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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 6  |  Page : 1038-1043
The risk factors for diabetes mellitus after kidney transplantation


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

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Date of Web Publication4-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 2019 Jul 21];21:1038-43. Available from: http://www.sjkdt.org/text.asp?2010/21/6/1038/72288

   Introduction Top


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 Top


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 Top


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 Top


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.

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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.

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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 Top


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 Top


This research project has been supported by the Urology Research Center, Sina Hospital, Tehran University of Medical Sciences, Tehran.

 
   References Top

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.  Back to cited text no. 1
    
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.  Back to cited text no. 2
    
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.  Back to cited text no. 3
    
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.  Back to cited text no. 4
    
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.  Back to cited text no. 5
    
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.  Back to cited text no. 6
    
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.  Back to cited text no. 7
    
8.Aker S, Ivens K, Guo Z, Grabensee B, Heering P. Cardiovascular complications after renal trans­plantation. Transplant Proc 1998;30(5):2039-42.  Back to cited text no. 8
    
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.  Back to cited text no. 9
    
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.  Back to cited text no. 10
    
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.  Back to cited text no. 11
    
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.  Back to cited text no. 12
    
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.  Back to cited text no. 13
    
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.  Back to cited text no. 14
    
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.  Back to cited text no. 15
    
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.  Back to cited text no. 16
    
17.Vareesangthip K, Tong P, Wilkinson R, Thomas TH. Insulin resistance in adult polycystic kidney disease. Kidney Int 1997;52(2):503-8.  Back to cited text no. 17
    
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.  Back to cited text no. 18
    
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.  Back to cited text no. 19
    
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.  Back to cited text no. 20
    
21.Kopple JD. Effect of nutrition on morbidity and mortality of maintenance hemodialysis patients. Am J Kidney Dis 1994;24(6):1002-9.  Back to cited text no. 21
    
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.  Back to cited text no. 22
    
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.  Back to cited text no. 23
    
24.Andrews RC, Walker BR. Glucocorticoids and insulin resistance: Old hormones, new targets. Clin Sci (Lond) 1999;96(5):513-23.  Back to cited text no. 24
    
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.  Back to cited text no. 25
    
26.Weir MR, Fink JC. Risk for posttransplant diabetes mellitus with current immunosup­pressive medications. Am J Kidney Dis 1999; 34(1):1-13.  Back to cited text no. 26
    

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Correspondence Address:
Effat Razeghi
Associate Professor, Internal Medicine and Nephrology, Sina Hospital, Hassan Abad Square, P.O. Box 11367-46911, Tehran
Iran
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PMID: 21060170

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    Materials and Me...
    Statistical Analysis
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