Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE

High Incidence of Tacrolimus-Associated Posttransplantation Diabetes in the Korean Renal Allograft Recipients According to American Diabetes Association Criteria

1 2 YOUNG MIN CHO, MD JONGWON HA, MD, PHD lograft rejection, posttransplantation dia- 1 2 KYONG SOO PARK, MD, PHD SANG JOON KIM, MD, PHD betes mellitus (PTDM) has become a 1 3 HYE SEUNG JUNG, MD BYOUNG DOO RHEE, MD, PHD 1 1 major drawback in its clinical application HYUN JUNG JEON, MD SEONG YEON KIM, MD, PHD 1 1 (8–12). A temporal trend of the incidence CURIE AHN, MD, PHD HONG KYU LEE, MD, PHD of PTDM has been demonstrated to show a bimodal pattern corresponding to the early kidney transplantation era using high-dose steroids in the 1960s and to the OBJECTIVE — The incidence of posttransplantation diabetes mellitus (PTDM) has been introduction of tacrolimus in the 1990s reported to vary according to different study populations or different definitions. In this study, (5). using American Diabetes Association criteria, the incidence and clinical characteristics of PTDM Tacrolimus inhibits the transcription of in Korean renal allograft recipients undergoing tacrolimus-based immunosuppression were the insulin gene by inhibition of calcineurin examined. after binding to FK506-binding protein 12 (FKBP12) (13,14). In contrast, sirolimus, RESEARCH DESIGN AND METHODS — A total of 21 patients taking tacrolimus as which also binds to FKBP12, interacts with primary immunosuppressant were recruited and tested with a serial 75-g oral glucose tolerance test at 0, 1, 3, and 6 months after renal transplantation. mammalian target of rapamycin, so-called mTOR, instead of calcineurin and fre- RESULTS — The cumulative incidence of PTDM was 52.4% at 1 month and 57.1% at 3 and quently causes hyperlipidemia by inhibi- 6 months. The baseline characteristics of the PTDM group were old age (especially Ͼ40 years), tion of insulin action (15). Tacrolimus- a high BMI, a high fasting glucose level, a high plasma insulin level, and increased insulin induced PTDM has been proven to be resistance. Among these parameters, old age was the only independent risk factor. The insulin reversible after withdrawing tacrolimus secretory capacity in the PTDM group was maximally suppressed 3 months after transplantation. (13,14,16), and we have recently reported a Thereafter, it was gradually restored along with dose reduction of tacrolimus. case showing complete insulin indepen- dence after severe diabetic ketoacidosis as- CONCLUSIONS — Routine screening for PTDM is necessary in patients over 40 years of age who are undergoing a relatively higher dose tacrolimus therapy during the early course of sociated with tacrolimus treatment (17). postrenal transplantation. It has been reported that PTDM is as- sociated with diabetic microvascular Diabetes Care 26:1123–1128, 2003 complications, an increased frequency of sepsis as a cause of death, and a risk of developing graft failure (18). Considering acrolimus is an effective alternative potential of tacrolimus is much higher the well-known serious clinical outcomes to cyclosporine as a primary immu- than that of cyclosporine in the early post- of hyperglycemia and the established nosuppressant after kidney trans- transplantation period (5–7). Despite its benefits of intensive glycemic control T (19,20), the chronic metabolic derange- plantation (1–4). The diabetogenic excellent prophylactic effect on renal al- ment in PTDM, even though the severity ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● of which is mild, could lead to many dia- From the 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; betes complications and should be cor- the 2Department of Surgery, Seoul National University College of Medicine, Seoul, Korea; and the 3Depart- rected appropriately. Therefore, in this ment of Internal Medicine, Inje University Medical College, Seoul, Korea. study, to define PTDM we used the Amer- Address correspondence and reprint requests to Kyong Soo Park, MD, PHD, Department of Internal ican Diabetes Association (ADA) criteria Medicine, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, Seoul, 110-744, Korea. E-mail: [email protected]. for the diagnosis of diabetes (21), which is Received for publication 12 September 2002 and accepted in revised form 10 January 2003. more stringent than ever. Abbreviations: 2-h PG, 2-h plasma glucose during an OGTT; AUC, area under the curve; FKBP, FK506- Ethnic difference contributes to the binding protein 12; FPG, fasting plasma glucose; HCV, hepatitis C virus; HOMA-BC, homeostasis model variable susceptibility to developing assessment for ␤-cell function; HOMA-IR, HOMA for insulin resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT, oral glucose tolerance test; PTDM, posttransplantation diabetes mellitus. PTDM (5,12,22,23). Interestingly, most A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion type 2 diabetic patients in Korea are char- factors for many substances. acterized by defects in insulin secretion

DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003 1123 PTDM associated with tacrolimus

Table 1—Comparison of baseline clinical characteristics Measurements The 75-g oral glucose tolerance test Non-PTDM PTDM P (OGTT) was used to assess the glucose tolerance and to measure the insulin re- n 912 sponse to a glucose load on four occasions Age 27 Ϯ 241Ϯ 4 Ͻ0.05 (day –1 and months 1, 3, and 6). OGTT Sex (male:female) 2:7 9:3 Ͻ0.05 was not performed (at months 3 and 6) in BMI (kg/m2) 20.1 Ϯ 1.0 23.1 Ϯ 0.9 Ͻ0.05 the patients who developed PTDM re- Family history of diabetes* 1/9 (11.1%) 3/12 (25.0%) NS quiring insulin or oral antidiabetic ther- Systolic blood pressure (mmHg) 144 Ϯ 3 140 Ϯ 6NSapy (n ϭ 4). All tests were performed in Diastolic blood pressure (mmHg) 86 Ϯ 380Ϯ 3NSthe morning after an overnight fast, and Fasting plasma glucose (mmol/l) 4.9 Ϯ 0.3 5.6 Ϯ 0.2 Ͻ0.05 the blood pressure, height, and weight Ϯ Ϯ HbA1c (%) 5.0 0.2 4.8 0.3 NS were measured before OGTT of each visit. Ϯ Ϯ Fasting plasma C-peptide (nmol/l) 2.4 0.6 2.3 0.2 NS The HbA1c, HLA type, anti-hepatitis C vi- Fasting plasma insulin (pmol/l) 55.8 Ϯ 35.2 80.4 Ϯ 18.9 Ͻ0.05 rus (HCV) antibody, total cholesterol, tri- HOMA-IR 2.5 Ϯ 1.7 3.5 Ϯ 0.9 Ͻ0.05 glyceride, and HDL cholesterol levels HOMA-BC 95.5 Ϯ 36.3 121.5 Ϯ 27.7 NS were measured by routine assays in the Insulinogenic index 2.3 Ϯ 1.4 5.8 Ϯ 4.5 NS Department of Clinical Pathology at Seoul Total cholesterol (mmol/l) 4.1 Ϯ 0.3 4.1 Ϯ 0.1 NS National University Hospital. The LDL Triglycerides (mmol/l) 1.1 Ϯ 0.1 1.6 Ϯ 0.3 NS cholesterol level was calculated by Friede- HDL cholesterol (mmol/l) 1.1 Ϯ 0.1 1.1 Ϯ 0.1 NS wald’s equation. The fasting plasma insu- LDL cholesterol (mmol/l) 2.5 Ϯ 0.2 2.3 Ϯ 0.2 NS lin and C-peptide levels were determined Data are means Ϯ SEM unless otherwise indicated. *Family history of clinical diabetes in a first-degree by radioimmunoassay (BioSource Europe relative. NS, not significant. S.A., Nivelles, Belgium) in a single large batch. Using the plasma glucose and insulin rather than insulin resistance (24,25). ceived a renal allograft from a living- data obtained from the OGTT, the ho- Thus, tacrolimus-based immunosuppres- related donor, and 3 patients received an meostasis model assessment of insulin re- sion, which causes ␤-cell toxicity and allograft from their spouse. Patients sistance (HOMA-IR) and ␤-cell function subsequent insulin secretory defects, may undergoing cadaver-donor kidney trans- (HOMA-BC) were calculated (26). The exert more detrimental effects in the Ko- plantation were not included. The insulinogenic index, which has been rean population. primary causes of renal failure were hy- demonstrated to show an excellent corre- In this background, we examined the pertension (n ϭ 3), IgA nephropathy (n ϭ lation with acute insulin response (27), incidence and clinical characteristics of 3), glomerulonephritis (n ϭ 2), systemic was used to estimate the early insulin se- PTDM defined by ADA criteria in the Ko- lupus erythematosus (n ϭ 2; they did not cretion using OGTT data. rean patients receiving tacrolimus-based take glucocorticoids at the time of trans- immunosuppression after kidney trans- plantation, because their disease was clin- Definition plantation. ically inactive), Alport’s syndrome (n ϭ In this study, the ADA criteria were used 1), solitary kidney (n ϭ 1), and an un- to diagnose PTDM. Briefly, the symptoms RESEARCH DESIGN AND known primary pathology (n ϭ 9). No of typical diabetes plus casual plasma glu- METHODS cose concentration Ն11.1 mmol/l, fasting patient tested positive for anti-GAD anti- plasma glucose (FPG) Ն7.0 mmol/l with bodies. Subjects no calorie intake for at least 8 h, or 2-h The following criteria were used to deter- plasma glucose during an OGTT (2-h PG) mine which patients were eligible to par- Ն11.1 mmol/l was defined as PTDM. In Immunosuppression ticipate in the study: age 18 years or older, addition, impaired fasting glucose (IFG) recipients of a kidney allograft, no known The immunosuppressive regimen con- and impaired glucose tolerance (IGT) history of clinical diabetes, no current use sisted of tacrolimus and glucocorticoid in were defined as FPG Ն6.1Ͻ7.0 mmol/l of steroids or other immunosuppressive all patients. The initial tacrolimus dose and 2-h PG Ն7.8 Ͻ11.1 mmol/l, agents, and no previous history of organ was 0.075 mg/kg body wt given twice respectively. transplantation. The study protocol was daily starting on day –1. The target approved by the Institutional Review plasma tacrolimus trough levels for all pa- Statistical analysis Board of Clinical Research Institute at tients were 10–15 ng/ml from day 1 until All continuous variables were expressed Seoul National University Hospital, and day 90. Thereafter, they were adjusted as mean Ϯ SEM. We performed Fisher’s informed consent was obtained from each gradually to 5–10 ng/ml. The steroid dose exact test, Mann-Whitney test, and mul- patient. A total of 21 patients (11 men and consisted of 300 mg methylprednisolone tiple logistic regression test using SPSS 10 women) from Seoul National Univer- on day 0. Thereafter, 60 mg prednisolone software (SPSS, Chicago, IL). For the se- sity Hospital were enrolled in this study. per day was administered, which was rial change in each variable, we per- The mean age of the patients was 35 years gradually tapered to a maintenance dose formed repeated measures ANOVA with (range 18–58). Altogether, 18 patients re- of 10–15 mg/day. GraphPad InStat (GraphPad software,

1124 DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003 Cho and Associates

Multiple logistic regression analysis re- vealed that only the age at transplantation has the predictive value for the future PTDM (P ϭ 0.039). Of note, all patients Ͼ40 years of age developed PTDM (n ϭ 7), and the relative risk of age Ͼ40 years in the development of PTDM was 2.8 (95% CI 1.39–5.66). Before transplantation, there were 10 patients with normal glucose tolerance, 2 with IFG, 7 with IGT, and 2 with both IFG and IGT. The category of glucose tol- erance at the baseline was not predictive for future PTDM. The frequency of HLA A11 and HLA B62 was higher in the PTDM group than in the non-PTDM group (28.5 vs. 0% and 23.8 vs. 0%, re- spectively), which was statistically signif- icant (P Ͻ 0.05). There were no baseline differences in blood pressure, serum lipid profile, plasma C-peptide level, HbA1c, HOMA-BC, insulinogenic index, or area under the curve (AUC) for plasma insulin during the OGTT (Table 1, Figs. 2 and 3). In addition, there was no difference in the frequency of ␤-blocker medication (33.3 vs. 44.4%), episode of acute rejection (8.3 vs. 11.1%), and seropositivity for HCV in- fection (0 vs. 11.1%) between the PTDM and non-PTDM groups, respectively.

Serial changes in insulin resistance and insulin secretion At baseline, both groups had a very high HOMA-IR, which showed a rapid decline after renal transplantation. The baseline HOMA-IR of the PTDM group was signif- icantly higher than that of the non-PTDM group, but it was similar between two groups at 1, 3, and 6 months after trans- plantation (Fig. 4). There was no remark- able change in the BMI of each group during the follow-up period (Fig. 4). Both the HOMA-BC and AUC for the Figure 1—Changes in plasma glucose and insulin level during OGTT before and after kidney plasma insulin level during the OGTT in transplantation. A–D: Plasma glucose level during OGTT. E– H: Plasma insulin level during the PTDM group showed a marked reduc- OGTT. E, non-PTDM; F, PTDM. *P Ͻ 0.05 compared with each control. Data are expressed as Ϯ tion compared with baseline values at 1 mean SEM. and 3 months after transplantation. Thereafter, this notably decreased San Diego, CA). A P value Ͻ0.05 was con- PTDM group required pharmacological HOMA-BC and AUC for the plasma insu- sidered statistically significant. treatment for glycemic control, and they lin level in the PTDM group and showed a all needed insulin therapy for Ͼ1 month tendency to be restored to that of the non- RESULTS during the study period. The baseline PTDM group after 6 months (Fig. 2). characteristics are summarized in Table 1, However, the insulinogenic index of the Incidence and clinical and the plasma glucose and insulin levels PTDM group was still lower at 6 months characteristics of PTDM during OGTT are shown in Fig. 1. At compared with that of the non-PTDM The cumulative incidence of PTDM ac- baseline, the PTDM group was older, had group (Fig. 3). There were no significant cording to ADA criteria was 52.4% (11 of a higher FPG level, a higher plasma insu- differences in the indexes of insulin secre- 21) at month 1 and 57.1% (12 of 21) at lin level, and a higher HOMA-IR than the tion in the non-PTDM group throughout months 3 and 6. Four patients in the non-PTDM group (Table 1 and Fig. 1). the study period.

DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003 1125 PTDM associated with tacrolimus

lin secretory defect (24,25), the Korean population may be more susceptible to the tacrolimus-associated PTDM. Second, the ADA criteria revised in 1997 are even stricter than other definitions previously used and have the power to detect mild asymptomatic diabetes. In reanalyzing our data using other definitions of PTDM used in previous studies, such as FPG Ն7.8 mmol/l alone or requirement of in- sulin therapy for more than 1 month, the incidence of PTDM was 28.6 and 19.0%, respectively. Thus, in this study, mild asymptomatic cases could be effectively detected by ADA criteria. Considering the serious clinical outcomes of chronic hyperglycemia in the patients with renal transplantation (18), the PTDM, even Figure2—SerialchangesintheHOMA- though the severity of which is mild, BC (A) and AUC (B) of the plasma in- sulin level during OGTT. *P Ͻ 0.05, should be detected and corrected **P Ͻ 0.01 compared with the baseline appropriately. value by repeated measures ANOVA, At baseline, the patients who devel- #P Ͻ 0.05 compared with that of the oped PTDM were older, had higher blood non-PTDM group. Data are expressed glucose and insulin values, a significantly as mean Ϯ SEM. higher frequency of insulin resistance, and a tendency for higher triglyceride val- Immunosuppressive treatment sporin A–based immunosuppression is ues, which are well-known risk factors for The plasma tacrolimus trough level did 23.7% (29), the incidence of PTDM in the development of diabetes (30). Multi- not show any difference between the two this study is very high. Several factors variate analysis revealed that only the age groups throughout the study period. The might explain this unexpectedly high in- at transplantation has the predictive value cumulative dose of prednisolone during cidence of PTDM. First, we can consider for the future PTDM. Therefore, the age the previous 30 days was also similar be- the ethnic difference. In general, non- itself might contribute to other features of tween both groups (Table 2). Caucasian patients experienced a twofold insulin resistance. Of note, all patients increase in the risk of PTDM compared Ͼ40 years developed PTDM, and the rel- CONCLUSIONS — In this study, the with Caucasian (5). Hricik et al. (23) re- ative risk of age Ͼ40 in the development cumulative incidence of PTDM according cently reported that African-Americans of PTDM was 2.8. to ADA criteria was 57.1% at 6 months of were more susceptible to PTDM than It has been hypothesized that the di- postrenal transplantation, which was Caucasians, despite similar doses of cor- abetogenic effect of tacrolimus may be en- considerably high compared with the in- ticosteroids and lower trough levels of ta- hanced by HCV infection (31), but we cidence of PTDM from previous studies crolimus. Because the main mechanism of could not test this hypothesis because (5). Considering that the prevalence of di- tacrolimus-associated PTDM is the de- only one patient turned out to be positive abetes in the age group of 30–64 years in crease in insulin secretory capacity for HCV infection. In addition, we could Korea is 7.2% (28), and the 1-year prev- (13,14,16), and most type 2 diabetic pa- not observe any difference in pred- alence of PTDM associated with cyclo- tients in Korea are characterized by insu- nisolone dose, use of ␤-blocker, episode

Figure 3—Comparison of the insulinogenic Figure 4—Comparison of the HOMA-IR indexes. *P Ͻ 0.05, **P Ͻ 0.01 vs. non-PTDM. and BMI. *P Ͻ 0.05 vs. non-PTDM. Data Data are expressed as mean Ϯ SEM. expressed as mean Ϯ SEM.

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Table 2—Comparison of the plasma tacrolimus trough level and the cumulative dose of mus therapy during the early course of prednisolone during the previous 30 days before each visit postrenal transplantation.

Non-PTDM PTDM P References Plasma tacrolimus trough 1. Shapiro R, Jordan M, Scantlebury V, Fung level (ng/ml) Ϯ Ϯ J, Jensen C, Tzakis A, McCauley J, Carroll 1 month 13.6 0.9 13.5 0.7 NS P, Ricordi C, Demetris AJ, Mitchell S, Jain Ϯ Ϯ 3 months 14.0 1.2 12.1 1.9 NS A, Iwaki Y, Kobayashi M, Reyes J, Todo S, 6 months 9.9 Ϯ 0.9 10.6 Ϯ 1.6 NS Hakala TR, Simmons RL, Starzl TE: FK Cumulative prednisolone 506 in clinical kidney transplantation. dose (g/previous 30 days) Transplant Proc 23:3065–3067, 1991 1 month 1.69 Ϯ 0.18 1.57 Ϯ 0.12 NS 2. Japanese FK506 study group: Japanese 3 months 0.35 Ϯ 0.04 0.41 Ϯ 0.02 NS study of FK 506 on kidney transplanta- 6 months 0.24 Ϯ 0.03 0.27 Ϯ 0.02 NS tion: results of late phase II study. Trans- Ϯ plant Proc 25:649–654, 1993 Data are means SEM. 3. Schleibner S, Krauss M, Wagner K, Er- hard J, Christiaans M, van Hooff J, Buist L, Mayer D: FK 506 versus cyclosporin in of graft rejection, BMI change, duration of study, the plasma tacrolimus trough level the prevention of renal allograft rejection: dialysis, and renal function between the was titrated at 5–10 ng/ml from 3 months European pilot study: six-week results. two groups (some data are not shown). after transplantation, the suppressed in- Transpl Int 8:86–90, 1995 We could observe a dramatic change sulin production gradually returned to 4. Pirsch JD, Miller J, Deierhoi MH, Vincenti in insulin secretory capacity in the PTDM normal thereafter. F, Filo RS: A comparison of tacrolimus group. Because the inhibitory effect of ta- By chance, a difference in sex in the (FK506) and cyclosporine for immuno- crolimus on insulin production is both incidence of PTDM was observed. How- suppression after cadaveric renal trans- plantation: FK506 Kidney Transplant time- and dose-dependent (13), and the ever, we could not confirm this result Study Group. Transplantation 63:977– tacrolimus trough level was titrated at firmly, as this study was not designed to 983, 1997 10–15 ng/ml during the first 3 months, examine differences in sex. In addition, 5. Montori VM, Basu A, Erwin PJ, Velosa JA, the maximally suppressed insulin pro- the frequency of HLA A11 and HLA B62 Gabriel SE, Kudva YC: Posttransplanta- duction might have resulted at ϳ3 was higher in the PTDM than in the non- tion diabetes: a systematic review of the months in this study. Thereafter, the sup- PTDM group. A few studies have reported literature. Diabetes Care 25:583–592, pressed insulin secretory capacity ap- that certain HLA types are associated with 2002 peared to be partially restored. However, the development of PTDM (38,39), 6. van Hooff JP, Christiaans MH: Use of ta- there was no difference in the plasma but there is no specific HLA antigen that crolimus in renal transplantation. Trans- trough level of tacrolimus between the can be used to predict future PTDM plant Proc 31:3298–3299, 1999 7. Knoll GA, Bell RC: Tacrolimus versus cy- two groups. It was reported that the phar- effectively. closporin for immunosuppression in re- macokinetic profiles of tacrolimus showed This study had limitations in that the nal transplantation: meta-analysis of considerable interindividual differences, number of patients was relatively small randomised trials. BMJ 318:1104–1107, and the trough plasma level might not be and because of the lack of a control group. 1999 a good pharmacokinetic parameter (32). Comparing with the historical control in 8. Scantlebury V, Shapiro R, Fung J, Tzakis In this regard, it appears that the plasma Korean patients under cyclosporin A A, McCauley J, Jordan M, Jensen C, trough value could not adequately reflect (29), the incidence of PTDM with tacroli- Hakala T, Simmons R, Starzl TE: New its actual pharmacological effect on the mus in the current study is still higher onset of diabetes in FK 506 vs cyclospor- development of PTDM. In addition, the (57.1 vs. 23.7%). ine-treated kidney transplant recipients. persistent hyperglycemia per se might Using ADA criteria, we showed a high Transplant Proc 23:3169–3170, 1991 ␤ 9. Furth S, Neu A, Colombani P, Plotnick L, contribute to the progressive -cell failure incidence of PTDM in the Korean renal Turner ME, Fivush B: Diabetes as a com- by way of glucose toxicity (33). allograft recipients treated with a tacroli- plication of tacrolimus (FK506) in pediat- It has been consistently reported that mus-based regimen. The baseline charac- ric renal transplant patients. Pediatr the PTDM associated with tacrolimus- teristics of the PTDM group were old age, Nephrol 10:64–66, 1996 based immunosuppression is reversible high BMI, high fasting glucose level, high 10. Tanabe K, Koga S, Takahashi K, Sonda K, in clinical studies (34,35), in in vivo and plasma insulin level, and high HOMA-IR. Tokumoto T, Babazono T, Yagisawa T, in vitro experiments (13,14,16), and in Among them, old age, especially Ͼ40 Toma H, Kawai T, Fuchinoue S, Teraoka our previous case report (17). Interest- years, was the only independent risk fac- S, Ota K: Diabetes mellitus after renal ingly, tacrolimus did not do any harm to tor. The insulin secretory capacity was transplantation under FK 506 (tacroli- the function of transplanted islet cells at maximally suppressed 3 months after mus) as primary immunosuppression. Transplant Proc 28:1304–1305, 1996 3– 6 ng/ml of the plasma trough level transplantation, when a relatively higher 11. Khoury N, Kriaa F, Hiesse C, Von Ey F, (35), and the addition of daclizumab to a dose of tacrolimus was administered. Durbach A, Ammor M, Hafi A, Djeffal R, tacrolimus-based regimen reduced the ta- Routine screening for PTDM is necessary Boubenider S, Droupy S, Hammoudi Y, crolimus dose and the subsequent devel- in patients Ͼ40 years of age who are un- Eschwege P, Benoit G, Charpentier B: opment of PTDM (37). Because, in this dergoing a relatively higher-dose tacroli- Posttransplant diabetes mellitus in kidney

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