| |
|
|
| Year : 2010 | Volume
: 21
| Issue : 6 | Page : 1038-1043 |
|
| The risk factors for diabetes mellitus after kidney transplantation |
|
|
Effat Razeghi1, Peimaneh Heydarian2, Monireh Amerian1, Gholamreza Pourmand3
1 Department of Nephrology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Endocrinology and Metabolism, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
3 Urology Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
Click here for correspondence address and email
| Date of Web Publication | 4-Nov-2010 |
|
|
 |
|
 Abstract | | |
Post-transplant diabetes mellitus (PTDM) is an adverse complication of kidney transplantation, associated with decreased graft and patient survival. We investigated the risk factors for PTDM and their relation to graft rejection in our kidney transplant recipients. We prospectively included 109 consecutive first kidney transplant recipients transplanted at the Sina Hospital in Tehran from June 2003 to May 2004. Patients were excluded if they had diabetes at the time of transplantation either as the cause of kidney failure or as a comorbidity. PTDM was defined by fasting blood sugar ≥126 mg/dL or random blood sugar ≥200 mg/dL on two occasions and the need for insulin therapy and/or oral hypoglycemic drugs for at least two weeks. Thirty non-diabetic transplant recipients were diagnosed as having PTDM during the six month followup period after transplantation. Sixty non-PTDM controls, matched for age, sex and immunosuppressive regimen, and transplanted as closely as possible to the PTDM cases, were randomly selected. The risk factors for PTDM were investigated in these 90 transplant recipients. Age older than 50 years (P = 0.04), history of hypertension (P = 0.02), polycystic kidney disease (P = 0.015), duration on dialysis more than one year (P < 0.0001), family history of diabetes mellitus (P < 0.0001), mean daily dose of prednisolone ≥15 mg/day (P < 0.0001) and cyclosporine ≥240 mg/day (P < 0.0001) were all more in the PTDM group. Also, the mean serum triglycerides was higher (P = 0.019) and there was an increased risk of graft rejection (P < 0.0001) in the PTDM group.
How to cite this article:
Razeghi E, Heydarian P, Amerian M, Pourmand G. The risk factors for diabetes mellitus after kidney transplantation. Saudi J Kidney Dis Transpl 2010;21:1038-43 |
How to cite this URL:
Razeghi E, Heydarian P, Amerian M, Pourmand G. The risk factors for diabetes mellitus after kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2021 Apr 10];21:1038-43. Available from: https://www.sjkdt.org/text.asp?2010/21/6/1038/72288 |
| Introduction | |  |
The relatively higher mortality, morbidity and complications in kidney transplant recipients is, in part, due to the comorbid medical illnesses and factors uniquely related to transplantation, including immunosuppression and other drug effects. [1],[2] One of the common adverse complications of solid organ transplantation is posttransplant diabetes mellitus (PTDM). While the prevalence of diabetes mellitus in the general population is almost four percent, a recent metaanalysis of observational studies and randomized controlled trials reported that the incidence of PTDM (variously defined) in the first year after transplantation varied from two to 50%. [3] The incidence of PTDM is higher in the first six months after transplantation. [4] Increased age, non-white ethnicity, obesity, metabolic syndrome, family history of diabetes mellitus, hepatitis C virus and cytomegalovirus infections, polycystic kidney disease, male donor, increased human leukocyte antigen mismatches, higher steroid dose and the use of tacrolimus as the initial maintenance immunosuppressive medication are considered as risk factors for PTDM. [5],[6],[7] The incidence of cardiovascular diseases and infections is higher in patients with PTDM, which influences their quality of life and graft survival. [4],[8],[9] We investigated the risk factors of PTDM and their relation to graft rejection in our kidney transplant recipients.
| Materials and Methods | | |
Patient population
We prospectively studied 109 consecutive first kidney transplant recipients transplanted at the Sina Hospital in Tehran from June 2003 to May 2004. Patients were excluded if they had diabetes at the time of transplantation either as the cause of kidney failure or as a comorbidity. The study was approved by the ethics committee of Tehran University of Medical Sciences.
Patient characteristics and follow-up program
After obtaining informed written consent, data were collected using standard questionnaires. The characteristics examined included demographic data, medical history of hypertension, polycystic kidney disease and glomerulonephritis, duration on dialysis before transplantation, family history of diabetes mellitus in first- and second-degree relatives, immunosuppressive regimen and body mass index (BMI), calculated as weight after dialysis (kg)/ height [2] in meters. Fasting blood sugar (FBS), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and triglycerides (TG) were measured after 10-12 hours of fasting and low-density lipoprotein (LDL) cholesterol was calculated (in serum samples with TG <400 mg/dL) using the Friedwald formula. [10]
Fasting and post-prandial blood glucose were measured two to four times daily during the hospitalization and followed several times weekly after discharge. Self-monitoring of blood glucose technique was evaluated both initially and at regular intervals thereafter. All included patients were followed-up for six months after transplantation in the transplant clinic, visited every one to four weeks as needed and any change in immunosuppressive regimen and function of the transplanted kidney was recorded. PTDM was defined by fasting blood sugar ≥126 mg/dL or random blood sugar ≥200 mg/dL on two occasions and the need for insulin therapy and/or oral hypoglycemic drugs for at least two weeks. Kidney rejection was determined by the exclusion of other causes of rise in serum creatinine and response to antirejection therapy, or by kidney biopsy. At the end of the study, weight and lipid profile were measured again.
Thirty non-diabetic transplant recipients were diagnosed with PTDM during the six-month follow-up. For each PTDM case, two nonPTDM controls matched for sex and immunosuppressive regimen and transplanted as closely as possible to the PTDM case were randomly selected. Finally, data analysis was performed for 90 transplant recipients, including 30 PTDM and 60 non-PTDM patients.
Laboratory methods
The laboratory samples were analyzed using the Selectra-two auto-analyzer (Vital Scientific, Spankeren, Netherlands). TC, TG and glucose were assayed using kits (Pars Azmoon Inc., Iran) by the enzymatic calorimetric method with cholesterol esterase and cholesterol oxidase and glycerol phosphate oxidase and glucose oxidase techniques, respectively. HDL cholesterol was measured after precipitation of the apolipoprotein B containing lipoproteins with phosphotungstic acid. Serum creatinine was measured using the Jaffe method.
| Statistical Analysis | | |
Categorical variables between case and control groups were compared using either the χ2 test or the Fisher's exact test. Means of laboratory indices before and after transplantation in each group were compared by Student's t-test. In the univariate analysis, the odds ratio was calculated for risk factors. For statistical analysis, SPSS 11.5 software package (SPSS Inc., Chicago, IL, USA) was used and P-values <0.05 were considered significant.
| Results | | |
In this study, 53.4% of the patients were male. Characteristics of risk factors for PTDM are summarized in [Table 1]. Age older than 50 years, history of hypertension, presence of polycystic kidney disease, duration on dialysis before transplantation more than one year, family history of diabetes mellitus, mean daily dose of prednisolone ≥15 mg/day and cyclosporine ≥240 mg/day were significantly higher in the PTDM group. | Table 1 :Characteristics of risk factors for post-transplant diabetes mellitus.
Click here to view |
Mean BMI, TC and LDL and HDL cholesterol were not significantly different within and between the two groups before and after transplantation [Table 2]. In the PTDM group, the mean TG was higher after transplantation (P = 0.019), but this was not significantly different within the non-PTDM group and between the two groups before and after transplantation. | Table 2 :Laboratory indices before and after transplantation in the two groups of patients.
Click here to view |
PTDM was also associated with increased graft rejection (56.6% compared with 6.6% in the non-PTDM group; odds ratio = 18.3, P < 0.0001).
| Discussion | | |
Recent evidence has suggested that PTDM has become increasingly common after kidney transplantation, which may adversely affect patient and graft survival. [11],[12],[13] Impaired non-oxidative glucose disposal explains the development of insulin resistance in patients with PTDM, similar to that observed in patients with type-2 diabetes in the general population. [14] Recipients with post-transplant impaired glucose tolerance are equally as insulin resistant as patients with PTDM, but have a more preserved insulin response. [15]
The study showed that age was an important risk factor for PTDM. Age older than 40 to 45 years has been most frequently cited as the threshold level associated with increased risk of PTDM. [5],[9]
The role of obesity as a risk factor for PTDM is controversial. Obesity increased the risk of PTDM in several reports, [9],[16] whereas in another systematic study, no association was found between BMI or body weight and PTDM. [3] One explanation is that obese patients were under-represented in that analysis; otherwise, intra-abdominal fat, not reported in any of the included studies, may be more important than total body weight. [16] In this study, mean BMI was normal in both groups and not significantly different before and after transplantation, probably related to the absence of overweight and obese patients in the study.
History of hypertension was significantly more in the PTDM group, and the mean serum TG increased after transplantation in this group. Ten weeks after renal transplantation, glucose intolerance was associated with a clustering of cardiovascular risk factors and metabolic abnormalities, consistent with post-transplant metabolic cardiovascular syndrome. [6]
Adult polycystic kidney disease patients are insulin resistant, and some patients are hyperinsulinemic. [17] History of polycystic kidney disease was reported as an important risk factor for PTDM. [18],[19] On the other hand, glomerulonephritis as the etiology for renal failure decreased the risk for PTDM. [5] The observed association between PTDM and history of polycystic kidney disease but not glomerulonephritis in this study may be due to the limited number of cases in the latter group.
The PTDM group had a significant longer duration on dialysis before transplantation. Poor nutrition during critical periods of fetal life and infancy with consequent impaired development of beta cell function coupled with abundant nutrition later in life might play a role in the pathogenesis of non-insulin dependent diabetes. [20] As a corollary, malnutrition, common in hemodialysis patients, may contribute to the pathogenesis of PTDM in a phenotypically predisposed population. [21],[22] The older patient with pre-transplant abnormal oral glucose tolerance test is at higher risk for developing PTDM. This risk may be increased if the patient is malnourished and shows a rapid increase in weight pre-transplant once hemodialysis is initiated, showing the interplay between factors that may all be associated with a declining pancreatic beta cell reserve. Pretransplant nutritional status thus has a discernible link to the development of PTDM. [23] Also, family history of diabetes mellitus was significantly higher in the PTDM group, as reported before. [6]
The mean daily dose of prednisolone and cyclosporine was significantly higher in the PTDM group compared with that in the controls. The effects of these drugs in the pathogenesis of PTDM were investigated in several studies. Increased prednisolone dose is strongly associated with the development of post-transplant glucose intolerance. [6] Increasing daily prednisolone dose was independently associated with insulin resistance as glucocorticoids promote gluconeogenesis in the liver, inhibit glucose uptake, diminish glycogen synthesis in skeletal muscle cells and also may attenuate insulin secretion from pancreatic 0-cells. [24],[25] Calcineurin inhibitors, tacrolimus and cyclosporine cause reversible toxicity to islet cells and may directly affect the transcriptional regulation of insulin expression. [26]
Finally, graft survival in the PTDM group was significantly lower than in the control group. Results suggest that PTDM is a common, potentially preventable complication that has adverse effects on patient and graft survival. It is even more plausible that the association between PTDM and death-censored graft survival was the result of early acute rejection that led to both PTDM and deathcensored graft survival. [5]
In conclusion, PTDM is an important complication of kidney transplantation, and several risk factors have a major role in its pathogenesis. It seems that identification and control of these risk factors, such as components of metabolic syndrome and immunosuppressive regimens, can reduce the risk for PTDM and the related graft rejection.
| Acknowledgement | | |
This research project has been supported by the Urology Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran.
| References | | |
| 1. | Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342(9):605-12. 
|
| 2. | Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000;57(1):307-13.
|
| 3. | Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Post-transplantation diabetes: A systematic review of the literature. Diabetes Care 2002;25(3):583-92.
|
| 4. | Sumrani NB, Delaney V, Ding ZK, et al. Diabetes mellitus after renal transplantation in the cyclosporine era-an analysis of risk factors. Transplant 1991;51(2):343-7.
|
| 5. | Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3(2):178-85.
|
| 6. | Hjelmesaeth J, Hartmann A, Kofstad J, et al. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 1997;64(7):979-83.
|
| 7. | Bloom RD, Rao V, Weng F, Grossman RA, Cohen D, Mange KC. Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus. J Am Soc Nephrol 2002;13(5):1374-80.
|
| 8. | Aker S, Ivens K, Guo Z, Grabensee B, Heering P. Cardiovascular complications after renal transplantation. Transplant Proc 1998;30(5):2039-42.
|
| 9. | Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. Transplantation 1987;44(3):376-81.
|
| 10. | Friedwald WT, Levy RI, Fredridson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18(6):499-502.
|
| 11. | Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM. Post-transplant diabetes mellitus: Increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int 2001;59(2):732-7.
|
| 12. | Revanur VK, Jardine AG, Kingsmore DB, Jaques BC, Hamilton DH, Jindal RM. Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation. Clin Transplant 2001;15(2):89-94.
|
| 13. | Schiel R, Heinrich S, Steiner T, Ott U, Stein G. Long-term prognosis of patients after kidney transplantation: A comparison of those with or without diabetes mellitus. Nephrol Dial Transplant 2005;20(3):611-7.
|
| 14. | Ekstrand AV, Eriksson JG, Gronhagen- Riska C, Ahonen PJ, Groop LC. Insulin resistance and insulin deficiency in the pathogenesis of posttransplant diabetes in man. Transplantation 1992;53(3):563-9.
|
| 15. | Midtvedt K, Hartmann A, Hjelmesxth J, Lund K, Bjerkely BL. Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients. Nephrol Dial Transplant 1998; 13(2):427-31.
|
| 16. | Kissebah AH, Vydelingum N, Murray R, et al. Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 1982;54(2):254-60.
|
| 17. | Vareesangthip K, Tong P, Wilkinson R, Thomas TH. Insulin resistance in adult polycystic kidney disease. Kidney Int 1997;52(2):503-8.
|
| 18. | Ducloux D, Motte G, Vautrin P, BressonVautrin C, Rebibou JM, Chalopin JM. Polycystic kidney disease as a risk factor for posttransplant diabetes mellitus. Nephrol Dial Transplant 1999;(5)14:1244-6.
|
| 19. | Mattos AM, Olyaei AJ, Prather JC, Golconda MS, Barry JM, Norman DJ. Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation. Kidney Int 2005;67:714-20.
|
| 20. | Hales CN, Barker DJ, Clark PM, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303(6809):1019-22.
|
| 21. | Kopple JD. Effect of nutrition on morbidity and mortality of maintenance hemodialysis patients. Am J Kidney Dis 1994;24(6):1002-9.
|
| 22. | Ramachandran A, Snehalatha C, Latha E, Viswanathan V, Viswanathan M. Rising prevalence of NIDDM in an urban population in India. Diabetologia 1997;40(2):232-7.
|
| 23. | Mathew JT, Rao M, Job V, Ratnaswamy S, Jacob CK. Post-transplant hyperglycaemia: A study of risk factors. Nephrol Dial Transplant 2003;18(1):164-71.
|
| 24. | Andrews RC, Walker BR. Glucocorticoids and insulin resistance: Old hormones, new targets. Clin Sci (Lond) 1999;96(5):513-23.
|
| 25. | Henriksen JE, Alford F, Ward GM, BeckNielsen H. Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients. Diabetologia 1997;40(12): 1439-48.
|
| 26. | Weir MR, Fink JC. Risk for posttransplant diabetes mellitus with current immunosuppressive medications. Am J Kidney Dis 1999; 34(1):1-13.
|
Correspondence Address:
Effat Razeghi
Associate Professor, Internal Medicine and Nephrology, Sina Hospital, Hassan Abad Square, P.O. Box 11367-46911, Tehran
Iran
  | Check |
PMID: 21060170 
[Table 1], [Table 2] |
|
|
|
|
|
|
|
|
|
|
|
|
|
| Article Access Statistics | | | Viewed | 3095 | | | Printed | 173 | | | Emailed | 0 | | | PDF Downloaded | 684 | | | Comments | [Add] | | |
|
|
