Thai Transplant Care Practice Guideline on Immunosuppressive Therapy for Adult Kidney Transplantation

ABSTRACT

The Thai Transplantation Society developed these clinical practice guidelines to establish a comprehensive standard for immunosuppressive therapy in adult kidney transplantation. While rooted in evidence‐based medicine, the objective of this document extends beyond local application, serving as a practical model for low‐to‐middle‐income countries, particularly within the Asia‐Pacific and Southeast Asian regions, where specific genetic profiles and resource limitations require tailored management strategies. This publication addresses a critical need in the field, as there has been no updated comprehensive international consensus on immunosuppression since the KDIGO Clinical Practice Guideline in 2009, over 17 years ago. These guidelines bridge this gap by synthesizing modern clinical data with practical applicability. The scope of the guidelines is extensive, covering all aspects of immunosuppression usage including induction, maintenance, therapeutic drug monitoring, and the treatment of rejection. Uniquely, this document addresses specific challenges relevant to resource‐limited settings, offering protocols for cost reduction through the use of generic drugs and the co‐administration of cytochrome P450 3A4 and 3A5 inhibitors to minimize dosage requirements. Furthermore, it provides distinct guidance for immunosuppression in special clinical settings, including management during periods of fasting, pregnancy, and malignancy. This guideline ultimately benefits clinicians by offering a pragmatic, updated reference that balances therapeutic efficacy with economic sustainability.

1. Strength of Recommendation and Quality of Evidence

1.1. Strength of Recommendation

• Strength of Recommendation “I” or “Recommended”: Evidence demonstrates that the measure or treatment provides benefit and is effective for the patient.

• Strength of Recommendation “II”: Evidence regarding the benefit and efficacy of the measure or treatment is conflicting.

  • ○
    Strength of Recommendation “IIa” or “Be Considered”: The weight of evidence favours the conclusion that the measure or treatment is beneficial and effective for the patient.
  • ○
    Strength of Recommendation “IIb” or “May Be Considered”: The evidence regarding the benefit and efficacy of the measure or treatment is not yet well established.

• Strength of Recommendation “III” or “Is Not Recommended”: Evidence suggests that the measure or treatment provides no benefit and, in some cases, may cause harm to the patient.

1.2. Quality of Evidence

• Level of Evidence A: High Quality. Further research is unlikely to change the confidence in the estimate of the effect. Sources include:

  • ○
    Multiple randomized controlled clinical trials (RCTs) with consistent results.
  • ○
    High‐quality meta‐analyses.
• Level of Evidence B: Moderate Quality. Further research may change the confidence in the estimate of the effect. Sources include:

  • ○
    A single randomized controlled clinical trial.
  • ○
    Large non‐randomized studies.
• Level of Evidence C: Low Quality. Further research is very likely to change the confidence in the estimate of the effect. Sources include:

  • ○
    Expert opinion accompanied by consensus based on clinical experience.
  • ○
    Retrospective studies.
  • ○
    Registries.

1.3. Levels of Recommendation Based on Context and Public Health Resources of Thailand

Recommendation weight	Definition	Term used
++	“Strongly recommend” represents a high level of confidence in the recommendation (should be performed/must do). The measure or treatment provides significant benefit and is cost‐effective and appropriate for the context and public health resources of Thailand.	Strongly recommend
+	“Recommend” represents a moderate level of confidence in the recommendation (should be performed/likely to do). The measure or treatment is beneficial to the patient and is likely cost‐effective and appropriate for the context and public health resources of Thailand.	Recommend
±	“Neither recommend nor against” represents a neutral level of confidence. There is insufficient evidence to support or oppose the measure or treatment regarding patient benefit. It may not be cost‐effective within the context and public health resources of Thailand, but does not increase harm to the patient. Therefore, the decision depends on other factors (may or may not do).	May consider
−	“Not recommend” represents a moderate level of confidence recommending against the action (should not do). The measure or treatment offers no benefit to the patient and is not cost‐effective (may be done in cases of necessity, but generally constitutes a “likely do not do”).	Not recommend
−	“Strongly not recommend” represents a high level of confidence recommending against the action (should not be performed/must not do) because the measure or treatment may cause harm or danger to the patient.	Strongly not recommend

2. Chapter 1: Introduction to Immunosuppressive Drugs

Solid organ transplantation offers improved survival and quality of life for patients with irreversible end‐stage organ failure. Despite these benefits, long‐term graft survival necessitates lifelong immunosuppression. Although modern immunosuppressive regimens have improved graft outcomes, they carry the risk of toxicity, specifically infection and malignancy, stemming from over‐immunosuppression. Therefore, these clinical practice guidelines were developed to address management strategies specific to the Thai population. Clinical decision‐making must be individualized, accounting for patient comorbidities and specific reimbursement coverage.

Immunosuppressive therapy is categorized into two phases: induction and maintenance. Induction therapy involves the administration of high‐intensity immunosuppression immediately post‐transplant to prevent acute rejection. Conversely, maintenance therapy employs reduced dosing to prevent long‐term allograft rejection while minimizing toxicity. The majority of these agents exert their effects through lymphocyte inhibition. The pharmacological profiles of immunosuppressants currently used in clinical practice are summarized in Table 1 [1, 2].

TABLE 1.

Immunosuppressants used in organ transplantation and mechanisms of action [1, 2].

Drug	Phase of use	Mechanism of action	Standard dose
Interleukin‐2 receptor antagonist (IL‐2RA): Basiliximab	Induction	Monoclonal antibody that binds to the α subunit of the interleukin‐2 receptor found on the surface of T‐lymphocytes, resulting in the inhibition of proliferation and differentiation of the cells.	Basiliximab: 20 mg intravenously on Day 0 and Day 4.
Anti‐thymocyte globulin (ATG) (specific to rabbit ATG (r‐ATG))	Induction	Polyclonal antibody that binds to various antigens on the surface of T‐lymphocytes, resulting in cell destruction via the complement system and apoptosis.	1–1.5 mg/kg/day intravenously for 3–9 days.
Methylprednisolone	Induction	Inhibits the function of T‐lymphocytes and B‐lymphocytes, including the inhibition of the production of various inflammatory mediators.	250–1000 mg/day intravenously for 3–5 days.
Rituximab	Induction	Binds to CD20 protein on the surface of B‐lymphocytes, resulting in cell death via the complement system and apoptosis.	375 mg/m2 or 200–500 mg intravenously.
Intravenous immunoglobulin (IVIG)	Induction	Binds to alloantibodies and leads to elimination; inhibits complement system activation; inhibits B‐lymphocyte activation; and reduces the production of various inflammatory mediators.	2 g/kg intravenously divided over 3–5 days, OR 0.1–0.15 g/kg after plasma exchange.
Calcineurin inhibitors (CNI)
Tacrolimus	Maintenance	Inhibits T‐lymphocyte activation.	0.1–0.2 mg/kg/day, administered in two divided doses (q12h)
Cyclosporine	Maintenance	Inhibits T‐lymphocyte activation.	8–10 mg/kg/day, administered in two divided doses (q12h)
Anti‐proliferative agents
Mycophenolic acid ‐ Mycophenolate mofetil (MMF) ‐ Enteric‐coated mycophenolate sodium (EC‐MPS)	Maintenance	Inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), which plays a key role in purine synthesis and lymphocyte proliferation.	MMF: 1000–2000 mg/day administered in two divided doses (q12h) EC‐MPS: 720–1440 mg/day administered in two divided doses (q12h)
Azathioprine	Maintenance	A purine analogue utilized in the DNA synthesis process, affecting RNA synthesis and inhibiting cell proliferation.	1–2 mg/kg/day once daily.
Others
Corticosteroids	Maintenance	Broad suppression of T‐ and B‐lymphocytes activation and inflammatory cytokine production	Prednisolone: 30–60 mg/day, gradually tapered to 2.5–5 mg/day.
Mammalian target of rapamycin (mTOR) inhibitors ‐ Sirolimus ‐ Everolimus	Maintenance	Binds to mTOR protein, inhibiting lymphocyte proliferation via a mechanism distinct from calcineurin inhibitors.	Sirolimus: 1–2 mg/day once daily. Everolimus: 1.5 mg/day administered in two divided doses (q12h)
Belatacept	Maintenance	Binds to CD80 and CD86 proteins on the surface of antigen‐presenting cells, inhibiting co‐stimulation of T‐lymphocytes and subsequently inhibiting B‐lymphocytes.	10 mg/kg intravenously on Days 1, 5, Weeks 2, 4, 8, and 12 post‐transplant, then 5 mg/kg every 4 weeks.

2.1. Side Effects of Immunosuppressants

The adverse event profiles of immunosuppressants vary by drug class and individual agent. Prompt recognition and management of these toxicities are essential for ensuring therapeutic success and preserving patient quality of life. Modifications to the regimen, such as dose reduction or agent substitution, must always be weighed against the risk of compromising immunosuppressive efficacy. Common adverse events associated with specific agents are summarized in Table 2 [1, 2].

TABLE 2.

Common side effects of each immunosuppressant [1, 2].

Immunosuppressant	Common side effects
IL‐2RA	Allergic reactions may occur, but incidence is very low.
r‐ATG	Fever, chills, joint pain (may be severe during the first administration), anaphylaxis, serum sickness, leukopenia, thrombocytopenia, opportunistic infections (especially Cytomegalovirus; CMV), post‐transplant lymphoproliferative disorder (PTLD).
Corticosteroids	Central obesity, diabetes mellitus, hyperlipidemia, osteoporosis, osteonecrosis (avascular necrosis), slow wound healing, cataracts, infection, myopathy, psychiatric disorders.
Intravenous immunoglobulin (IVIG)	Chills, facial flushing, joint pain while receiving the drug, acute kidney failure.
Rituximab	Fever, chills, hypotension while receiving the drug.
Calcineurin inhibitor in general	Nephrotoxicity, hyperkalemia, diabetes mellitus, hypertension, hyperlipidemia, elevated liver enzymes, infection, increased risk of cancer.
Tacrolimus	Diabetes mellitus (found more often than with cyclosporine), hair loss, nervous system side effects such as tremors, headache, numbness.
Cyclosporine	Hypertension, hyperuricemia, hyperlipidemia (found more often than with tacrolimus), hypertrichosis, gum hyperplasia, gynecomastia.
Mycophenolic acid	Gastrointestinal side effects (e.g., diarrhoea, nausea, vomiting, abdominal pain), anaemia, leukopenia, thrombocytopenia, opportunistic infections, congenital malformations (if used during pregnancy).
mTOR inhibitor	Proteinuria, slow wound healing, effects on the fetus during pregnancy, hyperlipidemia (found more often than with other groups), hyperglycemia, pneumonitis, acne, aphthous ulcers.
Azathioprine	Leukopenia, thrombocytopenia, abnormal liver enzymes.
Belatacept	Increased risk of PTLD.

2.2. Drug Interactions Affecting Immunosuppressant Levels

Maintenance of therapeutic immunosuppressant concentrations is critical for graft survival. Subtherapeutic exposure increases the risk of allograft rejection, while supratherapeutic levels may lead to complications such as nephrotoxicity or opportunistic infections. Since most immunosuppressants undergo hepatic metabolism, they are susceptible to interactions with concomitantly administered drugs. In some clinical scenarios, these interactions are leveraged therapeutically; for instance, azole antifungals, diltiazem, or verapamil may be coadministered with calcineurin inhibitors (CNIs) or mTOR inhibitors to ‘boost’ levels, thereby allowing for dose reduction and cost containment. However, the alteration or discontinuation of these interacting agents poses a significant risk of subtherapeutic exposure and subsequent rejection. Thus, a comprehensive understanding of these pharmacologic interactions is essential for the management of transplant recipients.

Both CNIs and mTOR inhibitors share a primary metabolic pathway via the hepatic cytochrome P450 3A (CYP3A) isoenzyme system. Consequently, co‐administration of these classes may result in competitive metabolic inhibition and elevated serum concentrations of both agents. Furthermore, any external agent that modulates CYP3A activity is likely to impact the pharmacokinetics of both CNIs and mTOR inhibitors similarly. A summary of drugs affecting these interactions is provided in Table 3 [1, 3, 4].

TABLE 3.

Drugs affecting CNI and mTOR inhibitor levels [1, 3, 4].

Effect on drug level	Drug group or type
Potent inhibitor (Increases AUC ≥ 5‐fold)	‐ Clarithromycin ‐ Azole antifungal group: itraconazole, ketoconazole, posaconazole, voriconazole ‐ Protease inhibitors: lopinavir/ritonavir, nelfinavir, saquinavir, indinavir, ritonavir, ritonavir/nirmatrelvir, darunavir/cobicistat ‐ Nefazodone ‐ Grapefruit juice
Moderate inhibitor (Increases AUC ≥ 2 to < 5‐fold)	‐ Erythromycin ‐ Azole antifungal group: fluconazole, isavuconazole ‐ Protease inhibitors: atazanavir, amprenavir, fosamprenavir ‐ Calcium channel blockers: diltiazem, verapamil ‐ Imatinib ‐ Ciprofloxacin
Weak inhibitor (Increases AUC ≥ 1.25 to < 2‐fold)	‐ Alprazolam ‐ Amlodipine ‐ Atorvastatin ‐ Amiodarone, ranolazine ‐ Azithromycin, isoniazid ‐ Bicalutamide ‐ Cilostazol ‐ Fluoxetine ‐ Oral contraceptive pill ‐ Ranitidine, vonoprazan
Strong inducer (Decreases AUC ≥ 80%)	‐ Carbamazepine, phenytoin, phenobarbital ‐ Rifampin, rifabutin ‐ St. John's wort
Moderate inducer (Decreases AUC 50%–80%)	‐ Bosentan ‐ Efavirenz, etravirine
Weak inducer (Decreases AUC 20%–50%)	‐ Pioglitazone ‐ Prednisolone

2.3. Additional Interactions for Other Agents

Unlike CNIs and mTOR inhibitors, mycophenolate is not metabolized via the cytochrome P450 system; therefore, it is distinct from the CYP3A‐mediated interaction profile. However, specific agents can significantly compromise mycophenolic acid (MPA) exposure:

• Cyclosporine reduces MPA exposure by inhibiting enterohepatic recirculation.

• Antacids, cholestyramine, sevelamer, and ferrous sulfate decrease intestinal bioavailability. These agents should not be administered simultaneously with mycophenolate.

• Rifampin induces multidrug resistance‐associated protein 2 (MRP‐2) and UDP‐glucuronosyltransferases (UGTs), accelerating MPA clearance and reducing active serum concentrations.

Although utilized less frequently in modern regimens, azathioprine carries a critical interaction with allopurinol (a xanthine oxidase inhibitor). Co‐administration blocks azathioprine metabolism, precipitating severe myelotoxicity, including profound leukopenia and thrombocytopenia. Consequently, this combination should be avoided. If co‐administration is clinically mandatory, the azathioprine dosage must be reduced to 25%–30% of the standard dose to mitigate toxicity.

3. Chapter 2: Induction Therapy

1. It is strongly recommended to use a combination of multiple immunosuppressive agents to prevent acute rejection, initiated prior to or during the kidney transplantation surgery [++, I, A].

2. It is strongly recommended to use methylprednisolone as one component of induction therapy [++, IIa, B].

3. It is strongly recommended to use biologic agents for induction therapy in kidney transplant recipients.

   • 3.1
     It is strongly recommended to use an interleukin‐2 receptor antagonist (IL‐2RA) as the first‐line drug for induction therapy [++, I, B].
   • 3.2
     It is recommended to use lymphocyte‐depleting agents in patients at high or very high risk for rejection [+, IIb, B].
   • 3.3
     Consideration may be given to withholding biologic induction therapy in patients at low risk for rejection [±, IIb, B].
   • 3.4
     The selection of induction therapy agents should consider efficacy and side effects, particularly infection risks and infection prophylaxis [+, IIb, C].

4. It is strongly recommended to perform desensitization prior to transplantation in patients at very high risk for rejection, depending on antibody levels and physician discretion [++, I, B].

3.1. Rationale and Evidence

These clinical practice guidelines recommend the administration of induction therapy based on the level of rejection risk. Risk is categorized into four levels: Low, Moderate, High, and Very High. Considerations for the use of biologic agents and desensitization are presented in Table 4.

TABLE 4.

Risk of kidney allograft rejection and recommendation on induction therapy [5, 6, 7, 8, 9].

Risk level	Details	IL‐2RA	ATG	Desensitization
Low risk	First kidney transplant recipient from a living donor with identical HLA a AND a PRA of 0.	±	−	−
Moderate risk	Kidney transplant recipient from a living donor who is not HLA identical or has a PRA between 0% and 49%, OR a recipient from a deceased donor not classified as high or very high risk.	+	±	−
High risk	Patient with a history of prior organ transplantation, OR PRA (peak or current) ≥ 50%, OR history of detectable donor‐specific antibody (DSA).	+	+	−
Very high risk	Patient with detectable DSA, OR a positive crossmatch, OR ABO‐incompatible kidney transplantation. b	±	+	+

^a HLA identical: Defined as matching HLA typing across all HLA antigens from a blood‐related donor.

^b In cases of ABO‐incompatible kidney transplantation, basiliximab may be considered as a substitute for ATG.

3.2. Administration Protocols

Methylprednisolone is another immunosuppressant used in induction therapy. It is administered intravenously at a dose of 250 to 1000 mg/day for 3 to 5 days, starting on the day of kidney transplantation surgery. Subsequently, the dosage is tapered to oral prednisolone.

Basiliximab is administered intravenously at a dose of 20 mg for two doses. The first dose is given prior to the kidney transplantation surgery, and the second dose is given on Day 4 post‐transplantation.

Rabbit anti‐thymocyte immunoglobulin (r‐ATG) is administered via a large vein or central venous line at a dose of 1 to 1.5 mg/kg/day for 3 to 9 days post‐transplantation (the recommended total cumulative dose is 3 to 13.5 mg/kg). Patients should receive premedication with corticosteroids, paracetamol, and antihistamines approximately 30 min to 1 h prior to r‐ATG administration to reduce infusion‐related reactions. Patients should receive CMV prophylaxis after receiving r‐ATG. However, retrospective studies indicate that using low‐dose r‐ATG (total dose of 2 mg/kg) is effective in preventing organ rejection without differing significantly from basiliximab, and does not increase the risk of overall infections, including CMV infection [10].

Comparative studies between basiliximab and r‐ATG found that r‐ATG is associated with a lower incidence of graft rejection and may improve graft survival rates, particularly in recipients of deceased donor kidneys [11]. However, among lymphocyte‐depleting agents, there is an increased risk of CMV and BK virus infections, as well as leukopenia and thrombocytopenia [7, 12].

In cases where the patient is at very high risk for organ rejection, desensitization should be performed prior to kidney transplantation. Pre‐transplant desensitization processes may include various methods such as plasmapheresis, double filtration plasmapheresis, immunoadsorption, intravenous immunoglobulin (IVIG) administration, and rituximab administration. The number of plasmapheresis sessions depends on the quantity of alloantibody or ABO antibody requiring removal. Protocols for IVIG and rituximab administration may vary by institution [13, 14, 15]. Patients should receive premedication with corticosteroids, paracetamol, and antihistamines prior to high‐dose IVIG and prior to rituximab administration.

4. Chapter 3: Maintenance Immunosuppression

1. It is strongly recommended to use tacrolimus, mycophenolic acid (MPA), and corticosteroids as the standard immunosuppressive regimen for kidney transplantation [++, I, A].

2. It is recommended to use an mTOR inhibitor in combination with tacrolimus and corticosteroids as an alternative regimen in patients with low to moderate risk of rejection [+, IIa, B].

3. Consideration may be given to using cyclosporine as a substitute for tacrolimus as an alternative regimen in cases where side effects occur or reduction of tacrolimus‐related side effects (e.g., hair loss or uncontrolled diabetes) is required [±, IIb, B].

4. It is not necessary to switch from cyclosporine to tacrolimus in kidney transplant recipients who have been receiving cyclosporine long‐term and are stable, with normal renal function and no proteinuria [+, IIb, C].

5. In cases where thrombotic microangiopathy (TMA) or posterior reversible encephalopathy syndrome (PRES) occurs, suspected to be caused by immunosuppressants (which can be caused by various drugs such as tacrolimus, cyclosporine, or mTOR inhibitors), the following management guidelines should be considered [+, IIa, C]:

   • If blood drug levels are high, consider dose reduction.
   • If blood drug levels are within the target range, consider switching the type of immunosuppressant.

4.1. Rationale and Evidence

The current standard regimen consists of a CNI, an antimetabolite, and corticosteroids, which have distinct mechanisms of action for preventing organ rejection. Tacrolimus is the primary CNI, and MPA is the primary antimetabolite currently used. The use of this standard regimen is based on a large randomized controlled trial, the ELITE‐Symphony study [16], which included 1645 transplant recipients from 15 countries. Patients were randomized to receive one of four regimens: standard‐dose cyclosporine (target trough level [C₀] 100–200 ng/mL), low‐dose cyclosporine (C₀ 50–100 ng/mL), low‐dose tacrolimus (C₀ 3–7 ng/mL), and low‐dose sirolimus (C₀ 4–8 ng/mL). The definition of “low‐dose” in this study referred to doses lower than the standard doses commonly used at that time; for instance, the tacrolimus C₀ target of 3–7 ng/mL was considered low compared to the standard era target of 10–15 ng/mL. All patient groups in this study received MMF 2 g/day combined with prednisolone and daclizumab as induction therapy, except for the high‐dose cyclosporine group which did not receive any induction therapy. The study results showed that the group receiving tacrolimus combined with MMF and corticosteroids had better kidney allograft function, a lower incidence of acute rejection, higher graft survival rates, and lower treatment failure rates compared to groups receiving other immunosuppressive regimens at 1 to 3 years of follow‐up [16, 17].

An alternative standard regimen is the use of an mTOR inhibitor (everolimus or sirolimus) combined with tacrolimus and corticosteroids, based on the TRANSFORM study (Transplant Efficacy and Safety Outcomes with an Everolimus‐based regimen). This was the largest RCT in kidney transplant recipients to date, including 2226 patients from 186 hospitals [18]. Patients were randomized to receive either a standard‐dose CNI combined with MPA (tacrolimus level C₀ 5–8 ng/mL or cyclosporine level C₀ 200–300 ng/mL) or a reduced‐dose CNI regimen (de novo CNI minimization) combined with everolimus (tacrolimus level C₀ 2–4 ng/mL or cyclosporine level C₀ 25–50 ng/mL combined with everolimus level C₀ 3–8 ng/mL). Both groups received basiliximab induction therapy. The results showed that the group using everolimus combined with reduced‐dose CNI had an incidence of biopsy‐proven acute rejection and proportion of patients with eGFR < 50 mL/min/1.73 m² at 12 months post‐transplant that was non‐inferior to the group receiving standard‐dose CNI. Simultaneously, the benefit of using an mTOR inhibitor with reduced CNI was a lower incidence of CMV and BK virus infections. However, the group using mTOR inhibitor combined with reduced CNI had a higher rate of drug discontinuation due to side effects. These results were consistent at both 12‐ and 24‐months post‐transplant [18, 19]. Nevertheless, long‐term results still require further study, particularly regarding DSA monitoring (which was not performed in all patients in this study). Furthermore, patients classified as high risk for rejection (according to the definitions of participating centers, such as having PRA higher than the specified threshold) were not included in this study; therefore, the use of mTOR inhibitors with reduced‐dose CNI in patients at high risk for rejection still requires further study.

Systematic review and meta‐analysis data found that tacrolimus reduced the rate of graft loss between 6 months and 3 years post‐transplant by 44% compared to cyclosporine. Additionally, tacrolimus reduced the rate of acute rejection at 1 year post‐transplant by 51% compared to cyclosporine [20]. However, the use of tacrolimus increased the incidence of post‐transplant diabetes mellitus (PTDM), hair loss, tremors, and gastrointestinal side effects more than cyclosporine [20, 21]. Data from the Thai Transplant Registry confirmed that tacrolimus use is associated with reduced graft loss and patient mortality when compared with cyclosporine [22].

Consideration for switching the CNI drug from tacrolimus to another agent should have clear indications, such as cases where the patient experiences severe side effects from tacrolimus even if drug levels are within the standard range, such as thrombotic microangiopathy (TMA) and posterior reversible encephalopathy syndrome (PRES), which are potentially life‐threatening conditions if not resolved [23, 24]. In such cases, it is recommended to switch tacrolimus to cyclosporine or a drug in the mTOR inhibitor group. However, there is insufficient evidence to recommend whether cyclosporine or an mTOR inhibitor should be the first choice in this situation. The decision should consider the risk of rejection and current renal function. It should be noted that cyclosporine and mTOR inhibitors can also cause TMA and PRES [24, 25]. In patients who have received cyclosporine for a long time and are stable, with normal renal function and no proteinuria, it is not necessary to switch from cyclosporine to tacrolimus. Surveillance allograft biopsy and/or DSA monitoring may be useful in helping decide to adjust the immunosuppressive regimen in this group of patients.

For some patients who cannot tolerate the side effects of tacrolimus, or are anticipated to be intolerant (e.g., hair loss or uncontrolled blood sugar), consideration may be given to switching from tacrolimus to cyclosporine. Patients should be informed about the lower efficacy of cyclosporine in preventing allograft rejection. Therefore, patients selecting cyclosporine combined with MPA and corticosteroids should be those at low or moderate risk of rejection. Additionally, the use of cyclosporine may increase the risk of CNI nephrotoxicity more than tacrolimus [26, 27, 28, 29, 30] and may result in poorer long‐term renal function [31]. One consideration when using cyclosporine with MPA is drug–drug interaction; cyclosporine can inhibit the enterohepatic recirculation of MPA, resulting in lower blood MPA levels in patients receiving cyclosporine compared to those receiving tacrolimus, which may affect efficacy in preventing acute rejection or may necessitate an increased MPA dose to maintain sufficient immunosuppression [32, 33].

Recommended immunosuppressant levels are shown in Table 5, which aggregates data from treatment protocols and drug levels used in past studies, including international recommendations [16, 17, 18, 19, 34, 35, 36]. Application of this data to the Thai population should be considered as appropriate, based on the recommendations in Table 5 combined with drug side effects occurring in each individual patient. One observation regarding MPA use is that the Asian population may not require as high a dose of MPA as the Caucasian population to achieve blood levels within the therapeutic range (AUC 30–60 mg·h/L).

TABLE 5.

Recommended levels and doses of immunosuppressants for maintenance therapy.

Time post‐transplant	TAC + MPA regimen		CsA + MPA regimen			TAC or CsA + mTORi regimen				Prednisolone
	TAC C0 (ng/mL)	MPA a (g/day)	CsA C0 (ng/mL)	CsA C2 (ng/mL)	MPA b (g/day)	TAC C0 (ng/mL)	CsA C0 c (ng/mL)	CsA C2 (ng/mL)	mTORi C0 (ng/mL)
0–3 months	7–12	1–2	150–300	800–1200	1.5–2	4–7	100–150	600–800	4–8	Administration guidelines vary by transplant center. May start at 1 mg/kg/day, then gradually taper down to 2.5–5 mg/day.
3–6 months	6–10	1–1.5	100–200	600–1000	1.5–2	2–5	50–100	300–600	4–8
6 months onward	5–8	1–1.5	80–150	500–800	1–2	2–4	25–50	150–200	4–8

Abbreviations: C₀, pre‐dose concentration; CsA, cyclosporine A; mTOR inhibitor, mammalian target of rapamycin inhibitor (everolimus or sirolimus); TAC, tacrolimus.

^a MPA dose in the form of mycophenolate mofetil (MMF): MMF 250 mg is equivalent to enteric‐coated mycophenolate sodium (EC‐MPS) 180 mg.

^b Due to cyclosporine inhibiting the enterohepatic recirculation of MPA, it is recommended to consider using MPA without reducing the dose.

^c In cases of cyclosporine combined with the mTOR inhibitor group, it is recommended to follow cyclosporine C₀ levels due to a reduction in the number of blood draws required for monitoring.

For immunosuppressive regimens consisting of an mTOR inhibitor and MPA used in patients who cannot tolerate CNI side effects, it is recommended to maintain mTOR inhibitor levels in the range of 6–10 ng/mL combined with MPA at a dose equivalent to MMF 1.0–1.5 g/day [37, 38, 39].

5. Chapter 4: Immunosuppressive Drug Monitoring

1. Calcineurin Inhibitor (CNI)

   • 1.1
     It is strongly recommended to measure CNI blood concentrations [++, I, B] in the following conditions:

     • Every 2–3 days during the postoperative period until the target is reached, and then at least every 3–6 months. [++, IIa, C]
     • Whenever immunosuppressive medication or dosage is changed, or there are conditions affecting blood concentrations. [++, IIa, C]
     • Whenever the kidney allograft function declines. [++, IIa, C]
     • Whenever there is allograft rejection. [++, IIa, C]
     • Whenever an adverse effect or toxicity is suspected. [++, IIa, C]
   • 1.2
     It is strongly recommended to measure CNI concentrations as a single time point level. [++, IIa, B]

     • It is recommended to monitor tacrolimus blood concentrations using the trough (C₀) level. [++, IIa, B]
     • It is recommended to monitor cyclosporine blood concentrations using the trough (C₀) level [++, IIb, C] or the 2‐h post‐dose (C₂) level. [++, IIa, C]
   • 1.3
     Measuring area under the concentration‐time curve (AUC) or abbreviated AUC of CNI using trapezoidal rule or limited sampling strategies may be considered [±, IIb, C] in the following conditions:

     • Allograft rejection occurs or is suspected, while the C₀ level is within the target range.
     • CNI toxicity occurs or is suspected while the C₀ level is within the target range.
     • Delayed absorption is suspected
   • 1.4
     Pharmacogenomic study for cytochrome P450 3A5 (CYP3A5) may be considered to determine the starting dosage of CNI, but it is not necessary. [±, IIb, C]

5.1. Rationale and Evidence

Calcineurin Inhibitors (CNIs) are the main immunosuppressive medications for kidney transplant recipients. Because of their narrow therapeutic index properties, they require therapeutic drug monitoring (TDM) [40, 41]. Especially during the immediate postoperative period, TDM should be performed every 2–3 days [34]. Whole blood samples should be used for measuring CNI levels because CNI is primarily distributed in red blood cells, and Ethylenediaminetetraacetic acid (EDTA) is the preferred anticoagulant. The area under the concentration‐time curve is the most precise TDM. However, it requires multiple blood samples at different time intervals, which is not practical. The trough (C₀) concentration of tacrolimus (TAC), measured as a single time point, is more practical and exhibits a good correlation with AUC_(0–12), providing a coefficient of determination (r ²) of 0.82–0.94 [35, 42, 43]. Furthermore, most clinical studies use the C₀ level as a predictor of transplant outcomes, both efficacy and adverse events. Thus, the C₀ level is recommended to monitor TAC exposure [40, 41]. Nevertheless, if the C₀ is suspicious not a good representative of the drug exposure (e.g., allograft rejection or CNI toxicity happened while C₀ level is within the target range), AUC_(0–12) measurement may be considered, with a target of 100–150 ng·hr/mL [41, 42]. AUC can be measured by using the trapezoidal rule or limited sampling strategies (LSS), as shown in Table 6.

TABLE 6.

Regression equations estimating AUC by multiple time points of TAC concentration.

References	Time point	Regression equations	r 2
AUC (0–12) of TAC for immediate‐release TAC
Tiankanon et al. [44]	C0, C2, C4	1.90 (C0) + 2.05 (C2) + 5.88 (C4) + 10.54	0.95
	C2, C4	2.07 (C2) + 6.21 (C4) + 14.65	0.96
Wong et al. [45]	C0, C2, C4	1.2 (C0) + 2.4 (C2) + 5.6 (C4) + 13.3	0.93
	C2, C4	2.4 (C2) + 5.9 (C4) + 16.2	0.93
AUC (0–24) of TAC for prolonged‐release TAC
Tiankanon et al. [44]	C0, C6, C12	0.97 (C0) + 5.79 (C6) + 18.97 (C12)—4.26	0.98
	C0, C4, C6	10.13 (C0) + 3.42 (C4) + 8.02 (C6) + 24.59	0.94
	C0, C4	11.64 (C0) + 8.9 (C4) + 32.68	0.92

Abbreviations: AUC, area under the concentration‐time curve; r ², coefficient of determination; TAC, tacrolimus.

While the C₀ level of cyclosporine (CsA) provides a fair correlation with AUC (r ² = 0.52–0.65), the 2‐h post‐dose (C₂) level performs better with r ² = 0.87–0.89 [35, 46]. The C₂ level is preferred for monitoring CsA exposure, especially in the immediate postoperative period, with a target range of 800–1500 ng/mL [35, 47]. However, most studies use C₀ as a predictor of clinical outcomes. Moreover, there is no difference in the incidence of allograft rejection or failure using C₀, C₂, or AUC_(0–4) monitoring. The C₀ is still acceptable to monitor CsA exposure [40]. In case of rejection or CNI toxicity occurs while the single time point drug concentration is within the target range, or delayed drug absorption is suspected, the other markers, either 6‐h post‐dose (C₆) level or AUC, may be considered. The target of full dose‐interval AUC_(0–12) is 9500–11 500 ng·hr/mL, and that for abbreviated AUC_(0–4) is 4400–5500 ng·hr/mL [47]. Regression equations estimating AUC for CsA are shown in Table 7.

TABLE 7.

Regression equations estimating AUC by multiple time points of CsA concentration.

References	Time point	Regression equations	r 2
AUC (0–12) for CsA
Yang et al. [48]	C0, C1, C2	9.171 (C0) + 0.868 (C1) + 2.144 (C2) + 273.7	0.99
	C0, C2, C6	5.437 (C0) + 2.211 (C2) + 4.155 (C6) + 551.2	0.98
	C0, C2	9.217 (C0) + 2.714 (C2) + 619.2	0.97
Abbreviated AUC (0–4) for CsA
David‐Neto et al. [49]	C0, C2	2.6 (C0) + 2.3 (C2) + 215	0.90

Abbreviations: AUC, area under the concentration‐time curve; CsA, cyclosporine; r ², coefficient of determination.

CNI is mainly metabolized in the liver by cytochrome P450 3A4 and 3A5 (CYP3A4 and CYP3A5). Patients expressing CYP3A5 (presence of at least one allele of CYP3A5*1) typically have a lower drug concentration at the same dosage compared to those who are CYP3A5 non‐expressers (homozygous CYP3A5*3/*3). Some recommendations suggest increasing the tacrolimus dosage by 30%–50% for CYP3A5 expressers if a pharmacogenomic study is conducted [41, 43].

• 2
  Mycophenolic Acid (MPA)

  • 2.1
    Measuring AUC_(0–12) of MPA may be considered [±, IIb, C] in the following conditions:

    • During the early postoperative period in patients at high risk of acute rejection. [±, IIb, C]
    • In patients with high body weight, fixed doses may be inadequate. [±, IIb, C]
    • Whenever an immunosuppressive medication regimen is changed, especially in the setting of CNI withdrawal. [±, IIb, C]
    • Whenever patients have some conditions or other drugs co‐administration altering drug concentration. [±, IIb, C]
    • Whenever allograft rejection occurs, or de‐novo donor‐specific antibody is detected. [±, IIb, C]
    • Whenever an adverse effect or toxicity is suspected. [±, IIb, C]
  • 2.2
    It is not recommended to monitor trough level (C₀) of MPA. [−, IIb, C]

5.2. Rationale and Evidence

Due to its complicated pharmacokinetics, the manufacturer and general practice recommend fixed‐dosing administration of mycophenolic acid (MPA). Non‐linear absorption kinetics, enterohepatic circulation, and inter‐ and intrapatient variability affect MPA exposure. Combination with tacrolimus and cyclosporine yields different results; specifically, tacrolimus increases the AUC of MPA, while cyclosporine decreases it. There is insufficient evidence to support the notion that MPA monitoring improves transplant outcomes [50, 51]. Furthermore, the trough (C₀) concentration of MPA provides a poor to fair correlation with AUC (r ² = 0.16–0.63). Thus, it is not recommended to use C₀ for monitoring [52]. Monitoring of MPA may be considered in patients with a high immunologic risk, whenever certain conditions or co‐administered drugs that may alter drug concentration are present, or whenever CNI is withdrawn [51, 53]. If considered, the full dose‐interval AUC_(0–12) should be used, estimated by limited sampling strategies, together with maximum a posteriori Bayesian estimation (MAP‐BE) or multiple linear regression. At least 2 time point measures for mycophenolate mofetil (MMF), and at least 3–4 time point measures for enteric‐coated mycophenolate sodium (EC‐MPS) are required. The target AUC_(0–12) of 30–60 mg·hr/L is recommended [52]. Regression equations estimating AUC for MPA are shown in Table 8. MPA concentration can be measured in either EDTA plasma, heparinized plasma, or serum, depending on the laboratory services.

TABLE 8.

Regression equations estimating AUC by multiple time points of MPA concentration.

References	Time point	Regression equations	r 2
AUC (0–12) of MPA for MMF, when combined therapy with tacrolimus
Larpparisuth et al. [54]	C0, C0.5, C1.5, C4	3.64 (C0) + 0.82 (C0.5) + 1.98 (C1.5) + 3.8 (C4) − 0.25	0.95
Pawinski et al. [55]	C0, C0.5, C2	6.49 (C0) + 0.76 (C0.5) + 2.43 (C2) + 7.75	0.86
Miura et al. [56]	C0, C2, C4	0.26 (C0) + 2.06 (C2) + 3.82 (C4) + 20.38	0.69
Barraclough et al. [57]	C0, C4	5.68 (C0) + 4.81 (C4) + 8.55	0.80
AUC (0–12) of MPA for MMF, when combined therapy with cyclosporine
Barraclough et al. [57]	C0, C1, C3, C6	3.77 (C0) + 1.33 (C1) + 1.68 (C3) + 2.96 (C6) + 9.02	0.84
AUC (0–12) of MPA for EC‐MPS, when combined therapy with tacrolimus
Jia et al. [58]	C0, C3, C4	8.029 (C0) + 0.592 (C3) + 1.786 (C4) + 6.629	0.91
Sánchez Fructuoso et al. [59]	C1, C2, C4	0.87 (C1) + 0.68 (C2) + 7.85 (C4) + 15.99	0.71
AUC (0–12) of MPA for EC‐MPS, when combined therapy with cyclosporine
Capone et al. [60]	C0, C1, C2	13.784 (C0) + 1.002 (C1) + 1.192 (C2) + 35.064	0.85

Abbreviations: AUC, area under concentration‐time curve; EC‐MPS, enteric‐coated mycophenolate sodium; MMF, mycophenolate mofetil; MPA, mycophenolic acid; r ², coefficient of determination.

• 3
  Mammalian target of Rapamycin (mTOR) inhibitor

  • 3.1
    It is strongly recommended to monitor mTOR inhibitor blood concentrations using the trough (C₀) level. [++, IIa, B].
  • 3.2
    It is strongly recommended to monitor the C₀ level at least 4–6 days for everolimus, and 5–7 days for sirolimus after initiation or dosage adjustment. [++, IIa, C].

5.3. Rationale and Evidence

Because mTOR inhibitor has a narrow therapeutic index, TDM is required. Like CNI, it is mainly distributed in the red blood cells; EDTA blood should be used for drug concentration measurement. Due to a good correlation with AUC, the trough (C₀) level is recommended for monitoring drug exposure [61, 62]. mTOR inhibitors have a long half‐life and high volume of distribution; therefore, they require at least 4–6 days for everolimus [61] and 5–7 days for sirolimus [63] to reach steady‐state concentrations. Thus, more frequent monitoring than the aforementioned should not be performed.

6. Chapter 5: Immunosuppressive Regimen for Special Conditions

6.1. Infection

1. It is recommended to adjust or reduce immunosuppressants in cases of infection, based on the type and severity of the disease in each individual patient [+, IIa, C].

2. Guidelines for adjusting immunosuppressants in cases of specific infections, such as CMV or BK virus, can be followed according to the international guidelines for transplant recipients with infections

6.2. Rationale and Evidence

Currently, there are no antiviral drugs with proven efficacy to inhibit BK virus replication. Treatment for BK virus infection in transplant recipients therefore focuses on the optimization of immunosuppression, with the objective of allowing T‐lymphocytes specific to the BK virus to recover and control the infection. The primary strategy involves a stepwise reduction of maintenance immunosuppression, starting with halving the mycophenolic acid dosage, lowering CNI trough levels, and minimizing prednisolone. If the viral load remains persistently high despite these initial reductions, switching from mycophenolic acid to an mTOR inhibitor can be considered while continuing to reduce calcineurin inhibitor trough levels. For CMV infection treatment, the strategy consists of reducing immunosuppressants to an appropriate level to allow the immune system specific to the infection to recover, in conjunction with antiviral administration. Further details regarding immunosuppressant adjustment and antiviral administration can be studied in the guidelines for transplant recipients with infections.

6.3. Malignancy

1. It is recommended to adjust immunosuppressants in patients with cancer, considering the following factors [+, IIa, C]:

   • Type and stage of cancer
   • Cancer stimulation by immunosuppressants.
   • Treatment for each specific cancer
   • Risk of rejection.
   • Drug–drug interactions between immunosuppressants and cancer therapies.

2. Consider reducing immunosuppressant levels, especially for cancers associated with viral infections, such as Post‐Transplant Lymphoproliferative Disorder (PTLD) and Kaposi's sarcoma (refer to additional guidelines for infection treatment post‐transplant).

3. It is recommended to use mTOR inhibitors combined with a reduction in other immunosuppressants, particularly in patients with Kaposi's sarcoma or non‐melanoma skin cancer [+, IIa, B].

6.4. Rationale and Evidence

Post‐kidney transplantation, the incidence of cancer is found to increase compared to the general population (Table 9). Beyond general risk factors for cancer, there are specific risk factors related to chronic kidney disease. Kidney transplantation results in the administration of immunosuppressants which affect the function of T‐lymphocytes, dendritic cells, and NK cells in eliminating impaired cells and also affects the occurrence of cancers associated with viral infections such as PTLD and Kaposi's sarcoma.

TABLE 9.

Standardized incidence ratio of post‐transplant cancer.

Standardized incidence ratio (SIR)	Type of cancer
High	Kaposi's sarcoma, vaginal, non‐Hodgkin lymphoma, non‐melanoma skin cancer
Moderate	Lung, colon, cervix, stomach, liver
No increased risk	Breast, prostate

Before patients undergo kidney transplantation, they should be screened for various cancers according to the screening recommendations for the general population by age and gender. However, in cases where patients develop cancer after kidney transplantation, they should receive standard cancer treatment combined with consideration of immunosuppressant reduction, particularly in viral‐associated cancers like PTLD and Kaposi's sarcoma, and surveillance for increased risk of organ rejection.

It has been found that mTOR inhibitors can inhibit the growth of T‐cells and B‐cells via the mTOR pathway, vascular endothelial growth factor (VEGF), and angiogenesis, which may result in the cure of Kaposi's sarcoma and reduce the chance of recurrence. However, side effects that may arise from this drug class should be monitored. Neither prednisolone nor MPA has been found to increase the risk of developing cancer post‐transplantation.

Patients with the following history: long‐term dialysis, family history of kidney cancer, acquired cystic kidney disease, or analgesic nephropathy should undergo screening for renal cell carcinoma by ultrasonography due to a high risk of developing cancer.

6.5. Elderly Patients

1. Consider using standard immunosuppressive regimens, adjusting levels and dosages to be appropriate for each individual patient, taking into account the risk of rejection and side effects from immunosuppressants [±, IIb, C].

6.6. Rationale and Evidence

Generally, as patients age (from 65 years and above), immune system function tends to decline, resulting in a reduced risk of organ rejection. Conversely, the risk of infection and cancer increases, including the chance of adverse drug reactions. Therefore, consideration of reducing the potency of immunosuppressants in this patient group may be an appropriate option [64, 65] to help reduce side effects.

6.7. Steroid Withdrawal Regimen

1. In cases where corticosteroid withdrawal is considered, it should be performed within 1 week after kidney transplantation surgery, after the patient has received appropriate induction therapy, specifically in patients with low risk for rejection and/or the following conditions [±, IIb, B]:

   • Severe osteoporosis.
   • Avascular necrosis in bone that has not yet undergone surgery

2. If the kidney transplant recipient has received corticosteroids for longer than 1 week, it is recommended to continue corticosteroids rather than considering withdrawal [±, IIb, C].

3. In patients at risk for recurrent glomerular disease post‐transplant, consideration should be given to avoiding corticosteroid withdrawal to prevent disease recurrence [±, IIb, C].

6.8. Rationale and Evidence

Corticosteroids act by inhibiting nuclear factor kappa B (NF‐κB), which is a key factor in the function of cytokines and T‐cells; thus, corticosteroids can help prevent organ rejection post‐transplant. However, the use of this drug class has several side effects, such as weight gain, osteoporosis, cataracts, growth retardation in children, hypertension, hyperglycemia, hyperlipidemia, and increased risk of infection.

In practice, corticosteroid administration begins immediately after kidney transplantation, followed by gradual dose tapering or consideration of withdrawal [66, 67], depending on immunological risk and risk of side effects. Stopping corticosteroids after more than 1 week post‐transplant may increase the risk of future rejection. Therefore, if a patient has received corticosteroids for longer than 1 week post‐surgery, it is recommended to continue corticosteroids at a low dose (not exceeding 5 mg/day). In cases where the cause of kidney failure is glomerulonephritis, particularly IgA nephropathy, consideration should be given to continuous corticosteroid administration to prevent recurrent glomerular disease [68].

6.9. Pregnancy and Fertility

1. It is recommended that patients can become pregnant at least 1 year after kidney transplantation, provided the patient has stable kidney function (serum creatinine < 1.5 mg/dL), proteinuria less than 1 g/day, and no organ rejection in the 6 months prior to pregnancy [++, IIb, C].

2. It is recommended to switch drugs in the MPA group to other immunosuppressants safe for pregnancy at least 6 weeks prior to planning pregnancy [+, IIa, A].

3. It is recommended to switch drugs in the mTOR inhibitor group to other immunosuppressants safe for pregnancy at least 12 weeks prior to planning pregnancy [+, IIa, B].

4. Drugs in the CNI group, azathioprine, and corticosteroids can be administered during pregnancy [+, IIa, C].

5. It is not necessary to stop MPA in male patients desiring children [+, IIb, B].

6. It is recommended to switch mTOR inhibitors to other drugs that do not affect fertility in male patients desiring children [+, I, B].

6.10. Rationale and Evidence

Transplant recipients can become pregnant when their kidney function is within normal criteria. They should have creatinine less than 1.5 mg/dL [69] and should be at least 1‐year post‐transplant to reduce the chance of rejection or infection. Additionally, prior to pregnancy, there should be no significant proteinuria or organ rejection. Pregnancy post‐transplant carries a high risk of hypertension, preeclampsia, preterm birth, low birth weight infants, and may require caesarean section.

MPA and mTOR inhibitors may cause fetal abnormalities during organogenesis. Therefore, stopping drugs that may affect the fetus should be considered prior to pregnancy. It is recommended that female patients stop drugs in the MPA and mTOR inhibitor groups and switch to CNI or azathioprine at least 6 weeks prior to pregnancy. CNI, azathioprine, and corticosteroids are considered relatively safe immunosuppressants and can be used during pregnancy.

Theoretically, MPA use in male patients may affect the abnormalities of the embryo conceived [67]. In the past, there was a recommendation for male patients to stop MPA at least 90 days prior to planning children. However, a study of 230 male kidney transplant recipients with a total of 350 children found that MPA use did not increase the risk of fetal abnormalities [70]. For drugs in the mTOR inhibitor group, they reduce the chance of having children in male patients because they result in reduced sperm quantity (oligospermia) and may also cause reduced testosterone levels. CNI, azathioprine, and corticosteroids are considered relatively safe immunosuppressants and can be used during pregnancy (Table 10).

TABLE 10.

Effects of immunosuppressive medications on pregnancy and lactation.

Immunosuppressant	Effect on fetus	Recommendation for use during pregnancy	Recommendation for use during breastfeeding
Cyclosporine	—	√	√
Tacrolimus	—	√	√
Prednisolone	(possible) oral cleft	√	√
Azathioprine	—	√	√
Mycophenolic acid	Cleft lip and palate, absent auditory canal, hypertelorism, microtia, brachydactyly of the 5th finger, hypoplastic toenails	×	×
mTOR inhibitors	—	×	Unknown

Note: (√ = Relatively safe, × = Not safe).

6.11. Interstitial Fibrosis and Tubular Atrophy (IFTA)

1. When transplanted kidney function declines, it is recommended to perform a pathological biopsy to determine the cause. In cases where interstitial fibrosis and tubular atrophy (IFTA) are found, it is recommended to proceed with differential diagnosis to identify the specific cause, particularly chronic antibody‐mediated rejection (ABMR) [+, IIb, C].

2. Consideration may be given to reducing CNI dose (CNI minimization) or switching to other groups instead of CNI (CNI conversion) in cases where IFTA is found to be caused by CNI toxicity without concurrent organ rejection [±, IIb, C].

3. Consideration may be given to using mTOR inhibitors in patients with IFTA caused by CNI toxicity or IFTA with no specific cause found, provided the patient has eGFR > 40 mL/min/1.73 m² and urine protein < 500 mg/day [+, IIa, C].

6.12. Rationale and Evidence

Chronic allograft dysfunction or chronic allograft injury, formerly called chronic allograft nephropathy, is one of the major causes of graft loss. Patients will experience a gradual decline in kidney function. Diagnosis requires a kidney biopsy, which often reveals pathology as IFTA. The majority of causes come from chronic antibody‐mediated rejection or CNI toxicity.

In cases where chronic allograft dysfunction is found to be caused by CNI toxicity, consideration may be given to using immunosuppressants in the mTOR inhibitor group, which act by inhibiting the growth of T‐cells and B‐cells. Side effects of this group include slow wound healing, lymphocele, oral ulcers, hyperlipidemia, interstitial pneumonitis, and proteinuria. The mechanism of proteinuria from mTOR inhibitors involves the reduction of protein reabsorption at the tubules and injury to podocyte cells. Therefore, use of this group should be avoided in patients with pre‐existing proteinuria. Results from the CONVERT study found that switching from CNI to sirolimus helped improve kidney function, specifically in patients with eGFR greater than 40 mL/min and a urine protein‐to‐creatinine ratio not exceeding 0.11 g/g (Table 11).

TABLE 11.

Studies comparing CNI to mTOR inhibitor with IFTA or kidney function as the outcomes.

Study	Comparison group	Study results
Spare‐the‐Nephron trial [37]	SRL + MMF vs. CsA + MMF	Not different in allograft function but with fewer deaths and a trend to less BPAR and graft loss
CONVERT [71]	CsA/Tac vs. Sirolimus	Success in eGFR > 40, urine protein‐to‐creatinine ratio < 0.11
ORION [72]	Group 1: SRL+ TAC; week 13 TAC elimination (n = 152) Group 2: SRL + MMF (n = 152) Group 3: TAC + MMF (n = 139)	Not different in allograft function (increased urine protein‐to‐creatinine ratio in SRL)
ZEUS [73]	EVL vs. CNI	EVL improve eGFR

Abbreviations: BPAR, biopsy‐proven acute rejection; CsA, cyclosporine; eGFR, estimated glomerular filtration rate; EVL, everolimus; MMF, mycophenolate mofetil; SRL, sirolimus; TAC, tacrolimus.

6.13. Administration of Immunosuppressants During NPO (Nothing Per Oral)

1. It is strongly recommended to switch CNI drugs from oral form to intravenous injection in cases where the patient must refrain from food and water (NPO). The starting intravenous dose for tacrolimus is 1 in 4 of the oral dose, and for cyclosporine is 1 in 3 of the oral dose [++, I, C].

2. It is recommended to monitor drug concentration levels until steady‐state concentration (C_steady) is reached, which generally takes 3 to 5 times the drug's half‐life (approximately 48 h after starting or adjusting the dose). However, blood can be drawn to check drug levels before this time to assess the trend of drug level changes [+, II, C].

3. Target levels of C_steady for CNI drugs can be calculated from the formula: Target tacrolimus C_steady = Target C₀ × 1.4, Target cyclosporine C_steady = Target C₀ × 2.55. Or calculated based on target AUC_(0–12) of each drug, then calculating Target C_steady from the formula: Target C_steady = Target AUC(0–12) ÷ 12 [+, II, C].

4. It is recommended to use corticosteroids in intravenous injection form, adjusting the dose appropriately [+, II, C].

6.14. Rationale and Evidence

In cases where the patient must be NPO, CNI immunosuppressants require adjustment of form and dosage to maintain immune system control efficacy. It is recommended to switch from oral form to intravenous injection because oral drugs may have inconsistent absorption during NPO. The starting intravenous dose of tacrolimus is 1 in 4 of the oral doses, and cyclosporine is 1 in 3 of the oral doses. Monitoring blood drug concentration until steady level (C_steady) is important. Generally, this level is reached after 3 to 5 times the drug's half‐life, or approximately 48 h. However, blood can be drawn to check drug levels before this time to assess trends.

Setting target levels for C_steady can be calculated from target C₀ levels or target AUC_(0–12) using the formulas provided [74]. This is because the graph of drug level versus time will have a rectangular shape when administered via continuous infusion.

Tacrolimus intravenous injection form can be mixed with 5% dextrose in water (D5W) or normal saline solution (NSS) to a concentration of 0.004 to 0.020 mg/mL (equivalent to 4 to 20 mg in 1000 mL solution). The mixed solution is stable for 24 h. Administration via continuous infusion. Use of tubing made from polyvinylchloride should be avoided because polyvinylchloride can adsorb tacrolimus. Additionally, the injection contains castor oil, which may dissolve phthalates from polyvinylchloride and may cause anaphylaxis. Therefore, the patient should be monitored closely, especially during the first 30 min of administration.

Cyclosporine intravenous injection form can be mixed with D5W or NSS to a concentration of 0.5 to 2.5 mg/mL. The mixed solution is stable for 24 h. Administered via continuous infusion or, in some institutions, may be mixed and given every 12 h. Use of tubing made from polyvinylchloride should be avoided because it can adsorb cyclosporine. The injection also contains castor oil, carrying similar risks of phthalate dissolution and anaphylaxis, so close monitoring is required, especially in the first 30 min.

Corticosteroids should be used in intravenous form, with dosage adjusted appropriately to the patient's condition, such as stress dose. Following these guidelines will help the patient receive immunosuppression appropriately and safely during NPO. When the patient can eat and drink, they can return to the original form of immunosuppressants.

7. Chapter 6: Treatment of Rejection

1. It is strongly recommended to perform a kidney allograft biopsy to confirm the diagnosis of allograft rejection before treatment. [++, I, B]

2. It is suggested to test for donor‐specific antibody, together with a kidney allograft biopsy, to diagnose ABMR. [+, IIa, B]

3. It is strongly recommended to treat clinical allograft rejection. [++, IIb, C]

4. It is recommended to treat subclinical allograft rejection. [+, IIb, C]

5. It is recommended to adjust immunosuppressive medication to the standard regimen (tacrolimus + mycophenolic acid + corticosteroids) and/or intensify dosage as proper. [++, IIa, B]

6. It is strongly recommended to inform the patients about drug adherence, especially in the case of allograft rejection. [++, I, A]

7. Treatment of acute T‐cell mediated rejection (TCMR)

   • 7.1
     It is recommended to treat acute TCMR with high‐dose corticosteroids: intravenous methylprednisolone 500–1000 mg/d or 10–15 mg/kg/d for 3–5 days, then followed by oral corticosteroids. [++, I, B]
   • 7.2
     Anti‐thymocyte globulin (ATG) 1–1.5 mg/kg/d, no more than 7 days [+, IIa, C] in the following conditions:

     • Refractory acute TCMR (unresponsive to corticosteroids)
     • Severe acute TCMR (Banff Grade II–III).
     • Recurrent acute TCMR.
   • 7.3
     After treatment of TCMR, corticosteroids may be considered to increase the dosage, or restore in patients with a steroid‐free regimen. [+, I, B]
   • 7.4
     Borderline TCMR may be considered to treat with optimization of immunosuppressive drugs or corticosteroids [±, IIa, C]
8. Treatment of antibody‐mediated rejection (ABMR)

   • 8.1
     It is recommended to treat active ABMR with the following (more than one option may be considered in combination) [+, IIb, C]:

     • Plasma exchange, double filtration plasmapheresis (DFPP), or immunoadsorption
     • Intravenous immunoglobulin (IVIg)
     • Anti‐CD20 monoclonal antibody: rituximab
     • Complement inhibitors: eculizumab
     • Proteasome inhibitors: bortezomib
     • Lymphocyte‐depleting agents: ATG
   • 8.2
     Chronic active ABMR and chronic ABMR may be treated with optimization of immunosuppressive medication to the standard regimen (tacrolimus + mycophenolic acid + corticosteroids) and/or intensifying dosage as proper. [+, IIa, B]
   • 8.3
     Chronic active ABMR may be considered to be treated as active ABMR [±, IIb, C]

7.1. Rationale and Evidence

Allograft rejection, the major complication and cause of allograft dysfunction, is classified into two histopathological groups: T‐cell mediated rejection (TCMR) and antibody‐mediated rejection (ABMR). Most allograft rejection is treated by intensification of immunosuppression. However, allograft dysfunction can be caused by other causes. Infection is one of those that requires a reduction in immunosuppression. Thus, the kidney transplant recipients with allograft dysfunction should be evaluated for causes and may require a kidney allograft biopsy. A biopsy performed due to allograft dysfunction is called an indicated biopsy, whereas some centers perform an allograft biopsy as scheduled, referred to as a surveillance biopsy. In cases where a histological finding reveals allograft rejection without an increase in serum creatinine or proteinuria, it is referred to as subclinical rejection.

Diagnosis and classification of allograft rejection are based on the Banff classification, which was first published in 1991 and periodically updated [75, 76]. The diagnosis of ABMR and TCMR can be established simultaneously.

1. Active antibody‐mediated rejection.

2. Chronic active antibody‐mediated rejection.

3. Chronic antibody‐mediated rejection.

4. Borderline T‐cell mediated rejection.

5. Acute T‐cell mediated rejection.

6. Chronic active T‐cell mediated rejection.

Some studies showed that treating subclinical rejection and borderline TCMR improves allograft survival [77]. A prospective study showed the worse outcomes of borderline TCMR in protocol biopsy. They have higher serum creatinine levels at 3 months, higher chronicity histological scores, a higher incidence of de novo donor‐specific antibodies (DSA) at 12 months, and a higher incidence of allograft rejection at 24 months [78].

The mainstays of acute TCMR treatment are corticosteroids, which are initially treated with intravenous methylprednisolone 500–1000 mg/day for 3–5 days, followed by oral corticosteroids. An observational study revealed a lower response rate to corticosteroids for treating acute TCMR Banff Grade II (arteritis is present) compared to acute TCMR Banff Grade IA, resulting in lower graft survival. The response rate is 36% when treating with corticosteroids only. However, 86% of patients with steroid‐resistant TCMR respond to anti‐thymocyte globulin (ATG) [79]. A systematic review reveals a similar response rate to corticosteroids of 44%–73% for Banff Grade IA‐IB and 52%–80% for Banff Grade IIA, while being significantly lower in Banff Grade IIB (10%) [80].

A lymphocyte‐depleting agent, thymoglobulin, 1–1.5 mg/kg/day for no more than 7 days [81], is recommended in refractory or recurrent TCMR. The suggested treatment of acute TCMR is shown in Table 12.

TABLE 12.

Treatment of acute T‐cell mediated rejection.

TCMR category	Treatment
Borderline acute TCMR, subclinical acute TCMR	Intravenous methylprednisolone may be considered. [IIa, C]
Acute TCMR Grade I	Intravenous methylprednisolone [I, B]
Acute TCMR Grade II–III	Intravenous methylprednisolone [I, B], together with ATG [IIa, C]
Refractory or recurrent TCMR	ATG [IIa, C]
All cases	Augment immunosuppressive drugs Advise compliance and adherence

Abbreviations: ATG, anti‐thymocyte globulin; TCMR, T‐cell mediated rejection.

The aim of ABMR treatment is to remove circulating DSA (Table 13). Plasmapheresis is the most common procedure. However, its efficacy is limited in removing circulating antibodies rather than endothelium‐bound antibodies. Furthermore, it does not diminish the inflammatory process nor inhibit the production of new antibodies. Thus, it is usually combined with other treatments, including intravenous immunoglobulin (IVIg), rituximab, lymphocyte‐depleting agents, proteasome inhibitors [82], and complement inhibitors [83]. A systematic review showed that plasmapheresis, combined with IVIg and corticosteroids, is the standard treatment [84, 85]. Immunoadsorption may be beneficial in refractory or severe ABMR [86].

TABLE 13.

Treatment of antibody‐mediated rejection.

ABMR category	Treatment
Active ABMR	Standard therapy Plasma exchange or DFPP IVIg Adjunctive therapy Anti‐CD20 monoclonal antibody: rituximab Proteasome Inhibitors: bortezomib Lymphocyte‐depleting agents: ATG Complement inhibitors: eculizumab Immunoadsorption Splenectomy
Chronic active ABMR	Standard therapy may be considered. Plasma exchange or DFPP IVIg
All cases	Augment immunosuppressive drugs Advise compliance and adherence

Abbreviations: ABMR, antibody‐mediated rejection; ATG, anti‐thymocyte globulin; DFPP, double filtration plasmapheresis; IVIg, intravenous immunoglobulin.

Rituximab, an anti‐CD20 monoclonal antibody, may be considered an adjunct to the standard treatment in severe ABMR (vascular rejection) or for the prevention of rebound DSA. However, some studies reveal no difference or a subtle benefit [82, 84, 87]. Thus, it is considered an adjunct to plasmapheresis and IVIg [85].

The recommended dosage of treatment for allograft rejection is shown below:

• Plasma exchange or double filtration plasmapheresis (DFPP) 1–1.5 times the plasma volume, 5–7 sessions depending on response

• Intravenous immunoglobulin (IVIg) 0.1–0.4 g/kg after each apheresis session, or 2 g/kg after the last session

• Rituximab 375 mg/m² for 1–2 doses with a 1–2 weeks interval

• Bortezomib 1.3 mg/m² at day 1, 4, 8, and 11

• Eculizumab 1200 mg at day 0, followed by 600 mg after apheresis session, and 900 mg weekly after completion of apheresis

8. Chapter 7: Strategy to Reduce Drug Costs

1. Induction Therapy

   • 1.1
     In kidney transplant recipients with a low risk of allograft rejection, Interleukin‐2 receptor antagonists (IL2‐RA) may be considered to be omitted. [±, IIb, B]
   • 1.2
     In kidney transplant recipients with a moderate risk of allograft rejection, low‐dose ATG (total 1.5–2 mg/kg), together with preemptive treatment for CMV infection, may be considered to reduce costs. [±, IIb, B]
2. Maintenance Immunosuppression

   • 2.1
     It is recommended to use non‐dihydropyridine calcium channel blockers (non‐DHP CCBs); diltiazem (60–240 mg/day) or verapamil (80–120 mg/day), together with calcineurin inhibitor (CNI) to reduce the dosage of CNI by 20%–50%. [+, IIb, B]
   • 2.2
     Low‐dose diltiazem (30 mg every 12 h) may be considered for use since the day of transplant in patients with a low trough concentration per daily dose (C₀/D) ratio < 1.05 ng/mL/mg or CYP3A5 expressers, and blood pressure is not lower than 110/70 mmHg, to increase the trough concentration of tacrolimus. [±, IIb, B]
   • 2.3
     Azoles (fluconazole 50–200 mg/d or ketoconazole 50–200 mg/day) may be considered for use together with CNI to reduce the dosage of CNI by 50%. The liver function test should be monitored. [+, IIb, B]
   • 2.4
     It is not recommended to use gemfibrozil or fenofibrate together with CNIs to reduce the dosage of CNI due to increased risk of rhabdomyolysis. [−, III, B]
   • 2.5
     Azathioprine may be substituted for mycophenolic acid in patients who have stable graft function and a low risk of rejection. [+, IIb, B]
   • 2.6
     It is recommended to use prednisolone in the long term to prevent allograft rejection. [+, IIa, A]
3. Generic Immunosuppressive Drugs

   • 3.1
     It is recommended to use generic immunosuppressive drugs with proven evidence of bioequivalence to the original drugs, and qualified by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), or Thai FDA. [+, IIa, C]
   • 3.2
     It is not recommended to use generic immunosuppressive drugs without a manufacturing quality pass. [−, III, C]
   • 3.3
     It is recommended to use generic immunosuppressive drugs with proven evidence of bioavailability and efficacy in the Thai population, if available. [+, IIa, C]
   • 3.4
     It is recommended to closely monitor the drug level until it reaches the target and steady state in case of switching from the original to the generic immunosuppressive drugs. [+, IIa, C]
   • 3.5
     It is recommended that switching from the original to the generic immunosuppressive drugs should be done under the expertise. [+, IIb, C]
   • 3.6
     It is recommended that the transplant physician, healthcare provider, and patients should be informed when the immunosuppressive drug brand is changed. [+, IIb, C]
   • 3.7
     It is not recommended to shuffle the immunosuppressive drug brand according to the hospital procurement policy because of drug exposure variability and increased risk of rejection. [−, III, C]

8.1. Rationale and Evidence

All healthcare benefit schemes in Thailand, Civil Servant Medical Benefit Scheme (CSMBS), Social Security Scheme (SSS), Universal Coverage Scheme (UCS), and others, cover kidney transplantation. The reimbursement is divided into two parts. First is for the kidney transplant operation, depending on immunologic risk, the use of induction therapy, and postoperative complications. Second is for the maintenance of immunosuppressive medication, which is a monthly flat rate and decreases over time.

The cost of immunosuppressive medication may exceed coverage, potentially hindering the kidney transplant program. Thus, reducing the cost of immunosuppressive drugs, weighing patient safety, and transplant outcome may be considered to maintain the growth of the kidney transplant program. The application of other drugs that interact with immunosuppressive drugs to increase their concentration is a commonly used option. Close monitoring and patient advice are essential.

CNI is mainly metabolized in the liver by CYP3A4 and CYP3A5. Drugs inhibiting CYP3A4 decrease CNI metabolism, resulting in an increase in CNI levels. Thus, co‐administration requires a lower dosage of CNI. Non‐dihydropyridine calcium channel blockers (diltiazem and verapamil) and azoles (fluconazole and ketoconazole) are commonly used for this purpose.

The transplant recipients who are CYP3A5 expressers have a higher rate of CNI metabolism and require a higher dose of CNI to achieve the target. The prevalence of CYP3A5 expressers is 50%–60% of the Thai population [88, 89]. Co‐administration of CYP3A4 inhibitors is pronounced benefit in this group. The CYP3A5 expressers can be identified through a pharmacogenetic test for CYP3A5 polymorphism or by screening for a trough concentration per daily dose (C₀/D) ratio [90]. The C₀/D ratio of tacrolimus < 1.05 ng/mL/mg suggests a fast or extensive metabolizer. This ratio should be calculated only when the drug reaches the steady state, which requires at least 7 days after transplantation. High‐dose corticosteroids may also affect CYP3A4 and require a higher dosage of tacrolimus [91].

Co‐administration of diltiazem or verapamil allows for a reduction in CNI dosage of approximately 20%–50%. A clinical study using diltiazem 30 mg every 12 h since the day of transplantation in patients who are CYP3A5 expressers or have C₀/D ratio < 1.05 ng/mL/mg, and blood pressure is not lower than 110/70 mmHg, increases tacrolimus concentration [92]. Co‐administration of azoles allows for a reduction in CNI dosage of approximately 50%.

However, strict caution must be exercised regarding the clinical risks associated with withdrawing these interacting drugs, as the timing of CNI dose reversal depends on the pharmacokinetic washout of the specific inhibitor. When non‐dihydropyridine calcium channel blockers (e.g., diltiazem) are discontinued, the CYP3A4/5 inhibitory effect dissipates rapidly; therefore, the CNI dose should generally be increased concurrently to prevent rapid subtherapeutic levels. Conversely, azole antifungals (e.g., fluconazole) have a prolonged half‐life of roughly 30 h, meaning CYP3A4/5 inhibition persists for 5 to 7 days after the last dose. Increasing the CNI dose on the exact day an azole is stopped can precipitate acute CNI toxicity. Instead, the CNI dose should be adjusted gradually over the subsequent days. In all cases, rigorous patient education and prompt therapeutic drug monitoring (TDM)—ideally performed within 3 to 5 days of discontinuation—are recommended during the inhibitor's washout period to safely restore pre‐inhibitor baseline CNI requirements.

Clinical studies demonstrating the efficacy and safety of immunosuppressive drugs in kidney transplantation primarily use the original drugs. Once the drug patent expires, generic drugs can be manufactured at a lower price. It is ideally bioequivalent to the original ones, but the evidence is limited [93]. Most immunosuppressive drugs in kidney transplantation have a narrow therapeutic index. If the generic drugs are considered to reduce cost, the bioequivalence should be qualified as all of the following [40, 67]:

• It should contain the same active ingredients.

• It should be equivalent in strength, dosage form, and route of administration.

• It should have the same indication.

• It should be proven for bioequivalence in bioavailability

• It should have the same standard qualification in identity, strength, purity, and quality.

• It should be manufactured under qualification control.

The drug procurement policy should be carefully considered for this immunosuppressive drug group. Brand shuffling may affect drug variability, which increases the risk of allograft rejection. If the immunosuppressive drug brand is changed, the transplant physician, healthcare provider, and patients should be informed.

9. Chapter 8: Cessation of Immunosuppression in Failing Kidney Transplantation

1. It is recommended to start considering the reduction of immunosuppressant levels by assessing patient risk and drug side effects in cases where eGFR < 20 mL/min/1.73 m², provided the patient has normal urine volume [+, IIb, C].

2. In cases where eGFR < 10 mL/min/1.73 m² and the patient still has urine volume > 400 mL/day, it is recommended to adjust immunosuppressant levels as follows:

   • 2.1
     If there is a plan for re‐transplantation within 1 year after starting renal replacement therapy, or a plan for preemptive kidney transplantation, consider reducing the dosage of immunosuppressants and maintaining them at a low level continuously until the new kidney transplantation is performed.
   • 2.2
     If there is no plan for re‐transplantation within 1 year, or it is anticipated that the wait for a new kidney transplant will be longer than 1 year, consider reducing immunosuppressants until they can be discontinued within 3–6 months after entering dialysis.

9.1. Rationale and Evidence

The definition of a Failing Kidney Transplant refers to a condition where the transplanted kidney has a continuously declining eGFR (< 20 mL/min/1.73 m²) without a reversible cause found to restore kidney function, and it is expected that renal replacement therapy will be required within 1 year [94, 95]. While the transplanted kidney enters the failing kidney transplant state, continuing immunosuppression has both pros and cons as follows [96]:

Disadvantages of Continuing Immunosuppression [97]:

• Increased risk of infection.

• Increased risk of certain malignancies.

• Possibility of complications from immunosuppressant use.

• Altered drug metabolism: As kidney function declines, the elimination of drug metabolites and drug excretion decreases, increasing the risk of toxicity or complications from immunosuppressants.

Disadvantages of Stopping Immunosuppression:

• Triggers acute rejection or graft intolerance syndrome.

• Secondary adrenal insufficiency.

• Loss of residual kidney function occurs more rapidly.

• Sensitization occurs.

• Anaemia develops more rapidly due to resistance to erythropoiesis‐stimulating agents (ESA resistance), which is a result of the inflammation.

Example for Tapering Immunosuppressants Protocol:

• CNI Group: Reduce dosage by maintaining tacrolimus C₀ at 2–5 ng/mL or cyclosporine C₀ at 25–75 ng/mL, then gradually taper the dose until discontinuation without the necessity of monitoring drug levels.

• Anti‐metabolite Group: Start by reducing the dose by 50% from the patient's original dose, and consider discontinuation in the subsequent step.

• Prednisolone: Administer at a dose of 2.5–5 mg/day.

The tapering of immunosuppressants can begin with either the anti‐metabolite group or the CNI group first, depending on the consideration of appropriateness for each individual patient. Discontinuation of prednisolone may be considered as the final step. As immunosuppression is withdrawn, patients must be closely monitored for graft intolerance syndrome (GIS), a state of chronic, immunologically driven inflammation directed at the failed organ. Clinically, GIS presents with localized symptoms such as graft tenderness, graft enlargement, and gross hematuria, alongside systemic inflammatory signs including persistent fever, malaise, weight loss, and elevated inflammatory markers (e.g., C‐reactive protein) that frequently exacerbate ESA‐resistant anaemia. If these symptoms of GIS develop during the tapering phase, they can often be managed initially by maintaining or temporarily increasing low‐dose corticosteroids. However, if medical management fails or the patient develops severe, refractory symptoms (such as persistent fever, intractable graft pain, or recurrent gross hematuria), a graft nephrectomy is indicated [96, 97].

10. Chapter 9: Combined Solid Organ Transplantation

1. Simultaneous Liver and Kidney Transplantation (SLK)

   • 1.1
     Indications for SLK [98, 99]:

     • 1.1.1
       Patients with decompensated liver cirrhosis combined with chronic kidney disease (CKD) with eGFR < 30 mL/min/1.73 m² [++, I, B].
     • 1.1.2
       Patients with decompensated liver cirrhosis combined with hepatorenal syndrome or acute kidney injury requiring renal replacement therapy for longer than 6–8 weeks [+, II, B].
     • 1.1.3
       End‐stage kidney disease (ESKD) patients with a cause from atypical hemolytic uremic syndrome due to abnormalities in complement regulation [+, II, B].
     • 1.1.4
       ESKD patients with a cause from primary hyperoxaluria Type 1 [+, II, B].
   • 1.2
     It is recommended to use an IL‐2RA as an induction therapy, or induction therapy may not be necessary in patients undergoing SLK [+, IIb, B].

     • 1.2.1
       In cases where the patient has pre‐transplant donor‐specific antibody (DSA), there are not yet sufficient studies to conclude the role of desensitization or the use of ATG for induction regarding patient and graft survival in SLK patients [±, IIb, C].
   • 1.3
     The main immunosuppressive regimen used in liver and kidney transplantation includes tacrolimus, MPA, and prednisolone [100, 101]. It has been found that the use of the CNI group and steroids in the immunosuppressive regimen is associated with better patient and graft survival rates [102] [++, II, B].
2. Heart and Kidney Transplantation

   • 2.1
     Indications for Simultaneous Heart and Kidney Transplantation:

     • 2.1.1
       End‐stage heart disease and the patient has eGFR < 30 mL/min/1.73 m² [+, II, B].
     • 2.1.2
       End‐stage heart disease and the patient has eGFR 30–45 mL/min/1.73 m² combined with acute kidney injury that recovers slowly, or is necessary to receive renal replacement therapy, or has small kidneys, or proteinuria > 0.5 g/day [+, II, B].
   • 2.2
     Consider selecting induction therapy and desensitization according to the guidelines of each institution [+, II, C].
   • 2.3
     Consider maintenance therapy administration by emphasizing the organ that requires higher levels of immunosuppression [103] [+, II, B].
3. Pancreas and Kidney Transplantation

   • 3.1
     Indications for Pancreas and Kidney Transplantation [+, I, A]:

     • 3.1.1
       Chronic kidney disease stage 4 (eGFR < 30 mL/min/1.73 m²) or end‐stage kidney disease combined with Type 1 Diabetes, with the following options [104]:

       • Perform kidney transplantation from a living donor (Living donor kidney transplantation) first, then consider performing pancreas transplantation (Pancreas transplantation) or islet transplantation (Islet transplantation) after the kidney transplant.
       • Perform simultaneous pancreas and kidney transplantation or simultaneous islet and kidney transplantation from a deceased donor.
     • 3.1.2
       ESKD combined with Type 2 diabetes in some cases, with the transplant center determining indications for each individual patient.
   • 3.2
     Consider using induction therapy in the lymphocyte‐depleting agents group [103], such as ATG [+, II, B].
   • 3.3
     Consider using tacrolimus combined with MPA and corticosteroids, adhering to the principle of administering based on the organ that requires higher levels of immunosuppression [103] [+, II, B].

10.1. Rationale and Evidence

Simultaneous liver and kidney transplantation has advantages in immunosuppressant management. Receiving organs from the same donor makes the immunological assessment less complex than receiving organs from different donors. Specifically, when one organ is the liver, it possesses mechanisms that help reduce the risk of organ rejection in several ways, such as having a large volume of blood supply and the ability of the liver to regenerate, which helps reduce the amount of alloantibody. Additionally, it is an organ with a reticuloendothelial system consisting of Kupffer cells, myeloid cells, plasmacytoid dendritic cells, and liver sinusoidal endothelial cells, which play important roles in helping to eliminate various foreign antigens [103].

Simultaneous liver and kidney transplantation can prevent or reduce the risk of kidney allograft rejection [105, 106]. There are not yet studies with sufficient methodology to identify clear guidelines for induction therapy usage. However, it has been found that not using induction therapy, using IL‐2RA, and using ATG result in no difference in allograft survival [102]. Some studies show that patients receiving ATG may have higher mortality rates than patients receiving IL‐2RA or no induction therapy [107]. There are not yet studies with sufficient evidence in cases where patients have pre‐transplant DSA to conclude the role of desensitization or ATG use in induction on patient and graft survival. It has been found that there is no significant difference in kidney allograft survival between patients with pre‐transplant DSA and patients without pre‐transplant DSA in the group undergoing simultaneous liver and kidney transplantation [103].

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.