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Vol. 73, 379–386, No. 3, February 15, 2002 Copyright 2002 by Lippincott Williams & Wilkins, Inc.
POSTTRANSPLANT DIABETES MELLITUS IN KIDNEY
ALLOGRAFT RECIPIENTS: INCIDENCE, RISK FACTORS, AND
MANAGEMENT1
M. ROY FIRST,2,7 DAVID A. GERBER,3 SUNDARAM HARIHARAN,4 DIXON B. KAUFMAN,5 AND University of Cincinnati Medical Center, Cincinnati, Ohio 45267; University of North Carolina at Chapel Hill, University of North Carolina Hospitals, Chapel Hill, North Carolina 27514; Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Northwestern University Medical School, Chicago, Illinois 60611; and Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213 Background.
Posttransplant
diabetes
mellitus
tion incidence and severity, as demonstrated in other
(PTDM), associated with the use of immunosuppres-
studies, outweighs the risk of PTDM.
sants, occurs at varying rates in kidney transplant
recipients.
Methods. Five transplant centers conducted a retro-
spective review of 435 kidney recipients completing at
Reports of the incidence of posttransplant diabetes melli- least 6 months of follow-up to determine risk factors,
tus (PTDM) historically, and more recently as the result of incidence, and management strategies for posttrans-
adopting newer agents into immunosuppressive regimens, plant glucose intolerance. A distinction was made be-
tween hyperglycemia and diabetes.
prompted the present review of PTDM at five U.S. kidney Results. The incidence of PTDM was found to be
transplant centers. Institutions experienced in the use of 4.9%. Among tacrolimus-treated patients it was 5.7%,
tacrolimus-based immunosuppression participated in the compared with 3.3% among cyclosporine-treated pa-
roundtable conference to evaluate the onset of PTDM as it tients (P؍0.453). Mean daily maintenance doses of
occurs in routine clinical practice. An additional aim of the prednisone and mycophenolate mofetil (MMF) were
conference was to develop guidelines for the management of significantly lower in tacrolimus-treated patients. Sig-
nificantly more tacrolimus-treated patients were
PTDM is recognized as an adverse event associated with prednisone-free (9.0%/0%; P<0.001). Logistic regres-
the use of corticosteroids, cyclosporine, or tacrolimus. Histor- sion analysis revealed that the absence of an antipro-
ically, immunosuppressive regimens consisting of corticoste- liferative agent correlated with the development of
PTDM (odds ratio؍3.56; P؍0.01).
roids and azathioprine have been associated with an inci- Conclusions. Based on this study, we propose man-
dence of PTDM as high as 46% (1, 2). More recently, the agement guidelines specifically for glucose intoler-
incidence of PTDM related to cyclosporine- and corticoste- ance developing after renal transplantation. Mainte-
roid-based regimens has been reported to be as high as 20% nance of blood glucose levels within strict limits is
among kidney allograft recipients (3–5). Most cases of PTDM recommended, and the contribution of immunosup-
occur during the first 3 months after transplantation or after pressive agents to the development of PTDM is ac-
treatment for rejection. Decreases in the release of insulin counted for. Gradual tapering of prednisone and ta-
and peripheral insulin resistance have been identified as crolimus is proposed for patients who develop PTDM
but also bear minimal risk of rejection. Tapering and
eventual withdrawal of insulin should be attempted
once blood glucose levels normalize. Switching to the
The U.S. Multicenter Phase III Trial of tacrolimus therapy alternative calcineurin inhibitor should only be con-
in kidney transplantation revealed an increased incidence of sidered as a late intervention. Tacrolimus therapy
PTDM among patients receiving tacrolimus (FK506, Prograf, should be considered even in patients at high risk for
Fujisawa Healthcare, Inc., Deerfield, IL) compared with cy- diabetes, because the benefit of reduced acute rejec-
closporine (CsA) (Sandimmune, cyclosporine, Novartis, EastHanover, NJ) at 1 year of follow-up (19.9% vs. 4.0%, respec- 1 This study was sponsored by Fujisawa Healthcare, Inc., Deer- tively, PϽ0.001 (11)). The incidence of PTDM among tacroli- mus-treated, African-American patients was higher (36.6% 2 Section of Transplantation, University of Cincinnati Medical vs. 12.2% among CsA-treated African-American patients; significance not reported (12)). On the other hand, the anal- 3 University of North Carolina at Chapel Hill, University of North ysis also revealed that significantly fewer African-American patients treated with tacrolimus required antilymphocyte antibody therapy to resolve acute rejection episodes (5.5% vs.
5 Northwestern University Medical School.
6 26.9% CsA-treated, African-American patients, PϽ0.01 (12)).
Thomas E. Starzl Transplantation Institute, University of Pitts- A multivariate analysis identified African-American recipi- ent race, high corticosteroid dose, and high tacrolimus trough Address correspondence to: M. Roy First, M.D., Director, Section of Transplantation, University of Cincinnati Medical Center, 231 levels as risk factors for the development of PTDM in this Bethesda Avenue, Cincinnati, OH 45267-0585.
Follow-up of this multicenter trial at 5 years revealed that TABLE 1. Patient demographics and recipient
overall 47% of tacrolimus-treated patients who developed characteristicsa
PTDM over the first year discontinued insulin and remained on tacrolimus therapy (13). The reduced mean daily dose and whole blood trough levels of tacrolimus at 5 years (0.12 mg/ kg/day and 8.4 ng/mL, respectively) compared to those ini- tially targeted (0.2 mg/kg/day and 10 –25 ng/mL, respec- tively) may have contributed to the reversal of insulin Most kidney transplant centers in the United States now incorporate mycophenolate mofetil (MMF) (CellCept, Hoff- mann-LaRoche Inc., Nutley, NJ) into immunosuppressive regimens. A recent report compared the use of tacrolimus or CsA (Neoral, cyclosporine, Novartis) combined with MMF in kidney transplant patients. The study revealed a low inci- dence of insulin use at 1 year of follow-up (2.2% among tacrolimus-treated patients vs. 6.5% among Neoral-treated patients (14)) and at 2 years (tacrolimus: 5.6%; Neoral: 4.0% Findings from another recent study corroborate these re- sults. In this dose-finding study of MMF in combination with tacrolimus (16), the incidence of PTDM was 4.8% among patients treated with tacrolimus plus a daily dose of 2 g of Center Participation and Patient Inclusion Criteria The purpose of the retrospective chart review was to collect data on individual patients that reflects the most current clinical practiceat kidney transplant centers experienced in the use of tacrolimus as a One, four, and one patient not accounted for with respect to primary immunosuppressive therapy. Five centers conducted a ret- gender, race, and number of transplants, respectively.
rospective analysis of the last 100 patients receiving kidney allo- grafts between January 1997 and July 1999 who had been followed c LURD, living-unrelated donor.
for at least 6 months after transplantation. Chart review was con-ducted according to institutional ethical guidelines.
TABLE 2. Immunosuppressive regimens
A total of 435 patients met the inclusion criteria for the review and were included in the analysis presented in this report. The partici- pating institutions were the University of Cincinnati Medical Cen- ter, University of North Carolina at Chapel Hill, Medical College of Wisconsin, Northwestern University Medical School, and the Thomas E. Starzl Transplantation Institute, University of Pitts- burgh Medical Center. Demographic profiles and relevant recipient factors are presented in Table 1. Mean follow-up was 561 days (Ϯ201, range 201–1336 days). After transplantation, patients were treated according to center-specific immunosuppressive protocols. A summary of treatment regimens is presented in Table 2.
a Three patients received neither tacrolimus nor CsA.
Patient chart review. We collected data on the immunosuppres- sive regimen (agents, doses, calcineurin inhibitor trough levels), and mean), oral prednisone dosing (median and mean), and serum incidence of PTDM, and management strategies at 1 week, 1 month, creatinine levels (median). Differences between measurements with 3 months, 6 months, and 12 months after transplantation. For pa- PՅ0.05, as determined by chi-square, Fisher’s exact, or Mann-Whit- tients who developed PTDM while receiving tacrolimus therapy, we ney U tests, as appropriate, were considered significant.
also analyzed the mean tacrolimus dose, trough blood levels, and A distinction was made between PTDM and hyperglycemia.
corticosteroid doses at the time of development of insulin depen- PTDM was defined as the requirement for insulin to normalize blood dence. Management strategies were summarized as the basis of the glucose levels in patients with no previous history of diabetes. Pa- tients who required oral antidiabetic agents to normalize blood glu- Data and statistical analysis. Data were entered into an Excel cose levels were described as being hyperglycemic.
(Microsoft) database and queried as appropriate for median or mean A multivariate analysis of the risk of developing PTDM was per- Ϯ SD (recipient demographic factors, doses of immunosuppressive formed using logistic regression analysis. The dependent variable agents, serum creatinine levels, serum glucose levels) and the inci- (PTDM) was analyzed against a series of eight independent recipient variables: age, gender, race, weight at time of transplantation, trans- Groups of patients maintained on tacrolimus- or CsA-based ther- plant number, type of calcineurin inhibitor used, use of an antipro- apy were compared for the incidence of PTDM, MMF dosing (median liferative agent (MMF, azathioprine, rapamycin, SDZ-RAD/everoli- mus, or none), and use of prednisone. Subsequently, repeated,weighted analyses were performed in which the effect of the leastsignificant independent variable was determined sequentially. Asecond analysis was conducted, including only patients who weremaintained on tacrolimus-based therapy, to evaluate risk factors.
Patient Demographics and Recipient Characteristics Included in the database were 435 patients from five cen- ters (Table 1). The majority of patients were male, Caucasianadults who had received primary cadaveric allografts. Hyper-tension was the primary diagnosis leading to transplantationin approximately 21% of patients. Approximately 15% ofpatients were diabetic at the time of transplantation.
Tacrolimus-based immunosuppression was the primary therapy in 65.1% of patients (Table 2). Over the course of thefollow-up period, 60 patients were switched from CsA-basedimmunosuppression to tacrolimus. The mean time of conver-sion was 157 days (Ϯ113; 31–365) after transplantation. Con-versely, six patients were switched to a CsA-based regimenfrom tacrolimus at a mean time of 147 days (Ϯ115; 15–396)after transplantation. With respect to PTDM, patients werecategorized according to the immunosuppressive therapythat they received at the time of diagnosis.
MMF was combined with calcineurin inhibitors in approx- FIGURE 1.
Median daily doses (A) and whole blood trough
imately 78% of patients. As part of the maintenance regimen, levels (B) of calcineurin inhibitors, with N values at each time
400 patients (92.0%) received prednisone. Five patients point appearing in the tables.
(1.1%) received azathioprine. Sirolimus was used in 19 pa-tients (4.4%), and 13 patients at one center (3.0% of thepopulation overall) were enrolled in a clinical trial of SDZ- 7.8Ϯ2.9 mg, respectively (Pϭ0.428). All patients receiving RAD/everolimus (vs. MMF) in kidney transplantation. All CsA were maintained on prednisone throughout the fol- patients enrolled in the SDZ-RAD/everolimus study received low-up period. In contrast, 25 patients (9.0%) receiving ta- CsA; one patient was switched to a regimen of tacrolimus ϩ crolimus therapy were prednisone-free at 1 year (PϽ0.001).
Median values for calcineurin inhibitor daily doses, trough blood levels, MMF and prednisone daily doses, and serum In the entire population, median serum creatinine levels creatinine levels are presented in Figures 1–3, respectively.
decreased from 1.95 mg/dL at 1 week after transplantation to Corresponding mean values at the time of latest follow-up 1.35 mg/dL at the time of latest follow-up (Fig. 3). Mean are described in the text that follows.
values at the time of latest follow-up were 1.5Ϯ0.6 mg/dL fortacrolimus-treated patients and 1.5Ϯ0.7 mg/dL for patients Dosing and Blood Levels of Immunosuppressants maintained on CsA (Pϭ0.407; range 0.5–5.2 mg/dL in the The median daily doses and median whole blood trough levels of tacrolimus and CsA are presented in Figure 1. Meandaily doses of both calcineurin inhibitors decreased over the Incidence of Dysregulated Glucose Metabolism follow-up period (12.8 –7.6 mg/day and 492–307 mg/day for PTDM was defined as the requirement for insulin to nor- tacrolimus and CsA, respectively). Mean trough blood levels malize blood glucose levels in patients with no previous his- of tacrolimus and CsA at latest follow-up were 10.1Ϯ10.5 tory of diabetes. Patients who required oral antidiabetic ng/mL and 221Ϯ86 ng/mL, respectively.
agents to normalize blood glucose levels were distinguished The median daily doses of MMF and prednisone are pre- sented in Figure 2. The mean daily dose of MMF over the A summary of the development of PTDM and hyperglyce- entire follow-up period was 1982Ϯ756 mg in patients main- mia appears in Table 3. Overall, 18 patients without a pre- tained on tacrolimus and 2084Ϯ589 mg in patients receiving vious history of diabetes developed PTDM over the course of CsA (Pϭ0.012). Mean dosing of MMF at the time of latest follow-up (18/369ϭ4.9%). After transplantation, 23 addi- follow-up was 1640Ϯ693 and 1831Ϯ565 mg in patients re- tional patients developed hyperglycemia (23/369ϭ6.2%).
ceiving tacrolimus or CsA, respectively (PϽ0.001). The mean Of the 369 patients with no history of diabetes at trans- daily oral prednisone dose over the entire follow-up period plantation, 245 received tacrolimus and 121 received CsA.
was 14.7Ϯ11.2 mg for tacrolimus-treated patients and Three patients included in the chart review who had no 20.0Ϯ18 mg for CsA-treated patients. Corresponding mean history of PTDM received neither calcineurin inhibitor. Four doses at the time of latest follow-up were 7.8Ϯ3.5 mg and patients receiving CsA (4/121ϭ3.3%) and 14 receiving ta- TABLE 3. Analysis of patients developing PTDMa or new
onset hyperglycemiab
a Defined as the requirement for insulin among patients without a b Defined as the requirement for treatment with (an) oral antidi- abetic agent(s) among patients without a pretransplant history ofdiabetes.
Median daily doses of MMF (A) and Prednisone
Three patients with no history of diabetes did not receive either (B), with N values at each time point appearing in the tables.
The incidence of PTDM was higher among African-Amer- ican compared with Caucasian patients (9.0% vs. 3.7%), butthe difference was not statistically significant (Pϭ0.549).
There was no statistically significant effect of primary diag-nosis on the incidence of PTDM (Pϭ0.599).
For tacrolimus-treated patients who developed PTDM, we collected data on tacrolimus dosing and whole blood troughlevels as well as prednisone dosing. The median daily dose oftacrolimus and the median whole blood trough level at thetime of diagnosis were 12.0 mg and 12.4 ng/mL, respectively.
Corresponding values at the time of latest follow-up beforediagnosis were 14.0 mg and 12.7 ng/mL. The median dailyprednisone dose was 13.8 mg at the time of latest follow-upbefore diagnosis. The median dose was 12.5 mg at the time ofdiagnosis of PTDM.
Multivariate Analysis of Risk Factors for the Development FIGURE 3.
Median serum creatinine, with N values at each
time point appearing in the table.
We conducted a multivariate analysis of the potential risk factors for the development of PTDM. Eight recipient demo-graphic and maintenance immunosuppression factors werechosen as independent variables: age, gender, race, weight at crolimus (14/245ϭ5.7%) developed PTDM (Pϭ0.453; Table transplantation, number of transplants, type of calcineurin 3). In addition, 15 tacrolimus- and 8 CsA-treated patients inhibitor (tacrolimus or CsA), use of an antiproliferative developed hyperglycemia (6.1% and 6.6%, respectively; agent (MMF, azathioprine, rapamycin, SDZ-RAD/everoli- Pϭ0.999; Table 3). There seemed to be differences among mus, or none), or use of prednisone. Only the absence of an centers with respect to the incidence of PTDM (range antiproliferative agent resulted in a significant, positive odds 0 –9.6%) and hyperglycemia (range 1.3–9.5%).
These findings prompted additional, weighted analyses in tation (see 17). However, the diagnostic criteria and proposed which the least significant independent variable was re- management strategies are based entirely on guidelines de- moved, and the data were re-analyzed. The order of removal veloped for the general population. The aims of this study of variables was: use of prednisone (yes/no), age, gender, were to evaluate the incidence of posttransplant diabetes number of transplants, race, calcineurin inhibitor, weight at (PTDM) in current practice and to develop diagnostic and transplantation, and use of an antiproliferative agent (yes/ management guidelines specifically for renal allograft no). Again, only the use of an antiproliferative agent retained statistical significance throughout the analysis.
Dysregulated glucose metabolism has been recognized as a In a subsequent univariate analysis, tacrolimus dosing and complication after kidney transplantation since the 1970s, blood trough levels were significantly higher among patients but inconsistent definitions of diabetes in the literature have who did not receive antiproliferative agent combination ther- complicated the interpretation of reports of immunosuppres- apy (nϭ30) compared with those who did (nϭ215; Fig. 4; P sion-related glucose intolerance. Definitions have ranged values: tacrolimus dosing PϽ0.001; tacrolimus blood trough from the requirement for de novo insulin therapy for greater levels PϽ0.001). There was a trend toward higher tacrolimus than two consecutive weeks to the determination of three doses in patients who developed PTDM compared with those consecutive elevated blood glucose levels (Ͼ140 mg/dL or Ͼ150 mg/dL) (1, 3–5).
The entire analysis was repeated, including only patients American Diabetes Association (ADA) guidelines do not who received tacrolimus therapy. Once again, the analysis account for the occurrence of diabetes among recipients of revealed that the absence of antiproliferative agents is re- organ allografts (18). According to a recent review of the lated to the development of PTDM (odds ratio 6.42; Pϭ0.008).
impact and management of PTDM among kidney allograftrecipients, the diagnosis of diabetes after kidney transplan- tation should coincide with the diagnosis in the general pop- Clinical focus on the improvement of long-term outcomes ulation (19). The authors suggest that the diagnosis should in renal transplantation has attracted attention to factors be made in any one of three sets of circumstances. In the first, impacting the development of diabetes after renal transplan- PTDM is diagnosed when random blood glucose levels exceed200 mg/dL and are accompanied by the clinical symptoms ofdiabetes (polyuria, polydipsia, and unexplained weight loss).
Another alternative for diagnosing PTDM is a fasting plasmaglucose of Ն126 mg/dL. The third indication is 2-hr plasmaglucose levels of Ն200 mg/dL in a standard oral glucosetolerance test (OGTT).
The Clinical Practice Guidelines Committee of the Ameri- can Society of Transplantation (AST) has published recom-mendations for outpatient surveillance of recipients of renalallografts (17). Blood glucose management is cited as a crit-ical focus of long-term patient management. The committeeacknowledges the variation in definition of PTDM in theliterature and suggests that a fasting plasma glucose level ofϾ126 mg/dL is an indication for oral glucose tolerance testingto establish the diagnosis of PTDM. These guidelines willprove instrumental to the prospective optimization of long-term kidney function and management of cardiovascular riskamong recipients of kidney allografts.
In this study, we have defined PTDM as the requirement for insulin to normalize blood glucose levels in patients withno pretransplant history of diabetes. Although the rationalefor our definition is based on the principles of diabetes diag-nosis and management described for the general population(18), we believe that kidney allograft recipients who developdiabetes after transplantation constitute a unique popula-tion. Therefore, PTDM warrants unique evaluation and man-agement strategies. This realization, supported by thedata retrieved from our clinical review, has prompted thedistinction between hyperglycemia and diabetes proposedin Figure 5.
PTDM occurred at relatively low frequency in the popula- tion of patients surveyed in this study (4.9%). In contrast tothe results of the Phase III Trial of tacrolimus in kidneytransplantation, there was no significant difference in theincidence of PTDM among patients treated with tacrolimus FIGURE 4.
Tacrolimus doses (A) and tacrolimus whole blood
trough levels (B) in patients who were maintained with and
or CsA. The majority of patients were followed for a period of without antiproliferative agent(s).
at least 1 year (mean follow-up 561Ϯ201 days). Furthermore, FIGURE 5.
Guidelines for the
management of PTDM.
this retrospective review focused on issues concerning the erative agents were associated with the development of development of PTDM and did not consider the incidence of PTDM. Additional, prospective study would be required to acute rejection. Longer follow-up among a larger population determine the reproducibility of this result and the contribu- of patients would be required to determine the rate of rever- tion of additional factors to the occurrence of PTDM under sal of insulin dependence among patients who develop PTDM maintenance on current immunosuppressive regimens.
under current clinical practice conditions.
Our proposed diagnostic and management strategies sup- Interestingly, the absence of an antiproliferative agent port the AST Committee’s opinion on the stringent manage- (MMF, azathioprine, sirolimus, or SDZ-RAD/everolimus) was ment of blood glucose levels (Fig. 5). Our strategies also the only significant positive factor identified in a multivari- account for the contribution of immunosuppressive agents to ate analysis of risk of developing PTDM. That is, patients the development of glucose intolerance. Finally, the scheme who did not receive an antiproliferative agent experienced an represented in Figure 5 recognizes that immunosuppression- increased incidence of PTDM. A high tacrolimus trough level related hyperglycemia and PTDM are reversible in some did not emerge as a risk factor for PTDM, as it did in the patients. In further agreement with the AST Committee multivariate analysis of risk conducted over the course of the guidelines, we recommend that blood glucose be monitored at Phase III Trial of tacrolimus in kidney transplantation (11).
However, in the present analysis, it was noted that higher In recipients of kidney allografts, blood glucose should be tacrolimus blood levels in patients not receiving antiprolif- monitored daily during the initial hospital stay. After dis- charge from hospital, patients with elevated blood glucose normalize blood glucose levels, those who experience serious levels should self-monitor at least twice daily (2– 4 times/day secondary complications of PTDM, or those in whom blood is recommended). In addition, blood glucose levels should be glucose levels remain unstable. The risk of rejection should verified at each regular outpatient clinic visit. Patients with be carefully evaluated before conversion, and patients should fasting blood glucose of Ͼ160 mg/dL or postprandial blood be monitored for rejection if conversion becomes necessary.
glucose of Ͼ200 mg/dL should be investigated for dysregu- CsA, and tacrolimus, have all been implicated in the devel- Hyperglycemia, defined as fasting blood glucose of 160 – opment of PTDM. Results of the present review suggest that 250 mg/dL, should be managed initially by administration of the incidence of PTDM is low under current immunosuppres- oral antidiabetic agents. The individual medical profile of the sive protocols, prompting reconsideration of previously iden- patient and the relative benefit/toxicity profile of each drug tified risk factors for developing dysregulated glucose metab- are definitive guides to choosing an appropriate oral agent.
olism after transplantation. Tacrolimus therapy should be Sulfonylureas or thiazolidinediones, a new class of antidia- considered even in patients at high risk for the development betic oral agent (20 –22), should be considered first.
of PTDM, because the benefits of reduced acute rejection Persistent elevation of blood glucose levels within this incidence and severity, as demonstrated in other studies (11, range (160 –250 mg/dL) might respond to an increased dose of 12, 14, 16, 28), outweigh the risk of developing PTDM.
a single agent or to an additional oral agent. Glycemic controlmay provide the opportunity to discontinue oral agents, be- Acknowledgments. The contributions of Teresa Brady and Malay cause the doses of immunosuppressive agents are naturally Shah to data management and statistical analysis are gratefullyacknowledged.
tapered over time after transplantation.
Insulin may be required to normalize blood glucose levels in patients whose fasting blood glucose exceeds 250 mg/dL.
Insulin tapering or discontinuation should be considered in 1. Gunnarsson R, Arner P, Lundgren G, Magnusson G, O Diabetes mellitus: a more-common-than-believed complication of renal patients whose fasting and bedtime blood glucose measure transplantation. Transplant Proc 1979; 11: 1280.
Յ80 mg/dL and whose postprandial blood glucose is Յ140 2. Gunnarsson R, Lundgren G, Magnusson G, Ost L, Groth CG. Steroid mg/dL. Insulin should be withdrawn or tapered over an ex- diabetes: a sign of overtreatment with steroids in the renal graft recip- tended period to ensure adequate glycemic control. During ient? Scand J Urol Nephrol 1980; 54: 135.
this time, oral agents may be used to control blood glucose 3. Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttrans- plant diabetes in renal allograft recipients. Transplantation 1987; 44: Modifying the immunosuppressive regimen should be con- sidered only in patients whose blood glucose levels remain 4. Roth D, Milgrom M, Esquenazi V, Fuller L, Burke G, Miller J. Posttrans- difficult to control. Tapering corticosteroid dose or discon- plant hyperglycemia: increased incidence in cyclosporine-treated renalallograft recipients. Transplantation 1989; 47: 278.
tinuing corticosteroid therapy should be considered before 5. Sumrani NB, Delaney V, Ding Z, et al. Diabetes mellitus after renal making adjustments to primary immunosuppressive agents.
transplantation in the cyclosporine era: an analysis of risk factors.
Published evidence suggests that safe and effective corti- costeroid withdrawal may be achieved in kidney allograft 6. Alejandro R, Feldman EC, Bloom AD, Kenyon NS. Effects of cyclosporin on recipients maintained on a tacrolimus-based regimen (23– insulin and C-peptide secretion in healthy beagles. Diabetes 1989; 38:698.
27). However, we caution that surveillance biopsies were not 7. Yale JF, Chamelian M, Courchesne S, Vigeant C. Peripheral insulin re- performed in the present patient population, and the fol- sistance and decreased insulin secretion after cyclosporine A treatment.
low-up period is relatively short. The possibility of indolent rejection should be considered when corticosteroids are 8. David DS, Cheigh JS, Braun DW Jr, Fotino M, Stenzel KH, Rubin AL.
HLA-A28 and steroid-induced diabetes in renal transplant patients.
When corticosteroid tapering is indicated, it should be 9. Hirano Y, Hisatomi A, Ohara K, Noguchi H. The effects of FK506 and achieved gradually, with concomitant monitoring for signs of cyclosporine on the exocrine function of the rat pancreas. Transplanta- acute rejection, including attention to clinical signs, mea- surement of serum creatinine levels, and kidney allograft 10. Tamura K, Fujimura T, Tsutsumi T, et al. Transcriptional inhibition of insulin by FK506 and possible involvement of FK506 binding protein-12 biopsy, if necessary. The relative merits of tapering insulin in pancreatic ␤-cell. Transplantation 1995; 59: 1606.
versus corticosteroids should be decided on an individual 11. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after ca- The early use of tacrolimus was associated with increased daveric renal transplantation. FK506 Renal Transplant Study Group.
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risk of developing PTDM (11). However, the incidence and 12. Neylan JF. Racial differences in renal transplantation after immunosup- severity of acute rejection episodes have been shown to be pression with tacrolimus versus cyclosporine. FK506 Kidney Trans- significantly reduced among tacrolimus-treated patients (11, plant Study Group. Transplantation 1998; 65: 515.
12, 14, 16, 28). In addition, the results of recent clinical trials, 13. Pirsch JD. Tacrolimus versus cyclosporine in kidney transplantation: five- particularly those evaluating the combination of tacrolimus year survival results of the U.S. multicenter, randomized, comparativestudy [Abstract]. FK506 Kidney Transplant Study Group. Transplan- with MMF, suggest that the incidence of PTDM is equivalent in patients receiving tacrolimus- or CsA-based immunosup- 14. Johnson C, Ahsan N, Gonwa T, et al. Randomized trial of tacrolimus pressive therapy (2.2–7%) (14, 16, 24, 28).
(Prograf) in combination with azathioprine or mycophenolate mofetil For patients who develop PTDM while receiving tacroli- versus cyclosporine (Neoral) with mycophenolate mofetil after cadaverickidney transplantation. Transplantation 2000; 69: 834.
mus therapy, conversion to CsA should be considered in cases 15. Gonwa TA, Johnson C, Ahsan N, et al. Two year followup of a randomized of severe manifestations of diabetes. Patients with severe multicenter kidney transplant study comparing tacrolimus (PG) ϩ aza- manifestations include those who require hospitalization to thioprine (AZA) vs. cyclosporine (Neoral) ϩ mycophenolate mofetil (MMF) vs. tacrolimus ϩ MMF [Abstract]. Transplantation 2000; 69: 24. Shapiro R, Jordan ML, Scantlebury VP, et al. A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone mycophe- 16. Miller J, Mendez R, Pirsch JD, Jensik SC. Safety and efficacy of tacrolimus nolate mofetil in renal transplant recipients. Transplantation 1999; 67: in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant 25. Buell JF, Kulkarni S, Grewal HP, et al. Early corticosteroid cessation at Study Group. Transplantation 2000; 69: 875.
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Vol. 73, 386–394, No. 3, February 15, 2002 Copyright 2002 by Lippincott Williams & Wilkins, Inc.
Ki67, E-CADHERIN, AND p53 AS PROGNOSTIC INDICATORS OF
LONG-TERM OUTCOME AFTER LIVER TRANSPLANTATION FOR
METASTATIC NEUROENDOCRINE TUMORS
JENS ROSENAU,1,2 MATTHIAS J. BAHR,1,2 REINHARD VON WASIELEWSKI,3 MICHAEL MENGEL,3 HARTMUT H. J. SCHMIDT,1,4 BJO¨RN NASHAN,5 HAUKE LANG,5,6 JU ICHAEL P. MANNS,1,7 AND KLAUS H. W. BOEKER Departments of Gastroenterology and Hepatology, Visceral and Transplantation Surgery, and Institute for Pathology, Medical School of Hannover, 30171 Hannover, Germany Background. Patients suffering from hepatic metas-
able, prognostic indicators are required. The aim of
tases of neuroendocrine tumors (NET) are potential
our study was to identify predictors of long-term sur-
candidates for orthotopic liver transplantation. Be-
vival with a focus on the impact of tumor biology.
cause recurrence rates are high and outcome is vari-
Methods. We retrospectively analyzed 19 patients
who received an orthotopic liver graft for metastatic
NET at the Medizinische Hochschule Hannover. Ex-
Department of Gastroenterology and Hepatology, Medical School pression of Ki67, E-cadherin, and p53 was studied im-
munohistochemically in metastases of neuroendo-
These authors have contributed equally contributed to this crine tumors of the explanted livers.
Results. Patients were followed up to 146 months
Department of Pathology, Medical School of Hannover.
after liver transplantation. Six patients died during
Current affiliation: Department of Gastroenterology, Hepatol- follow-up. The resulting 1-, 5-, and 10-year survival
ogy, and Endocrinology, Charit´e, Humboldt University, Berlin, rates are 89%, 80%, and 50%, respectively. All deaths
during long-term follow-up were tumor-associated.
Department of Visceral and Transplantation Surgery, Medical Recurrence was diagnosed in 12 patients between 2
6 Current affiliation: Department of General and Transplantation weeks and 48 months after liver transplantation.
Surgery, University of Essen, Essen, Germany.
Three patients are without tumor recurrence more
7 Address correspondence to: Michael P. Manns, M.D., Depart- than 8 years after liver transplantation. Survival in
ment of Gastroenterology and Hepatology, Medizinische Hochschule the 5 patients with low Ki67 and regular E-cadherin
Hannover, Carl-Neuberg-Str. 1, 30623 Hannover, Germany. E-mail staining was significantly better than in the 12 pa-
tients with high Ki67 or aberrant E-cadherin expres-

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