How to improve the survival of the kidney transplant – is it only the pharmaceutical management?

Abstract

Kidney transplantation is the best treatment option in chronic kidney disease patients. Despite the new potent immunosuppressants, the long-term graft survival has not significantly improved. This is a rather complex issue with interrelationship between pretransplant donor–recipient variables, recipient post-transplant perioperative non/immunological factors, the combination/dose of maintenance immunosuppression and the general noncompliance of the patient. The recipients with an increased immunological risk should be maintained on triple therapy with steroids, preferably tacrolimus (Tac) or cyclosporine (CsA) plus mycophenolate mofetil (MMF). Eventual calcineurin inhibitor (CNI) minimization should be coupled with either protocol biopsies or frequent biochemistry monitoring including periodical assessment of anti-human leukocyte antigen and donor-specific antibodies. Recipients with standard immunological risks may be considered for as low as possible triple immunosuppression (steroids, Tac/CsA, MMF) after a period of 6 – 12 months. In cases of CNI minimization, a modification with a higher dose of the other two drugs in the triple therapy combination might be considered. The nonadherence to the prescribed maintenance therapy should be regularly checked-up. In conclusion, antibody induction, MMF, steroids and low-dose Tac/CsA should be the mainstream therapy in majority of patients. The short- and mid-term encouraging results for CNI minimization/withdrawal seem to correspond to recent findings of chronic antibody-mediated rejection, and long-term results need further evaluation.

Keywords::

• antibody-mediated rejection
• calcineurin inhibitors
• kidney transplantation
• maintenance immunosuppression

1. Introduction

Kidney transplantation is the best renal replacement treatment (RRT) option in chronic kidney disease patients. However, despite of the advanced immunological knowledge and recent potent immunosuppressants, a couple of constraints do not allow a larger number of transplanted patients compared with other types of RRT and an improved graft survival. Namely, the organ shortage leaves open the possibility for paid donation and associated consequences, especially in developing countries where many important data for follow-up and graft survival are missing [1]. Furthermore, the use of advanced age, expanded criteria that is, marginal donors [2] and ABO-incompatible kidney donors [3] are encouraged but the long-term graft survival data are still debatable. On the other hand, an increasing number of old and diabetic recipients with their comorbidities as well as highly sensitized anti-HLA recipients [4] are scheduled for transplantation subsequently increasing the risk for inferior long-term patient and graft survival.

The second issue that has impact on graft survival is the individual patient's adherence to drug treatment [5] and dietetic measures that prevent metabolic syndrome. Finally, the pharmaceutical impact on graft survival is mainly monitored through surrogate markers (biopsy/histology, anti-HLA antibodies, serum creatinine, proteinuria) and long-term survival data are more scarce. Thus, despite the initial improvement with the lower incidence of acute rejections, the long-term results have not been significantly improved [6].

In the June edition of the Expert Opinion on Pharmacotherapy, Schaefer et al. [7] presented a comprehensive review on various combinations of immunosuppressive regimens for prevention of kidney transplant rejections. However, they acknowledged that there is no real recipe on how to get an optimal long-term graft survival considering characteristics of the donated kidney as well as the recipient. Having in mind the three above-mentioned variables for graft survival, it is reasonable to assume an individual approach to immunosuppressive therapy based on patients and graft characteristics. Beyond all, once we get failing kidney allograft, an appropriate diagnosis is needed in order to reevaluate therapeutic possibilities. Thus, these questions remain to be elucidated.

2. Variables that influence graft survival

Risk factors associated with inferior graft survival may be divided into variables presented prior to transplantation (donor and recipient), perioperatively and those related to the recipient that appear after transplantation (nonimmunological and immunological factors) (Table 1).

Table 1. Donor and recipient risk factors associated with inferior graft survival.

Donor	Recipient
Nonimmunological	Nonimmunological	Immunological
Prior to transplantation (surgery)
Cadaveric graft	Donor size mismatch	Prior transplantation/sensitization
Non-heart beating donor	Younger age	Presence of anti-HLA antibodies
Older age	Female sex	Presence (titer) of DSA
Female sex	Smoking tobacco	Panel reactive antibodies
Comorbidities (hypertension, obesity, proteinuria, hematuria, glucose intolerance)	Comorbidities (hypertension, obesity, proteinuria, hematuria, glucose intolerance, anemia)	HLA mismatch
Perioperatively
Low CVP during surgery Cold ischemia time	Low CVP perioperatively Bladder catheter DGF	Hyper/acute rejection
Post-transplantation
	NODAT	Recurrence of underlying disease
	Hypertension	Infections (CMV, EBV, BK virus)
	Obesity	Chronic rejection
	Proteinuria	Anti-HLA antibodies
	Anemia	Subclinical rejection
	CNI nephrotoxicity	Immunosuppressant treatment
	Noncompliance	Nonadherence to treatment

Modified with permission from Moreso and Hernández [8] and Lebranchu et al. [9].

CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; CVP: Central venous pressure; DGF: Delayed graft function; DSA: Donor specific antibodies; EBV: Epstein–Barr virus; NODAT: New onset of diabetes after transplantation.

In addition to the nonimmunological demographic characteristics and lifestyle habits of both donors and recipients and their associated comorbidities prior to transplantation, there might be another set of variables presented perioperatively [8,9]. Nowadays, immunological impact derived from prior transplantation and sensitization is defined by the presence of anti-HLA and donor-specific antibodies (DSA) that are associated with decreased graft survival. Although being of minor importance in the era of modern immunosuppression, the number of HLA mismatches yet correlates with a reduced graft survival [10].

There are plenty of nonimmunological factors after transplantation that influence graft and patient survival but a vast majority may be prevented or carefully treated. Importantly, many of them correlate with the immunosuppression type. So, the tiny balance between the drug toxicity or side effect on the one hand and development of late acute, subclinical or chronic humoral rejection with DSA antibodies on the other hand should be achieved individually [11]. In this regard, the monitoring of trough and/or C2 levels as well as immunological status for the presence of antibodies has been greatly facilitated as the only available tool for evaluating adherence to treatment. Conversely, the appearance of various adverse effects may point out to an individual variability in absorption and kinetic or susceptibility for a particular drug or group of pharmacotherapeutics.

3. Achieving fine balance between immunosuppression and other factors for improving graft survival

The complex question for therapeutic balance in kidney transplant recipients should take into account the following issues: the pretransplant fixed factors (demography and comorbidities); trends in biochemical and clinical parameters observed throughout the regular outpatient follow-up visits within the post-transplant monitoring; and repetitive check-up on the presence of nonadherence to treatment or general noncompliance of the patient by simple questions on the drug intake and adherence to the medical advices. In this regard, the probability of developed graft disease based on histological diagnosis might be observed in function of time after transplantation and possible nonadherence as presented in Table 2 [11].

Table 2. Probability of developed graft disease based on biopsy as a gold standard for underlying histological diagnosis in function of time and possibility of nonadherence (low < 10, low to medium 10 – 25, medium 26 – 50, high > 50%).

Histological diagnosis	0 – 1 month	1 – 6 months	6 – 12 months	> 12 months
Antibody-mediated rejection (AMR)	Low	Low	Low	Medium
Probable AMR	Low	Low	Low	Low
Mixed rejection	Low	Low	Low	Low to Medium
T-cell-mediated rejection	Low	Medium	Low	Low
Borderline rejection	Low	Low	Low to Medium	Low
BK nephropathy	Low	Low	Low to Medium	Low
Recurrent glomerular disease	Low	Low	Low	Low to Medium
No major abnormalities	High	Medium	Low to Medium	Low to Medium
Atrophy-fibrosis	Low	Low	Low	Low to Medium
CNI nephrotoxicity	Low	Low	Low to Medium	Medium
Nonadherence	Low	Low	Low	High

Modified from Sellarés et al. [11].

CNI: Calcineurin inhibitor.

Nowadays, there is a growing understanding that antibody-mediated rejection (AMR) or mixed (cellular and antibody-mediated) rejection may increase graft loss by as much as sixfold [12]. Having in mind such multivariable and interrelated complex set-up of factors, it is a real challenge to anticipate what would be the appropriate immunosuppressive combination/dose that might extend the graft survival following transplantation as clinical priority.

4. Expert opinion

The care of transplant patient should begin before transplantation by selection of the donor, if possible, and the recipient, ameliorating the pretransplant risk factors that are manageable. In recipients with absence of pretransplant immunological risks and without rejection in early post-transplant period, steroids may be withdrawn but real benefits remain unclear [13]. The most frequent cause of their graft loss is death with functioning graft due to cardiovascular events and tumors where an alternative treatment option with mammalian target of rapamycin (mTOR) inhibition should be considered.

The young recipient-related risk for acute rejection and recipients with increased immunological risk (presence of anti-HLA and panel reactive antibodies, higher number of mismatches) should be managed by somewhat higher immunosuppression dose. This group of patients should be treated with antibody induction and steroids, preferably tacrolimus (Tac) or cyclosporine (CsA) plus mycophenolate mofetil (MMF), and maintained on triple therapy [14]. If decided on a light minimization of the immunosuppression (Tac trough levels [7.5 – 10 ng/ml], CsA-C2 levels [600 – 800 ng/ml] or steroids [5 – 7.5 mg/day]) it should be coupled with either protocol biopsies or careful and frequent biochemistry check-ups including periodical assessment of anti-HLA/DSA. It should minimize drug adverse effects and reduce the rate of chronic (cellular or antibody mediated) rejection and eventually prevent the recurrence of the underlying kidney disease. At the same time, the nonspecific and potentially protective treatment of heart and kidney diseases should be undertaken in order to modify the nonimmunological progression towards chronic graft dysfunction.

Recipients with absence of pretransplant immunological risks may be considered for as low as possible triple immunosuppression dose (steroids < 5 mg, Tac [5 – 7.5 ng/ml]/CsA-C2 [400 – 600 ng/ml], MMF [1.5 – 2 g/day]) after a period of 6 – 12 months. DSA levels should be assessed before the initiation of such minimization as well as in the following 6 – 12 months in order to evaluate AMR at later stage, which is associated with inferior graft survival [15].

In general, in cases of calcineurin inhibitor (CNI) minimization a modification with higher dose of the other two drugs in the triple therapy combination may be an option. Importantly, the nonadherence to the prescribed maintenance therapy should be checked-up at each outpatient visit.

In conclusion, antibody induction, MMF, steroids and low-dose Tac/CsA should be the mainstream therapy in majority of patients. The short- and mid-term encouraging results for CNI minimization/withdrawal seem to correspond to recent findings of chronic AMR, and long-term results need further evaluation.

Declaration of interest

The authors have no competing interests to declare and have received no funding in preparation of the manuscript.