Objectives: Although steroid withdrawal has been attempted to ameliorate various complications in kidney transplant recipients, a steroid-sparing strategy has more frequently led to acute rejection. We investigated the use of everolimus to safely overcome steroid withdrawal in kidney transplant recipients with posttransplant diabetes mellitus under maintenance immunosuppressive therapy.
Materials and Methods: A total of 75 de novo consecutive kidney transplant recipients received conventional immunosuppressive therapy comprising tacrolimus (trough level of 5 ng/mL), mycophenolate mofetil (1000 mg), and methylprednisolone (4 mg). Patients with posttransplant diabetes mellitus underwent simultaneous everolimus administration (trough level of 3-5 ng/mL) and steroid withdrawal at 1 to 15 months after transplant. Graft outcomes were compared between the everolimus and steroid groups. In the everolimus group, renal function and hemoglobin A1c levels at 12 months after administration were compared with values before everolimus administration.
Results: The mean posttransplant follow-up period in the everolimus (n = 25) and steroid (n = 50) groups was 672 and 747 days, respectively. All grafts survived in both groups, and biopsy-proven acute rejection rates did not significantly differ between the groups (16% vs 12%; P = .72). Furthermore, no acute rejection occurred after everolimus administration. In the everolimus group, hemoglobin A1c significantly declined at 9 months after everolimus administration (6.94% vs 6.53%; P = .047). In addition, both serum creatinine levels and estimated glomerular filtration rates in the everolimus group were stable for 12 months after everolimus administration.
Conclusions: Steroid withdrawal using everolimus as maintenance immunosuppressive therapy for kidney transplant recipients may safely ameliorate posttransplant diabetes mellitus, achieve better glycemic control, and maintain stable renal function.
Key words : Acute rejection, Kidney transplantation, Steroid withdrawal
Steroids are one of the oldest and still important immunosuppressants for induction and maintenance immunosuppressive therapy in kidney transplant recipients. However, various complications caused by steroids, such as diabetes mellitus, osteoporosis, avascular osteonecrosis, gastric ulcer, cataract, glaucoma, and increased risk factors for cardiovascular disease, cannot be ignored because they result in the deterioration of quality of life and increase the risk of death with a functioning graft.1 Therefore, many studies have attempted steroid avoidance regimens for kidney transplant; however, some have reported a significant increase in acute rejection rates after early steroid withdrawal.2,3
The most common primary cause of renal failure among new dialysis patients in Japan is diabetic nephropathy (43.8%), which is also the most common primary disease amo ng the entire dialysis patient population (37.6%). Moreover, the incidence of diabetic nephropathy has been increasing.4 Recently, occurrence of type 2 diabetes mellitus among dialysis patients has spread worldwide. The use of steroids is associated with a potential risk of not only the deterioration of preexisting diabetes mellitus before transplant but also an increased incidence of new-onset diabetes after transplant (NODAT).5 Posttransplant diabetes mellitus (PTDM) includes both preexisting diabetes mellitus before transplant and NODAT, which is an independent predictor of reduced survival in kidney transplant recipients.6 Although steroid withdrawal can reduce the incidence of PTDM, this strategy has been associated with an increased risk of graft rejection, which may in turn increase the requirement for steroids and the incidence of PTDM.5 Unfortunately, safe and secure steroid withdrawal protocols for PTDM remain undetermined.
In this study, we investigated the use of a new tool, everolimus (an inhibitor of the mammalian target of rapamycin),7 to safely overcome steroid withdrawal in kidney transplant recipients under maintenance with conventional immunosuppressive therapy.
Materials and Methods
Study design and immunosuppression
We performed a prospective, observational, cohort study of 75 de novo consecutive adult kidney transplant recipients who underwent transplant procedures at our hospital from July 2013 to June 2016. This study was conducted in accordance with the principles of the Declarations of Helsinki and Istanbul.
All kidney transplant recipients received immunosuppressive therapy for induction, which included tacrolimus (0.1 mg/kg/day), mycophenolate mofetil (30 mg/kg/day), methylprednisolone (starting dose of 250 or 500 mg/day), and basiliximab (20 mg/day) at postoperative days 0 and 4. Desensitization for ABO-incompatible and donor-specific antibody-positive recipients was performed before transplant, through 0 to 4 sessions of double-filtration plasmapheresis or plasma exchange and rituximab administration of 1 or 2 times at a dose of 100 mg according to the quantity of antibody. All recipients were maintained on the triple-drug combination therapy of tacrolimus (trough level = C0, 5 ng/mL), mycophenolate mofetil (1000 mg/day), and methylprednisolone (4 mg/day) from 3 months posttransplant and onward. Among the recipients, patients with PTDM, including both preexisting diabetes mellitus before transplant and NODAT, underwent simultaneous everolimus administration (C0, 3-5 ng/mL) and methylprednisolone (steroid) withdrawal at 1 to 15 months after transplant (Figure 1). Patients who were not eligible for steroid withdrawal, including those with glomerulonephritis due to long-term steroid administration and those with a urine protein level of > 0.5 g/day (because everolimus may worsen urine protein levels), continued the triple-drug combination therapy with steroids. We used American Diabetes Association criteria for NODAT diagnosis, which is defined as fasting blood glucose ≥ 126 mg/dL at 2 measurements, or glucose ≥ 200 mg/dL at 1 measurement, or hemoglobin A1c (HbA1c) ≥ 6.5% at 2 measurements, or glucose ≥ 126 mg/dL and HbA1c ≥ 6.5% simultaneously at 1 measurement.8
Acute rejection rate and renal function on the latest day of posttransplant follow-up were compared between the everolimus and steroid groups. Serum creatinine levels and estimated glomerular filtration rate (eGFR), which were measured using the Japanese GFR equation,9 were used to evaluate renal function.
In the everolimus group, we compared the administration frequencies of oral hypoglycemic agents and insulin for diabetes mellitus before and after everolimus administration. Renal function (assessed by serum creatinine levels and eGFR) and presence of diabetes mellitus (estimated by HbA1c and glycoalbumin levels) during the 12 months of everolimus administration were compared with values before everolimus administration.
Patient characteristics were compared between the everolimus and steroid groups and are expressed as numbers, percentages, means with standard deviations, and medians with their ranges. Continuous variables were assessed using unpaired or paired t tests or Mann-Whitney U tests, as appropriate. Comparisons between categorical variables were assessed using Fisher exact test. A statistically significant difference was determined when the two-tailed P value was < .05. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan),10 which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).
Among 25 patients in the everolimus group, the number of preexisting diabetes mellitus and NODAT cases was 16 and 9, respectively. Proportions of male patients and of those with diabetes as the primary cause of chronic kidney disease were significantly higher in the everolimus group than in the steroid group. Body mass index and HbA1c levels before transplant were significantly higher in the everolimus group than in the steroid group. In contrast, the proportion of patients with glomerulonephritis as the primary cause of chronic kidney disease was significantly higher in the steroid group than in the everolimus group (Table 1).
All grafts survived in both the everolimus and steroid groups, and biopsy-proven acute rejection rates were not significantly different between the 2 groups (Table 2). Furthermore, no acute rejection occurred after everolimus administration. The actual administered dose of everolimus was 1.0 to 1.5 mg daily, under C0 of 3.0 to 5.0 ng/mL. Renal function on the latest day of posttransplant follow-up was not significantly different between the everolimus and steroid groups (Table 2).
Posttransplant diabetes mellitus and renal function in the everolimus group
In the everolimus group, the frequency of insulin use alone for the treatment of diabetes mellitus was similar before and after everolimus administration (Figure 2). Only 2 of 8 patients receiving treatment with a combination of oral hypoglycemic agents and insulin could switch to oral hypoglycemic agents after everolimus administration (Figure 2). Nevertheless, HbA1c levels significantly declined at 9 months after everolimus administration; moreover, the HbA1c level at 12 months after everolimus administration was < 6.5% (Figure 3). In addition, renal function in the everolimus group was stable for 12 months after everolimus administration (Figure 4).
In this study, we demonstrated important clinical observations for immunosuppressive therapy in kidney transplant recipients. This study clarified the usefulness of conversion from steroid to everolimus in maintenance kidney transplant recipients with PTDM. Our novel protocol for steroid withdrawal using everolimus could ameliorate PTDM and maintain stable renal function.
Steroid withdrawal in kidney transplant recipients is an attractive protocol because various complications can be avoided. However, many studies have reported a significant increase in acute rejection rates after early steroid withdrawal.2,3 Therefore, we used everolimus administration to compensate for the lack of immunosuppression that accompanies steroid withdrawal. As a result, no acute rejection was observed, and renal function was stable for 1 year after everolimus administration. However, the risk of acute rejection and the benefit of avoiding various complications have to be observed on a long-term basis.
Our novel protocol of steroid withdrawal using everolimus could ameliorate PTDM without requiring additional administration of insulin. This strategy is more beneficial for kidney transplant recipients with PTDM than conventional therapies involving steroid use. However, as anticancer agents, inhibitors of the mammalian target of rapamycin (ie, everolimus and temsirolimus) have been associated with a high incidence of hyperglycemia and new-onset diabetes.11 Conversely, the incidence of hyperglycemia directly attributed to everolimus use is decreased with the lower doses (1.5–3 mg/day) used after organ transplant compared with the higher doses (10 mg/day) used for cancer therapy.10 Therefore, the induction of hyperglycemia by everolimus may be dose dependent. Our study showed that, in terms of improving glucose metabolism, steroid withdrawal is more beneficial than administration of low-dose everolimus.
The earlier period of steroid withdrawal may be more useful to reduce the adverse effects of steroids. For example, application of a steroid-free regimen immediately after transplant has the potential to prevent the deterioration of PTDM. In our study, steroid withdrawal was performed during the maintenance period after transplant because we were concerned about the adverse effects of everolimus, such as edema, delayed wound healing, and lymphocele after surgery. However, no patients in our study had to discontinue everolimus administration because of its side effects.
Several limitations of this study should be acknowledged. Although patient characteristics and graft outcomes were compared between the everolimus and steroid groups, PTDM was estimated in the single arm of the everolimus group without a control group. However, the effects of PTDM in the everolimus group were observed by HbA1c levels over 12 months of everolimus administration. Ideally, a randomized controlled trial should be performed to evaluate treatment effects on PTDM. In addition, further study is needed to clarify the long-term outcomes for this new immunosuppressive protocol of steroid withdrawal using everolimus.
In conclusion, this study clearly demonstrated that conversion from steroid to everolimus as maintenance immunosuppressive therapy for kidney transplant recipients may safely ameliorate PTDM, achieve better glycemic control, and maintain stable renal function. This new immunosuppressive protocol involving everolimus administration may contribute to improved patient and graft survival.
Volume : 17
Issue : 1
Pages : 47 - 51
DOI : 10.6002/ect.2017.0178
From the Surgical Branch, Institute of Kidney Diseases, Jichi Medical University
Hospital, Shimotsuke, Japan
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Koji Nanmoku, Surgical Branch, Institute of Kidney Diseases, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 3290498, Japan
Phone: +81 285588859
Figure 1. Flow Chart of Patients Through the Study
Figure 2. Frequency of Use of Oral Hypoglycemic Agents and Insulin for Diabetes Mellitus Treatment
Figure 3. Time Course of HbA1c (A) and Glycoalbumin (B) Levels for 12 Months After Everolimus Administration
Figure 4. Time Course of Serum Creatinine (A) and Estimated Glomerular Filtration Rate (B) Levels for 12 Months After Everolimus Administration
Table 1. Patient Characteristics in the Everolimus and Steroid Groups
Table 2. Graft Outcomes in the Everolimus and Steroid Groups