Objectives: We review different immunosuppressant protocols used for living-donor kidney transplant recipients at our center.

Materials and Methods: Many prospective randomized studies from our center have been reported between March 1976 and 2016, with more than 2700 renal transplant procedures conducted. The first study was a prospective randomized trial of azathioprine versus cyclosporine. The second study compared triple therapy (prednisolone + azathioprine + cyclosporine) versus conventional therapy (prednisolone + aza­thioprine). The third study was a cost-saving study, in which 100 patients received ketoconazole along with the triple regimen. Another trial demonstrated the advantages of a microemulsion form of cyclosporine.

A subsequent trial compared calcineurin inhibitor minimization versus avoidance protocols. Rescue therapies were carried out to intensify immuno­suppressive regimens after repeated rejection. In addition, steroid-free regimens were evaluated during both short- and long-term treatment. A recent trial reported a step-forward avoidance protocol with a calcineurin inhibitor and a steroid-free regimen, whereas another current study is the TRANSFORM one. The rationale behind antibody therapy was tho­roughly evaluated among living-donor renal trans­plant recipients with different agents, including basiliximab, daclizumab, antithymocyte globulin, and alemtuzumab.

Results: Earlier studies have demonstrated the efficacy of conventional regimens without induction therapy, especially in longer follow-up. The standard triple therapy has emerged with intensified immuno­suppressive and lowered dose of each drug, especially cyclosporine. In minimization studies, no significant differences were encountered regarding patient and graft survival, even in the long-term. Steroid avoidance was safe and effective. Calcineurin inhibitors and steroid-free regimens have shown comparable patient and graft survival. Induction therapy has lowered the incidence and severity of acute rejection.

Conclusions: A better 5-year graft survival and less posttransplant complications have been achieved with steroid avoidance after induction with basiliximab. Induction therapy did not affect graft and patient survival rates despite lowered incidence and severity of acute rejections.

Key words : Immunosuppression, Induction therapy, Living-donor kidney transplant

Introduction

Renal transplant is the best modality for renal replacement therapy for patients with stage 5 chronic kidney disease because it improves quality of life and patient survival and is cost-effective.¹ When a kidney is transplanted from a human leucocyte antigen nonidentical donor, the recipient mounts an alloimmune response that leads to T-lymphocyte activation, antibody production, complement activation, allograft rejection, and transplant failure.² In recent decades, immunosuppressive drug development has slowed from its accelerated pace in the late 1990s, but it still shows steady growth. With improvements in efficacy and specificity of existing agents, it is increasingly difficult to develop an agent that meets superiority and safety measures necessary to gain regulatory and public opinion approval.³ Most transplant centers prefer the administration of a maintenance regimen with a calcineurin inhibitor (CNI), an antimetabolite, and prednisone; this is consistent with the 2009 KDIGO clinical practice guidelines for kidney transplant.⁴

Materials and Methods

In the many consecutive prospective randomized immunosuppressive studies conducted between March 1976 and March 2016 in living-donor renal transplant recipients at the Urology & Nephrology Center (Mansoura, Egypt), 2700 consecutive living-donor renal transplant procedures were performed. The first study was a prospective randomized trial of azathioprine versus cyclosporine, in which 112 patients were enrolled into 2 groups. The second prospective randomized study compared triple therapy (prednisolone + azathioprine + cyclosporine) versus conventional therapy (prednisolone + azathioprine); this study comprised 100 patients (50 in each group). The third study was cost-saving study, where 100 patients were evaluated in a prospective randomized design to receive ketoconazole in addition to triple regimen. The fourth study highlighted the results of conversion to cyclosporine microemulsion. The fifth study compared CNI minimization versus avoidance protocols, with 132 patients enrolled. All patients received basiliximab, steroids, and sirolimus. Randomization was carried out to receive either tacrolimus or mycophenolic acid (MPA). In a 2:1 randomization, a subsequent rescue study replaced azathioprine with MPA (147 patients) or cyclosporine was shifted to tacrolimus (65 patients). This study targeted patients with repeat rejection and increasing creatinine level. In a 7th study, steroid avoidance (short and long term) was evaluated. A recent trial used a step-forward avoidance protocol by treating patients with a CNI-free and steroid-free regimen, whereas the current study was the TRANSFORM one. The rationale behind antibody therapy was thoroughly evaluated among living-donor renal transplant patients. Different agents were used, including basiliximab, daclizumab, antithymocyte globulin (ATG), and alemtuzumab for variable follow-up.

All protocols, involving human participants were approved by the ethical committee of the Mansoura University before the study began, and the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from patients or their guardians.

Results

Prospective randomized trial of azathioprine versus cyclosporine
The study enrolled 112 patients, who were divided into 2 groups, with group 1 (n = 54) receiving prednisolone and azathioprine and group 2 (n = 58) receiving prednisolone and cyclosporine.⁵ During the follow-up (50 ± 8 mo), patient and graft survival rates did not significantly differ between the 2 groups. Moreover, overall frequency of acute rejection episodes was not different, although the number of patients who experienced repeated rejections was higher in group 1, with mean serum creatinine levels markedly higher among the recipients in group 2. A subsequent publication suggested satisfactory results in group 1 patients despite the higher mortality rate versus group 2. However, more recipients in group 2 developed posttransplant diabetes mellitus (PTDM) and bacterial infections.⁶ A long-term evaluation at 20 years showed comparable graft survival with comparable graft function, rejection frequency, malignancy, and hepatic impairment (Table 1).⁷

Prospective randomized study comparing triple therapy (prednisolone + azathioprine + cyclosporine) versus conventional therapy (prednisolone + azathioprine)
This study, which comprised 100 patients (50 in each group), showed no differences in patient and graft survival rates (at 1 and 3 y), graft function, and incidence of acute rejection episodes. However, recipients who received conventional therapy had significantly higher incidence of systemic infections. The study demonstrated that, after exclusion of high-risk patients, conventional therapy is as effective as triple therapy in maintaining patient and graft survival.⁸ The long-term results after 20 years reported that triple therapy patients experienced higher incidence of both chronic rejection and liver diseases (Table 2).⁹

Ketoconazole coadministration to triple (pred­nisolone + azathioprine+ cyclosporine) regimen
In this cost-saving trial, 100 patients were evaluated in a short-term prospective study to receive ketoconazole in addition to the triple regimen (prednisolone + azathioprine + cyclosporine; 51 patients comprising group 1) or control without ketoconazole (prednisolone + azathioprine + cyclos­porine; 49 patients comprising group 2). After 1 year of follow-up, it was concluded that addition of ketoconazole to cyclosporine not only saved costs but also had a favorable effect on graft function, chronic cyclosporine nephrotoxicity, chronic rejection, and fungal skin infection.¹⁰ After 54 months, dose reduction of cyclosporine was 72.9%. Moreover, metabolic consequences (lipid profile, bone mineral content, vitamin D blood levels) were not affected by long-term ketoconazole coadministration to cyc­losporine.¹¹ At 10-year follow-up, no differences were shown between groups regarding hepa­totoxicity and acute rejection, whereas chronic allograft nephropathy was statistically less in the ketoconazole group.¹²

The same idea was applied with tacrolimus,¹³ with dose reduction by 58.7% at 6 months and significant improvement in graft function and reduction of gastrointestinal upset episodes and hospital stay. At 2 years, the safety of this com­bination was confirmed with outstanding impact on costs and improvement in graft outcomes.¹⁴ Therefore, these studies changed our policy of immuno­suppressant maintenance and resulted in substantial cost savings. Currently, however, keto­conazole has a warning sign on PubMed for the safety of its use; therefore, we stopped its use in our maintenance therapy and now build up doses of CNIs.

Conversion to microemulsion form of cyclosporine
With the introduction of cyclosporine micro­emulsion, a 1-to-1 conversion study was designed for 400 patients (300 with normal liver functions, 100 with abnormal liver functions) to be followed for 1 year. This study evaluated the effects of conversion to microemulsion on hepatic and nonhepatic renal transplant recipients and compared the short-term results of microemulsion overall regarding graft function, frequency of rejection episodes, cyclos­porine doses, and hypertension in the 2 groups. The cyclosporine dose was reduced in the hepatic group by 16% versus 10% for nonhepatic recipients. The study concluded that 1-to-1 conversion to cyclosporine microemulsion is safe and easy to monitor and adjust (Table 3). Moreover, the hepatic status did not affect handling of cyclosporine microemulsion. The similarities in l-year results for either cyclosporine or its microemulsion indicate the mandatory need for long-term evaluations.¹⁵

Indeed, subtle but steady deterioration of graft function has been consistently observed in most patients who receive cyclosporine microemulsion compared with the conventional regimen.¹⁶

Calcineurin inhibitor minimization/avoidance trial
The new immunosuppressant era has witnessed minimization/sparing protocols for CNIs or steroids. In a prospective randomized trial, CNI minimization was compared versus avoidance protocols.17 For the 132 patients enrolled, all patients received basi­liximab, steroids, and sirolimus. Randomization was conducted, with 65 patients receiving tacrolimus (group 1) and 67 patients receiving mycophenolate mofetil (MMF; group 2). No significant differences were shown between both groups regarding patient and graft survival or protocol biopsy findings by chronic allograft damage index at 1 year. During the same period, group 2 recipients experienced less biopsy-proven acute rejections, although differences did not rank to statistical significance (13.5% vs 18.5%; P = .06) and showed better graft function, as estimated by serum creatinine level (1.25 vs 1.43 mg%; P = .02) and calculated glomerular filtration rate (94.0 vs 79.6 mL/min; P = .005) at 2 years. Long-term results at 5 years revealed no significant differences in patient and graft survival.¹⁸ However, group 2 had better graft functions and less changes in their primary immunosuppression (20.8% vs 53.8%; P = .001). The study highlighted the safety and efficacy of a CNI-free regimen among low to moderate immunologic risk recipients.

Rescue therapies
The rationale of the rescue therapy trial was to intensify immunosuppressive regimens after repeated rejections. Here, most of our patients were maintained on prednisolone, cyclosporine, and azathioprine as primary plan for immuno­suppression.¹⁹ A 1:2 ratio randomization was conducted by replacing either cyclosporine with tacrolimus (65 patients) or azathioprine with MMF (147 patients) for patients who had graft function impairment secondary to histopathologically documented chronic allograft nephropathy. No statistically significant differences were noted between the 2 groups regarding rejection-free patients or those who experienced one or more episodes of acute rejection (P > .5). In tacrolimus group and MMF groups, graft survival rates were 87.3% and 96.3% at 2 years and 78.7% and 80% at 5 years (P = .07). The corresponding patient survival rates were 98.4% and 98.5% at 1 year, 98.4%,and 97.7% at 2 years, and 94.4% and 94.4% at 5 years (P = .65). There were more patients with PTDM and serious bacterial infections in the tacrolimus group than in the MMF group (P = .001 and .04). This study showed that rescue conversion to tacrolimus or MMF instead of cyclosporine or azathioprine is equipotent. Therefore, we are tailoring our policy regarding rescue therapy to either tacrolimus or MMF according to the situation and with consideration of each recipient individually.

Steroid-free regimen
One hundred patients were randomized to receive tacrolimus, MMF, basiliximab induction, and steroids for 3 days only (study group, 50 patients) or tacrolimus, MMF, basiliximab induction, and steroid maintenance (control group, 50 patients). The median follow-up was 12 months, and patient and graft survival rates were 100% in both groups. The rate of biopsy-proven acute rejection was 16% in both groups. For patients in the control group, the mean serum creatinine level was 111.22 μmol/L compared with 110.39 μmol/L in patients in the study group. Posttransplant hypertension was encountered in 4% of patients in the study group compared with 24% of patients in the control group (P = .0009). Post­transplant diabetes mellitus occurred in 4% of the patients in the study group compared with 16% of the patients in the control group (P = .037). Post­transplant weight gain was reported in 6% of the patients in the study group compared with 15% of the patients in the control group (P = .001). The chronic allograft damage index results of biopsy specimens at 1-year follow-up were comparable in both groups (2.48 vs 2.28; P = .16).²⁰

Long-term steroid avoidance was assessed in
428 patients (214 patients in each group), with median follow-up of 66 ± 41 months. At long-term follow-up, both groups showed comparable graft and patient survival, rejection episodes, and graft function. Posttransplant hypertension was detected in 40% of the steroid-free group and 80% of the steroid maintenance group (P = .05), whereas PTDM was detected in 5% of patients who discontinued steroids and in 15% with steroid maintenance (P = .3; Table 4). The conclusion was that, among low-immunologic risk recipients of living-donor renal transplants, steroid avoidance was feasible, safe, and had less morbidity with basiliximab induction than with tacrolimus and MPA as maintenance immuno­suppression.²¹ Steroid avoidance was associated with a lower total cost despite comparable immuno­suppression cost, which was attributed to the lower cost of associated morbidities.²²

Calcineurin inhibitors and steroid-free regimen
Forty low immunologic risk patients who received basiliximab induction were maintained on steroids for a minimum of 5 days until they achieved satisfactory tacrolimus levels. All patients were maintained on tacrolimus and MMF for the first 3 months. Protocol biopsies were done for all patients 3 months after transplant. Patients with normal protocol biopsies at 3 months were randomized into 2 groups, receiving tacrolimus (n = 20) or sirolimus (n = 20). At 1 year after renal transplant, protocol biopsies were done again. All patients received clinical and laboratory follow-up for 2 years after transplant. In the sirolimus group, we recorded 3 patients who resumed tacrolimus, 1 patient because of thrombocytopenia, 1 patient due to de novo focal segmental glomerulosclerosis, and 1 patient due to acute cellular rejection. At 1-year protocol biopsy, 1 patient experienced subclinical acute rejection. In the tacrolimus group, we had one patient with PTDM. Two patients had severe intractable diarrhea, which was thoroughly investigated and necessitated shifting to azathioprine and steroid for 1 patient and changing from tacrolimus to cyclosporine for another. Patient and graft survival rates were comparable in both groups during follow-up. Moreover, posttransplant complications (infections) were also comparable.

TRANSFORM study
We currently participate in this international multicenter prospective randomized trial, which is still ongoing.

Induction therapies
The rationale behind antibody therapy was thoroughly evaluated among living-donor renal transplant, with different agents use (basiliximab, daclizumab, and ATG) for variable follow-ups for up to 10 years.

Basiliximab study
In this study, 100 adult recipients of first kidney allo­graft were randomized into 2 groups, with 50 patients receiving basiliximab and 50 patients serving as a control group (without induction). All patients rece­ived maintenance triple immuno­suppressive therapy (steroids, cyclosporine micro­emulsion, and azathio­prine). At 1-year follow-up, basiliximab signi­ficantly reduced the proportion of patients who experienced acute rejection (36% vs 62%); in addition, the cumulative steroid dose at 12 months was significantly less in the basiliximab group. The posttransplant complications were comparable in the 2 groups. It was concluded that prophylactic basiliximab is well tolerated and effectively reduces the acute rejection episodes in living-donor renal transplant recipients.²³

There were no differences in patient and graft survival at 5 years (100% and 86% for basiliximab group, 96% and 88% for control group). In addition, 10-year patient and graft survival rates were 92% and 76% for the basiliximab and 90% and 68% for the control group. Basiliximab reduced the proportion of patients who experienced an acute rejection in the first year (36%) compared with the control group (62%; P = .009) and at 10 years (56%) when compared with the control group (72%; P = .059).²⁴

Daclizumab study
In this study, 21 adult recipients were allocated to receive daclizumab with triple immunosuppression therapy (prednisolone + cyclosporine + MMF); these patients were compared with 50 patients without induction, who were maintained on triple immuno­suppressive regimen. Follow-up extended up to 5 years. The daclizumab group experienced a sig­nificantly marked reduction in acute rejection (33%) compared with the second group (62%; P = .01), with subsequent reduction of cumulative steroid dose at last follow-up. No significant differences were noted regarding patient and graft survival rates (95.3% and 85.7% for daclizumab and 96% and 88% for the second group). The incidence of post­transplant complications was comparable for both groups. It was concluded that daclizumab drastically reduced the incidence of acute rejection with no effect on either patient or graft survival at long term.²⁵

Antithymocyte globulin trial
We previously reported on 50 recipients who were treated locally at Mansoura with ATG for steroid-resistant acute rejection,²⁶ documenting its efficacy in reversal of steroid-resistant rejection. Variable dose schedules were adopted for ATG use. A single bolus high-dose ATG induction has not been adequately studied; therefore, we aimed to evaluate its long-term effects in living-donor renal transplant patients. Eighty renal allograft recipients were randomized into 2 equal groups, with the first receiving an intraoperative single bolus of ATG (9 mg/kg) and the second group serving as the control group (no induction). Triple maintenance immunotherapy was used (steroid, CNI, antiproliferative agent) in both groups. At 5 years, ATG significantly reduced the incidence of acute rejection, cumulative steroid dose with comparable posttransplant complications, and patient and graft survival (100% and 85% for ATG and 95% and 92% for control group). This study showed the efficacy of a bolus ATG dose in reducing acute rejection, with subsequent patient and graft survival being comparable.²⁷

Alemtuzumab study
A pilot study was carried out in 2 phases by using alemtuzumab (30 mg) induction. In phase 1, 21 patients were randomized to receive either tacrolimus (11 patients) or sirolimus (10 patients). A short course of steroids (5 days) was given to both groups. Moreover, azathioprine (1 mg/kg) was initiated when white blood cell count exceeded 4000/cm. Follow-up was a minimum of 4 years. The incidence of acute rejection episode was comparable (5 vs 2). Crossover was indicated in certain situations (resistant rejection, proteinuria, and throm­bocytopenia neces­sitated shift to tacrolimus; however, Kaposi sarcoma indicated sirolimus conversion). Currently, 8 patients from the tacrolimus group and 6 recipients from the sirolimus group are steroid free. In phase 2, we enrolled 20 patients initially to start tacrolimus for the first 2 months before shift to sirolimus. The mean follow-up was 28.3 ± 2.1 months. Incidence of rejection was 20% (all were borderline rejection). At present, 75% of patients are CNI free and steroid free and showing perfect graft function. An extension of phase II, which included another 20 patients, revealed similar results. This study highlighted the efficacy and safety of steroid-free, CNI-free maintenance immunosuppressive regimen after alemtuzumab induction.²⁸

Discussion

As delineated in numerous multicenter randomized controlled trials and meta-analyses, triple immuno­suppressive regimens are generally associated with greater than 90% allograft survival at 1 year in combination with acute rejection rates of less than 20%. These are the clinical outcomes traditionally used to compare the efficacy of various immuno­suppressive regimens and issues surrounding the relative benefits and risks of administering cyclosporine versus tacrolimus, mycophenolate versus azathioprine, and/or sirolimus in triple drug regimens.²⁹ However, a principal unresolved issue is the relation between maintenance immuno­sup­pressive regimens and long-term allograft survival among the transplant population. An accurate assessment of this correlation is limited by even the pivotal trials’ ability to accurately anticipate and enroll a truly representative sample of the real world transplant population.³⁰ Our earlier studies demon­strated the efficacy of a conventional regimen (prednisolone + azathioprine) without induction therapy, especially in longer term follow-up. Thus, researchers were invited to design studies (with induction therapy) and investigate a better anti­proliferative such as MMF in the long term. Previous triple therapy regimen (prednisolone + cyclosporine + azathioprine) underwent intensified immuno­suppressive action in addition to lowered doses of each drug (especially cyclosporine) to alleviate its short- and long-term adverse effects. Tacrolimus was used to replace, to a great extent, cyclosporine, with improvement in survival rates. The trend is to minimize the toxicity associated with triple immunosuppressive regimens and possibly enhance long-term allograft survival without compromising short-term allograft survival. These regimens frequently involve minimization, withdrawal, or avoidance of either corticosteroids or CNIs or double immunosuppressive therapy with a CNI, and an antimetabolite is therefore administered in some centers.³¹ Our minimization study for CNI has had good results that warranted longer term evaluation. The steroid-free regimen was safe, effective, and had good results at both short- and long-term follow-up. Calcineurin inhibitors and steroid-free regimens have been promising protocols that minimize posttransplant complications with comparable safety regarding patient and graft survival rates.

Induction therapy is intense immunosuppressive therapy administered at the time of kidney trans­plant to reduce the risk of acute allograft rejection. In general, induction immunosuppressive strategies used by kidney transplant centers fall into 1 of 2 categories. One strategy relies on high doses of conventional immunosuppressive agents, whereas the other uses antibodies directed against T-cell antigens in combination with lower doses of conventional agents. The optimal prophylactic induction immunosuppressive therapy to prevent kidney transplant rejection remains controversial.⁴ Our induction therapy trials that use different agents concluded that induction therapy had a superior role in decreasing the incidence and the severity of the acute rejection episodes but with no significant effects on patient and graft survival rates.

Conclusions

Despite achievements in immunosuppressive ar­mament, many grafts are still lost due to rejection episodes. The future ambition is to overcome xeno-transplant barriers and move toward induction of immunologic tolerance after transplant. Different induction agents, despite their efficacy in lowering the incidence and severity of acute rejection episodes, have failed to produce any effects on patient and graft survival at longer follow-up. The ideal immunosuppression agent is not yet identified, and many drugs are in the pipeline for the near future.

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