Objectives: There is no systematic review and meta-analysis for pediatric solid-organ transplants in India. The objective of the study was to collect high-evidence data in this regard.
Materials and Methods: A systematic review and meta-analysis was performed for pediatric solid-organ transplants in India. We used the search engines of PubMed, Google Scholar, PubMed Central, Embase, and MEDLINE from beginning of data availability until April 26, 2022. Data from 2 participating centers were also used. Analyses were performed by the DerSimonian random model.
Results: Of 50?000 primary searches, only 31 studies were included for analysis. In total, data for pediatric kidney (n = 1057), liver (n = 914), and heart (n = 117) were reported. For the pediatric kidney, the 1-year, 5-year, and 10-year patient survival rates were 96% (range, 93%-99%; I2 = 91.17%, H2 = 11.33, P < .01), 90% (range, 85%-94%; I2 = 93.54%, H2 = 15.47, P < .01), and 75% (range, 62%-88%; I2 = 97.36%, H2 = 37.82, P < .01), respectively. The 1-year, 5-year, and 10-year renal graft survival rates were 93% (range, 90%-96%; I2 = 63.82, H2 = 2.76, P < .01), 83% (range, 76%-89%; I2 = 86.39%, H2 = 7.35, P < .01), and 66% (range, 57%-75%; I2 = 81.68%, H2 = 5.46, P < .01), respectively. The acute rejection rate was 23% (range, 20%-27%; I2 = 5.44%, H2 = 1.06, P = .39). For the pediatric liver transplant, the 1-year and 5-year survival rates were 92% (range, 89%-95%; I2 = 49.96%, H2 = 2, P < .04) and 88% (range, 85-90%; I2 = 0; H2 = 1, P = .72), respectively.
Conclusions: The outcomes of pediatric solid-organ transplants in India are comparable to those of the Western world. However, cause of graft loss and patient death is largely attributed to infections, unlike the experiences reported in the West. An effective registry is a primary pillar to expand pediatric solid-organ transplants in India.
Key words : Kidney transplants, Living donor, Liver transplants
Pediatric solid-organ transplantation (SOT) remains an evolving field in the Indian context, as facilities and specialization are at an incipient stage at many of the centers with adult organ transplant programs. Moreover, compared with the developed world, where deceased donation is firmly established, progress in this part of the world is lagging behind. This worsens the situation of expanding the donor pool, especially in pediatric SOT. As of April 12, 2022, the Organ Procurement and Transplantation Network registry1 reported a total of 888?209 SOT performed, of which 9216, 16?200, 9618, and 24?071 SOT belonged to age groups <1 year, 1 to 5 years, 6 to 10 years, and 11 to 17 years, respectively. Unfortunately, in the Indian context, no updated national registry exists to account for the actual number of pediatric patients on the wait list or scheduled for transplant. In India, the transplant programs are mostly dominant in private sectors, and their contribution in national registry is unsatisfactory, which partly explains the reason for the problems in maintaining a robust registry. Largely, the data regarding the pediatric SOT originate from the premier institutes and premier transplant centers. At this point, it is clear that this area of medical care has many hurdles, from the access to care for organ failure to posttransplant care. Hence, we conducted a systematic review and meta-analysis, by digging into the published literature on the outcomes of pediatric SOT performed in India. This report will help to assess the current status and help to better align future goals to fill the deficit in this less-developed field of medical care.
Materials and Methods
Literature search strategy
The search engines we used in our study were PubMed, PubMed Central, Bookshelf, MEDLINE, Embase, and Google Scholar. We excluded non-peer-reviewed publications, works that included only abstracts, or any other gray literature. We used English language publications only. Other languages were excluded from the search results. We used the following Medical Subject Headings (MeSH terms) “pediatric”, or “child” and “transplant”, and “India”, and “liver”, or “kidney”, or “renal”, or “heart”, or “lung”. We have not used selective key words such as graft survival” or “patient survival” or “living donation” or “deceased donation” so as to avoid missing any reports. The search was performed by 2 authors (HSM and VBK), individually and separately. The manual search was performed according to forward and backward snowballing methods. Two authors (SC and VBK) independently assessed the validity of the titles, abstracts, or full texts of each published article.
Inclusion and exclusion criteria
After completion of the search process, any conflict or dilemma for inclusion or exclusion of items in the search results was discussed in-person between HSM and VBK, and the final decision was reserved until after consultation with SC. The eligible articles in our report were any pediatric SOT performed in Indian settings that included outcome data. We accepted the definition of pediatric population according to the description in each respective study, and there was no cutoff age for inclusion. Also, all of these articles were included irrespective of the organ transplanted. We included heart, lung, liver, kidney, and pancreas. Hemopoietic stem cell transplants were excluded from our report. The search was performed from April 12, 2022, through April 26, 2022. There were some restrictions to type of publications, and we included only original articles. Review articles, correspondence, letters to editor, meta-analyses, case reports, commentaries, and editorials were excluded from the search results. We have contacted an individual participating center (Dr. Rela Institute and Medical Centre; and Institute of Kidney Diseases and Research Center and Dr. H. L. Trivedi Institute of Transplantation Sciences [IKDRC-ITS], Ahmedabad, Gujarat, India) for updated data on pediatric SOT, and we included the data in the systematic review and meta-analysis.
Our methods in this systematic review and meta-analysis were reported in accordance with the guidelines of the Meta-Analyses Of Observational Studies in Epidemiology checklist. Most of the pediatric SOT performed in an Indian scenario are living related (85%) and deceased donors (15%). The relationship of the living donors to the recipients was either parent or grandparent. The transplants performed in all the centers are in accordance with the Declaration of Istanbul, Helsinki, and the Transplantation of Human Organ and Tissue Act, India.
Data extraction was done by 2 authors (VBK and SC) in an open-ended approach, and no fixed parameters were prerequisite, as the data concerned are sparse and heterogenous. This method was used with a goal toward creation of a more comprehensive review of the available literature. Data assembled in the report included year of publication, authorship, setting, year of publication, age, etiology of organ failure, sex, and survival rates for patient and graft.
The primary outcome for the meta-analysis was the patient and graft survival at 1 year, 5 years, and 10 years for kidney transplant, as well as the patient and graft survival for the available follow-up of other organs. The other relevant data were accumulated and reported as a part of this systematic review, and no statistical analyses were performed, because the data were highly heterogeneous across the published literature.
The analyses were performed by HSM with Stata statistical software (release 16, StataCorp). The data were checked by VBK before analysis. In (Table 1) and (Table 2), categorical outcomes were reported as frequencies and percentages, whereas continuous outcomes were reported as median, mean, standard deviation, interquartile range, and range as appropriate. To perform meta-analyses of proportion (the primary outcome), metaprop commands were used, which are an extension of the Stata software. The metaprop extension allows computation of 95% confidence intervals (CI) from the score statistic and the exact binomial method. We used the DerSimonian-Laird random effect model as the statistical method. The outcomes were reported as effect size with the 95% CI. We reported the I statistic to assess the heterogeneity of the pooled estimate, in which a value >0.5 indicated substantial heterogeneity.2 Data visualization for the primary outcomes was completed by forest plots with reference line and triangle effect size and bubble plots. Publication bias was depicted with funnel plots and Egger tests. Sensitivity analysis was performed according to a fixed model with some studies, instead of a random model. P < .05 indicates statistical significance.
In this systematic review and meta-analysis, last searched through April 26, 2022, from search engines of Google Scholar, PubMed, PubMed Central, Bookshelf, Embase, and MEDLINE, we screened more than 50?000 articles. After initial survey and screening, 431 records were identified, which were further refined for data of interest. Thirty-one reports were finally included for inclusion in the study. Fifteen studies were included for pediatric kidney transplant (PKT) and 8 for pediatric liver transplant (PLT) in the statistical calculation. Only 2 studies were found for pediatric heart transplant. We collected data from PKT (n = 1057), PLT (n = 914), and pediatric heart transplant (n = 117). In this report the individual data contributions were 439 PKT cases from IKDRC-ITS, Ahmedabad, and 500 PLT cases from the Dr. Rela Institute and Medical Centre, Chennai, India. (Figure 1) shows a flow chart summary of the study process. (Table 1) shows the published studies with PKT. We have included all possible important studies. For the analysis, we have selected the most recent studies, which have already been included in previous published results. (Figure 2) (top right) shows the sex disparity in PKT recipients. The proportion of male recipients in PKT was 74% (range, 68%-81%; I2 = 76.84%, H2 = 4.32). The heterogeneity in the study was also not exceedingly high. (Figure 2) depicts the forest plot for outcomes of patient survival in PKT from Indian studies. The 1-year, 5-year, and 10-year patient survival rates were 96% (range, 93%-99%; I2 = 91.17%, H2 = 11.33, P < .01), 90% (range, 85%-94%; I2 = 93.54%, H2 = 15.47, P < .01), and 75% (range, 62%-88%; I2 = 97.36%, H2 = 37.82, P < .01), respectively. It is notable that the individual center data from IKDRC-ITS as of 2020 for outcomes were not analyzed, because the center had not reported official statistics, but the outcome was roughly above 90% for the first year and above 80% for the 5-year survival rates for patients and grafts. (Figure 3) shows the forest plot for outcomes of graft survival in PKT. The 1-year, 5-year, and 10-year graft survival rates were 93% (range, 90%-96%; I2 = 63.82, H2 = 2.76, P < .01), 83% (range, 76%-89%; I2 = 86.39%, H2 = 7.35, P < .01), and 66% (range, 57%-75%; I2 = 81.68%, H2 = 5.46, P < .01), respectively. (Figure 3) (bottom left) shows the acute rejection rate in PKT. The rejection rate on cumulative basis from the centers was observed as 23% (range, 20%-27%; I2 = 5.44%, H2 = 1.06, P = .39). The reported heterogeneity was not significant, which shows the uniform protocol of immunosuppression drugs and acute rejection rate in the transplant centers. (Figure 4) shows the publication bias for patient and graft survival in PKT. The presence of bias was expec-ted with the small number of studies with diverse timelines and remote geographic areas. (Table 2) sum-marizes the PLT data from India. The most common etiology for PLT in many centers was biliary atresia. The follow-up data were reported for 1 year, and a very few studies reported long-term data for PLT. (Figure 5) shows the forest plot for patient survival after PLT at 1 year and 5 years. The 1-year and 5-year survival rates were 92% (range, 89%-95%; I2 = 49.96%, H2 = 2, P < .04) and 88% (range, 85-90%; I2 = 0, H2 = 1, P = .72), respectively. The uniform outcomes in the PLT centers are depicted by the low heterogeneity in the studies. (Figure 6) shows the publication bias for the PLT studies. We have also conducted the sensitivity analysis for both PKT and PLT from a fixed model, and the results were similar.
To the best of our dedicated literature search, we report the first systematic review and meta-analysis on outcomes of pediatric SOT in Indian settings. From the results of our study, it is evident that pediatric SOT in India is in a very early stage. India represents the second leading nation with respect to living donor SOT numbers in the world. However, pediatric SOT is considerably less developed. There is no adequate registry for pediatric transplant in India. The extent of deficiency in this field can be estimated by comparing the Indian scenario, where there is no active registry, versus the North American Pediatric Renal Trials and Collaborative Studies of America, which was established in 1987 and currently has 108 participating centers with 21?332 pediatric patients.2 Also, in our analysis, the cumulative transplant data are from 1200 pediatric patients. As such, if we closely scrutinize the data, exclusion of the individual participation data from 2 institutes (IKDRC-ITS, Ahmedabad; and the Dr. Rela Institute and Medical Centre, Chennai, India) would reduce the transplant numbers by half. Hence, the real-world situation is grossly underrepresented for India. In our analysis, there was a clear preponderance of male patients in almost all of the studies, especially for PKT. This disparity is slightly less for PLT. The reason for this disparity is a complex amalgamation of various factors, which requires deep understanding and integrated efforts for solutions.In our report, the outcomes of PKT are quite excellent, and this holds true for 5-year and 10-year outcomes as well. On close inspection, the patient and graft survival rates have only improved over the decades. In most cases in India, deaths are caused by infections, which is dissimilar to the experiences reported in the Western world. Malignancy, which is common to the Western world, is exceptionally rare in the Indian scenario. In the 21-year experience of PKT at the All India Institute of Medical Sciences, New Delhi, there were only 4 cases of posttransplant lymphoproliferative disorder reported.3 The incidence of rejection in the report is not homogeneous for the studies, and the rates are acceptable and did not result in graft losses. In this systematic review, a concerning observation is the involvement of only a few PKT centers in the data set. This provides a glimpse of the whole story of PKT in India. In a study that highlighted barriers of PKT in a low-resource setting, it was shown that the problem begins at the onset of end-stage kidney disease itself.4 Another important observation was that the lost to follow-up patients were those who withdrew from care and mostly of low socioeconomic status. They also reported that medical challenges and negative attitudes toward transplant and organ donation are still prevalent.In our analysis, the median age of transplant is higher, which reflects the late referral and problem in initial care and management. The state of PKT can be grossly understood from the results of a recent survey of 26 adult nephrologists.5 Only 16 nephrologists (61.5%) were involved in pediatric transplantation. Most of the centers performing PKT were private institutions, with only 3 government sectors undertaking it. There were only a few centers in the country routinely doing >5 pediatric transplants per year. Also, preemptive transplants and protocol biopsies were rare. In the survey, however, induction and the immunosuppressant use were quite similar to the Western registry. Thus, the survey identified a prime deficiency present in PKT. Still, there is ongoing progress in PKT. In the world literature, the first report of a patient with anti-complement factor H antibody-associated hemolytic uremic syndrome who underwent living-related PKT from an Indian center6 was characterized with a thrombosed inferior vena cava, so splenic vein was used.7 Stem cell therapy in PKT was reported as early as 2002 by a tertiary transplant center in Western India.8 An Indian center has reported good outcomes in robotic PKT.9 The first case series of immuno-adsorption in a case of ABO-incompatible PKT was reported from an Indian center.10Liver transplantation in India has definitely shown an exponential growth in past decades, but only 10% of these transplants comprised PLT.11 The first PLT was performed at the Institute of Liver and Biliary Sciences (New Delhi, India) in 2001. The youngest 6-month-old12,13 with extrahepatic biliary atresia was performed in 2009, with 2 at the Institute of Liver and Biliary Sciences. In our analysis, the survival rates in most of the reports are above 90% for the first year, which is a remarkable achievement with respect to the fact that there are resource limitations, as well as other psychosocial and financial issues in the targeted population. In our report, biliary atresia remains the major indication for PLT. However, with advancement, the centers are including more patients with liver-based metabolic disorders and other difficult-to-treat conditions. In a similar trend, the Dr. Rela Institute and Medical Centre has recently reported successful PLT for nitisinone tyrosinemia type 1 among 9 of their 203 PLT cases in the year 2021.14 There are reports of PLT in cases that were considered unsuitable for transplant, such as nonstandard hepatic venous reconstruction (NHVR) and hepatopulmonary syndrome (HPS), and these patients are now being successfully treated with innovations and dedicated team efforts. In 2021, PLT for NHVR was reported by an Indian PLT center.15 This was a successful case series of 15 cases among the 304 PLT procedures performed at the center. No differences in patient and graft survival rates were reported compared with non-NHVR cases. Chaubal and colleagues reported PLT in a patient who weighed less than 6 kg in an Indian experience.16 The ABO-incompatible barrier was once considered to be an important hurdle in this field but is now successfully tackled. Mohan and colleagues17 reported 8 ABO-incompatible PLT among the 203 PLT performed at the Medanta, Gurugram, center for liver transplantation. Living donor or split-liver transplants are safe with short-term or long-term outcomes per the data from the United Network for Organ Sharing.18 Also, the first case in the world literature of monosegment robotic hepatectomy for a child less than 6 kg body weight with extrahepatic biliary atresia was reported from the Dr. Rela Institute and Medical Centre.19 Hepatopulmonary syndrome is highly associated with morbidity and mortality, and 25 PLT recipients with HPS were reported by the Dr. Rela Institute and Medical Centre in cooperation with a liver transplant center in the United Kingdom.20 The recent report from the Organ Procurement and Transplantation Network registry also showed similar outcomes with HPS.21 Infectious encounters in the field of pediatric SOT require special attention, because otherwise rare entities are relatively common in this part of the world. For example, the first case of fascioliasis in a PLT recipient was reported from an Indian center.22Another exceptional example is a case of varicella infection in an immunized PLT recipient, also reported from an Indian center.23 The report of uncommon presentation in PLT, such as recurrent diaphragmatic hernia, from an Indian center highlights that there is unparalleled scope for further research and expansion. Solid-organ transplants with organs like lung and heart are performed in low numbers of patients in India, because a robust deceased donor program is not present.24 The first lung transplant unit in India reported that deceased donor organ donation is a viable option in patients; if patients are referred in early phase of illness, the outcome of transplant is better even in low-resource settings like India.25 Similarly, the MGM Hospital, Chennai, has reported outcomes of 257 HT procedures and proved that successful midterm outcome is possible even with resource restrictions typical in India.26 There are only a few published studies of pediatric heart transplant, with 20 done in Mumbai27 and 97 one in Chennai,28 India.In brief, the initiation of even a small pediatric transplant program would require a multidisciplinary action and involvement of a team of experts, as well as long-term care services after transplant, in view of financial burden in the lower middle-income nations like India. In this part of the world, an important goal is the establishment of a pediatric transplant program that would be available, affordable, acceptable, and sustainable. There are some limitations in this report. The most important limitation is the possibility of exclusion of some important studies or data that may have not been discovered in our searches (for example, if such reports were vague with regard to the adult vs pediatric nature of a transplant program). Also, many reports are published without peer review or in publications that are not included in the standard research indexes. We have excluded conference papers and studies for which only an abstract has been published; also, because the data about SOT from India are not robust compared with the Western world, the chances are low for a study to published as a complete article in an indexed journal. Only 2 individual center data analyses were done. Addition of other data from other centers could improve the cumulative analysis.
In summary, we have shown that persistence is required to maintain an active and successful pediatric SOT program with transparent and updated pediatric registry. In our report, although there are fewer studies, the medical outcomes reported are comparable to the Western world, which is an encouraging sign, considering the limited manpower, logistics, and infrastructure. Any successful SOT program for the pediatric population should ensure the availability of inexpensive immunosuppressive drugs, establish additional transplant centers, whether partially or completely dedicated to pediatric patients, and include a robust deceased donor program. We emphasize that the efforts of medical professionals would not be sufficient for success, and involvement of both state and national government officials, as well as other nongovernmental agencies, would be required to establish a successful national-level pediatric SOT program.
Volume : 20
Issue : 12
Pages : 1058 - 1068
DOI : 10.6002/ect.2022.0207
From the 1Department of Nephrology and Transplantation and the 6Department of Obstetrics and Gynaecology, Institute of Kidney Diseases and Research Center, Dr. H. L. Trivedi Institute of Transplantation Sciences, Ahmedabad; the 2Institute of Liver Disease and Transplantation,
Dr. Rela Institute and Medical Centre, and Bharath Institute of Higher Education and Research, Chennai; the 3Department of Nephrology, Fortis Group of Hospitals, New Delhi; the 4Department of Nephrology, Sir Ganga Ram Hospital, New Delhi; and the 5Department of Nephrology, MGM Healthcare, Chennai, India
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Vivek B. Kute, Department of Nephrology and Transplantation, Institute of Kidney Disease and Research Center, Institute of Transplantation Sciences, Ahmedabad, 380016 Gujarat, India
Table 1. Summary of the Studies Published With Reports of Pediatric Kidney Transplant
Table 2. Pediatric Liver Transplant Studies From India
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses Flow Chart Diagram for the Study
Figure 2. Forest Plots for Sex Distribution and Patient Survival in Pediatric Kidney Transplant
Figure 3. Graft Survival and Acute Rejection in Pediatric Kidney Transplant
Figure 4. Publication Bias for the Pediatric Kidney Transplant Analyses
Figure 5. Pediatric Liver Transplant Outcomes in Indian Centers
Figure 6. Publication Bias in the Studies
Table 1. Patient Characteristics