Clinical perspectives towards improving risk stratification strategy for renal transplantation outcomes in Indian patients

The use of induction therapy for appropriate patient risk profile can be corroborated with the current clinical practice. Induction immunosuppression could be tailored based on the risk stratification (considering demographic factors of recipients as well as donor, immunological characteristics of recipient and transplant-related factors). Potent induction agent may help in reducing both incidence and severity of acute rejection after renal transplantation with good safety profile.

This survey discusses the risk factors in kidney transplants and provides direction towards evidence- and clinical experience based risk stratification for donor/recipient and transplant-related characteristics, with a focus on living donor transplantations

Risk Factors in Renal Transplant

Rationale

• Applicability of KDIGO guidelines and risk stratification in renal transplantation has been a challenge in Indian setting given the country’s socio-economic status, limitations in physician and patient awareness of the disease state and resource availability. Therefore, adaptation/modification of the KDIGO guidelines in Indian settings is necessary
• There is a need for a comprehensive risk stratification strategy to ensure the use of precise immunosuppressive regimens in Indian clinical practice

Methodology

• To discuss the current clinical practice in renal transplantation and assess the concordance of Indian practice with Western guidelines and recommendations, 3 expert committee meetings were conducted between April 2017 and February 2018; a total of 29 subject matter experts from across India participated in these meetings
• A questionnaire was prepared based on experts’ clinical experience in kidney transplantation centers across India, as well as evidence from randomized clinical studies, and relevant prospective and retrospective studies

Importance of Risk Stratification

Risk stratification based on donor, recipient, and transplant-related factors is an important method to:

• Select the appropriate immunosuppression regimen for a patient 
• Help strike a balance between avoiding AR and excessive immunosuppression (reducing infection risk)
• Reduce other adverse events such as new-onset diabetes mellitus, dyslipidemia, and nephrotoxicity

Results from the Survey

Donor-related factors

• Deceased donor - The experts further suggested that as an individual factor type of donor (living or deceased) may not be a significant risk; however, DGF which is much higher in the deceased donor may pose this type of transplantation at a higher risk of rejection. In cases of DCD, there is a higher risk of DGF which provokes the formation of anti-HLA antibodies. 4.17% experts in the survey, considered this to be a very high risk for rejection

• Live donor - Live donor transplants were considered safe by the group of participating experts, irrespective of whether the donor is an immediate family member or not; with the only exception being spousal donor transplant (higher risk because of HLA mismatch and antigen sensitization)

Recipient-related factors

• Dialysis history - A recipient having dialysis vintage of <1 year before transplantation is a favorable situation and does not pose any risk for rejection in renal transplantation. While a patient with 3–5 years of dialysis may impose a moderate risk, having a dialysis history of >5 years is a significant risk factor for rejection due to sensitization as perceived by more than 30% experts who participated in the survey
• Previous transplantation - The experts agreed that the first transplantation in isolation is safe, and number of transplantations only increase the risk of rejection if the recipient has received more than 2 transplantations
• Age and weight of the recipient - Although transplantation is not contraindicated due to high donor-recipient age difference, it is notable that younger the recipient and older the donor, the rate of rejection is high. However, a significant mismatch in donor-recipient weight (donor<recipient) may be associated with a higher risk of death-censored graft loss in kidney transplantation
• Donor specific antibodies - All the participating experts agreed that presence of DSA increases the risk of rejection. The experts suggested that immunological conflict should be avoided by performing cytotoxic cross match, flow cross match in all patients and DSA (single antigen bead) whenever considered clinically relevant

Transplant-related factors

• HLA and risk of rejection in renal transplant patients - HLA mismatch is not sufficient; it is also important to consider at what locus the mismatch occurs. The type of mismatch is also important, for example, determining whether it is a DR mismatch and whether an epitope matching should also be considered (Figure 1)

Figure 1: HLA antibodies as a risk factor for AR in renal transplant

• PRA and risk of rejection in renal transplant patients - Most of the experts felt that having PRA in between 0–20% is a mild risk factor for AR, 50% believed that 20%–40% PRA score was moderate to high risk and all the participating experts considered a score >40% as a high to extremely high risk for rejection; PRA does not add value to risk stratification in living donor transplantation (Figure 2)

Figure 2: PRA as a risk factor for AR in renal transplant

• CIT and risk of rejection in renal transplant patients - In the present survey, a cut-off of 24 h was used and all the experts agreed that a CIT of <24 h is an important factor in decreasing the risk of rejection

Summary of Clinical Insights

• Risk evaluation strategies should consider recipient related factors (dialysis, comorbidities, and age), donor related factors (age, BMI, type – living or deceased) and other factors (CIT, mismatch, DSA)
• Immunological conflict should be avoided by performing cytotoxic cross match, flow cross match and DSA (if possible)
• HLA mismatches, presence of DSA, and DGF, along with donor/recipient age, CIT etc., are associated with increased risk of rejection
• The risk of rejection in living donor transplant is similar to deceased donor recipients

Conclusion

• The use of induction therapy for appropriate patient risk profile can be corroborated with the current clinical practice
• Induction immunosuppression could be tailored based on the risk stratification (considering demographic factors of recipients as well as donor, immunological characteristics of recipient and transplant-related factors)
• Potent induction agent may help in reducing both incidence and severity of AR after renal transplantation with good safety profile