© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 512–519 DOI: 10.1111/ctr.12329
Clinical Transplantation
Opinion and Hypothesis Section
High impact of rejection therapy on the incidence of post-transplant diabetes mellitus after kidney transplantation Schweer T, Gwinner W, Scheffner I, Schwarz A, Haller H, Blume C. High impact of rejection therapy on the incidence of post-transplant diabetes mellitus (PTDM) after kidney transplantation. Abstract: Background: Although major risk factors for posttransplant diabetes (PTDM) after kidney transplantation have been identified, a systematic study on the impact of rejection and rejection therapy is missing so far. Methods: Five hundred and twenty-six kidney transplant recipients transplanted in the years 2000–2007 were included. PTDM was defined according to WHO guidelines, and patients’ data were compared with special attention to protocol and for cause biopsies and rejection therapies. Survival analyses were made for graft loss and patient death. Results: 16.7% of all patients developed PTDM. Among common risk factors as higher age, body mass index (BMI), and others, the factor “acute cellular rejections” was comparably most relevant with a hazard ratio of 3.7. Consequently, antirejective treatment with steroid pulses and conversion to tacrolimus was the factor with the highest relative risk for the onset of PTDM (RR 3.5). PTDM itself had no impact on graft or patients’ survival, but the decreased graft survival in PTDM patients was dominantly influenced by the higher frequency of acute cellular rejections, and patients’ survival was reduced due to higher age. Conclusion: Based upon a higher rate of acute rejections (AR), the necessity of frequent antirejective treatments was more relevant for the induction of PTDM than age or BMI.
Post-transplant diabetes (PTDM) has become an increasing problem in kidney transplant recipients (KTRs) (1), with an incidence of 10–20% (2–5). A large study with more than 11 000 patients conducted in the United States of America (4) identified age, body mass index (BMI), male donor gender, hepatitis C infection, polycystic kidney disease (PCKD) (6, 7), and the use of tacrolimus as risk factors for PTDM. According to other studies, PTDM was linked to steroid usage (8), but there is no systematic analysis of the role of rejection episodes and changes in immunosuppression at the onset of PTDM. Moreover, PTDM was shown to be limiting for patient and graft survival (4). The present retrospective analysis examines the role of
512
Torben Schweer, Wilfried Gwinner, Irina Scheffner, Anke Schwarz, Hermann Haller and Cornelia Blume Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
Key words: immunosuppressive therapy – PTDM – rejection therapy – renal transplant biopsies Corresponding author: Torben Schweer, Virchowstr. 8 h, 31226 Peine, Germany. Tel.: 01725429731; fax: 051715458929; e-mail: [email protected] Conflict of interest: None. Accepted for publication 13 January 2014
acute rejection (AR) episodes and the type of rejection therapy and immunosuppression for the development of PTDM based upon multivariate analysis. We further explored the impact of PTDM on patient and graft survival using the data of a protocol biopsy program.
Materials and methods Patient groups and data collection
All kidney transplant recipients (KTRs) followed in this study were participants of the “protocol biopsy program” with routine renal biopsies at six, 12, and 26 wk after kidney transplantation
High impact of rejection therapy on PTDM Maximal follow up: 11 years
Tx
526 kidney transplant recipients
Fig. 1. Patient flow chart. Patient flow chart of the routine biopsy program. Five hundred and twenty-six kidney transplant recipients were addressed to the biopsy program immediately after transplantation and were closely visited within the first year after kidney transplantation (tx) and maximally followed up until 11 yr after tx.
Transplantation between 2000 and 2007
(tx) including patients biopsied for specific indications, generally creatinine increase or proteinuria that is established in our center since 2001 (Fig. 1). Our Internal Review Board (Ethical Committee) reviewed the protocol, and written informed consent was obtained from all patients. The study population consisted of 526 Caucasian KTRs transplanted between 2000 and 2007 at the Hannover Medical School (Table 1). All “for cause” biopsies of these patients were documented up to 10 yr after transplantation (506/ 3132 (16%) of all biopsies analyzed in this study). All KTRs of the program had a very close follow-up with documentation of patients’ demographics, data on the allograft, pre- and post-transplant morbidities, immunosuppressive treatment medication and co-medications, as well as biopsy results scored according to BANFF criteria (Fig. 1). The mean observation time post tx (mean SD) was 6.6 2.1 yr. Data on patient and graft survival were included until November 2011; the maximal follow-up was 11 yr. The frequencies of renal diseases as cause for renal sufficiency were comparable in both groups (Table 2) with a slightly bigger part of Table 1. The table shows the patient characteristics of the total patient cohort
First year of close follow up including routine graft biopsies at 6 weeks, 3 months and 6 months post tx
Monthly visits
Long term follow up including indication biopsies and clinical data
Visits 1 to 2 times a year
Table 2. Renal disease in PTDM patients and non-PTDM patients according to frequencies PTDM patients
Non-PTDM patients
46.6% renal disease unknown 23.9% glomerulonephritis 17.0% polycystic kidney disease 4.5% chronic pyelonephritis 4.5% hypertensive nephropathy 3.4% Alport syndrome
46.6% renal disease unknown 30.4% glomerulonephritis 13.0% polycystic kidney disease 8.2% Alport syndrome 5.5% reflux nephropathy 4.1% chronic pyelonephritis 4.1% hypertensive nephropathy
The table shows all factors analyzed within the study.
ADPKD patients in the group of PTDM patients. Patients that were lost to follow-up in the first year after tx and patients with pretransplant diabetes mellitus or combined pancreas/kidney transplantation were excluded. Ninety-four patients (17.9%) participated in the “Senior program of Eurotransplant.” In the present study, “new onset of PTDM” was diagnosed when non-fasting blood glucose (RBG) levels were above the limit of 11.1 mM (rsp. 200 mg/dL) in at least two consecutive measurements, and/or the HbA1c level was >6.5%. Elevated glucose values in the first week after transplantation induced by high-dose steroid induction therapy were not regarded.
Patient characteristics Age (yr) BMI HLA mismatches (A,B,DR) Recipient sex Hepatitis C Status Best serum creatinine after tx (lM) Delayed graft function Cold ischemia time (h), CIT Initial tacrolimus therapy Initial cyclosporine therapy
49 14 24 3.4 2.2 1.6 57% male 2.6% (14/525) 142 64 28% (148/524) 15 8 15.0% (77/525) 78.5% (412/525)
Immunosuppression protocols and rejection therapies
Until 2004, KTRs with low immunological risk (first transplant, no relevant pre-sensitization) received a dual immunosuppression (cyclosporine and steroids after induction therapy with basiliximab). Beginning in the second half of 2004, the regular immunosuppressive protocol included a triple therapy (cyclosporine, mycophenolate, and steroids after basiliximab). Immunized KTRs
513
Schweer et al.
with a panel reactive antibody >60% received Thymoglobulin for induction therapy. Immunized KTRs and recipients of living donations, or a regraft were treated with tacrolimus instead of cyclosporine from the start. The target blood levels for cyclosporine were 100–130 lg/L in the first three months, 90–100 lg/L up to six months and – in case of a stable graft function - 60 lg/L one yr post tx according to the LC-MS/MS method (The LC-MS/MS method for measuring cyclosporine blood levels is more specific for the active metabolite than the ACMIA method, and therefore, the target levels are 25–40% lower compared to the ACMIA results.) Trough levels of tacrolimus were aimed at 10–15 lg/L within the first three months after tx, followed by 8–12 lg/L up to six months after tx and 6–8 lg/L thereafter. Maintenance therapy included CNI, eventually mycophenolate depending on the date of transplantation and a steroid dosage of 0.1 mg/kg body weight. Acute cellular rejections (AR) were treated with one cycle of steroid pulse therapy, comprising 500 mg prednisolone intravenously per day on three consecutive days. Patients with a T-cell-mediated rejection scored as “borderline changes,” and a rise of serum creatinine of more than 20% from baseline received dosages of 250 mg prednisolone per day on three consecutive days. As intensified rejection treatment in cyclosporine-treated patients with AR later than three months post tx, tacrolimus was introduced after steroid pulse therapy. Statistical analysis
All clinical data were transferred to univariate analysis using Kruskal–Wallis test and Mann– Whitney U-test. Proportions were compared by chi-square analysis or Fisher’s exact test. p-values 65 yr and using an allocation without regarding HLA mismatches. Therapies with carvedilol, central sympatholytics, and the active form of vitamin D, statins, nitrates, acetylsalicylic acid, or allopurinol were significantly more prevalent among PTDM patients (Table 3). Anyhow, the initial transplant function of PTDM patients determined as best serum creatinine value in a time frame of six to eight wk after tx was not worse as compared to non-PTDM function (serum creatinine 150 67 vs. 141 63 lM, p = ns). Acute rejections. Two hundred and fourteen (40.7%) of all KTRs had acute cellular rejection episodes (BANFF I or II) or “borderline changes” including subclinical rejections detected by protocol biopsies. ARs were more frequent in PTDM patients than in non-PTDM patients (47.7% vs. 29.7%; p < 0.001, Table 3), and ARs occurred in 92% before onset of PTDM.
Results Incidence of PTDM
In this study, the incidence of PTDM was 16.7% (88 of 526 patients), with a median time to onset of
514
Influence of immunosuppression. Due to more frequent ARs, PTDM patients received more often steroid pulse therapy (46/88; 52.3% vs. 158/438; 36.1% of non-PTDM patients, p < 0.003) and
High impact of rejection therapy on PTDM Table 3. Univariate analysis of rejection episodes and other risk factors for PTDM: the percental frequency of the individual factors within PTDM or non-PTDM patients was compared
Univariate analysis of potential risk factors for PTDM
PTDM (n = 88) Age (yr) 56.1 11.1 BMI (kg/m2) 25.6 3.5 Male gender (n) 56 (63.6%) PCKD (n) 15 (17%) Male donor (n) 55 (63%) Donor age (yr) 52.2 16.1 Cyclosporine initial (n) 73 (17.7%) Tacrolimus initial (n) 6 (7.8%) Acute cellular rejections (n) 42 (47.7%) Acute cellular rejections 9 (36%) of “Senior patients” (n) Steroid pulse therapy (n) 46 (52.3%) Intensified rejection 32 (36.4%) treatment (n) Steroid pulse therapy 11 (44%) in “Senior patients” (n) HLA mismatches 2.5 1.7 (A, B, DR; n) HLA mismatches 3.6 2 in “Senior patients (A, B, DR; n)” Medication with Carvedilol (n) 8 (9.1%) Central sympatholytic 34 (38.6%) drugs (n) Vitamin D (active) (n) 61 (69.3%) Statin (n) 59 (67.0%) Nitrates (n) 10 (11.4%) ASS (n) 24 (27.3%) Allopurinol (n) 36 (40.9%)
Table 4. The table shows an increasing PTDM rate according to the number of applied steroid boli in patients with intensified rejection therapy (conversion to tacrolimus after steroid pulse therapy) compared to patients only receiving steroid pulses
No PTDM (n = 438)
Significance
Total number
47.9 13.6 23.7 3.2 244 (55.7%) 57 (13%) 215 (49.5%) 49 15 340 (82.3%) 71 (92.2%) 130 (29.7%) 16 (23.2%)
Clin Transplant 2014: 28: 512–519 DOI: 10.1111/ctr.12329
Clinical Transplantation
Opinion and Hypothesis Section
High impact of rejection therapy on the incidence of post-transplant diabetes mellitus after kidney transplantation Schweer T, Gwinner W, Scheffner I, Schwarz A, Haller H, Blume C. High impact of rejection therapy on the incidence of post-transplant diabetes mellitus (PTDM) after kidney transplantation. Abstract: Background: Although major risk factors for posttransplant diabetes (PTDM) after kidney transplantation have been identified, a systematic study on the impact of rejection and rejection therapy is missing so far. Methods: Five hundred and twenty-six kidney transplant recipients transplanted in the years 2000–2007 were included. PTDM was defined according to WHO guidelines, and patients’ data were compared with special attention to protocol and for cause biopsies and rejection therapies. Survival analyses were made for graft loss and patient death. Results: 16.7% of all patients developed PTDM. Among common risk factors as higher age, body mass index (BMI), and others, the factor “acute cellular rejections” was comparably most relevant with a hazard ratio of 3.7. Consequently, antirejective treatment with steroid pulses and conversion to tacrolimus was the factor with the highest relative risk for the onset of PTDM (RR 3.5). PTDM itself had no impact on graft or patients’ survival, but the decreased graft survival in PTDM patients was dominantly influenced by the higher frequency of acute cellular rejections, and patients’ survival was reduced due to higher age. Conclusion: Based upon a higher rate of acute rejections (AR), the necessity of frequent antirejective treatments was more relevant for the induction of PTDM than age or BMI.
Post-transplant diabetes (PTDM) has become an increasing problem in kidney transplant recipients (KTRs) (1), with an incidence of 10–20% (2–5). A large study with more than 11 000 patients conducted in the United States of America (4) identified age, body mass index (BMI), male donor gender, hepatitis C infection, polycystic kidney disease (PCKD) (6, 7), and the use of tacrolimus as risk factors for PTDM. According to other studies, PTDM was linked to steroid usage (8), but there is no systematic analysis of the role of rejection episodes and changes in immunosuppression at the onset of PTDM. Moreover, PTDM was shown to be limiting for patient and graft survival (4). The present retrospective analysis examines the role of
512
Torben Schweer, Wilfried Gwinner, Irina Scheffner, Anke Schwarz, Hermann Haller and Cornelia Blume Division of Nephrology and Hypertension, Department of Internal Medicine, Hannover Medical School, Hannover, Germany
Key words: immunosuppressive therapy – PTDM – rejection therapy – renal transplant biopsies Corresponding author: Torben Schweer, Virchowstr. 8 h, 31226 Peine, Germany. Tel.: 01725429731; fax: 051715458929; e-mail: [email protected] Conflict of interest: None. Accepted for publication 13 January 2014
acute rejection (AR) episodes and the type of rejection therapy and immunosuppression for the development of PTDM based upon multivariate analysis. We further explored the impact of PTDM on patient and graft survival using the data of a protocol biopsy program.
Materials and methods Patient groups and data collection
All kidney transplant recipients (KTRs) followed in this study were participants of the “protocol biopsy program” with routine renal biopsies at six, 12, and 26 wk after kidney transplantation
High impact of rejection therapy on PTDM Maximal follow up: 11 years
Tx
526 kidney transplant recipients
Fig. 1. Patient flow chart. Patient flow chart of the routine biopsy program. Five hundred and twenty-six kidney transplant recipients were addressed to the biopsy program immediately after transplantation and were closely visited within the first year after kidney transplantation (tx) and maximally followed up until 11 yr after tx.
Transplantation between 2000 and 2007
(tx) including patients biopsied for specific indications, generally creatinine increase or proteinuria that is established in our center since 2001 (Fig. 1). Our Internal Review Board (Ethical Committee) reviewed the protocol, and written informed consent was obtained from all patients. The study population consisted of 526 Caucasian KTRs transplanted between 2000 and 2007 at the Hannover Medical School (Table 1). All “for cause” biopsies of these patients were documented up to 10 yr after transplantation (506/ 3132 (16%) of all biopsies analyzed in this study). All KTRs of the program had a very close follow-up with documentation of patients’ demographics, data on the allograft, pre- and post-transplant morbidities, immunosuppressive treatment medication and co-medications, as well as biopsy results scored according to BANFF criteria (Fig. 1). The mean observation time post tx (mean SD) was 6.6 2.1 yr. Data on patient and graft survival were included until November 2011; the maximal follow-up was 11 yr. The frequencies of renal diseases as cause for renal sufficiency were comparable in both groups (Table 2) with a slightly bigger part of Table 1. The table shows the patient characteristics of the total patient cohort
First year of close follow up including routine graft biopsies at 6 weeks, 3 months and 6 months post tx
Monthly visits
Long term follow up including indication biopsies and clinical data
Visits 1 to 2 times a year
Table 2. Renal disease in PTDM patients and non-PTDM patients according to frequencies PTDM patients
Non-PTDM patients
46.6% renal disease unknown 23.9% glomerulonephritis 17.0% polycystic kidney disease 4.5% chronic pyelonephritis 4.5% hypertensive nephropathy 3.4% Alport syndrome
46.6% renal disease unknown 30.4% glomerulonephritis 13.0% polycystic kidney disease 8.2% Alport syndrome 5.5% reflux nephropathy 4.1% chronic pyelonephritis 4.1% hypertensive nephropathy
The table shows all factors analyzed within the study.
ADPKD patients in the group of PTDM patients. Patients that were lost to follow-up in the first year after tx and patients with pretransplant diabetes mellitus or combined pancreas/kidney transplantation were excluded. Ninety-four patients (17.9%) participated in the “Senior program of Eurotransplant.” In the present study, “new onset of PTDM” was diagnosed when non-fasting blood glucose (RBG) levels were above the limit of 11.1 mM (rsp. 200 mg/dL) in at least two consecutive measurements, and/or the HbA1c level was >6.5%. Elevated glucose values in the first week after transplantation induced by high-dose steroid induction therapy were not regarded.
Patient characteristics Age (yr) BMI HLA mismatches (A,B,DR) Recipient sex Hepatitis C Status Best serum creatinine after tx (lM) Delayed graft function Cold ischemia time (h), CIT Initial tacrolimus therapy Initial cyclosporine therapy
49 14 24 3.4 2.2 1.6 57% male 2.6% (14/525) 142 64 28% (148/524) 15 8 15.0% (77/525) 78.5% (412/525)
Immunosuppression protocols and rejection therapies
Until 2004, KTRs with low immunological risk (first transplant, no relevant pre-sensitization) received a dual immunosuppression (cyclosporine and steroids after induction therapy with basiliximab). Beginning in the second half of 2004, the regular immunosuppressive protocol included a triple therapy (cyclosporine, mycophenolate, and steroids after basiliximab). Immunized KTRs
513
Schweer et al.
with a panel reactive antibody >60% received Thymoglobulin for induction therapy. Immunized KTRs and recipients of living donations, or a regraft were treated with tacrolimus instead of cyclosporine from the start. The target blood levels for cyclosporine were 100–130 lg/L in the first three months, 90–100 lg/L up to six months and – in case of a stable graft function - 60 lg/L one yr post tx according to the LC-MS/MS method (The LC-MS/MS method for measuring cyclosporine blood levels is more specific for the active metabolite than the ACMIA method, and therefore, the target levels are 25–40% lower compared to the ACMIA results.) Trough levels of tacrolimus were aimed at 10–15 lg/L within the first three months after tx, followed by 8–12 lg/L up to six months after tx and 6–8 lg/L thereafter. Maintenance therapy included CNI, eventually mycophenolate depending on the date of transplantation and a steroid dosage of 0.1 mg/kg body weight. Acute cellular rejections (AR) were treated with one cycle of steroid pulse therapy, comprising 500 mg prednisolone intravenously per day on three consecutive days. Patients with a T-cell-mediated rejection scored as “borderline changes,” and a rise of serum creatinine of more than 20% from baseline received dosages of 250 mg prednisolone per day on three consecutive days. As intensified rejection treatment in cyclosporine-treated patients with AR later than three months post tx, tacrolimus was introduced after steroid pulse therapy. Statistical analysis
All clinical data were transferred to univariate analysis using Kruskal–Wallis test and Mann– Whitney U-test. Proportions were compared by chi-square analysis or Fisher’s exact test. p-values 65 yr and using an allocation without regarding HLA mismatches. Therapies with carvedilol, central sympatholytics, and the active form of vitamin D, statins, nitrates, acetylsalicylic acid, or allopurinol were significantly more prevalent among PTDM patients (Table 3). Anyhow, the initial transplant function of PTDM patients determined as best serum creatinine value in a time frame of six to eight wk after tx was not worse as compared to non-PTDM function (serum creatinine 150 67 vs. 141 63 lM, p = ns). Acute rejections. Two hundred and fourteen (40.7%) of all KTRs had acute cellular rejection episodes (BANFF I or II) or “borderline changes” including subclinical rejections detected by protocol biopsies. ARs were more frequent in PTDM patients than in non-PTDM patients (47.7% vs. 29.7%; p < 0.001, Table 3), and ARs occurred in 92% before onset of PTDM.
Results Incidence of PTDM
In this study, the incidence of PTDM was 16.7% (88 of 526 patients), with a median time to onset of
514
Influence of immunosuppression. Due to more frequent ARs, PTDM patients received more often steroid pulse therapy (46/88; 52.3% vs. 158/438; 36.1% of non-PTDM patients, p < 0.003) and
High impact of rejection therapy on PTDM Table 3. Univariate analysis of rejection episodes and other risk factors for PTDM: the percental frequency of the individual factors within PTDM or non-PTDM patients was compared
Univariate analysis of potential risk factors for PTDM
PTDM (n = 88) Age (yr) 56.1 11.1 BMI (kg/m2) 25.6 3.5 Male gender (n) 56 (63.6%) PCKD (n) 15 (17%) Male donor (n) 55 (63%) Donor age (yr) 52.2 16.1 Cyclosporine initial (n) 73 (17.7%) Tacrolimus initial (n) 6 (7.8%) Acute cellular rejections (n) 42 (47.7%) Acute cellular rejections 9 (36%) of “Senior patients” (n) Steroid pulse therapy (n) 46 (52.3%) Intensified rejection 32 (36.4%) treatment (n) Steroid pulse therapy 11 (44%) in “Senior patients” (n) HLA mismatches 2.5 1.7 (A, B, DR; n) HLA mismatches 3.6 2 in “Senior patients (A, B, DR; n)” Medication with Carvedilol (n) 8 (9.1%) Central sympatholytic 34 (38.6%) drugs (n) Vitamin D (active) (n) 61 (69.3%) Statin (n) 59 (67.0%) Nitrates (n) 10 (11.4%) ASS (n) 24 (27.3%) Allopurinol (n) 36 (40.9%)
Table 4. The table shows an increasing PTDM rate according to the number of applied steroid boli in patients with intensified rejection therapy (conversion to tacrolimus after steroid pulse therapy) compared to patients only receiving steroid pulses
No PTDM (n = 438)
Significance
Total number
47.9 13.6 23.7 3.2 244 (55.7%) 57 (13%) 215 (49.5%) 49 15 340 (82.3%) 71 (92.2%) 130 (29.7%) 16 (23.2%)
