Early post‐transplant conversion from tacrolimus to belatacept for prolonged delayed graft function improves renal function in kidney transplant recipients

Prolonged delayed graft function (DGF) in kidney transplant recipients imparts a risk of poor allograft function; tacrolimus may be detrimental in this setting. We conducted a retrospective single center analysis of the first 20 patients converted to belatacept for prolonged DGF as part of a clinical protocol as a novel treatment strategy to treat prolonged DGF. Prior to conversion, patients underwent an allograft biopsy to rule out rejection and confirm tubular injury. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months post‐transplant; secondary outcome was the change in eGFR 30 days post‐belatacept conversion. At 1 year post‐transplant, the mean eGFR was 54.2 (SD 19.2) mL/min/1.73 m². The mean eGFR on the day of belatacept conversion was 16 (SD 12.7) mL/min/1.73 m² and rose to 43.1 (SD 15.8) mL/min/1.73 m² 30 days post‐conversion (P<.0001). The acute rejection rate was 20% with 100% patient survival at 12 months post‐transplant. There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy. Belatacept conversion for prolonged DGF is a novel treatment strategy that resulted in an improvement in eGFR. Additional follow‐up is warranted to confirm the long‐term benefits of this strategy.     

Conversion to belatacept maintenance immunosuppression in HIV-positive kidney transplant recipients

There are only scattered case reports documenting belatacept use in HIV + kidney transplant recipients. We performed a retrospective review to describe short-term outcomes following conversion to belatacept in a cohort of HIV + patients. Patients were included if they were converted to belatacept between May 2015 and May 2019, had an HIV- donor, and received ≥4 doses of belatacept. All patients were treated with non-depleting induction and triple maintenance immunosuppression. Allograft and HIV-related outcomes were collected from the date of belatacept infusion until May 2020. Ten HIV + kidney transplant recipients were identified, who were converted to belatacept a median of 364 days post-transplant. At last follow-up (median 3.3 years), 8 patients remained on belatacept therapy, and all patients were alive with functioning allografts. Mean estimated glomerular filtration rates (eGFR) improved from 31.6 mL/min at baseline to 42.8 mL/min at 1 year (P = .03). Two patients developed acute rejection, with one necessitating conversion back to tacrolimus. All patients maintained undetectable HIV-1 viral loads at last follow-up. One patient each developed pneumocystis pneumonia and Kaposi sarcoma following conversion, which were responsive to standard medical therapy. In our cohort of stable HIV + kidney transplant recipients, conversion to belatacept was associated with excellent early patient and allograft survival and improved eGFR at 1 year.     

The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function

The introduction of cyclosporine (CYA) to the immunosuppressive armamentarium has had a significant effect on graft survival. An improvement in the formulation from the oil-based to a microemulsion-based form has resulted in better absorption and more predictable CYA bioavailability. Since the introduction of the first microemulsion form (Neoral), several bioequivalent formulations are now available and are switched in a 1:1 fashion at pharmacies to curtail costs. The purpose of our study was to study the effect of a 1:1 switch from Neoral to Gengraf on CYA trough levels and serum creatinine (SRC) in renal transplant recipients with stable graft function. Eighty-two renal transplant recipients with stable graft function were enrolled in the study, and of these, 73 were switched to Gengraf, whereas nine remained on Neoral. The 13 patients switched to Gengraf required a dosage change after the mean CYA trough levels changed from 234 +/- 96 ng/mL at baseline to 289 +/- 102 ng/mL (p < 0.05) at 2 wk. With the adjustments in dosage, the levels approached the baseline trough concentrations (239 +/- 151 ng/dL). The nine patients who remained on Neoral had no change in the CYA levels or SCR. Nearly 20% of patients who switched to a bioequivalent CYA preparation required a dose adjustment to return to pre-conversion CYA trough levels. Our study raises serious concerns regarding the switchability of generic CYA for Neoral without careful follow-up therapeutic drug monitoring.     

Paired kidney analysis of tacrolimus and cyclosporine microemulsion-based therapy in Chinese cadaveric renal transplant recipients

Few studies used paired kidneys for comparison between tacrolimus and cyclosporine in renal transplantation. Most of the published data used whole blood trough levels for drug monitoring. However, the use of limited sampling strategy and abbreviated formula to estimate the 12-h area under concentration-time curve (AUC(0-12)) allowed better prediction of drug exposure. Sixty-six first cadaveric renal transplant recipients receiving paired kidneys were randomized to receive either tacrolimus-based (n = 33) or cyclosporine microemulsion (Neoral)-based therapies (n = 33). Abbreviated AUC(0-12) was used for drug monitoring and dose titration. Mean follow-up duration was 2.8 +/- 2 years. The patient and graft survival were comparable. Fewer incidence of acute rejection was observed in tacrolimus group (15% vs. 27.3%) though the difference was not significant (P = 0.23). The absolute value and the rate of decline of creatinine clearance were both significantly better in tacrolimus-treated patients. Prevalence of hypertension, post-transplant diabetes mellitus, infection, and malignancy were similar in both groups. Prevalence of hypercholesterolemia (11/33 vs. 4/33) and gum hypertrophy (6/33 vs. 1/33) was more common in cyclosporine-treated patients (P = 0.04 in both parameters). This was the first prospective, randomized study with paired kidney analysis showing the renal function was significantly better in tacrolimus-treated patients than in cyclosporine-treated patients.     

Switchover to generic cyclosporine in stable renal transplant recipients: a single unit experience

BACKGROUND: The introduction of the immunosuppressant cyclosporine has significantly improved renal transplant survival. It is an expensive drug and generic alternatives may offer cost advantages. However, generic alternatives must be shown to provide equivalent therapeutic efficacy and safety. This study reports our experience of a switch from the microemulsion formulation of cyclosporine, Neoral (Novartis), to the generic equivalent, Cysporin (Mayne Pharma). METHOD: A two-period, single-sequence, cross-over study was done to compare cyclosporine blood levels and the area under the curve (AUC) of Neoral with Cysporin 2 weeks after a 1:1 dose switch. cyclosporine blood levels were measured at time points 0, 2, 4 and 8 h (C0, C2, C4, C8) after the switch. The cyclosporine AUC at 0-4 h and 0-12 h were calculated using the trapezoidal method. The two formulations were considered to result in equivalent blood levels if the 95% confidence interval (CI) of the ratio of the two levels was within 0.8-1.25. RESULTS and CONCLUSION: A total of 38 stable renal transplant patients aged 49.79 +/- 11.38 years (mean +/- SD), who were 7.84 +/- 3.97 years postrenal transplantation, were studied. The Neoral dose at the time of the switch was 2.38 +/- 1.21 mg per kg bodyweight. At all measured time points the 95% CI for the cyclosporine drug level ratio was between 0.9 and 1.15. There were no significant adverse events during the period of study. We conclude that the generic formulation of cylosporin, Cysporin, after a 1:1 switch from Neoral results in equivalent blood levels in stable renal transplant recipients. After switchover cyclosporine levels at C0 or C2 can continue to be monitored as per the institution's current monitoring practice.     

Weak antibody response to three doses of mRNA vaccine in kidney transplant recipients treated with belatacept

Poor responses to mRNA COVID-19 vaccine have been reported after 2 vaccine injections in kidney transplant recipients (KTRs) treated with belatacept. We analyzed the humoral response in belatacept-treated KTRs without a history of SARS-CoV-2 infection who received three injections of BNT162b2-mRNA COVID-19 vaccine. We also investigated vaccine immunogenicity in belatacept-treated KTRs with prior COVID-19 and characterized symptomatic COVID-19 infections after the vaccine in belatacept-treated KTRs. Among the 62 belatacept-treated KTRs (36 [58%] males), the median age (63.5 years IQR [51–72]), without COVID-19 history, only four patients (6.4%) developed anti-SARS-CoV-2 IgG with low antibody titers (median 209, IQR [20–409] AU/ml). 71% were treated with mycophenolic acid and 100% with steroids in association with belatacept. In contrast, in all the 5 KTRs with prior COVID-19 history, mRNA vaccine induced a strong antibody response with high antibody titers (median 10 769 AU/ml, IQR [6410–20 069]) after two injections. Seroprevalence after three-vaccine doses in 35 non-belatacept-treated KTRs was 37.1%. Twelve KTRs developed symptomatic COVID-19 after vaccination, including severe forms (50% of mortality). Breakthrough COVID-19 occurred in 5% of fully vaccinated patients. Administration of a third dose of BNT162b2 mRNA COVID-19 vaccine did not improve immunogenicity in KTRs treated with belatacept without prior COVID-19. Other strategies aiming to improve patient protection are needed.     

Renal function with cyclosporine C2 monitoring, enteric-coated mycophenolate sodium and basiliximab: a 12-month randomized trial in renal transplant recipients

BACKGROUND: Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C(2)) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C(2) maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction. METHODS: In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C(2) range) or group B (lower-C(2) range). RESULTS: Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p < 0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA >35% or >4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients. CONCLUSIONS: Low cyclosporine C(2) levels are associated with improved renal function compared with higher C(2) levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C(2) levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients.     

Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients.

BACKGROUND: The calcimimetic drug cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia and hyperparathyroidism; however, the interaction with calcineurin inhibitors and mycophenolate has not been evaluated. METHODS: In the present study the effects of cinacalcet on the pharmacokinetics of cyclosporine A (CsA), tacrolimus (Tac) and mycophenolate were investigated in 14 renal transplant recipients with stable renal function (mean creatinine 126.4 +/- 45.3 micromol/L). The patients were treated with either CsA (n = 8) or Tac (n = 6) in combination with mycophenolate/azathioprine and steroids. Twelve-hour pharmacokinetic investigations to measure CsA and its six main metabolites, Tac and mycophenolate concentrations were performed before and after 1-week treatment with 30 mg cinacalcet once daily. RESULTS: Cinacalcet treatment induced a significant 14.3 +/- 12.1% decrease in Tac AUC(0-12) (P = 0.039). Tac C(max), T(max) and T(1/2) also tended to decrease. The pharmacokinetics of CsA and mycophenolate were not significantly affected by concomitant treatment with cinacalcet. However, the secondary CsA metabolite, AM19, showed a significant increase of 9.0 +/- 9.5% during cinacalcet treatment (P = 0.040). Renal function decreased significantly from 78 +/- 11 to 72 +/- 12 mL/min (P = 0.019) and correlated with the increased levels of metabolite AM19 in the CsA group. Renal function was unchanged in the Tac group. CONCLUSION: Cinacalcet treatment showed a moderate effect on the Tac, but not CsA or mycophenolate, pharmacokinetics after 1-week concomitant treatment. This interaction appears to have minor clinical relevance. However, it is advisable to monitor renal function in CsA-treated patients due to the observed decrease in renal function.     

Long term efficacy of simvastatin in renal transplant recipients treated with cyclosporine or tacrolimus

BACKGROUND: Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. METHODS: In this study, 14 patients who had hypercholesterolemia [total cholesterol (TC) >200 mg/dL] and hypertriglyceridemia [triglyceride (TG) >150 mg/dL] 1 month after renal transplantation (post-transplantation), seven patients each under the treatment with immunosuppressant, either cyclosporine or tacrolimus started simvastatin treatment of 5-10 mg/d and continued the treatment for 4 yr. The effect of simvastatin treatment was assessed by comparison in serum lipid levels (TC, TG, cholesterol in lipoprotein fractions, and apolipoproteins) and the lipid metabolism related enzyme activities for post-transplantation, after 6-month and 4-yr simvastatin treatment. RESULTS: Simvastatin treatment of 4 yr significantly decreased the elevated levels of serum TC from 234.5 +/- 30.8 to 186.3 +/- 20.5 mg/dL (p < 0.001), low density lipoprotein cholesterol (LDL-C) from 116.7 +/- 22.5 to 82.7 +/- 16.6 mg/dL (p < 0.05) and TG from 200.3 +/- 109.2 to 97.0 +/- 45.2 mg/dL (p < 0.001). In addition, there were significant decreases in elevated serum very-low-density lipoprotein cholesterol (VLDL-C) from 47.8 +/- 18.4 to 28.6 +/- 9.5 mg/dL (p < 0.001) and LDL2 cholesterol (LDL2-C) from 20.8 +/- 8.2 to 5.7 +/- 1.8 mg/dL (p < 0.001). CONCLUSION: The results indicate that 4-yr treatment of simvastatin improves profiles of the atherogenic lipids in renal transplant patients with immunosuppressant caused hypercholesterolemia and hypertriglyceridemia treated either cyclosporine or tacrolimus in similar manner.     

Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in adult kidney transplant recipients

The clinical profile of belatacept in kidney transplant recipients was evaluated to determine if earlier results in the BENEFIT study were sustained at 3 years. BENEFIT is a randomized 3 year, phase III study in adults receiving a kidney transplant from a living or standard criteria deceased donor. Patients were randomized to a more (MI) or less intensive (LI) regimen of belatacept, or cyclosporine. 471/666 patients completed ≥3 years of therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) of patients survived with a functioning graft. The mean calculated GFR (cGFR) was ～21 mL/min/1.73 m(2) higher in the belatacept groups versus cyclosporine at year 3. From month 3 to month 36, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m(2) /year (MI) and +1.2 mL/min/1.73 m(2) /year (LI) versus a decline of -2.0 mL/min/1.73 m(2) /year (cyclosporine). One cyclosporine-treated patient experienced acute rejection between year 2 and year 3. There were no new safety signals and no new posttransplant lymphoproliferative disorder (PTLD) cases after month 18. Belatacept-treated patients maintained a high rate of patient and graft survival that was comparable to cyclosporine-treated patients, despite an early increased occurrence of acute rejection and PTLD.     

Steroid withdrawal in living donor renal transplant recipients using tacrolimus and cyclosporine: a randomized prospective study.

Steroids have been a mainstay of immunosuppressive regimens in renal transplantation despite their adverse effects. The introduction of new immunosuppressant has improved the survival rates and prompted trials of steroid withdrawal. We conducted a randomized prospective study to compare steroid withdrawal at 6 months post-transplant between tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine A + MMF (CsA group). Steroid was withdrawn at 6 months post-transplant under the condition of no rejection episode proven by biopsy and maintenance of serum creatinine level <2.0 mg/dl. Fourteen recipients were excluded because of acute rejection within 6 months or protocol violation. Steroid could be tapered off in 62 in FK group and 55 in CsA. Three cases in FK group and five in CsA had acute rejection within another 6 months after steroid withdrawal (P > 0.05). At 12 months, the incidence of post-transplant diabetes was 18.6% vs. 8.0% in FK and CsA group. And hypercholesterolemia was presented in 8.5% vs. 2.0%, hypertension in 47.5% vs. 56.0%, and serum creatinine level 1.18 +/- 0.24 mg/dl vs. 1.18 +/- 0.20 mg/dl, respectively (P > 0.05). Steroid withdrawal may be carried out successfully using both FK and CsA with MMF, but long-term follow-up is necessary.     

Efficacy and safety of conversion from cyclosporine to everolimus in living‐donor kidney transplant recipients: an analysis from the ZEUS study

Conversion of living‐donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 μmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post‐transplant. In a post hoc analysis of 80 living‐donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m² with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m²) with cyclosporine, a difference of 10.5 ml/min/1.73 m² in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m² with everolimus versus ?0.7 (95% CI [?4.6, 3.1]) ml/min/1.73 m²) (P < 0.001) with cyclosporine. There were six biopsy‐proven acute rejection episodes in everolimus‐treated patients (five Banff grade I) and one episode in cyclosporine‐treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post‐transplant that is observed in both living and deceased‐donor recipients. (clinicaltrials.gov NCT00154310)     

Conversion from calcineurin inhibitor–based immunosuppression to mammalian target of rapamycin inhibitors or belatacept in renal transplant recipients

The calcineurin inhibitors (CNIs) remain the standard of care for maintenance immunosuppression following renal transplantation. CNIs have demonstrated their effectiveness in reducing acute cellular rejection; however, some evidence suggests that these compounds negatively affect native renal function and are associated with allograft injury in renal transplant recipients. CNIs have also been linked with hypertension, new‐onset diabetes after transplantation, tremor, and thrombotic microangiopathy, which have significant consequences for long‐term allograft function and patient health overall. Thus, converting patients to a non‐CNI‐based regimen may improve renal function and also provide extrarenal benefits. A number of studies have been conducted that explore CNI conversion strategies in renal transplant recipients in an effort to improve long‐term allograft function and survival. These include converting to alternative, non‐nephrotoxic, maintenance immunosuppressants, such as the mammalian target of rapamycin inhibitors (sirolimus and everolimus) and the costimulation blocker belatacept. In this review of literature, evidence for the potential renal and extrarenal benefits of conversion to these non‐CNI‐based regimens is evaluated. Clinical challenges, including the adverse event profiles of non‐CNI‐based regimens and the selection of candidates for conversion, are also examined.     

Analysis of liver function in renal transplant recipients undergoing C2-monitoring for cyclosporine.

There exists no systematic evaluation of liver function in renal allograft recipients undergoing C2-monitoring with Neoral [cyclosporine A (CsA)-microemulsion]. In the present cohort analysis, we compared the hepatic profiles of C2-monitored (n = 80), C0-monitored (n = 81), and non-CsA-treated renal allograft recipients (n = 29), transplanted between 1/1999 and 2/2004 in our institution. While the C2-targets were set in accordance with (n = 72) or below (n = 8) the consensus on Neoral (1500 +/- 200 ng/ml), non-CsA-patients received FK506 (n = 29), partially in combination with rapamycin (n = 13) as primary immunosuppression. Analysis of maximum hepatic laboratory parameters and also repeated measures by anova within 30 days post-transplant revealed highly significant elevations of direct, indirect and total bilirubin, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase (P < 0.001) in the C2-group, in comparison with the C0- and the non-CsA-group. Bilirubin-levels were by far the most affected of all hepatic parameters, and correlated with C2-levels (r2 = 0.62). Seventeen CsA-patients had excessive bilirubin-elevations (>4 mg/dl) and were therefore considered to be 'CsA-sensitive' [14 C2-patients (17% of all C2-patients), 3 C0-patients (4% of all C0-patients)]. Bilirubin- and the other parameter elevations in these patients were reversible upon withdrawal or lowering of CsA. Most 'CsA-sensitive' patients (n = 12, 70%) displayed pre-transplant hepatic impairment, indicating a pre-existing liver instability. Collectively, our data emphasize the need for increased awareness toward individual predispositions for CsA-sensitivity.     

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients. This paper was presented at the 7th international congress of pediatric nephrology.     

Conversion to belatacept within 1-year of renal transplantation in a diverse cohort including patients with donor-specific antibodies

Early conversion from a calcineurin inhibitor to belatacept has the potential to improve long-term renal allograft function; however, there remains limited experience with this strategy among African Americans and patients with preformed donor-specific antibodies (DSA). To examine these subgroups, we performed a single-center review of kidney transplant recipients converted to belatacept within 1-year of transplant between 01/2011 and 10/2017. All patients received lymphocyte-depleting induction with maintenance tacrolimus and mycophenolate +/− corticosteroids. Patients were switched to belatacept for clinical indication and followed from date of conversion until allograft failure or study conclusion. The primary endpoint at 1-year was a composite of allograft loss, biopsy proven rejection, de novo DSA formation, proteinuria, and declining renal function. Thirty-two patients were included in the review. The majority were African American, and 28.1% had DSA at transplant. Patient and allograft survival at 1-year was 96.9% and 93.8%, respectively, and estimated glomerular filtration rate improved from 41.9 to 58.4 mL/min. No African Americans or patients with pretreatment DSA developed rejection or allograft failure within 1-year. The only clinical variable correlated with suboptimal allograft function was baseline weight ≥80 kg (OR = 6.2; 95% CI, 1.2-32.3). Early conversion to belatacept appears safe for select patients with DSA and African Americans receiving lymphocyte-depleting induction.     

Glucose metabolism before and after conversion from cyclosporine microemulsion to tacrolimus in stable renal recipients.

BACKGROUND: Tacrolimus is more diabetogenic than cyclosporine. However, this difference is only discernible in the first few months after renal transplantation. In randomized trials, investigating the effects of immunosuppression after renal transplantation, no increase in diabetes mellitus has been reported. However, no sensitive technique was used in these trials, so subclinical alteration of glucose metabolism cannot be excluded. METHODS: We, therefore, decided to use an intravenous glucose tolerance test (IV-GTT), to investigate whether conversion from cyclosporine-based immunosuppression, with a median trough level of 120 microg/l, to tacrolimus-based immunosuppression with a median trough level of 6.5 microg/l influences glucose metabolism and whether patients on steroids behave differently from those not on steroids. RESULTS: Thirty stable, non-diabetic patients, transplanted 10 or more years earlier, were converted from cyclosporine to tacrolimus without changing their concomitant medication. IV-GTT's were performed before and 2.5 months after the conversion. Before conversion, 40% of the patients had an abnormal glucose disappearance rate (kG): in 7%, kG was below 0.8 (abnormal range) and in 34%, kG was between 0.8 and 1.2 (indeterminate range). After conversion, stimulated insulin production, kG, HbA1C and fasting glucose did not change significantly. Insulin resistance (HOMA-R) of the whole group increased significantly, mainly due to a rise in HOMA-R in patients on steroids (n = 18). None of these patients developed overt diabetes mellitus. CONCLUSIONS: Some 40% of long-term cyclosporine-treated patients had an abnormal glucose metabolism. Conversion from cyclosporine to tacrolimus does not negatively influence stimulated glucose metabolism or insulin resistance in stable, steroid-free renal transplant recipients. However, in patients receiving steroids, conversion leads to an increase in insulin resistance while insulin output remains the same.     

Long‐term graft function with tacrolimus and cyclosporine in renal transplantation: Paired kidney analysis

Aim: The first prospective, randomized trial with paired kidney analysis was conducted to compare the efficacy and safety of tacrolimus with cyclosporine‐based immunosuppressive therapy in renal transplant recipients. This paper reports the long‐term follow‐up results of the authors' previously published study, with the main focus on graft survival and renal function. Methods: Chinese patients transplanted in our centre between June 1998 and June 2005 with their first deceased renal transplant were included. Patients were included if both kidneys were received by the authors' centre, thus allowing a paired analysis. Patients were randomized to receive triple immunosuppressive therapy with either tacrolimus or Neoral cyclosporine, concomitantly with prednisolone and azathioprine therapy. Results: Seventy‐six patients received cadaveric kidneys from 38 donors. Each pair of kidneys was randomly assigned to a separate group (38 subjects/group). The mean follow‐up duration was 6.1 ± 1.8 years. The mean calculated creatinine clearance was significantly higher in patients receiving tacrolimus‐based therapy. The rate of biopsy‐proven acute rejection was lower in the tacrolimus group (18.4% vs 42.1%, P = 0.03). The patient and graft survival were comparable in both treatment arms. Significantly fewer patients on tacrolimus‐based therapy developed hypercholesterolaemia (P = 0.05). However, there was no significant difference in the development of post‐transplant diabetes mellitus, hypertension, opportunistic infection and malignancy between both groups. Conclusion: Using the immunosuppressive regimen, tacrolimus‐based therapy provided adequate immunosuppression with better renal function and less acute rejection, as compared with cyclosporine‐based therapy.     

Incidence of anemia in sirolimus-treated renal transplant recipients: the importance of preserving renal function.

Sirolimus (SRL) has a concentration-related effect on hematopoiesis. In this study, 430 renal transplant recipients were randomized (1:1) 3 months post-transplantation to continue SRL-cyclosporine (CsA)-steroids (ST) or to have CsA withdrawn (SRL-ST). Over 5 years, on therapy calculated glomerular filtration rate (GFR), hematological indices, erythropoietin (EPO) use, and rates of mild, moderate, and severe anemia were determined. Longitudinal analyses using linear mixed models examined covariates predicting hemoglobin (Hgb) levels. Mean Hgb was significantly lower with SRL-ST at 6 months; but subsequently became significantly higher (at 2 years, 129 vs. 135 g/l, SRL-CsA-ST vs. SRL-ST, P<0.001). Mean corpuscular volume was low with both therapies, and significantly lower with SRL-ST. EPO use was similar in the two groups, approximately 30% during the first year and 10% thereafter. The incidence of anemia was significantly higher with SRL-CsA-ST>or=2 years. At year 5, only 39.1% of SRL-CsA-ST patients had normal Hgb vs. 68.5% of SRL-ST patients. GFR and recipient age as well as the interaction term x treatment time were significant covariates predicting Hgb. CsA withdrawal followed by SRL immunotherapy resulted in significantly less anemia than SRL-CsA-ST, despite twofold higher SRL exposure. This suggests that the improvement in GFR accompanying CsA withdrawal may mitigate the effect of SRL on hematopoiesis. (ClinicalTrials.gov number: NCT00428064).     

Conversion to tacrolimus once-daily from ciclosporin in stable kidney transplant recipients: a multicenter study

This 24-week, open, single-arm, prospective, multicenter study evaluated the effects of conversion from ciclosporin to Tacrolimus QD in adult kidney transplant patients. Stable patients receiving ciclosporin were converted to Tacrolimus QD at 0.1mg/kg/day. Relative change in renal function (primary endpoint) was assessed using estimated creatinine clearance (eCrCl) with a noninferiority margin set at -10%. A total of 346 patients were enrolled; and 301 patients were treated per protocol (PPS) in the hyperlipidemia (n=42), hypertrichosis (n=106), hypertension (n=77) and gingival hyperplasia (n=76) groups. Relative change in eCrCl was -0.6% in all PPS patients (95% CI, -2.2; 0.9) and -5.3% in the hyperlipidemia (CI, -9.59; -0.97), 0.9% in the hypertrichosis (CI, -2.59; 4.45), -0.1% in the hypertension (CI, -3.8; 3.68), and -1% in the gingival hyperplasia groups (CI, -4.63; 2.65) (PPS), meeting noninferiority criteria. There was no acute rejection. Decreases in serum lipids and blood pressure were moderate but without meaningful change in the number of treatment medications. Substantial decreases in severity of ciclosporin-related cosmetic side effects were evident from investigator and patient self-report of symptoms. Renal function remained stable after conversion to Tacrolimus QD. The effect of conversion on cardiovascular parameters was not clinically meaningful, however, marked improvement in ciclosporin-related cosmetic side effects was observed. (ClinicalTrials.gov number: NCT00481481).