|Year : 2022 | Volume
| Issue : 2 | Page : 145-154
Clinical perspectives towards improving risk stratification strategy for renal transplantation outcomes in Indian patients
Vijay Kher1, Vivek B Kute2, Sarbeswar Sahariah3, Deepak S Ray4, Dinesh Khullar5, Sandeep Guleria6, Shyam Bansal1, Sishir Gang7, Anil Kumar Bhalla8, Jai Prakash9, Abi Abraham10, Sunil Shroff11, Madan M Bahadur12, Pratik Das4, Urmila Anandh13, Arpita Ray Chaudhury14, Manoj Singhal15, Jatin Kothari16, Sree Bhushan Raju17, Dilip Kumar Pahari18, G Vishwanath Siddini19, G Sudhakar19, Santosh Varughese20, Tarun K Saha21
1 Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta-The Medicity, Gurugram, Haryana, India
2 Department of Nephrology, Institute of Kidney Diseases and Research Centre, Dr. HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India
3 Department of Transplantation Surgery, KIMS Hospital, Hyderabad, India
4 Department of Nephrology, Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, India
5 Department of Nephrology, Max Saket Complex, Max Super Speciality Hospital, Saket, Delhi, India
6 Department of Transplantation Surgery, Indraprastha Apollo Hospital, Varanasi, Uttar Pradesh, India
7 Department of Nephrology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India
8 Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India
9 Department of Nephrology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
10 Department of Nephrology, VPS Lakeshore Hospital, Kochi, Kerala, India
11 Managing Trustee, MOHAN Foundation, Chennai, Tamil Nadu, India
12 Department of Nephrology, Jaslok Hospital and Research Centre, Mumbai, Maharastra, India
13 Department of Nephrology, Yashoda Hospitals, Secunderabad, Telangana, India
14 Department of Nephrology, Institute of Post-Graduate Medical Education and Research, Kolkata, West Bengal, India
15 Department of Nephrology, Max Super Specialty Hospital, Vaishali, Ghaziabad, India
16 Department of Nephrology, Nanavati Max Hospital, Mumbai, Maharastra, India
17 Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
18 Department of Nephrology, Medica Super Specialty Hospital, Kolkata, West Bengal, India
19 Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
20 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
21 Department of Nephrology, Apollo Hospital, Secunderabad, Telangana, India
|Date of Submission||17-Mar-2021|
|Date of Acceptance||03-Nov-2021|
|Date of Web Publication||30-Jun-2022|
Dr. Vivek B Kute
IKDRC-ITS, Ahmedabad, Gujarat
Source of Support: None, Conflict of Interest: None
Graft loss and rejections (acute/chronic) continue to remain important concerns in long-term outcomes in kidney transplant despite newer immunosuppressive regimens and increased use of induction agents. Global guidelines identify the risk factors and suggest a framework for management of patients at different risk levels for rejection; however, these are better applicable to deceased donor transplants. Their applicability in Indian scenario (predominantly live donor program) could be a matter of debate. Therefore, a panel of experts discussed the current clinical practice and adaptability of global recommendations to Indian settings. They also took a survey to define risk factors in kidney transplants and provide direction toward evidence- and clinical experience-based risk stratification for donor/recipient and transplant-related characteristics, with a focus on living donor transplantations. Several recipient related factors (dialysis, comorbidities, and age, donor-specific antibodies [DSAs]), donor-related factors (age, body mass index, type – living or deceased) and transplantation related factors (cold ischemia time [CIT], number of transplantations) were assessed. 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. HLA mismatches, presence of DSA, along with donor/recipient age, CIT, etc., were associated with increased risk of rejection. Furthermore, the panel agreed that the risk of rejection in living donor transplant is not dissimilar to deceased donor recipients. The experts also suggested that induction immunosuppression could be individualized based on the risk stratification.
Keywords: Acute rejection, donor-specific antibody, human leukocyte antigens, immunosuppression, Indian patients, living donors, renal transplantation
|How to cite this article:|
Kher V, Kute VB, Sahariah S, Ray DS, Khullar D, Guleria S, Bansal S, Gang S, Bhalla AK, Prakash J, Abraham A, Shroff S, Bahadur MM, Das P, Anandh U, Chaudhury AR, Singhal M, Kothari J, Raju SB, Pahari DK, Siddini G V, Sudhakar G, Varughese S, Saha TK. Clinical perspectives towards improving risk stratification strategy for renal transplantation outcomes in Indian patients. Indian J Transplant 2022;16:145-54
|How to cite this URL:|
Kher V, Kute VB, Sahariah S, Ray DS, Khullar D, Guleria S, Bansal S, Gang S, Bhalla AK, Prakash J, Abraham A, Shroff S, Bahadur MM, Das P, Anandh U, Chaudhury AR, Singhal M, Kothari J, Raju SB, Pahari DK, Siddini G V, Sudhakar G, Varughese S, Saha TK. Clinical perspectives towards improving risk stratification strategy for renal transplantation outcomes in Indian patients. Indian J Transplant [serial online] 2022 [cited 2022 Oct 1];16:145-54. Available from: https://www.ijtonline.in/text.asp?2022/16/2/145/349329
| Introduction|| |
Acute cellular rejection (ACR) and acute and chronic antibody-mediated rejection (ABMR) are important determinants of long-term outcome in kidney transplant. Although the rates of ACR and acute ABMR have come down significantly with newer immunosuppressive regimens, increased use of induction agents and better immunological evaluation prior to transplant,, chronic ABMR remains the most common cause of death censored graft loss after first year of transplant. Several factors such as type of donor (living or deceased), duration of dialysis, recipient characteristics influence graft outcome.
The type of donor organ is an important factor predicting the graft survival. While only ~40% of renal allografts in the US are obtained from living donors, in Indian transplant centers, the proportion is >80%. Living donor transplantations reduce the delays associated with long waiting times for deceased donors, while providing the advantage of an elective procedure, thereby reducing the time on dialysis.,, Living donor transplantations are also perceived to have a relatively lower immunological risk compared to deceased donor transplantation., However, contrary to this perception among nephrologists, the incidence of acute rejection rates are comparable for living and deceased donor recipients.
The Kidney Disease: Improving Global Outcomes (KDIGO) 2009 guidelines, while listing risk factors in renal transplantation and providing a framework for therapies to be used for patients at different risk levels, the application of these guidelines globally are lacking., In addition, the guideline has not been updated since 2009., The utility of KDIGO guidelines in Indian population also needs to be assessed, as the criteria used for risk assessment in the guidelines were based on data from studies conducted in the Caucasian population, and the guidelines were established in the cyclosporine era while the immunosuppression today is mostly tacrolimus based. Revised guidelines are awaited and expected to be available soon.
There is dearth of publication on long-term outcome data of kidney transplant recipients in India. The study from AIIMS has reported 10-year graft survival in 30% of the cohort –most of whom were below 30 years of age, had chronic glomerulonephritis as a cause of end-stage kidney disease and were on cyclosporine and azathioprine. This contrasts with the state of practice in the western world as well as in India. Thus an expert forum was identified to revisit the guidelines and adapt the immunosuppressive regimens tailored toward Indian patients requiring renal transplantation. This is especially important as induction therapy is largely applied in both deceased and living donor transplantations in India., Taken together, there is a need for a comprehensive risk stratification strategy to ensure the use of precise immunosuppressive regimens in Indian clinical practice.
In this article, we aim to define risk factors in kidney transplants and provide direction toward evidence- and clinical experience- based risk stratification for donor/recipient and transplant-related characteristics, with a focus on living donor transplantations.
| Defining Risk in Renal Transplantation: Donor, Recipient, Transplant-Related Factors|| |
Importance of risk stratification in renal transplantation
Risk stratification based on donor, recipient, and transplant-related factors is an important method to select the appropriate immunosuppression regimen for a patient; it can help strike a balance between avoiding acute rejection and excessive immunosuppression (reducing infection risk) and reduce other adverse events such as new-onset diabetes mellitus, dyslipidemia, and nephrotoxicity. Risk stratification is also the key to individualized therapy following kidney transplantation., [Table 1] provides an overview of the impact of various donor, recipient, and transplant-related risk factors on renal transplantation outcomes. Based on a questionnaire-based survey, followed by discussions on the survey results, Indian experts in the field of renal transplantation unanimously agreed on the need for risk stratification criteria for kidney transplantations which will be applicable to India.
Factors influencing the outcomes of renal transplantation
The outcome of renal transplantation depends on various clinical and immunologic risk factors. Identification and management of such factors may improve the overall outcomes of the transplantation procedure.
- Clinical risk factors (donor/recipients): Age, gender, body mass index, race, viral infections such as cytomegalovirus (CMV), BK virus and human immunodeficiency virus (HIV), immunosuppressive drug noncompliance.
- Immunological risk factors: Degree of human leukocyte antigen (HLA) mismatch, pre-transplant donor-specific antibodies (DSAs), panel reactive antibodies (PRAs) mostly in deceased donation, alloantigen specific memory B cells, presence of cross reactive and donor-specific memory T cells and presence of antibodies against non-HLA antigens like auto antigens or MHC class 1-related chain A (MICA). Pre-transplant levels of soluble CD30 (sCD30) has also been studied as a risk factor; however, there is no compelling evidence for it.
Although the independent risk factors have been discussed before, a holistic risk stratification scoring system is needed to understand the effect of these on the outcomes of renal transplant. Owing to several challenges in utilizing KDIGO 2009 guideline in the Indian transplant settings, there are differences in perspective regarding its implementation. KDIGO definition of high-risk factors for acute rejection has been described in the Supplementary Section.
| Methodology of Developing Questionnaire and Conduct of Survey|| |
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. At the end of 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.
Topics discussed by experts
- Question 1: Do you consider younger recipient age as a risk factor for acute rejection?
- Question 2: Do you consider recipients of Asian ethnicity to have a higher risk for acute rejection?
- Question 3: Do you consider HLA mismatches as a risk factor for acute rejection? If so, how important is it and do you quantify it?
- Question 4: Do you consider low DSA titers as a risk factor for rejection?
- Question 5: Do you consider PRA positive as a risk factor for acute rejection?
- Question 6: Do you consider deceased donor transplant riskier than living donor transplants if cold ischemia time is not very high?
- Question 7: Do you consider older donor as a risk factor for acute rejection?
- Question 8: Do you consider transplants with high risk for delayed graft function (DGF) as high risk for acute rejection?
- Question 9: Should induction agents be used in high-risk transplants?
- Question 10: Are KDIGO 2009 guidelines applicable to the Indian setting?
The risk stratification scoring system discussed by our expert committee is presented in [Figure 1].,,,,
|Figure 1: Risk stratification criteria in kidney transplantation. AR: Acute rejection, CI: Confidence interval, DSA: Donor-specific antibody, HLA: Human leukocyte antigen, HR: Hazard ratio. Source: Lim et al. Do Nguyen et al. Lebranchu et al. Molina et al. Prezelin-Reydit et al.,,,,|
Click here to view
| Results from the Survey and its Comparison with the Rest of the World Guidelines|| |
Renal transplantation from deceased donor is considered to be an alternative to matched live donor transplants., Having a deceased donor was thought to be an independent risk factor by 10%–12% of the experts. In line with the reports available in literature, 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 deceased donations, the cause of death does not have substantial impact on renal transplant outcomes if blood circulation is maintained at the time of donation. Hypertension, diabetes mellitus, and other comorbidities may be important considerations as they may alter the blood supply to the kidney. An exception to this is cases of death due to sepsis, where higher chances of acute rejection have been noted.
The experts stated that in cases of donation after cardiac death (DCD), there is a higher risk of DGF which provokes the formation of anti-HLA antibodies. This increases the risk of rejection. Similar reports are available in literature that indicate that DCD kidneys have higher rates of primary nonfunction, DGF, and rejection,, than donation after brain death (DBD). Around 4.17% expert in the survey, considered this to be a very high risk for rejection. Though in India, live donor transplants are most performed, rate of graft and patient survival rate of transplant from deceased donor in a study conducted at tertiary care Centre in India was equally satisfactory. The authors suggested that there is a need to sensitize and expand the rate of deceased transplantation to upsurge the donor pool.
Live donor transplants in the western world have gained significant importance in recent times due to organ shortage. Continued research and growth in medical science has enabled successful donation from unrelated individuals and even individuals with ABO-incompatibilities. 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. They form the largest group of living kidney donors in India and are at a higher risk because of HLA mismatch and antigen sensitization and more so when the donor is the husband.
Living donor who is not an immediate family member may impose some risk. Conflicting results are evidenced in literature; a few studies indicated that grafts received from live related donors and live unrelated donors had comparable patient and graft survival outcomes, however, poorer outcomes with live unrelated donor transplants compared to live related donor transplants have been also reported.
Other donor characteristics
Donor age and body mass index (BMI) do not impose additional risk in cases of renal transplantation. A study by Sekito et al. demonstrated that kidney grafts from elderly living donors (≥60 years) were not associated with a decline in renal function, and their pathologic findings were comparable with those of young donors for up to 2 years' post-transplantation. Preimplantation renal histology in elderly donors may be helpful for predicting renal outcomes. Obese donors do not change the graft outcomes, however, it is advisable to not choose such individuals as donors as the risk is more for the donor than the recipient., Nevertheless, to increase the donor pool, obese individuals are now being considered both in case of living and deceased donors. If selected, when the donor work-up is done, underlying risk of obesity related kidney disease should be ruled out. A study by Alhamad et al. suggested that donor BMI 30 to 35 kg/m2, does not impact kidney allograft failure. CMV is regarded as the most common viral infection in adults after renal transplantation and its rate is significantly more frequent in older recipients. Other risk factors for CMV include positive donor serostatus, T-cell depleting induction, and other co-infections. Risk associated with D+/R-; D+/R+; and D-/R + as well as D-/R-; D+/R-serostatus is different and development of CMV infection in the recipient not only impacts the mortality but increases the risk of rejection. factors., Hepatitis C-infected (HCV+) deceased donors were underutilized for renal transplantation before the introduction of direct-acting antiviral agents.,, With high cure rates with newer therapies, a donor with HCV positive status is also considered for transplantation in current times. In a use of HCV+ donor and the HCV-uninfected recipients, we might be transferring the risk of infection and strategies to prevent HCV infection in HCV − recipients should be followed stringently.
HIV in the recipient may be a risk factor for acute rejection, a fact contrary to a general opinion. A multicenter case–control study compared outcome of renal transplant in HIV-positive (n = 20) patients with those who were HIV-negative (n = 40). Although there was no difference in the survival rate, HIV-positive recipients demonstrated lower incidence of immediate renal function and more acute rejection. However, another study from France suggested that post-transplant infections and not the HIV status, have detrimental effects on patient and graft survival. Locke et al. opined that proper donor selection and transplant recipient management, including the avoidance of prolonged cold ischemic time, use of living donors, and determination of optimal immunosuppression dosing before transplant, are key factors that determine the long-term graft survival HIV-positive patients.
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. The risk may increase slightly as the dialysis vintage increases. 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.
This is particularly relevant in the patients who remain on the deceased donation waiting list for a long time. On the other hand, living donation happens usually within a year of starting dialysis. Few experts believe that the duration of dialysis as a risk is only valid if sensitization has happened; the chances of sensitization are high in patients with long-term dialysis. If they have not received blood transfusions, the risk is comparable with other patients. This is in line with the results of a case-control study conducted by Masaki et al. which compared graft and patient survivals between the recipients who are on dialysis for >20 years and those with <20 years of dialysis vintage. The outcomes were comparable in both groups.
The long-term outcomes also do not vary based on the type of dialysis; graft survival being similar in both the patients undergoing peritoneal dialysis and hemodialysis. However, DGF and rejection rate may be higher in patients undergoing hemodialysis.
Advances in the understanding of renal transplantation techniques and outcomes have made renal re-transplantation possible, but the outcome of third and fourth transplant remains controversial. Han et al. established that graft survival of second renal transplantation was not significantly different from that of first renal 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.
A retrospective analysis assessed outcomes of patients who underwent third and fourth transplantation in 16 patients and showed that cases of third kidney transplantation showed satisfactory patient and graft survival. However, in cases of fourth transplant, the graft survival was on 33.3% at the end of 1 year. It is interesting to note that quality of the donor is an important determinant for graft survival in re-transplantation cases and living donor re-transplants are associated with similar outcomes as with the first transplant. Our survey results also indicated that third or fourth transplantation are associated with significant risk as suggested by around 30% of the experts.
Age and weight of the recipient
Although the survey categorized age as >60 years and ≤60 years, the experts believed that we cannot compare the risk of rejection between a 59-year-old and a 20-year-old recipient. Although both are <60 years of age; the immunologic and comorbid risk in these patients is different. Evidence suggests that recipient's age does not have a significant predictive value on outcomes of renal transplant. However, experts suggest that the rejection rate varies with age and a pediatric patient has a different rejection rate than the adolescent and a person in his 30s or 40s. The rejection risk is low in older recipients. The significance of donor-recipient age difference as a prognostic indicator on short- and long-term graft and patient survival has also been investigated.,, Although the 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.
A recipient with a BMI <25 kg/m2 is comparatively at a lower risk than a recipient with a BMI >35 kg/m2. A retrospective study conducted by Liese et al. also confirmed that increased recipient BMI at the time of renal transplantation is a prognosticator of adverse outcomes, including DGF. A systematic review and meta-analysis exploring the correlation between recipient obesity and mortality, death-censored graft loss and DGF subsequent to kidney transplantation, concluded that even though there seems to be an increased possibility of DGF, obese transplant recipients have only a slightly higher risk of graft loss. They have similar graft survival when compared to recipients with normal BMI. 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
DSA has been recognized as a standard biomarker in predicting transplant outcomes, and its presence has been associated with a higher incidence of antibody-mediated rejection, graft dysfunction, and lower graft survival. Patients with high titers of preformed DSAs (mean fluorescence intensity >1000) need desensitization prior to transplant to prevent acute antibody-mediated rejection., Around 13%–30% of formerly non-sensitized patients develop de novo DSAs, primarily targeted to donor HLA class 2 mismatches, after renal transplant.,,,,,,, Non-HLA antibodies such as preformed hemagglutinin A and/or B antibody, MICA and angiotensin II type 1 receptor can also cause antibody-mediated rejection and graft loss.
Through HLA typing and identification of ABO blood types and titers, autologous HLA and non-HLA antibodies and complement dependent cytotoxicity (CDC) crossmatch techniques, identifying patients at higher risk of rejection is possible. All the participating experts agreed that presence of DSA increases the risk of rejection. The risk ranges from moderate to very high, on the other hand, the absence of DSA is important to prevent rejection. Interestingly, pretransplant DSA may recede immediately after transplantation in several patients without any clinical effect, whereas in others, even weak pretransplant DSA persist and result in severe consequences leading to rejection.,
The basis of selecting immunosuppressive therapy for living donor renal transplantation needs to be guided by comprehensive assessment of immunological risks for individual patients.
HLA and risk of rejection in renal transplant patients
Antibodies to HLA molecules, the polymorphic antigens that comprise an immunodominant alloreactive trigger for the immune response, are known to be associated with late graft loss, lower graft survival, poor transplant function, and proteinuria.,, HLA class 1 antigens (A, B, and C) are expressed on all nucleated cells, whereas HLA class 2 antigens (DR, DQ, and DP) are normally confined to antigen-presenting cells (dendritic cells, B cells, and macrophages). The formation of pretransplant HLA class I and II alloantibodies can be induced through exposures to blood transfusions, prior transplants, and pregnancy.
Flow cytometric cross match increases the sensitivity of antibody detection and is useful when solid phase assays are not available or possible due to financial constraints. It helps to select patients who need to do solid phase assays (i.e., CDC negative, flow positive). Solid phase immunoassays such as enzyme linked immunoassays and single antigen bead assays on the Luminex platform have significantly improved the precision of detecting antibodies. For stratification of risk in this survey, the HLA matching score was categorized into three different groups: <3, =3, and >3 [Figure 2]. Although a definite consensus was not achieved, the experts suggested that only assessing HLA mismatch is not sufficient; it is also important to consider at what locus the mismatch occurs. Secondly, 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 2: HLA antibodies as a risk factor for acute rejection in renal transplant: Survey results. HLA: Human leukocyte antigen|
Click here to view
PRA and risk of rejection in renal transplant patients
Recipients who have previously formed DSAs (anti-HLA antibodies) and non-HLA antibodies and/or a historical positive crossmatch by CDC and/or flow cytometry are cases with high risk of hyperacute or accelerated acute rejections., The estimation of PRA prior to transplantation forms the basis of deceased donor organ allocation and is an important step to identify sensitized patients. The present survey grouped PRAs as 0%–20%, 20%–40% and >40%; while most of the experts felt that having PRA in between 0–20% is a mild risk factor for acute rejection, 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 [Figure 3]. PRA does not add value to risk stratification in living donor transplantation.
|Figure 3: PRA as a risk factor for acute rejection in renal transplant: Survey results. PRA: Panel reactive antibodies|
Click here to view
Cold ischemia time and risk of rejection in renal transplant patients
Increased cold ischemia time (CIT) is the most important risk factor for DGF and suboptimal graft outcomes after kidney transplant. Delayed graft function in turn is associated with higher rejection rates and worse outcomes in renal transplant patients., Immunological investigations before deceased donor transplant leads to prolonged CIT and delays the process especially in highly sensitized patients and patients receiving kidney from marginal donors., Hansson et al. established that the risk of graft loss increased, with a CIT cutoff of ≥14 h as compared with CIT <14 h. Another study stated that CIT >20 h is a risk factor for DGF. In the present survey, we used a cut-off of 24 h 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 (cold ischemia time, 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.
| Risk Stratification Strategy|| |
- In an economically diverse country like India, risk stratification strategy should consider whether a test is absolutely necessary for stratifying risk
- Precision tests should be done only where there are doubts regarding risk stratification
| Conclusion|| |
There is a long waiting list of patients requiring deceased donor transplantation across India. 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. Based on risk stratification strategy, tailored immunosuppression regimens can be selected to avoid the risk of acute rejection. 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 rejections after renal transplantation with good safety profile.
Financial support and sponsorship
Medical writing and open access-related charges were paid for by Sanofi India. The authors received no honoraria from Sanofi directly or indirectly related to the development of this publication.
Conflicts of interest
There are no conflicts of interest.
| Supplementary Section|| |
KDIGO definition of highrisk factors for acute rejection
- The number of HLA mismatches (A)
- Younger recipient age (B)
- Older donor age (B)
- African American ethnicity (in the United States) (B)
- Panel Reactive Antibody (PRA) >0% (B)
- Presence of a donor-specific antibody (DSA) (B)
- Blood group incompatibility (B)
- Delayed onset of graft function (B)
- Cold ischemia time >24 hours (C)
(where A is the universal agreement, B is the majority agreement and C is a single study)
| References|| |
Clayton PA, McDonald SP, Russ GR, Chadban SJ. Long-term outcomes after acute rejection in kidney transplant recipients: An ANZDATA analysis. J Am Soc Nephrol 2019;30:1697-707.
Radhakrishnan R, Basu G, Mohapatra A, Alexander S, Valson A, Jacob S, et al.
Utility of induction agents in living donor kidney transplantation. Indian J Transplantat 2019;13:202-9.
Chauhan R, Tiwari A, Rajvanshi C, Mehra S, Aggarwal G, Bansal S, et al.
Evaluation of screening tests for pre-transplant compatibility testing in live-related kidney transplants: Single-center report from India – A prospective observational study. Indian J Transplant 2021;15:99-103. [Full text]
Naesens M, Kuypers DR, De Vusser K, Vanrenterghem Y, Evenepoel P, Claes K, et al.
Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure. Am J Transplant 2013;13:86-99.
Lentine KL, Patel A. Risks and outcomes of living donation. Adv Chronic Kidney Dis 2012;19:220-8.
Kute VB, Agarwal SK, Sahay M, Kumar A, Rathi M, Prasad N, et al.
Kidney-paired donation to increase living donor kidney transplantation in India: Guidelines of Indian Society of Organ Transplantation-2017. Indian J Nephrol 2018;28:1-9.
] [Full text]
Rudge C, Matesanz R, Delmonico FL, Chapman J. International practices of organ donation. Br J Anaesth 2012;108 Suppl 1:i48-55.
Qiu J, Li J, Chen G, Huang G, Fu Q, Wang C, et al.
Induction therapy with thymoglobulin or interleukin-2 receptor antagonist for Chinese recipients of living donor renal transplantation: A retrospective study. BMC Nephrol 2019;20:101.
Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. Transpl Int 2013;26:662-72.
Matas AJ, Smith JM, Skeans MA, Thompson B, Gustafson SK, Stewart DE, et al.
OPTN/SRTR 2013 annual data report: Kidney. Am J Transplant 2015;15 Suppl 2:1-34.
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9 Suppl 3:S1-155.
Nga HS, Garcia PD, Contti MM, Takase HM, de Carvalho MF, de Andrade LG. Different induction therapies for kidney transplantation with living donor. J Bras Nefrol 2015;37:206-11.
Gaber AO, Matas AJ, Henry ML, Brennan DC, Stevens RB, Kapur S, et al.
Antithymocyte globulin induction in living donor renal transplant recipients: Final report of the TAILOR registry. Transplantation 2012;94:331-7.
Agarwal SK, Dash SC, Mehta SN, Gupta S, Bhowmik D, Tiwari SC, et al.
Results of renal transplantation on conventional immunosuppression in second decade in India: A single centre experience. J Assoc Physicians India 2002;50:532-6.
Khullar D, Gaikwad J, Malik M, Ojha S, Gupta A, Bhalla AK, et al.
ATG induction in renal transplantation – A single center experience: 1961. Transplantation 2008;86:645.
Kute VB, Gumber MR, Patel HV, Shah PR, Vanikar AV, Modi PR, et al.
Outcome of kidney paired donation transplantation to increase donor pool and to prevent commercial transplantation: A single-center experience from a developing country. Int Urol Nephrol 2013;45:1171-8.
Lentine KL, Kasiske BL, Levey AS, Adams PL, Alberú J, Bakr MA, et al.
KDIGO clinical practice guideline on the evaluation and care of living kidney donors. Transplantation 2017;101:S1-109.
Pratschke J, Dragun D, Hauser IA, Horn S, Mueller TF, Schemmer P, et al
. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplant Rev 2016;30:77-84.
Ledesma-Gumba MA, Danguilan RA, Casasola CC, Ona ET. Efficacy of risk stratification in tailoring immunosuppression regimens in kidney transplant patients at the national kidney and transplant institute. Transplant Proc 2008;40:2195-7.
Lim WH, Chadban SJ, Clayton P, Budgeon CA, Murray K, Campbell SB, et al.
Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients. Clin Transplant 2012;26:E428-37.
Do Nguyen HT, Wong G, Chapman JR, McDonald SP, Coates PT, Watson N, et al.
The association between broad antigen HLA mismatches, eplet HLA mismatches and acute rejection after kidney transplantation. Transplant Direct 2016;2:e120.
Lebranchu Y, Baan C, Biancone L, Legendre C, Morales JM, Naesens M, et al.
Pretransplant identification of acute rejection risk following kidney transplantation. Transpl Int 2014;27:129-38.
Molina J, Navas A, Agüera ML, Rodelo-Haad C, Alonso C, Rodríguez-Benot A, et al.
Impact of preformed donor-specific anti-human leukocyte antigen antibody C1q-binding ability on kidney allograft outcome. Front Immunol 2017;8:1310.
Prezelin-Reydit M, Combe C, Harambat J, Jacquelinet C, Merville P, Couzi L, et al.
Prolonged dialysis duration is associated with graft failure and mortality after kidney transplantation: Results from the French transplant database. Nephrol Dial Transplant 2019;34:538-45.
Corry RJ, Thompson JS, Freeman RM, Colville DS. Critical comparison of renal transplant survival between recipients of live related donor and cadaver organs. Surg Gynecol Obstet 1978;146:519-23.
Mukherjee D, Nair RK, Sharma S, Datt B, Rao A, Prakash S. Cadaveric renal transplantation: Our experience at a tertiary care centre in India. Med J Armed Forces India 2020;76:58-62.
Snoeijs MG, Winkens B, Heemskerk MB, Hoitsma AJ, Christiaans MH, Buurman WA, et al.
Kidney transplantation from donors after cardiac death: A 25-year experience. Transplantation 2010;90:1106-12.
Weber M, Dindo D, Demartines N, Ambühl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med 2002;347:248-55.
Cho YW, Terasaki PI, Cecka JM, Gjertson DW. Transplantation of kidneys from donors whose hearts have stopped beating. N Engl J Med 1998;338:221-5.
Nöhre M, Pollmann I, Mikuteit M, Weissenborn K, Gueler F, de Zwaan M. Partnership satisfaction in living kidney donors. Front Psychiatry 2018;9:353.
Matter YE, Nagib AM, Lotfy OE, Alsayed AM, Donia AF, Refaie AF, et al.
Impact of donor source on the outcome of live donor kidney transplantation: A single center experience. Nephrourol Mon 2016;8:e34770.
Humar A, Durand B, Gillingham K, Payne WD, Sutherland DE, Matas AJ. Living unrelated donors in kidney transplants: Better long-term results than with non-HLA-identical living related donors? Transplantation 2000;69:1942-5.
Sekito S, Nishikawa K, Masui S, Hasegawa Y, Kanda H, Arima K, et al.
Effect of donor age on graft function and pathologic findings in living donor transplantation. Transplant Proc 2018;50:2431-5.
Lim K, Lee YJ, Gwon JG, Jung CW, Yang J, Oh SW, et al.
Impact of donor age on the outcomes of kidney transplantation from deceased donors with histologic acute kidney injury. Transplant Proc 2019;51:2593-7.
Locke JE, Reed RD, Massie A, MacLennan PA, Sawinski D, Kumar V, et al.
Obesity increases the risk of end-stage renal disease among living kidney donors. Kidney Int 2017;91:699-703.
Locke JE, Reed RD, Massie AB, MacLennan PA, Sawinski D, Kumar V, et al.
Obesity and long-term mortality risk among living kidney donors. Surgery 2019;166:205-8.
Cantarelli C, Cravedi P. Criteria for living donation from marginal donors: One, no one, and one hundred thousand. Nephron 2019;142:227-32.
Alhamad T, Malone AF, Lentine KL, Brennan DC, Wellen J, Chang SH, et al.
Selected mildly obese donors can be used safely in simultaneous pancreas and kidney transplantation. Transplantation 2017;101:1159-66.
Hemmersbach-Miller M, Alexander BD, Sudan DL, Pieper C, Schmader KE. Infections after kidney transplantation. Does age matter? Clin Transplant 2019;33:e13516.
Leeaphorn N, Garg N, Thamcharoen N, Khankin EV, Cardarelli F, Pavlakis M. Cytomegalovirus mismatch still negatively affects patient and graft survival in the era of routine prophylactic and preemptive therapy: A paired kidney analysis. Am J Transplant 2019;19:573-84.
Gatault P, Al-Hajj S, Noble J, Chevallier E, Piollet M, Forconi C, et al.
CMV-infected kidney grafts drive the expansion of blood-borne CMV-specific T cells restricted by shared class I HLA molecules via presentation on donor cells. Am J Transplant 2018;18:1904-13.
Chen K, Lu P, Song R, Zhang J, Tao R, Wang Z, et al.
Direct-acting antiviral agent efficacy and safety in renal transplant recipients with chronic hepatitis C virus infection: A PRISMA-compliant study. Medicine (Baltimore) 2017;96:e7568.
Colombo M, Aghemo A, Liu H, Zhang J, Dvory-Sobol H, Hyland R, et al.
Treatment with ledipasvir-sofosbuvir for 12 or 24 weeks in kidney transplant recipients with chronic hepatitis C virus genotype 1 or 4 infection: A randomized trial. Ann Intern Med 2017;166:109-17.
Fernández I, Muñoz-Gómez R, Pascasio JM, Baliellas C, Polanco N, Esforzado N, et al.
Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C. J Hepatol 2017;66:718-23.
Sise ME, Wojciechowski D, Chute DF, Gustafson J, Chung RT, Williams WW, et al.
Process of selecting and educating HCV-uninfected kidney waiting-list candidates for HCV-infected kidney transplantation. Artif Organs 2019;43:913-20.
Durand CM, Bowring MG, Brown DM, Chattergoon MA, Massaccesi G, Bair N, et al.
Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients: An open-label nonrandomized trial. Ann Intern Med 2018;168:533-40.
Locke JE, James NT, Mannon RB, Mehta SG, Pappas PG, Baddley JW, et al.
Immunosuppression regimen and the risk of acute rejection in HIV-infected kidney transplant recipients. Transplantation 2014;97:446-50.
Mazuecos A, Fernandez A, Andres A, Gomez E, Zarraga S, Burgos D, et al.
HIV infection and renal transplantation. Nephrol Dial Transplant 2011;26:1401-7.
Ailioaie O, Arzouk N, Valantin MA, Tourret J, Calin RO, Turinici M, et al.
Infectious complications in HIV-infected kidney transplant recipients. Int J STD AIDS 2018;29:341-9.
Locke JE, Montgomery RA, Warren DS, Subramanian A, Segev DL. Renal transplant in HIV-positive patients: Long-term outcomes and risk factors for graft loss. Arch Surg 2009;144:83-6.
Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for renal transplant outcomes: A paired donor kidney analysis. Transplantation 2002;74:1377-81.
Masaki N, Iwadoh K, Kondo A, Koyama I, Nakajima I, Fuchinoue S. Influence of long-term dialysis on the outcome of kidney transplantation: A single-center study. Transplant Proc 2017;49:959-62.
Dębska-Ślizień A, Bobkowska-Macuk A, Bzoma B, Moszkowska G, Milecka A, Zadrożny D, et al.
Paired analysis of outcomes after kidney transplantation in peritoneal and hemodialysis patients. Transplant Proc 2018;50:1646-53.
Han SH, Go J, Park SC, Yun SS. Long-term outcome of kidney retransplantation in comparison with first transplantation: A propensity score matching analysis. Transplant Proc 2019;51:2582-6.
Friedersdorff F, Patabendhi S, Busch J, Kempkensteffen C, Halleck F, Fuller TF, et al.
Outcome of patients after third and fourth kidney transplantation. Urol Int 2016;97:445-9.
Bellini MI, Courtney AE, McCaughan JA. Living donor kidney transplantation improves graft and recipient survival in patients with multiple kidney transplants. J Clin Med 2020;9:2118.
Abou-Jaoude MM, Khoury M, Nawfal N, Shaheen J, Almawi WY. Effect of recipient age on the outcome of kidney transplantation. Transpl Immunol 2009;20:118-20.
Kute VB, Vanikar AV, Shah PR, Gumber MR, Patel HV, Engineer DP, et al.
Does donor-recipient age difference matter in outcome of kidney transplantation? Implications for kidney paired donation. Ren Fail 2014;36:378-83.
Shin M, Park JB, Kwon CH, Joh JW, Lee SK, Kim SJ. Enhanced significance of donor-recipient age gradient as a prognostic factor of graft outcome in living donor kidney transplantation. World J Surg 2013;37:1718-26.
Shin M, Moon HH, Kim JM, Park JB, Kwon CH, Joh JW, et al.
Implication of donor-recipient age gradient in the prognosis of graft outcome after deceased-donor kidney transplantation. Transplant Proc 2013;45:2907-13.
Liese J, Bottner N, Büttner S, Reinisch A, Woeste G, Wortmann M, et al.
Influence of the recipient body mass index on the outcomes after kidney transplantation. Langenbecks Arch Surg 2018;403:73-82.
Hill CJ, Courtney AE, Cardwell CR, Maxwell AP, Lucarelli G, Veroux M, et al.
Recipient obesity and outcomes after kidney transplantation: A systematic review and meta-analysis. Nephrol Dial Transplant 2015;30:1403-11.
Miller AJ, Kiberd BA, Alwayn IP, Odutayo A, Tennankore KK. Donor-recipient weight and sex mismatch and the risk of graft loss in renal transplantation. Clin J Am Soc Nephrol 2017;12:669-76.
Zhang R. Donor-specific antibodies in kidney transplant recipients. Clin J Am Soc Nephrol 2018;13:182-92.
Itabashi Y, Aikawa A, Muramatsu M, Hyoudou Y, Shinoda K, Takahashi Y, et al.
Living-donor kidney transplant with preformed donor-specific antibodies. Exp Clin Transplant 2019;17:43-9.
Glotz D, Russ G, Rostaing L, Legendre C, Tufveson G, Chadban S, et al.
Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies. Am J Transplant 2019;19:2865-75.
Malheiro J, Tafulo S, Dias L, Martins S, Fonseca I, Beirão I, et al.
Determining donor-specific antibody C1q-binding ability improves the prediction of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation. Transpl Int 2017;30:347-59.
Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, et al.
Evolution and clinical pathologic correlations of de novo
donor-specific HLA antibody post kidney transplant. Am J Transplant 2012;12:1157-67.
Ntokou IS, Iniotaki AG, Kontou EN, Darema MN, Apostolaki MD, Kostakis AG, et al.
Long-term follow up for anti-HLA donor specific antibodies postrenal transplantation: High immunogenicity of HLA class II graft molecules. Transpl Int 2011;24:1084-93.
Guidicelli G, Guerville F, Lepreux S, Wiebe C, Thaunat O, Dubois V, et al.
Non-complement-binding de novo
donor-specific anti-HLA antibodies and kidney allograft survival. J Am Soc Nephrol 2016;27:615-25.
Fichtner A, Süsal C, Höcker B, Rieger S, Waldherr R, Westhoff JH, et al
. Association of C1q-fixing DSA with late graft failure in pediatric renal transplant recipients. Pediatr Nephrol 2016;31:1157-66.
Sutherland SM, Chen G, Sequeira FA, Lou CD, Alexander SR, Tyan DB. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss. Pediatr Transplant 2012;16:12-7.
Süsal C, Wettstein D, Döhler B, Morath C, Ruhenstroth A, Scherer S, et al.
Association of kidney graft loss with de novo
produced donor-specific and non-donor-specific HLA antibodies detected by single antigen testing. Transplantation 2015;99:1976-80.
Ramon DS, Huang Y, Zhao L, Rendulic T, Park JM, Sung RS, et al.
Use of complement binding assays to assess the efficacy of antibody mediated rejection therapy and prediction of graft survival in kidney transplantation. Hum Immunol 2017;78:57-63.
Michielsen LA, van Zuilen AD, Krebber MM, Verhaar MC, Otten HG. Clinical value of non-HLA antibodies in kidney transplantation: Still an enigma? Transplant Rev (Orlando) 2016;30:195-202.
Montgomery RA, Tatapudi VS, Leffell MS, Zachary AA. HLA in transplantation. Nat Rev Nephrol 2018;14:558-70.
David-Neto E, Souza PS, Panajotopoulos N, Rodrigues H, Ventura CG, David DS, et al.
The impact of pretransplant donor-specific antibodies on graft outcome in renal transplantation: A six-year follow-up study. Clinics (Sao Paulo) 2012;67:355-61.
Alagoz S, Seyahi N. Frequency of human leukocyte antigens and donor specific antibodies in long-term living donor kidney transplantation. Transplant Proc 2019;51:2302-7.
Alelign T, Ahmed MM, Bobosha K, Tadesse Y, Howe R, Petros B. Kidney transplantation: The challenge of human leukocyte antigen and its therapeutic strategies. J Immunol Res 2018;2018:5986740.
Lefaucheur C, Loupy A, Hill GS, Andrade J, Nochy D, Antoine C, et al.
Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol 2010;21:1398-406.
Meng HL, Jin XB, Li XT, Wang HW, Lü JJ. Impact of human leukocyte antigen matching and recipients' panel reactive antibodies on two-year outcome in presensitized renal allograft recipients. Chin Med J (Engl) 2009;122:420-6.
İnal A, Özçelik Ü, Ogan Uyanık E, Külah E, Demirağ A. Analysis of panel reactive antibodies in renal transplant recipients detected by luminex: A single-center experience. Exp Clin Transplant 2016;14:401-4.
Hansson J, Mjörnstedt L, Lindnér P. The risk of graft loss 5 years after kidney transplantation is increased if cold ischemia time exceeds 14 hours. Clin Transplant 2018;32:e13377.
Tugmen C, Sert I, Kebabcı E, Murat Dogan S, Tanrısev M, Alparslan C, et al.
Delayed graft function in kidney transplantation: Risk factors and impact on early graft function. Prog Transplant 2016;26:172-7.
Mannon RB. Delayed graft function: The AKI of kidney transplantation. Nephron 2018;140:94-8.
Lauronen J, Peräsaari JP, Saarinen T, Jaatinen T, Lempinen M, Helanterä I. Shorter cold ischemia time in deceased donor kidney transplantation reduces the incidence of delayed graft function especially among highly sensitized patients and kidneys from older donors. Transplant Proc 2020;52:42-9.
Postalcioglu M, Kaze AD, Byun BC, Siedlecki A, Tullius SG, Milford EL, et al.
Association of cold ischemia time with acute renal transplant rejection. Transplantation 2018;102:1188-94.
Gorayeb-Polacchini FS, Caldas HC, Fernandes-Charpiot IM, Ferreira-Baptista MA, Gauch CR, Abbud-Filho M. Impact of cold ischemia time on kidney transplant: A mate kidney analysis. Transplant Proc 2020;52:1269-71.
[Figure 1], [Figure 2], [Figure 3]