Individualized immunosuppression represents a paradigm shift in kidney transplant from traditional “trial-and-error” dosing strategies toward individualized regimens. Precision immunosuppression is informed by pharmacogenetics, biomarkers, therapeutic drug monitoring, and recently artificial intelligence-based prediction models, although stratified risk assessment of patients is still mandatory. This review investigated the current evidence on individualized induction and maintenance immunosuppression. In addition, the roles of pharmacokinetics, pharmacogenomics, and emerging biomarker platforms were reviewed and future pathways for tailored posttransplant care were outlined. In summary, the data indicate that optimized immunosuppressive therapy improves graft outcomes, reduces toxicity, and enables targeted minimization strategies in selected recipients.

Key words : Immunosuppressive therapy, Renal transplant, Therapeutic drug monitoring

Introduction
Conventional immunosuppressive management of kidney transplant recipients relies heavily on standardized dosing protocols and dose titration based on plasma trough levels. This approach, described as “trial and error,” often fails to account for interindividual variabilities related to genetics, metabolism, immune risk, comorbidities, and drug interactions, resulting in both under- and overimmunosuppression, increased toxicity, and higher morbidity and cost of care.¹ Precision immunosuppression seeks to individualize therapy by using pharmacogenomics, proteomics, epigenetic markers, and noncoding RNAs to tailor treatment to each recipient’s biological profile.¹ The goals are to prevent acute rejection while minimizing long-term maintenance immunosuppression and its associated complications. This review focuses on individualization of induction and maintenance therapy, which follows the therapeutic drug monitoring (TDM) and genetic foot print.

Individualization of Induction Therapy

Risk-based selection of induction agents
Induction therapy typically consists of biologic antibodies, that is, rabbit antithymocyte globulin (rATG) or interleukin 2 receptor antagonists (IL-2RA), which are combined with high-dose corticosteroids. Based on data from the United Network for Organ Sharing, the weight of induction immunosuppression increased with increasing immunological risk.² Current guidelines recommend biologic induction for most kidney transplant recipients, whereas IL-2RAs are preferred for low-risk patients and rATG for high-risk patients. On the basis of guidelines from the American Society of Transplantation,³ induction therapy is recommended with a biologic agent as part of the initial immunosuppressive regimen in kidney transplant recipients. Use of rATG is suggested, rather than IL2-RA, for kidney transplant recipients with high immunologic risk, and use of IL2-RA is recommended as the first-line of induction therapy among kidney transplant recipients without high immunological risk. The best induction therapy is based on the risk assessment. Factors incorporated into risk stratification are shown in Figure 1.2

Evidence supporting individualized induction therapy
High-risk recipients benefit from rATG, which is associated with reduced antibody-mediated rejection rates and lower incidence of de novo donor-specific antibodies compared with IL-2RA. This beneficial effect of rATG is not the same for everyone, as pharmacogenetic variations influence diversity of induction outcomes. Tumor necrosis factor α polymorphisms have been shown to modulate acute rejection risk and response to rATG.⁴ In this regard, induction therapy with ATG may be effective only with tumor necrosis factor-α gene polymorphism of GA but not of GG genotype. Novel agents such as siplizumab, a new monoclonal anti-CD2 antibody, have shown selective CD4+ T-cell depletion while preserving regulatory T cells, suggesting potential utility in highly individualized induction regimens.⁵ In high risk patients, IL-2RA is sometimes replaced with rATG, especially when the recipient has leukopenia, thrombocytopenia, or hemodynamic instability. In such cases, rATG is contraindicated, making IL-2RA the preferred and safer alternative induction therapy.

Individualization of Maintenance Therapy

Principles of precision maintenance immunosuppression
Maintenance regimens typically include a calcineurin inhibitor (CNI), an antimetabolite, and corticosteroids, most commonly tacrolimus, mycophenolate mofetil (MMF), and prednisone, respectively. The intensity of therapy is adjusted based on immunologic risk similar to induction therapy.⁶ Both under- and overimmunosuppression must be avoided; clinical outcomes depend heavily on correctly balancing rejection risk with drug toxicity.

Factors influencing maintenance therapy selection
Factors influencing maintenance therapy selection is based on the nongenetic and genetic factors (Figure 2). Nongenetic determinants include age, sex, graft function, albumin level, hematocrit, body mass index, microbiome composition, and concomitant medications, which markedly modify pharmacokinetics and pharmacodynamics of immunosuppressive drugs. Genetic and irreversible factors include polymorphisms in CYP3A4/5 and P-glycoprotein transporters, which markedly affect tacrolimus and cyclosporine metabolism. These factors should be interpreted carefully when TDM is considered as a guide to individualized drug dose adjustment.

Policy of personalized therapy against immunosuppressive complications
Certain adverse effects need prompt specific therapeutic adjustments or changes (Table 1). In cases of severe and intractable “H” complications (hypertension, hyperplasia of gum, hirsutism, hyperlipidemia, and humoral rejection), it is reasonable to change from cyclosporine to tacrolimus. In cases of severe “N” complications secondary to tacrolimus (nephrotoxicity, new-onset diabetes after transplant, nutritional disorders), therapy can be switched to cyclosporine.

Calcineurin inhibitor reduction and withdrawal
Complete CNI withdrawal is associated with increased rejection and inferior long-term graft survival.⁷ Dual MMF-steroid therapy can improve renal function but at the cost of increased rejection. Although long-term treatment with CNIs prevents tolerance induction, CNI withdrawal after years of treatment must be avoided even in highly selective long-term stable kidney transplant recipients.

Corticosteroid withdrawal
Although steroid-free or rapid-withdrawal protocols are feasible in low-risk settings (such as those used in the HARMONY trial⁸ and the SAILOR study⁹), long-term CNI therapy continues to play a role in maintaining tolerance. Rapid steroid withdrawal in a low-dose tacrolimus and MMF-based therapy regimen has the potential to become the standard immunosuppressive strategy for renal transplant recipients with low immunological risk, if induction therapy with rATG has already been administered. Corticosteroid withdrawal is not recommended for patients at high immunological risk. Because steroids decrease CNI drug trough levels by increasing CYP3A5D enzyme, steroid withdrawal can predispose transplant recipients to CNI toxicity. In such cases, serum monitoring of CNI trough levels is mandatory.

Therapeutic Drug Monitoring
Therapeutic drug monitoring is essential for immunosuppressive drugs with narrow therapeutic index such as CNIs, MMF, and mammalian target of rapamycin (mTOR) inhibitors, but not in cases of steroids or azathioprine. Intracellular and circadian variations in tacrolimus levels can affect interpretation of trough levels; night-time dosing results in lower intracellular and serum concentrations, reflecting circadian metabolism.¹⁰ Oral ingestion of the drug could be more convenient for the patient and may promote therapy adherence, but through level will be decreased. This reduced tacrolimus exposure requires postprandial adjustments.¹¹ Because the area under the curve of suppository CNI is higher than other administrative routes, rectal tacrolimus can be clinically effective when oral administration is not possible, especially while patients are in the intensive care unit or in the postsurgical period.¹²

Impact of Age and Obesity on Pharmacokinetics

Age-related effects
Age-related reductions in drug absorption, distribution, metabolism, and excretion lead to increased susceptibility to drug toxicity. Older patients require lower CNI doses and faster steroid tapering and may benefit from mTOR-based CNI minimization.¹³ In general, for older patients, the recommendation is to leave out basiliximab induction therapy, as IL-2 effects are decreased in older patients. Although no significant differences in pharmacokinetics of mycophenolic acid between older and younger patients exist, a lower dose of CNI in older transplant recipients is needed. This need is secondary to decreased T-cell populations during aging. Among fragile older patients with increased numbers of complications, glucocorticoids could be tapered more rapidly than among younger patients. Older patients could have CNI replaced with mTOR inhibitors. This is because IL-2 production is decreased in the elderly, and tacrolimus could be less effective than shown in younger patients.

Obesity-related effects
Accelerated gastric emptying, higher cardiac output, and changes in enterohepatic recirculation in obesity have been implicated as factors that may lead to changes in drug absorption among obese transplant recipients. Obesity alters volume of distribution and increases risk of drug toxicity. Increased lymphatic collagen may impair lymphocyte trafficking, influencing immunologic responses to therapy.¹⁴

Biomarkers for Precision Immunosuppression

Categories and clinical utility of biomarkers
Biomarkers derived from blood, urine, and tissue aid in identifying candidates for immunosuppression minimization, predicting acute rejection, monitoring drug toxicity, and guiding weaning strategies. Key categories include transcriptomics (global gene expression profiling), proteomics (urine and tissue protein signatures for rejection risk), metabolomics (metabolic profiles indicating immune activation), and genomics and epigenomics (polymorphisms, microRNA, and methylation patterns influencing drug response).¹⁵ Molecular diagnostic platforms, such as molecular microscopy diagnostics, enable genome-wide assessment of 19 000 transcripts, refining diagnosis and treatment response.¹⁶ Monitoring of DSAs supports early detection of antibody-mediated rejection and evaluation of therapeutic response. Plasma cell-free DNA (dd-cfDNA) correlates with both antibody-mediated rejection and T-cell-mediated rejection, providing a way for noninvasive graft injury monitoring (Table 2).

Pharmacogenomics and Personalized Dosing
Impact of CYP3A5 and related genotypes Recipient and donor CYP3A5 genotype greatly influences tacrolimus metabolism and graft outcomes. Findings point toward the need to evaluate the effects of both recipient and donor CYP3A5 genotypes on renal function in organ transplant recipients who receive maintenance cyclosporine A immunosuppression.¹⁷ The recommended starting doses of CNI vary by genotype: those who express CYP3A4*22 require higher doses of tacrolimus (0.4 mg/kg/day) and those who do not express CYPA⁴*22 require lower doses (0.14 mg/kg/day) of tacrolimus.¹⁸ Hence, genetic polymorphisms could predict susceptibility to CNI nephrotoxicity in the long term.

Pediatric considerations
Combined CYP3A5 and UGT1A9 genotyping improves dosing accuracy for tacrolimus and MMF in pediatric recipients. Evidence has supported that these combination genotypes in pediatric recipients might be useful and advisable to guide tacrolimus and mycophenolic acid dosing and monitoring in children who undergo kidney transplant.¹⁹

Tolerance prediction algorithms
Genomic assays incorporating a 10-gene signature predict tolerance probability and may guide CNI minimization strategies.²⁰ A validated and highly accurate gene expression signature can be reliably used to identify patients suitable for reduction of immunosuppression, irrespective of the immunosuppressive drugs that they are receiving. The probability of tolerance was unchanged even after steroid withdrawal.

Artificial Intelligence Models for Transplant Precision
Artificial intelligence models offer new capabilities in donor-recipient matching, prediction of immunosuppressive drug response, graft survival forecasting, and integration of molecular, clinical, and demographic data into individualized dosing calculators. With future implementation of artificial intelligence models in transplantation, drug toxicity could be minimized and graft survival could be improved.

Conclusions
Precision immunosuppression integrates pharmacogenomics, biomarker-guided monitoring, TDM, and individualized risk stratification to optimize posttransplant outcomes. Although minimization of CNI is feasible in select low-risk populations, complete withdrawal remains risky for most recipients. Biomarker-driven approaches and advanced genomic profiling promise improved identification of candidates for tailored regimens. Leveraging of demographic, genetic, epigenetic, and environmental data through artificial intelligence-driven predictive models will further enhance immunosuppressive precision, reducing toxicity and improving long-term graft survival.