Introduction:
As kidney transplantation improves the quality of life and life expectancy over renal dialysis, it is seen to be the best alternative for treating patients with advanced renal failure. It is also the most economical option when compared to dialysis. More than 95% of kidney transplants in Brazil are carried out under the Sistema Único de Saúde (SUS), which also ensures that transplant patients have free access to immunosuppressants.
Brazil's recommended maintenance immunosuppression follows worldwide standards, which call for a triple regimen consisting of an antiproliferative drug (Azathioprine or Mycophenolate), a Calcineurin Inhibitor (CNI) (Cyclosporine or Tacrolimus), and a corticosteroid. Alternatively, the mammalian target of Rapamycin (mTOR) may replace one of the two aforementioned medication groups.
Chronic baseline immunosuppression is necessary to suppress the immune response to allograft. As the risk of acute rejection declines, the level of chronic immunosuppression is gradually reduced to help reduce the cumulative risk of infection and malignancy, which are risks directly correlated with the degree of overall immunosuppression.
What Are the Immunosuppression Maintenance Therapy After Kidney Transplantation?
Long-term immunosuppressive management is still a story of instant gratification, difficulties, and disappointments. An era of enhanced maintenance immunosuppressive efficacy began with the advent of Calcineurin inhibitors and Mycophenolate as immunosuppressive treatments.
Acute short-term rejection rates dropped, and one-year results improved. Regretfully, long-term kidney allograft survival has not improved at a pace commensurate with this short-term success. Examining this disparity between short- and long-term results, it becomes clear that long-term exposure to the same maintenance immunosuppression that yields good short-term results may increase graft attrition.
Calcineurin Inhibitors
In the United States, Calcineurin inhibitor-based immunosuppression combined with Tacrolimus and Mycophenolate has become the standard of care for kidney transplant immunosuppression. With or without steroids, these two medications are used to maintain over 90% of patients in the US. This is primarily due to the historical studies that support Mycophenolate over Azathioprine due to reductions in early acute rejection rates and the groundbreaking Symphony trial, which showed superior outcomes in terms of both acute rejection rates and GFR at 1 in 3 years using a Tacrolimus-based regimen when compared with Cyclosporin- or Sirolimus-based regimens. However, the ideal tacrolimus dosage and Mycophenolate exposure are still debatable to provide the best long-term immunosuppression.
Crucially, in the Symphony trial, the actual attained Tacrolimus C0 exposure averaged 6.4 ng/ml at 12 months and 6.5 ng/ml at 36 months, despite the Tacrolimus trough (Tacrolimus C0) level goals being protocol stated at 3 to 7 ng/ml. Therefore, a more reasonable reading of the Symphony trial would be that the standard of care should be a Tacrolimus C0 dose range of 5 to 8 ng/ml.
Regimens Based on Non-Calcineurin Inhibitors:
Even though Calcineurin inhibitors are the primary immunosuppressant medication used in the United States, they have a number of off-target side effects. An increased risk of post-transplant hyperglycemia, raised blood pressure, increasing hyperlipidemia, neurotoxicity, and acute and chronic nephrotoxicity have all been linked to calcineurin inhibitors.
The US Food and Drug Administration (FDA) has only approved Belatacept with Mycophenolate and corticosteroids as a Calcineurin inhibitor-free regimen for adult kidney transplant recipients who are seropositive for the Epstein-Barr virus. A soluble fusion protein called Belatacept binds to antigen-presenting cells' CD80 and CD86 surfaces to prevent CD28-mediated T-cell costimulation.
Conversion of Calcineurin Inhibitor
Belatacept or mTOR inhibitors, as the principal immunosuppressive medication, have been used in a number of Calcineurin inhibitor conversion regimens that aim to prevent acute rejection early on while maintaining kidney function over the long run. Regarding the former, a randomized trial was conducted in which 173 patients between 6 and 36 months after transplantation were either kept on a calcineurin inhibitor-based regimen (n = 89) or moved to Belatacept (n = 84). In the Belatacept group, the mean increases from baseline eGFR at month 12 were 7±11.99 ml/min per 1.73 m2, while in the calcineurin inhibitor continuation group, the mean increases were 2.1±10.34 ml/min per 1.73 m2. The Belatacept and calcineurin inhibitor groups had 100% and 99% patient and graft survival rates, respectively.
Removal of Steroids
While 30% of kidney transplant recipients in the United States are still on Tacrolimus / Mycophenolate steroid-free immunosuppression one year after transplant, early corticosteroid withdrawal (within the first week post-transplant) is a popular immunosuppressive technique. It is unclear, though, what the long-term advantages (and disadvantages) of steroid-free regimens are. A well-conducted 5-year follow-up randomized control trial showed no differences in the incidence of post-transplant diabetes, weight gain, cardiovascular risk factors, or graft or patient survival; however, the steroid-containing arm experienced fewer bone complications and more acute rejection than the early corticosteroid withdrawal arm. Depleting antibody induction can reduce, but not eliminate, the rise in acute rejection rates associated with early corticosteroid cessation.
Are There Any Upcoming Immunosuppressive Drugs?
Few new maintenance immunosuppressive drugs are being developed right now. A phase-2 trial has examined Iscalimab, an anti-CD40 mAb, and preclinical development is underway for additional drugs that target costimulation blocking. Thus, it is up to clinicians to decide how best to maximize the agents that are currently on the market, such as once-daily Tacrolimus formulations, alternative Belatacept dosing strategies, and risk assessment of patients (using both clinical and emerging immune monitoring tools) in whom it is desirable to deviate from standard immunosuppression. For novel immunosuppressive treatments and immunosuppressive techniques to become popular, future research must look at clinically significant endpoints beyond 1-year graft and patient survival and 1-year rejection rates.
How to Diagnose and Managing Chronic Nephrotoxicity and Alloimmunity Risk?
The conflict between chronic nephrotoxicity and chronic alloimmunity (chronic antibody-mediated rejection) has emerged as the fundamental issue in Tacrolimus-based immunosuppression. The most recent thorough surveillance biopsy study that detailed histologic damage in functional grafts 10 years after transplant may be the finest example of the negative effects of Tacrolimus-based immunosuppression. Mesangial sclerosis, global glomerulosclerosis, and arteriolar hyalinosis were the most frequently found lesions in 50% – 70% of the 145 surveillance biopsies conducted ten years after the transplant. The systemic and vascular effects of calcineurin inhibitors are frequently linked to these lesions, which are typically thought to be nonimmunologic in character.
These results contrast with earlier research on kidneys biopsied "for cause" (failure at a median of 2.7 years after biopsy) or in a state of impending failure (mean 4.2 years after transplant), where the most common findings were glomerular lesions and antibody-mediated injury. Controlling alloimmunity is crucial in the short term, but doing so comes with a subsequent risk of nephrotoxicity. The negative consequences of calcineurin inhibitor-based immunosuppression limit long-term transplant results, at least in part. This has prompted researchers to seek mitigation or removal strategies, such as those mentioned above. A thorough meta-analysis provides the best summary of the numerous reports, which occasionally lead to improved kidney function and are frequently associated with an increased risk of rejection.
Conclusion:
It is still difficult to maintain maintenance immunosuppression in kidney transplant recipients over the long term. For most patients, Mycophenolate and the Calcineurin inhibitor Tacrolimus are the primary treatment, either with or without corticosteroids. To prevent rejection, a tacrolimus trough goal of 5 to 8 ng/ml appears ideal; however, nephrotoxicity and long-term Tacrolimus-related side effects justify the continued assessment of non-calcineurin inhibitor-based regimens.
