|Year : 2008 | Volume
| Issue : 6 | Page : 904-910
|Post transplantation diabetes mellitus in kidney allograft recipients: Current concepts
Emeka A Nwankwo1, Abubakar A Bakari2, Aloy C Ene3
1 Department of Medicine, University of Maiduguri, Nigeria
2 Department of Surgery, University of Maiduguri, Nigeria
3 Nigerian Institute of Medical Research, Maidguri Out-station, Nigeria
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| Abstract|| |
The number of kidney allograft recipients has been increasing worldwide and along with that is a proportional rise in the number of individuals who develop posttransplantation diabetes mellitus (PTDM). It is therefore necessary that physicians who render care to transplant recipients, be conversant with the current issues that relate to this relatively common complication. We searched the Medline using the keywords diabetes, transplantation, kidney and PTDM, and retrieved all relevant articles that were published in the last 15 years up to 2008. Post-transplantation diabetes mellitus is a common complication following renal transplantation affecting approximately 10 to 20% of such patients. In the majority of the studies we reviewed, PTDM was similar to diabetes in non-transplant patients and the risk factors included older age at transplantation, family history of diabetes, obesity, elevated body mass index, nonwhite ethnicity and the use of steroids and several immunosuppressive agents. Curtailment of the heavy disease burden associated with PTDM should lay emphasis on pro-active preventive measures that are aimed at modifying the known risk factors and the individualized use of immunosuppressive agents determined by the pre-transplant risk profile of the patient.
Keywords: PTDM, Diabetes, Transplantation, Kidney
|How to cite this article:|
Nwankwo EA, Bakari AA, Ene AC. Post transplantation diabetes mellitus in kidney allograft recipients: Current concepts. Saudi J Kidney Dis Transpl 2008;19:904-10
|How to cite this URL:|
Nwankwo EA, Bakari AA, Ene AC. Post transplantation diabetes mellitus in kidney allograft recipients: Current concepts. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Nov 22];19:904-10. Available from: http://www.sjkdt.org/text.asp?2008/19/6/904/43463
| Introduction|| |
Kidney transplantation offers the patient with kidney failure the most cost effective treatment option yielding the best quality of life among the different modalities that are available to such individuals. Even this preferred treatment option for kidney failure has some complications, one of them being post-transplantation diabetes mellitus (PTDM). The development of PTDM is not restricted to the kidney allograft recipients but can occur in practically all solid organs transplantations including those patients that have received lungs, liver and heart allografts. ,, Not only is diabetes mellitus (DM) the predominant co-morbid condition in patients developing kidney failure worldwide, but the successful treatment of kidney failure by transplantation may unfold a whole new chapter of PTDM with its own challenges. Post-transplant diabetes mellitus is present when persistent hyperglycemia occurs in the period after transplantation in an individual who was previously a non-diabetic. Diabetes mellitus in transplant recipients greatly increases the already elevated risk profile of cardiovascular disease, graft loss and death in that patient. The criteria for the diagnosis of diabetes mellitus in the post-transplant period are the same as those set out by the American Diabetes Association  for the definition of diabetes mellitus in clinical practice namely; fasting plasma glucose that is equal or greater than 7.0 mmol/L (126 mg/dL) or two-hours post prandial plasma glucose greater than 11.1 mmol/dL (200 mg/dL) and random plasma glucose equal or greater than 11.1 mmol/L (200 mg/dL) on more than two occasions [Table 1]. PTDM in effect encumbers the patient with both the usual complications of diabetes such as retinopathy, neuropathy and nephropathy in addition to those complications that are unique to the allograft recipient.
| Epidemiology|| |
Diabetes mellitus is more common in transplant recipients than in the general population with some estimating that there is a nine-fold increase in the risk of diabetes in solid organ recipients than their age-matched controls.  Whereas up to 40% of patients with PTDM will require insulin therapy,  the majority of patients however, have features of type-2 DM and do not require insulin.  There are disparities in the reported frequencies of PTDM that could be related to geographic, ethnic or socioeconomic peculiarities of the study population. Moreover, the design of the study from which the frequency of occurrence of PTDM was reported is to be considered while comparing prevalence rates. Studies that reported retrospective analysis of a data base often state the cumulative frequencies while some others have tended to differentiate the prevalence rates on temporal basis thus separating early, late and transient PTDM patient-groups. For example Hur et al  reported an overall incidence of PTDM of 39% at one year and 35.1% at seven years for PTDM but went on to differentiate between persistent PTDM (23.4%) who had hyperglycemia within the first year of transplantation that continued unto the seventh year post-transplant and others. Yet other subgroups in their study had transient PTDM (15.6%) in which hyperglycemia started and ended within the first year and late PTDM (11.7%) who developed hyperglycemia after the first year post-transplantation. The widespread application of the recommendations of the clinical practice guidelines will go a long in harmonizing data collection methods which will be necessary for research. The European Best practice guidelines for renal transplantation has recommended regular measurement of fasting glucose and hemoglobin A1c at three-monthly intervals.  A study that was carried out in Kuwait reported the prevalence of PTDM over a 15-year period to be 21.2% but a subgroup of Arab ethnicity had a higher rate of 29.6%.  In Saudi Arabia, the prevalence of PTDM was reported to be 17% and like in some other studies there was no demonstrable gender bias.  In Europe, a report from Warsaw put the prevalence rate of PTDM at 10.5%. PTDM was present in 45% of Indian post-transplant patients and a rapid gain on the dry weight while on hemodialysis was reported to be a unique risk factor for PTDM in that study.  Gourishankar et al  reported a preva-lence rate of 9.8% for PTDM among Canadian kidney transplant recipients. The prevalence rate of PTDM in the USA is similar to the Canadian report. Using the United States Renal Data System (USRDS) records, Kasiske et al  reported a cumulative incidence rate of 9.1% at three months, 16% at 12 months and 24% at 36 months post-transplantation.
The known risk factors for the development of PTDM include older age at the time of transplantation, non-white races like the African Americans and Hispanics and higher patient weight and body mass index. Cadaveric allograft recipients have been associated with higher rates of PTDM than those who received live donor kidneys. The immunosuppressive agents that are used in the post-transplant period have been the most incriminating of the risk factors for PTDM. It has been suggested that the use of tacrolimus (TAC) may greatly increase the risk of PTDM when compared to cyclosporine (CsA), but that observation has remained controversial and not generally accepted.  In their analysis, Ligtenberg et al  observed that converting patients from TAC to CsA was associated with detrimental consequences on blood pressure and cholesterol levels. While TAC is considered by some to have a higher degree of diabetogenicity than CsA, the conversion from the latter to sirolimus was reported to result in the regression of PTDM in 60% of young African Americans.  That observation has not in any way exonerated sirolimus as a culprit in the list of immunosuppressive agents that are associated with PTDM. Recently, in a report that used data from the USRDS, it was noted that the use of sirolimus was associated with new onset diabetes in kidney transplant recipients.  The conversion from TAC to CSA was reported to decrease the need for treatment with insulin and oral hypoglycaemic agents in PTDM patients when compared to a control group that continued TAC.  The epidemiologic association made between the use of immunosuppressive agents on the one hand and the prevalence of PTDM has been known for several years but it is recently becoming obvious that treatment with the monoclonal antibody against inter-leukin 2 is also implicated in occurrence.  of PTDMInfection with organisms such as cytomegalovirus (CMV) and hepatitis C virus (HCV) have been linked in certain cases to the onset of PTDM. Leung et al  described two cases of post-transplant CMV infection that coincided with the onset of PTDM. Both the infection and the diabetes remitted with antiviral treatment using valganciclovir. HCV infection has been associated with the development of PTDM based on epidemiologic observations.  Finni et al  reported that PTDM occurred more frequently among HCVpositive transplant recipients, particularly when TAC was used as part of the immunosuppression. Smoking has been associated with the development of PTDM and as such, cessation of smoking is one factor that both the physician and recipients should strive to achieve. 
| Pathogenesis|| |
The underlying pathogenesis of PTDM has been explained by two mechanisms. In the first hypothesis, insulin resistance in the pretransplantation stage of the kidney failure is thought to be responsible. The insulin resistance that occurs in the end-stage kidney is aggravated in the post-transplantation period as a result of the additional diabetogenic environment brought about by the immunosuppressive treatment. In this respect, the development of PTDM is thought to be similar to that of type-2 DM in the general population where insulin resistance is a prominent feature. In the second hypothesis, PTDM is believed to be a consequence of an acquired, but potentially reversible, defect in insulin secretion. Nam et al  demonstrated among Korean subjects that the insulin sensitivity index was not significantly different between their PTDM patients, those with impaired glucose tolerance and normolycemic individuals after an oral glucose tolerance test and concluded that beta cell dysfunction culminating in impaired insulin secretion rather than insulin resistance was the cause of PTDM. At Maastritcht, it was demonstrated that treatment with TAC resulted in a dose-related reduction in insulin secretion without any alteration in the insulin resistance.  A compromise position is to see PTDM as the unmasking of an underlying metabolic disorder by the additional stress imposed upon the patient by immunosuppressive therapy.
There are contradictory reports on the role of HLA antigens in the pathogenesis of PTDM. While a report from Saudi Arabia did not find any association between the development of PTDM  and HLA antigens, Wyzal et al  noted that HLA A3 was over represented in their study of over a thousand kidney transplant recipients who developed PTDM. TorresRomerro et al  also found higher frequencies of A3 and DR3 among PTDM but the association was not statistically significant. In recent times, attention has been drawn to the association between a variant of the Transcription Factor 7-Like 2 (TCF7L2) gene polym orphism and the development of PTDM.  This genetic variation has been linked to type2 DM and it has been suggested that it predisposes patients to diabetes by causing a defect in insulin secretion. 
| Clinical Correlates of PTDM|| |
It has been suggested that through the intermediary of the metabolic syndrome which is a risk factor for de novo PTDM; chronic graft dysfunction, graft loss and patient death are all increased in PTDM patients compared to controls. 
There is an associated increase in cardiovascular risk profile and cardiovascular mortality among patients with PTDM when compared to controls. Gonzalez-Possada et al  studied Spanish kidney transplant recipients and reported an association of PTDM with increased traditional cardiovascular risk profile and total long-term mortality. Those Spanish transplant recipients tended to be older, with higher BMI, higher blood pressure, higher cholesterol and triglycerides than controls.
Poorer short-term outcomes have also been described in PTDM. Besides the better researched long-term outcomes of the extra disease burden of PTDM, such short-term complications as infection, recurrence of infection and hospital admission rates have been reported to be worse in the PTDM group compared to the non-PTDM group as well as the previously diagnosed diabetic patients. 
Diabetic nephropathy has been reported to develop de novo in PTDM patients.  After an initial description of nodular glomerulosclerosis in two patients, other histologic patterns have also been reported. In addition to the classic Kimmelstein Wilson lesions, cases of diffuse diabetic glomerulosclerosis have been described, usually in a background of transplant glomerulopathy.  Moreover, it now appears that de novo diabetic nephropathy is not as uncommon as was earlier thought, especially with the increase in both the posttransplant period and the duration of PTDM.
The presence of PTDM increases the health challenges of the post-transplant patient. Von Kiparski et al  reported a significantly higher rate of cardiovascular complications when they compared the allograft recipient who developed diabetes against those that did not have diabetes. After a mean follow-up of 8.5 years, Miles et al  reported a relative risk of 1.9 for stroke and 0.95 for myocardial infarction in patients with PTDM compared to non-diabetic transplant recipients.
When compared to kidney transplant recipients who did not develop diabetes, patients with PTDM had a significant decrease in graft survival at three and four years with a 63% increase in graft loss among Medicare population and a relative risk of graft loss of 3.72 at 12 years (USRDS). In addition, infection rate was reported to be 53% in PTDM patients compared to 16% in controls. 
| Intervention Measures in PTDM|| |
The risk factors for the development of PTDM can be classified as either modifiable or non-modifiable. For the non-modifiable risk factors such as older age at transplantation, black and non-white ethnicity and family history of diabetes, not much can be done in terms of risk reduction but a lot can be done with respect to the modifiable risk factors. Early detection and adequate management of PTDM will go a long way in preventing the development of the long-term complications. The attainment of normoglycemia and normal glycosylated hemoglobin should be possible when the physician and patient set that goal.
The improvements made on prevention of HCV infection, the use of lesser doses of steroids and improvements in the area of immunosuppressive therapy, have led to a demonstrable decrease in the prevalence of PTDM in Norway.  With the many immunosuppressive agents available in the market, efforts should be made to use the agent with the least diabetogenic potential, particularly in patients that are at elevated risk for PTDM, such as the obese, older patient of especially African descent with a positive family history of diabetes. It is therefore logical that pre-transplant risk assessment and early detection of glucose intolerance and PTDM will greatly reduce the consequences of PTDM. In line with this approach, Kuypers et al  described their findings on early detection of PTDM stating that the oral glucose tolerance test and proteinuria on the fifth post-transplant day were good discriminatory tests. Individuals with normal oral glucose tolerance test on this day were reported to be at a reduced risk while those with proteinuria were at high-risk of developing PTDM.
| Conclusion|| |
Preventive strategies should be geared towards the reduction of the modifiable risk factors for PTDM. Physicians that are involved in the care of kidney transplant recipients need to be fully aware of the relative benefit of individual immunosuppressive agents over others in terms of their diabetogenic potential.
Immunosuppressive treatment should be individualized and tailored according to the pre-transplantation risk assessment of the allograft recipients in order to minimize the risk of developing PTDM.
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Emeka A Nwankwo
Department of Medicine, University of Maiduguri, Maiduguri
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