|Year : 2022 | Volume
| Issue : 2 | Page : 211-215
A prospective comparative study from India between living genetically related and unrelated donor renal transplants
Nitin Agarwal, Anil Kumar Singh Rana, Aakansh Jain
Department of Surgery and Transplant, Atal Bihari Vajpayee Institute of Medical Sciences, Dr. Ram Manohar Lohia Hospital, New Delhi, India
|Date of Submission||18-May-2021|
|Date of Acceptance||29-Jul-2021|
|Date of Web Publication||30-Jun-2022|
Prof. Nitin Agarwal
Room 304, Guest House, Atal Bihari Vajpayee Institute of Medical Sciences, Dr. Ram Manohar Lohia Hospital, New Delhi 110 001
Source of Support: None, Conflict of Interest: None
Background: India has a significant backlog in terms of renal transplant waiting lists, and progress of deceased donor transplant is limited by social and cultural hurdles. Newer strategies in living donation are needed. Materials and Methods: A prospective comparative study was conducted at our tertiary hospital over 3 years, between living related donor (LRD) and living unrelated donor (LURD) renal transplant outcomes, chiefly acute rejection and graft dysfunction. Confounding variables and outcome parameters such as mortality, hospital stay >21 days, and complications were recorded for 6 months. Results: LRD (n = 78) and LURD (n = 42) groups differed significantly in median recipient age (25 [22–34] vs. 40 [33–50] years; P < 0.001) and human leukocyte antigen (HLA) mismatches >3 (3/78 [3.8%] vs. 32/78 [76.2%]; P < 0.001, respectively). Yet, there was no significant difference in donor age, gender, immunosuppression, preoperative hemodialysis, nephrectomy time, or warm ischemia time. No significant difference was noted between LRD and LURD in acute rejection rate, graft dysfunction at 1 week and 6 months, mortality, hospital stay >21 days, or complication rate. Among factors predictive for acute rejection, only anastomotic time had a significant association (β coefficient = 0.006 [0.001–0.010]; Pearson's coefficient “r” =0.208; P < 0.01), while for early graft dysfunction, it was only mean donor nephrectomy time in minutes (β coefficient=-0.002 [−0.004–0.000]; Pearson's coefficient “r” = −0.158; P = 0.042). Conclusion: Despite differences in HLA-mismatches and age, LRD and LURD had a similar short-term outcome with respect to acute rejection and graft dysfunction. This is linked to better and standardized immunosuppression available, making it possible to expand the scope of LURD beyond spousal, within the legal and ethical boundaries.
Keywords: Acute rejection, living related donors, renal transplant, unrelated spousal donors
|How to cite this article:|
Agarwal N, Rana AK, Jain A. A prospective comparative study from India between living genetically related and unrelated donor renal transplants. Indian J Transplant 2022;16:211-5
|How to cite this URL:|
Agarwal N, Rana AK, Jain A. A prospective comparative study from India between living genetically related and unrelated donor renal transplants. Indian J Transplant [serial online] 2022 [cited 2022 Aug 15];16:211-5. Available from: https://www.ijtonline.in/text.asp?2022/16/2/211/349357
| Introduction|| |
Chronic kidney disease is a major cause of mortality and morbidity in India, due to the disproportionately high prevalence of diabetes mellitus and hypertension (HT). Despite the documented benefits of early transplant for patients of end-stage renal disease in terms of survival and quality of life, the shortfall remains at over 150,000 cases every year. Mortality on the waiting list is high, compounded by the limited facilities for hemodialysis across the country. Due to many sociocultural and religious factors, compounded by poor infrastructure and personnel, the ratio of deceased donor to live donor renal transplants is also poor (<1:10). These problems call for various strategies to increase both living and deceased donation in India.
Attempts to increase the number of unrelated living transplants have met both scientific and societal hurdles. Poor genetic and human leukocyte antigen (HLA) matches seen in unrelated pairs till recently were associated with poor graft outcomes; newer guidelines and the use of quadruple regimens (interleukin (IL)-2 receptor antagonists such as basiliximab and rabbit-derived antithymocyte globulin [rATG]) have negated the role of HLA to a large extent, especially with respect to acute rejection. Paid donation as seen in parts of Asia has had mixed results and raises many ethical and psychological issues., Hence, all types of unrelated and altruistic donations should be increased to contribute to a significant change in donor numbers.
Many authors have compared living-related donor (LRD) versus living unrelated donor (LURD) transplants in the past two decades. It was initially established that LURD was superior or equivalent to deceased donor renal transplants, in terms of graft and patient survival., This was attributed to better HLA compatibility. Subsequently, there have been attempts to compare LRD and LURD renal transplants in many large series; a systematic review of 12 studies was also published in 2017., The available evidence suggests that LURD is equivalent to LRD in terms of graft survival and acute rejection, despite some studies reporting poor HLA matching in LURD. However, the data are mostly retrospective, and adequate matching of confounding factors has not been done. We planned a prospective study in this regard.
| Materials and Methods|| |
This prospective comparative study was conducted in the renal transplant unit of our tertiary care hospital in north India, over a 3-year period, involving the departments of nephrology, surgery, and anesthesia. Written informed consent from the participants and due clearance from the institutional ethics committee (No. 1-40/45/2014/IEC/Thesis/PGIMER-RMLH/1489 dated October 2014), as per the Declaration of Helsinki guidelines, were completed. The evaluation started preoperatively in the transplant clinic, where prospective live donors underwent a routine hematological and biochemical screening along with blood grouping and HLA typing. Screening for viral illnesses (HIV, HBsAg, hepatitis C virus, cytomegalovirus [CMV]), and common malignancies (breast, prostate, lung, cervix etc.,) was performed as per protocol. Comorbidities such as HT, diabetes, coronary artery disease, and hyperthyroidism were also ruled out or optimized as per guidelines. After the prospective donation was deemed safe and legally valid, computed tomography angiography of the renal vessels, DTPA scan for individual kidney function, and crossmatch for B and T lymphocytes including DNA typing, were performed. The recipient underwent simultaneous evaluation for fitness for the procedure and compatibility with the donor. Duplex imaging was used to assess the site of anastomoses. The relationship between the donor and recipient was sought and confirmed; Group 1 was designated as live-related donors (LRD), comprising all genetically related donors (parents, siblings, grandparents, etc.,), whereas Group 2 was designated as live unrelated donors (LURD) comprising spouses and other genetically unrelated donors. Deceased donor renal transplant pairs and were excluded from the study. All procedural and legal forms were completed as per the guidelines issued by the National Organ and Tissue Transplant Organization. The group allocation was sequential and nonrandomized. Demographic and clinical details of the enrolled transplant pairs were recorded in the case record forms.
The renal transplant procedure was performed by a standard technique; open donor nephrectomy was performed for all cases. The graft kidney was anastomosed into the recipient in an extraperitoneal location (mostly right) using vascular and ureteric anastomoses. All operative details and complications were recorded. The two groups were compared; the primary outcome parameter was acute rejection proved by graft biopsy. Other outcome parameters were postoperative graft dysfunction (1 week and 6 months), graft arterial stenosis/thrombosis, hospital stay >21 days, and mortality. The same group of surgeons was involved in all cases including the chief surgeon. All variables expected to affect the primary outcome measure such as age, gender, induction regimen, duration of preoperative dialysis, duration of donor nephrectomy, warm ischemia time (anastomotic time), supernumerary arteries, and HLA mismatch ≥3 were recorded. For the purpose of the study, graft dysfunction was defined as the need for postoperative hemodialysis and/or serum creatinine >2 in the postoperative period (analyzed at week 1 and month 6).
Data were analyzed using SPSS (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp, USA) Trial version 2019–20 for PCs. Descriptive statistics were used for clinical and demographic characteristics. Both groups were compared with respect to the primary outcome measure, i.e., rate of acute rejection. For analytical statistics, the Chi-square test and t-test were used for qualitative and quantitative variables; if distribution was nonparametric, the Fisher's exact test or Mann–Whitney U-test was used accordingly. Confidence intervals were taken within 95% and a significant P < 0.05. To identify risk factors for outcomes like acute rejection and graft dysfunction in all patients, linear and binary logistic regression was used, with Pearson's coefficient “r” and standardized β coefficient.
The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.
Institutional Ethics Committee, ABVIMS and Dr. RMLH, Delhi, India; (No. 1 40/45/2014/IEC/Thesis/PGIMER RMLH/1489 dated October 2014). The study was performed according to the guidelines in Declaration of Helsinki.
| Results|| |
In a period of 23 months, we recruited 134 consecutive donor-recipient pairs; we performed 7 deceased donor renal transplants in this phase which were excluded from the study. Final eligible pairs were 120; 78 were evaluated in Group 1 or LRD. Of these, 44/78 were mothers (56%), 15/78 were fathers (19%), 13/78 were sisters (17%), 4/78 were brothers (5%), one each were maternal aunt and grandmother. In Group 2 or LURD, 39/42 were wives (93%), while 3/39 were husbands (7%). Fourteen pairs were excluded for the following reasons: Recipient death (4), lack of recipient fitness for surgery (3), lost to follow-up (3), unsuitable donor vasculature (2), and refusal due to undisclosed reasons (2).
[Table 1] summarizes the demographic and clinical details of all the patients. Except for recipient age and HLA mismatch of 3 or more, all other parameters were matched between the groups. Blood group “O” was the most common in both donors and recipients (54%), while “A” was the second most common (40%). Injection basiliximab (20 mg on day 0 and day 4) was administered to high-immunological risk patients (≥3 HLA mismatches, ABO incompatible). Plasmapheresis was used in 2–3 sessions in ABO incompatible cases; which was also the case with ATG (4–6 mg/kg intravenously). Supernumerary arteries were managed without joining the two walls before anastomosis.
[Table 2] reveals the outcomes in both groups. The primary outcome parameter i.e., acute rejection, as well as other parameters, were all comparable between Groups 1 and 2. Acute rejection was proven by graft biopsy in all but 2 of the 13 cases, where coagulopathy obviated the biopsy, and pulse methylprednisolone rescue therapy response suggested the diagnosis of rejection. Biopsy revealed acute cellular rejection in 11, and antibody-mediated (C4d) rejection in two patients. Cyclosporine was substituted for tacrolimus in 4 cases of rejection, and two other cases of tacrolimus-induced microangiopathy. Graft dysfunction, by the study definition, was treated supportively like acute tubular necrosis, if biopsy did not reveal rejection. Graft nephrectomy was performed for florid CMV nephritis in two patients, and ischemic graft necrosis in one.
Binary logistic and linear regression were performed to predict risk factors for acute rejection and early graft dysfunction; for the former, only warm ischemia or anastomotic time had a significant association (β coefficient = 0.006 [0.001–0.010]; Pearson's coefficient “r” =0.208; P < 0.01). For early graft dysfunction, only mean donor nephrectomy time in minutes was significantly associated (β coefficient = −0.002 (−0.004–0.000); Pearson's coefficient “r” = −0.158; P = 0.042). No other suspected factor–age and gender of donor and recipient, HLA mismatch >3, duration of dialysis and type of induction, had a significant association.
| Discussion|| |
The first successful renal transplant is widely attributed to Dr. Murray and colleagues in 1954, performed for genetically identical twins. For a long time, genetic matching continued to play a major role in preventing rejection and improving graft survival. However, with the advent of quadruple immunosuppressive regimens including rATG or basiliximab as induction agents, poor HLA matches and high-risk pairs (high panel-reactive antibody [PRA]) are increasingly taken up safely for transplant. We used standard triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone; induction was upgraded from methylprednisolone to rATG or basiliximab in almost 80% LURD recipients since the HLA mismatch was more than 3. Despite the significant HLA mismatches, acute rejection episodes were comparable, and all rejection was easily salvaged. Some authors opine that anti-HLA antibodies may be more important in mediating chronic rejection., In a retrospective analysis of 322 patients (LRD = 261, LURD = 61); Ahmad et al. found the proportions of acute rejection, graft survival, and estimated GFR comparable despite differences in demographics, HLA matching and re-transplants of recipients. They reasoned a younger age of recipient and HLA mismatch were both factors in acute rejection. Ferreira and colleagues followed up 281 related versus 108 unrelated donor transplants over 10 years; they found that despite higher age, more HLA incompatibility and more induction therapy, the two groups had similar rates of acute rejection at 1 year, and graft and patient survival at 10 years. They advocated unrelated donation to be the second choice after related donation, and higher than cadaveric kidneys. These studies highlight the limitation of our study in terms of a short follow-up of 6 months, where we were not able to assess chronic rejection. The success of newer immunosuppressive regimens has rendered the evaluation of sensitization or microchimerism/tolerance superfluous (see later).
A randomized study on the subject is probably not feasible, hence a prospective comparative study with a large sample size would be the best evidence. A systematic review in 2017 by Simforoosh et al. examined the short-term (1-year), medium-term (1 to 5 years) and long-term (10 years) outcomes, as well as acute rejection rates in studies comparing living related and unrelated renal transplants. They evaluated 12 studies, encompassing 9952 patients, and concluded no significant differences in the said outcomes in both groups. Most of these studies were retrospective, albeit with a satisfactory follow-up. The added advantage of a prospective study like ours, is that confounding variables expected to alter outcomes like acute rejection and graft dysfunction, can be better matched. We compared duration of preoperative dialysis, duration of donor surgery, warm ischemia time, supernumery arteries, amongst others, for this reason. The family dynamics of our donors is also uniquely linked to socio-cultural practices; all LURDs were spouses (only 2 husbands) with a 5:1 preponderance of females amongst LRDs. While technically spouses are LURD, a few authors have compared spousal donation separately. Kute et al. compared spousal donors with live related donors and live unrelated donors in 3 groups; they found comparable rates of acute rejections and graft survival in all 3 groups. In another similar study from Japan, Ishikawa et al. compared 66 living related donors with 44 unrelated donors (all but 2 were spousal); they found equivalent results with respect to rejection and graft function. However, they performed these 112 living renal transplants over 8 years. We did not see merit in differentiating between spousal and other unrelated donors; the HLA difference in spouses is present due to genetic differences, whereas, HLA similarities in LURDs can be attributed to ethnic homogeneity. Issues of sensitization due to pregnancy have also been negated largely with modern immunosuppressants (vide infra). In Asian countries, where deceased donation faces cultural and social hurdles, spousal and LURD can bridge the gap in demand., Another highlight of our study is the broad definition of graft dysfunction, including the need for dialysis as well as persistent serum creatinine. This ensured that the effect size was not weakened by the small sample size.
The present study is one of the few prospective data on the subject, and one of the first from our country. Our donor profile is slightly different from similar studies in that female donors predominate (~5:1), while LURDs are 100% spouses (vide infra). Using this data gainfully can drive policy changes, within the legal and ethical framework. The law permits altruistic donation, but with stringent checks and balances, to ensure safety and integrity of societal norms. The transplant situation in India is set to undergo a drastic change in the next decade, with large-scale initiatives to step up deceased donor transplantation taken by governmental and nongovernmental organizations. However, this is a slow change, governed by changing societal behavior and socio-geographical variability. Till such time, efforts can also be made to simultaneously increase living donor transplantation. Presently, families are the main donors; even amongst our unrelated donors, we had 100% spouses. This is because families in India function as informal caregivers for chronic patients in India, and suffer financial and quality of life issues along with the patient. LRD is also encouraged by the transplant laws. Altruism can be difficult to establish in countries with wide socio-economic variations. It has been reliably shown that paid donation, as in Iran, may not have desired consequences in donor quality of life. An added benefit of LURD would be the improvement of the quality of life and psychological health of caregivers and other donors after successful transplantation. This has been shown in many studies, and our data in this regard is also in the process of publication. Hence, we can infer that LURD including altruistic donation is a useful concept to increase transplant numbers, keeping in mind the equivalence with LRD in terms of graft outcomes. This is chiefly the result of superior immunosuppression, including the routine use of calcineurin inhibitors and interleukin-2 receptor antibodies (basiliximab).
Sensitization versus microchimerism/tolerance in LRD transplants.
An important issue to consider before labeling all LRD transplants as immunologically safe is the effect of pregnancy on future transplants. It is well-established that pregnancy leads to complex interactions between the “invasive” placenta and the maternal circulation, leading to nests of fetal cells hence paternal HLA antigens in the mother. This phenomenon of microchimerism may persist for decades and is seen to increase with successive pregnancies., This could confer tolerance to future organ transplants, or, on the other hand, lead to sensitization and the presence of anti-HLA antibodies in the mother, with subsequent high PRA titres. This sensitization could be a potential cause of both hyperacute and acute rejection, especially in offspring to mother transplants. Many authors earlier have tried to retrospectively study the effect of different living donor relationships on graft outcomes, with inconsistent results. Miles et al. analyzed 23,064 renal transplants over a 9-year period; they found that HLA-identical siblings had expectedly the best outcomes, while mother-to-child transplants had the poorest graft survival. Similar results were reported by Choi et al. in 374 LDRT patients with the poorest graft survival seen in mother-to-child transplants; these studies indicate that microchimerism is associated with sustained sensitization rather than tolerance. More recently, Kim and colleagues categorized 390 female recipients into 3 groups-offspring-to-mother, husband-to-wife, and unrelated. It was seen that none of the graft or recipient outcomes differed between groups, suggesting a diminished role of pregnancy-related sensitization. As discussed earlier, newer immunosuppressive regimens probably have salvaged many of these issues like anti-HLA antibodies and poor HLA matches. Many transplant units including ours do not perform routine or screening PRA tests, except in suspected sensitization cases. It is also not clear if PRA activity purely represents postpregnancy alloimmunization status.
| Conclusion|| |
Despite differences in HLA mismatches and age, LRD and LURD had a similar short term outcome with respect to acute rejection and graft dysfunction. This is linked to better and standardized immunosuppression available, making it possible to expand the scope of LURD beyond spousal, within the legal and ethical boundaries.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]