERATURE REVIEW

2.1 DEFINITIONS:

Diabetes is a term that describes several diseases of abnormal carbohydrate metabolism that are characterized by hyperglycemia. It is associated with a relative or absolute impairment of insulin secretion, together with differing degrees of peripheral resistance to the actions of insulin.

According to the American diabetes association (ADA) diagnosis of diabetes is based on one of four abnormalities as shown in table 1 (8).

Impaired glucose tolerance describes individuals who during oral glucose tolerance test (OGTT) have blood sugar values between those in normal subjects and those in patients with overt diabetes (140 to 199mg/dl{ 7.8 to 11mmol/l} (8).

Impaired fasting glucose is defined as a fasting blood sugar of 100 to 125mg/dl (5.6 to 7 mmol/l) (8).

Categories of increased risk of diabetes includes IFG, IGT and A1C – Persons with 5.7 to 6.4 percent (39 to 46 mmol/mol), (6.0 to 6.4 percent [42 to 46 mmol/mol] in the International Expert Committee report (16)) are at highest risk, although there is a continuum of increasing risk across the entire spectrum of A1C levels less than 6.5 percent (48 mmol/mol) . These together with diabetes are occasionally also termed as dysglycemic states.

New onset diabetes after transplantation (NODAT) also known as post transplantation diabetes mellitus (PTDM) after the International consensus guidelines meeting (17), is the diabetes defined by World Health Organization (WHO) and American Diabetes Association (ADA) that develops for the first time after transplantation. The diagnosis is as per the WHO/ADA criteria (see table 1)of diabetes mellitus only that HBA1C is not recommended for diagnosis until after 3 months post transplantation, this is to allow new hemoglobin to be synthesized and glycated for appropriate period in the diabetogenic post transplantation setting (18).

Table 1 ADA criteria for the diagnosis of diabetes (8)

1 A1c greater or equal to 6.5 %. The test should be performed in a laboratory using a method that is NGSP certifies and standardized to the DCCT assay. OR
2 FBG >/=126mg/dl( 7.0 mmol/l). Fasting is defined as no caloric intake for at least eight hours OR
3 Two-hour plasma glucose >/= 200mg/dl(11.1 mmol/l) during an OGTT. The test should be done as described by WHO, using a glucose load containing equivalent of 75 gram anhydrous glucose dissolved in water. OR
4 In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose >/=200mg/dl(11.1mmol/l)

2.2 EPIDEMIOLOGY

There has been a significant growth of incidence and prevalence of diabetes mellitus throughout the world. According to the WHO, in 2014 the global prevalence of diabetes was estimated to be 9% among adult age 18 years and above (19). In 2012, an estimated 1.5 million deaths were directly caused by diabetes (20). The information to worry about was that more than 80% of the diabetes deaths occur in low and middle income countries (20).

The increase in the number of people developing diabetes has had a major impact on the development of diabetes kidney disease (DKD). Notably, diabetes is the leading cause of ESRD, accounting for approximately 50% of cases in the developed world. Sheikh et al. (2) did a study on prevalence of cardiovascular risks among patient with renal failure and found diabetes as a cause of CKD had a prevalence of 28.9%. Among the KTRs studied by Maina et al. (21) in 2014 he noted that 20% of them had diabetes as a cause of their ESRD. Wagude et al. in their study on cardiovascular risks factor in KTRs attending nephrology clinics in Nairobi found a prevalence of 49.5 for dysglycemic states (22).

Early dysglycemia, that is, period of hospitalization post- transplant is common. This should always be taken seriously as majority of this patients are at risks of developing NODAT such that day 7 FBS may be predictive at year one (23). A study which was done recently (24) measured continuous capillary blood sugar levels for the first 4 days post-transplant in 43 patients. There was an increased level of hyperglycemia and 43% of patients spent more than 12 hours per day with blood sugar levels above 7.7mmol/l. After a mean follow up of 72 months, NODAT was frequently seen.  Moreover, a normal OGTT within the first week has been shown to have a high negative predictive value of 97.6% for future development of NODAT (25).  Early hyperglycemia does not necessary predict future permanent dysglycemic states. There is variability in impairment of glucose metabolism and considerable degree of transiency. A Chinese study done in 428 patients who were not diabetes before surgery found an incidence of 20.32% for NODAT after a mean follow up of 5.65 years in patient who survived more than one year post transplantation. Among these 65.5 % developed NODAT within 1 year and 17.2% had transient NODAT (26).

Studies done using current WHO/ADA diagnostic criteria suggest that up to one third of non-diabetic KTRs develop persistently dysglycemia by six month post transplantation. In a study done by Valderhaug et al. (27) found an incidence of NODAT to be 14-17%. This was by using OGTT at 10 weeks. A retrospective South African study on 221 KTRs showed an incidence of 22.6% (28). These and other studies on dysglycemia on KTRs are summarized in table 2. Of note, whilst there is consensus regarding cut off blood glucose levels, it’s not clear which tests should be used and which time post-transplant (29). Some studies had witnessed remission of some patients with dysglycemia (though not commonly documented) to normoglycemia post-transplant (30), further complicates analysis of rates of new onset post-transplant abnormalities in glucose metabolism.

Table 2 Selection of studies that reported rates of abnormalities in glucose metabolism post renal transplantation

References Study Design Criteria Sample size Rates
Valderhaug et al. (27) Cross sectional OGTT 1410 17% NODAT at 10weeks

47.8% other dysglycemia

Vincenti et al. (10) Prospective randomised OGTT 682 30% at 6 month dysglycemia
Cosio et al. (31) Retrospective Use of medication, FBGL, 490 13% at 1yr. 33% dysglycemia
Bapoo et al. (28) Retrospective Patient records documentation 221 22.6 with NODAT
Cole et al. (6) Prospective pilot study Use of medication, FBGL, OGTT 49 4% at 6 mo
Wagude et al. (22) Cross sectional F BGL and self-reporting 91 49.5%

2.3 RISK FACTORS

 

2.3.1 Immunosuppressive therapy

The medications that contribute to impairment glucose metabolism of include glucocorticoids, calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors. These are potentially modifiable risk and are transplant related. The antimetabolites including mycophenolate mofetil and azathioprine are not diabetogenic.

2.3.2.1 Glucocorticoids

Systemic (oral) glucocorticoid is the backbone drug for many antirejection regimen therapies. Its effect on impairment of glucose metabolism has been well documented and this is mainly by cumulative exposure. Several data show different incidence rates( ranges 1-22%) over 1-5 year period post transplantation when analyzing on glucocorticoid withdrawal , glucocorticoids free and rapid tapering which compares with rates of 15%-35% in regimens without glucocorticoids maintenance (29).

Not all studies analysis found benefit in glucocorticoids withdrawal. A meta-analysis of high quality trials in which glucocorticoids withdrawal done on day 14 post transplantation while treating them with CNI/MMF did not find a reduction in NODAT (32). Though insulin therapy was not required in the arm of patients with early withdrawal of glucocorticoids i.e. at day 7, and there was no difference in the rate of NODAT. This was from the largest randomized placebo-controlled trial (33). Nevertheless, many other studies find an advantage to glucocorticoid avoidance. United States renal data system (USRDS) found that patients discharged on glucocorticoid containing regimen had an OR of 1.42 for NODAT compared to those on glucocorticoid free regimen (34). Another one, a pilot study (n=49) of thymoglobulin induction, MMF , low dose CsA and rapid glucocorticoid reduction in low immunological risks patients found that  42 out of 49 patients being normoglycemic at 6 months (30). Questions to glucocorticoid effect may be answered in an ongoing multicenter study (SAILOR). The study compares a steroid free, CNI/MMF maintenance with thymoglobulin induction and another arm on basixilimab induction and ongoing steroid exposure (35). Frequent acute rejection episodes necessitating pulsing with glucocorticoid have been attributed to an increased risk of developing  NODAT (36).

2.3.2.2 Calcineurin inhibitors

The calcineurin inhibitors (CNI), includes cyclosporine (CsA) and tacrolimus (Tac). Their usage and especially Tac, have been associated with less acute rejection and improved graft function but at the expense of an increased incidence in abnormalities of glucose metabolism especially NODAT (33). In a large international randomized trial comparing glucose metabolism disorders and outcomes with cyclocporine versus tacrolimus . They found 6-mo cumulative incidence of 33.6% in Tac treated KTRs and 26% in CsA treated KTRs.  Moreover more patient in the Tac group required hypoglycemic agents and more in the CsA treated group who were not treated with hypoglycemic agents had an improvement in their glycemic state at 6-mo (10). However, this was at the era of high trough target level of the drugs. There is also evidence that the impairment of glucose metabolism is also associated with the degree of CNI exposure. Chan et al. (37) found that NODAT was significantly less frequent in the low dose Tac ( 17% versus 31%). This was a 6-month prospective open label, multicenter study, de novo KTRs were randomized (1:1) to low dose or standard dose Tac with basiliximab, enteric coated mycophenolate sodium (EC-MPS), and steroids. A larger study; Efficacy limiting toxicity eliminating (ELITE)- SYMPHONY, also suggested a dose dependent relationship. It found higher rates of NODAT in the low dose Tac group( 12%), compared with low dose CsA (5%),low dose sirolimus (8%) or standard dose CsA (8%). (38)

 

2.3.2.3 Mammalian target of rapamycin: Sirolimus

Sirolimus is oftenly used in conjunction with or instead of CNI. Clinical data suggest that the risk of abnormality in glucose metabolism is not low. Analysis of USRDS of 2598 KTRs having received sirolimus and CNI created a higher HR for cumulative 1 year incidence of NODAT compared to CNI with MMF/AZA or sirolimus with MMF/AZA (27). Conversion to sirolimus from Tac or CsA  has also been associated with significant worsening in insulin resistance (39). However, there has been some inconsistency finding on sirolimus. A study done recently (n=440) found higher doses of Tac but not high or standard dose of sirolimus contributed to NODAT (40).

2.3.2 Age

Age at time of kidney transplantation has been reported to be an independent risk factor for NODAT.  Age older than 40 to 45 years is most frequently cited as the threshold level that is associated with markedly increased risk. Casio et al. found up to 2.2 times higher risks of NODAT development in KTRs older than 45years compared with younger recipient (41). Similarly, USRDS data show a strong relationship between age of recipients and NODAT development. KTRs age 45-59 years had 1.9 times higher risk than recipients age 18-33 years and the KTRs older than 60 years the risk was double that of younger recipients(11).  There is usually an important interaction between modifiable factors such as antirejection medicines and non-modifiable factors such as older age. Multivariate analysis has found that older age and higher sirolimus trough levels were associated with increased hazard for NODAT (42).

2.3.3 Overweight and Obesity

Overweight and obesity is a known modifiable risk factor for cardiovascular disease. Obesity independently correlates with development of NODAT (11). Weight gain after transplantation is common. These is because of several factors, including increase of appetite after reversal of the uremia, relatively high doses of steroids especially in early post-transplant period and also reduced physical activity (43).  An analysis of 15,309 adult kidney recipients using the Organ procurement and Transplant Network/United network for Organ Sharing (OPTN/UNOS) database found that the risk of NODAT increased 1.4 fold for those with BMI of 25-30 and almost double for those with BMI more than 30 (44). Central obesity as measured by waist circumference has been associated with increased risk of NODAT. Using univariate analysis, Kodgire et al. (45) found statistically significantly greater waist circumference in patient at time of transplantation later developed NODAT when followed up 12 months post transplantation.

2.3.4 Family History of DM

Family history of diabetes has been associated with NODAT. For example, Hjelmesaeth et al. using univariate analysis revealed that family history of diabetes was associated with NODAT (46).

2.3.5 Lifestyle factors

Cigarette smoking, poor diet and physical inactivity are known risk factors for diabetes in the general population (8). Patients post transplantation have improved appetite which can lead to unhealthy eating leading to obesity which has been shown to be correlated with NODAT (11).  However not well studied, good dietary diet intake, increased physical activity and smoking cessation improve dysglycemia in KTRs.

2.4 PATHOGENESIS

The pathogenesis of dysglycemia is complex and usually widely assumed to be closely aligned to the pathogenesis of type 2 diabetes mellitus (T2DM). KTRs are considered to be at a chronic kidney state and not forgetting the impact of the end stage renal failure and dialysis on glucose hemeostasis. Insulin resistance and insulin secretion changes have both been shown to be responsible for the development of abnormalities in glucose metabolism states in post kidney transplantation. The changes are dynamic and occasionally transient, particularly in early post-transplant period.

2.4.1 Insulin resistance

It refers to decreased action of insulin at the target cells, that is, a state in which a given concentration of insulin produces a less than expected biological effect. Glucocorticoids cause an increase in insulin resistance. Their effects are mediated by cytosolic glucocorticoids receptors and result from both genomic and non-genomic mechanisms that also have a role in the therapeutic effects of these agents(9).  Glucocorticoids impair peripheral glucose uptake, impair hepatic glycogen synthesis and enhance gluconeogenesis. At higher doses they may induce pancreatic beta cell apoptosis (47). The diabetogenic effect has not only been associated with high doses but also prolonged exposure even at low doses (48). The desired anti-inflammatory effects of glucocorticoids are mainly mediated via repression of genes transcription and the side effects largely from transactivation (9).

The persistent state of CKD (49) post transplantation contributes to the dynamic nature of post transplantation dysglycemia. These patients prior to being transplanted have had a considerable period of ESKD requiring dialysis, therefore uremia effect to insulin resistance (49). A study done comparing 27 diabetic patients and 35 non-diabetes ESKD patients to assess insulin resistance using a homeostatic model assessment-insulin resistance model found increased insulin resistance in the diabetes. There was an elevated C-peptide in the non-diabetic patients with increased insulin resistance, indicating a compensatory response maintaining non diabetes state (50).

2.4.2 Insulin secretion

Several studies done showed decreased insulin secretion in KTRs who had developed NODAT. For example study done by Nagaraja et al. (51) described insulin indices pre and followed up patient at 3 and 12 months post-transplant. Patient developed NODAT at 12 months had improved insulin resistance but low insulin secretion. This also explains that despite reducing doses of glucocorticoids and improvement of peripheral insulin resistance the level of insulin secretion failed to be compensatory (51). Nam et al. (52) first demonstrated abnormal insulin secretion as a component of pathogenesis. They followed up 144 patients pre and post-transplant and noted that those who developed impairment in glucose metabolism, at 9-12 months post-transplant had significantly lower insulin secretion despite improved insulin resistance. Inversely, another longer study (53) followed up patient up to 6 years, noted that patients who were dysglycemic at 10 weeks and became normoglycemmic had improvement in insulin resistance and a non-significant impairment of insulin secretion, thus retaining a compensatory response.

CNI is the main cause of abnormal insulin secretion post transplantation. Pancreatic beta cell function is impaired due to the inhibition of calcinuerin. Calcineurin is a cytosolic phosphatase that has two targets in the beta cell: the nuclear factor of activated T cells and cyclic AMP responsive element binding protein transcription co-activator (29) .

Hyperglycemia by itself is a recognized stressor for beta cells, suppressing insulin secretion and or leading to beta cell apoptosis. Beta cell failure plays a major role in type 2 DM development (54) and is thus very likely to play a key role in the development of NODAT.

-Calcineurin inhibitors

– Chronic hyperglycemia

-Glucocorticoid therapy

-CKD state

Increased Insulin resistance

Reduced Insulin secretion

Dysglycemia

Figure 1 : Summary of pathogenesis of  dysglycemia in KTRs

2.5 CLINICAL OUTCOMES

 

2.5.1 Patient survival

The development of dysglycemia post transplantation, especially diabetes has adverse effect on patient survival. In one study, one year survival was 83% and 98% in those KTRs with and without NODAT respectively (5).A subsequent report found that 5 year survival with NODAT was 87% versus 93% among nondiabetes patients (55). The development of NODAT correlates with increased cardiovascular mortality, which is the most prevalent cause of poor long term survival (27) (43) .  Excess risk is sometime associated with coexistence of other cardiovascular risk factors, particularly increased age and dyslipidemia (56). Though limited by the short period of follow up; 1.5 years, the effect of pre transplant diabetes in all cause cardiovascular mortality is more than the new onset diabetes (57).

2.5.2 Allograft survival

The effect of diabetes on allograft survival is due to the increase mortality associate with it. For example, a retrospective analysis of 27,707 KTRs, NODAT was associated with increased risk of allograft failure from any cause, but not for death-censored graft loss (or graft loss without death (6). Acute rejection has been noted to be the most significant potentially modifiable factor in allograft survival. This shows the importance of maintaining sufficient immunosuppression to prevent rejection even at the expense of developing glucose metabolism impairment particularly diabetes (58).

2.5.3 Infections

With hyperglycemic effect on immune system, diabetes in KTRs has been associated with an increased risk of infections and sepsis (5) (7) (56). The commonly reported infections from similar studies include urinary tract infections (UTI), pneumonia and cytomegalovirus (CMV).

2.6 SCREENING AND DIAGNOSIS

OGTT is the gold standard for diagnosis of dysglycemia, that is, NODAT and IGT. However, it’s not an easily completed test. Although they have some limitations, simple office or laboratory tests may adequately screen KTRs especially those at high risk include fasting blood glucose (F BGL), 4 pm capillary blood glucose or HbA1c. A study of 374 non diabetes patients found a normal F BGL in 59% of patients with abnormal OGTT over the first 12 months period (59). Any red cell abnormalities could also impact on HbA1c results such as anemia, transfusions, erythropoietin administration and hemoglobin abnormalities. A recently done study, using combined test of HbA1c >or = 6.5% and FBGL >or = 7.0 a Norwegian group (n=1619) have demonstrated a negative predictive value (NPV) of 97.4% for NODAT, using OGTT as gold standard at 10 weeks post transplantation (60). The combination of two tests had very little additive value, and lower cut off value of HbA1c made little difference in exclusion of NODAT ( >/=5.5% NPV 97.5% compared with >/= 6.5% NPV 93%.  This shows that HBA1c can be used as a screening test but not recommended to be used as a diagnostic test in transplant patients. FBGL may underestimate dysglycemia especially in patients who take the glucocorticoids in the morning. Recently it has been shown that there is an increased afternoon or evening blood glucose for patients who take morning glucocorticoid (approximately 7-8 hours). Therefore 4 pm capillary blood glucose can be a good screening test for such patients.

2.7 MANAGEMENT

Management principles of post-transplant dysglycemia are pre transplant risk assessment, early detection, appropriate therapy to reduce the poorer outcomes in whom post-transplant glucose metabolism abnormalities develop and good glycemic control of pre transplant diabetes patients.  The pre transplant variable described as predictors for glucose impairment post transplantation include age, BMI, fasting and random blood glucose, IGT on OGTT and metabolic syndrome (61) (62) (63). Kidney disease improving global outcome (KDIGO) recommends screening all non-diabetic KTRs with fasting plasma glucose, OGTT and or HBA1c at least weekly for 4 weeks, every 3 months for 1 year and annually thereafter (12).

2.7.1 Adjusting immunosuppression

Adjustment of immunosuppression therapy aiming at improving glucose tolerance may be considered among patients who develop NODAT. The benefit must be weighed against risk of allograft rejection. These considerations include glucocorticoid dose tapering, starting a patient on cyclosporine instead of tacrolimus and maintaining a low trough level of tacrolimus. Switching of tacrolimus to cyclosporine is not recommended unless there are other Tac related side effects. This is because the effect of Tac on glucose tolerance may be reversible without been discontinued (13). One other study reported an improved graft survival with Tac therapy despite increased in NODAT rates (64). Conversion to sirolimus is not recommended. Sirolimus may worsen insulin resistance (39). Belatacept, a co-stimulatory blockade agents, usage have shown an improved cardiovascular and metabolic risks factors including NODAT compared with cyclosporine ( BENEFIT and BENEFIT-EXT studies) (65).

2.7.2 Lifestyle changes

There some data showing low physical activity post-transplant especially in patients whose appetite may have improved have greater cardiovascular and all-cause mortality risk . Improved diet, increased physical activity and weight loss has been shown to improve dysglycemia in KTRs.

2.7.3 Intensive and early glycemic control

Immediate post-operative day up to 3 months post transplantation, KTRs are usually on high dose of diabetogenic immunosuppressive drug and a large proportion of them experience abnormalities in glucose metabolism. Concept of “resting” pancreatic beta cells has been explored. Hecking et al. (15) TIP STUDY (Treat to Target Trial of Basal Insulin in Post-transplant Hyperglycemia) n=50, randomized patients to early basal insulin or standard therapy. By 12 months no patients in the treatment group required hypoglycemic agents compared to 8 in the control group. The majority of the patient on basal insulin did not need any hypoglycemic agent after 120 days. There were no changes in insulin resistance in both groups but better results in the group of patients whose beta cells were “rested” at time of maximal stress. The limitations of this study were a small number of patients and shorter follow up period.

2.7.4 Standard hypoglycemic agents

The 2003 international consensus guideline-based stepwise approach to the management of NODAT, namely non pharmacological therapy including diet, weight reduction and exercise, followed by oral  monotherapy, oral combination, insulin +/- oral agent and ultimately insulin monotherapy (66), provided metabolic decompensation has not occurred which would require earlier insulin initiation. There is limited data on use of hypoglycemic agent within KTRs. However drug selection should consider efficacy, side effects and costs.

 

2.7.5 Glycemic targets

Studies done in the general population for example Diabetes control and Complication Trial(DCCT) (67), United Kingdom Progressive Diabetes Study (UKPDS) (68), Action to Control Risks in Diabetes (ACCORD) (69) and ADVANCE (70)  have shown a lower target of HbA1c reduces the risks of  microvascular complications(includes retinopathy, nephropathy and neuropathy) and UKPDS when follow up the patients for another ten years noted a reduction in macrovascular complications( coronary diseases, stroke and peripheral arterial diseases). Although other studies some had to be stopped for example the Action to Control cardiovascular Risks in Diabetes( ACCORD) (69) ,because  mortality was seen to be high in the arm of patients which intensive glucose control program(target HBA1c < 6.0%). This was a study in adult with T2DM for a longer duration of time (10years). Similarly, the ADVANCE (70)  (target HBA1c  was<  6.3%) study failed to demonstrate more intensive glycemic control compared to standard practice had reduced CVD events. These results may not apply to CKD patients or KTRs with diabetes but show serious doubts on advisability of targeting low HbA1c.  KTRs with diabetes, and especially those who diabetes was the cause of ESRD often has difficult-to-control diabetes with advanced autonomic neuropathy causing diabetes gastroparesis and hypoglycemia unaware.  A RCT was done on KTRs comparing intensive glucose control with usual care show a significant incidence of hypoglycemia (67). Therefore it may be difficult to achieve HbA1c <7.0 percent. ADA recommends target of less than 7% for most patients while KDIGO recommend HBA1c target to be between 7.0 to 7.5% for KTRs. Similarly to the diabetes, patient with IFG and IGT should be closely monitored and aggressive intervention put in place aiming at decreasing others cardiovascular risk such as lipid and blood pressure control.

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