Objectives: Evidence on living donor kidney transplant procedures when both the donor and recipient have had a history of COVID-19 infection is scarce.
Materials and Methods: We retrospectively explored the protocol, outcomes, and follow-up of 64 donors and recipients of living donor kidney transplant who had recovered from COVID-19. This was a multicenter (n = 12) study from India that included transplants between October 29, 2020, and December 1, 2021. Induction and immunosuppression regimens for those with different severities of COVID-19 were similar to standard practice.
Results: COVID-19 clinical severity ranged from asymptomatic/mild (not requiring oxygen therapy) in 49 recipients (77%) and 63 donors (95.4%) and moderate/severe (requiring oxygen therapy) in 15 recipients (23%) and 1 donor (4.6%). Mean wait time ± SEM (SD) from first documented negative reverse transcriptase-polymerase chain reaction test to surgery for recipients and donors was 90.9 ± 9.27 (74.1) and 47 ± 4.5 (29.2) days, respectively. Six episodes (9.3%) of biopsy-proven acute rejection were reported at follow-up of 214 ± 14.8 (119) days and median of 227 (interquartile range, 109-309) days. The locally weighted scatter plot smoothing curve for creatinine during follow-up in donor-recipients pairs showed no trends of increased creatinine in the context of wait time from COVID-19 to transplant surgery. No graft loss, death, reactivation/reinfection, and complications related to surgery or COVID-19 were reported.
Conclusions: Our report showed excellent outcomes and follow-up data of living donor kidney transplant in recovered donor-recipient pairs with the standard immunosuppression protocol. To our knowledge, this is the first and the largest study of donor-recipient living donor kidney transplant pairs when both donors and recipients had prior COVID-19.
Key words : Induction, Post-COVID-19, Recovery, Solid-organ transplantation
COVID-19 has universally affected all medical specialties, and transplant communities are among the worst affected. SARS-CoV-2 infection has unduly affected transplant services around the world, with considerable geographic and timeline variations.1 With the number of COVID-19 infections increasing, the scenario of encountering transplants from COVID-19-recovered donors and recipients would be expected. The framework for such transplant procedures involves both medical and ethical issues. The concerning reports in the general population about persistent symptoms and sequelae after recovery from SARS-CoV-2 infection further complicate the situation. Further studies are needed on the long-term consequences of COVID-19.2 In the context of transplant, a double challenge is the scenario of both donors and recipients having had COVID-19; both wait time and choice of induction for this scenario are unclear in present practices. The risks of recurrent COVID-19 symptoms, suboptimal graft response, and long-term sequalae posttransp-lant are at stake in undertaking such transplants. The safety of the donor-recipient pair needs to be addressed, and high-level data are needed. Although a previous study reported 12 such transplants where both the donor and recipient had COVID-19,3 the existing literature has not reached a definitive conclusion in this context, as follow-up and details have been limited.
In this study, our goal was to present outcomes and follow-up of living donor kidney transplant (LDKT) when both the donor and recipient are post-COVID-19. Our aim is to provide further data on transplant after COVID-19 recovery and to guide other transplant professionals across the world.
Materials and Methods
Design, study participants, and settings
Our retrospective, observational study included nationwide participation of 12 kidney transplant centers (Institute of Kidney Diseases and Research Centre, Dr. HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, IQRAA International Hospital, and Research Centre Calicut, Kozhikode, Kerala, Kovai Medical Center, and Hospital, Coimbatore, Tamil Nadu, Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, VPS Lakeshore Hospital, Kochi, Manipal Hospital, Bangalore, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, Nizam's Institute of Medical Sciences Panjagutta, Hyderabad, BGS Global hospital, Bengaluru, Karnataka, Postgraduate Institute of Medical Education and Research, Chandigarh, Kingsway Hospitals, Nagpur, Maharashtra and Fortis Group of Hospitals, New Delhi) from different regions of India. Our study period was from October 26, 2020, through December 1, 2021. Study eligibility of donors and recipients was the confirmation of SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction test through the nasophar-yngeal route. All suspected cases, clinically compatible cases, and COVID-19 cases detected by SARS-CoV-2 antibody tests were excluded from the study.
A standard and uniform data collection sheet was distributed to all participating centers; the primary investigator integrated the data before analyses. Data were frozen for analysis on December 1, 2021. Data were collected from electronic systems and medical records at each center. Data on comorbidities (hypertension, diabetes, heart disease, cerebrovascular accident, and others) and cumulative symptoms were from self-reported records. Laboratory data included information on hemoglobin levels, white blood cell counts, lymphocyte percentage, neutrophil percentage, and C-reactive protein, D-dimer, interleukin 6, and ferritin levels. We collected chest radiography and/or high-resolution computed tomography data. We collected information to understand the chronology from SARS-CoV-2 infection to last follow-up for each donor-recipient pair. The protocol for conducting LDKT in the pandemic has been previously described in our studies.4,5 Follow-up of the donor-recipient pairs was done in the respective centers as standard practices, and clinical examinations and routine laboratory tests performed at 1 month, 3 months, 6 months, and 1 year were retrieved.
We previously reported the evaluation of donors and recipients who recovered from SARS-CoV-2 infection.4,5 We adhered to the position statements from the Indian Society of Organ Transplantation for LDKT in recipients and from donors who recovered from SARS-CoV-2 infection6 and National Organ and Tissue Transplant Organization transplant-specific guidelines with reference to COVID-19.7 Transplants were thus performed with the following safety measures: (1) 2 consecutive negative PCR tests before the scheduled transplant surgery; (2) donor-recipient pairs being asymptomatic for 4 weeks; (3) normal chest radiology; and (4) written informed consent, including individualized benefit-risk analysis that included, but was not limited to, reactivation or recrudescence of COVID-19 symptoms, impact on the kidney allograft, and potential for poor long-term graft outcome; (5) COVID-19-free transplant pathway with dedicated multidisciplinary transplant team; and (6) compliance of COVID-19-appropriate behavior practiced by donors, recipients, caretakers, and health care workers throughout the process.
The primary outcome measured in the study was kidney outcomes in the donor-recipient pairs, which was reported in terms of serum creatinine levels in both the donor and the recipient and acute rejection or graft loss in the recipient. The secondary outcomes were the induction regimen used, all-cause mortality, and wait time for the donor-recipient pair.
A 2-tailed P value of <.05 was denoted as significant. We used IBM SPSS version 25 for analyses. We used scatter plots to show trends of serum creatinine levels in donor-recipient pairs corresponding to the wait times from RT-PCR positivity to transplant/nephrectomy and used locally weighted scatter plot smoothing (LOESS) curves to show 95% confidence intervals (95% CI) for the estimated mean. We used R software version 4.1.2 to generate plots. We divided COVID-19 severity for recipients into 2 broad categories: (1) mild infection and (2) moderate-severe infection for simplicity in the data analysis. The categories for COVID-19 severity were adapted from WHO, where mild infection meant no oxygen requirement and moderate-severe meant cases with oxygen support.8 We reported our results as frequencies (percentages) or mean ± SEM (SD) or median and interquartile range (IQR). We compared the categorical data with the Pearson chi-square test or chi-square with Yates correction or Fisher test depending on the frequency of data. We also expressed data as odds ratio (OR) with accom-panying 95% CI. For continuous data, we made comparisons with t tests. We did not perform multivariable analysis because of multicollinearity and low frequency of events. We also made no formal sample size calculations. Missing data for any variable were dealt with as available case analysis. There was no loss to follow-up, and hence it was not a potential for significant bias. Information and recall bias owing to the retrospective design would be insignificant, as clinical history and evaluation of donor-recipient pairs were done systematically by the nephrology team of the individual transplant centers.
We followed the STROBE statement9 for obser-vational studies. The study protocol was approved by our ethical committee (ECRl143/Inst/GJ/20 13/RR-19). The Declaration of Helsinki, Istanbul, and Transplantation of Human Organs and Tissues Act, India was rigorously followed across all institutions, and no transplant procedures involved prisoners. The anonymity and privacy of the participants were respected in each step of the research.
Data pertaining to any of the donors or recipients who could disclose their identity were removed. Informed consent for publication was not
required as the data were collected and analyzed retrospectively.
Between October 29, 2020, and December 1, 2021, the participating centers performed 64 LDKT procedures in which both the donor and the recipient had a previous history of COVID-19. Follow-up time from transplant or nephrectomy to last follow-up was mean ± SEM (SD) of 214 ± 14.8 (119) days and median of 227 days (IQR, 109-309 days). Follow-up time ranged from a minimum of 21 days to a maximum of 398 days. Wait time from first documented negative RT-PCR to surgery for recipient and donor was 90.9 ± 9.27 (74.1) days and 47 ± 4.5 (29.2) days, respectively. The shortest wait time reported from being RT-PCR positive to surgery for recipients and donors was 21 and 7 days, respectively.
Baseline features and COVID-19 course description for donors are shown in Table 1. The mean age of donors was 43.6 years. In 60.3% of cases, the donor was female. The relationships of paired kidney donors included parents, spouse, siblings, and extended family in 32, 17, 4, and 9 cases, respectively. The blood group typing for donors was A, B, AB, and O for 18, 9, 2, and 27 donors, respectively. The majority had left donor nephrectomy, and only 5 donors underwent right nephrectomy. Of the donors, 22 had open nephrectomy and 42 had laparoscopic nephrectomy. Three donors were current or ex-smokers. Only 2 donors were obese and had a prior history of hypertension before donation. The cumulative major symptoms of donors during COVID-19 infection were fever, cough, dyspnea, anosmia/ageusia, and diarrhea in 26, 13, 5, 11, and 8 donors, respectively. Three donors required oxygen during COVID-19 infection. Days from SARS-CoV-2 RT-PCR positivity to first documented negative test in donors was 4.47 ± 0.42 (2.78) days. Wait time from SARS-CoV-2 RT-PCR positivity to surgery for donors was 32 days (IQR, 29-42 days). The minimum number of days for nephrectomy from the first positive report was 28 days, and the maximum was 180 days. The total number of documented RT-PCR tests done for donors was 2, 3, and ≥4 tests in 19, 18, and 27 donors, respectively.
Baseline features and COVID-19 course for recipients are shown in Table 2.The mean age of the recipient was 39.8 years. Among the recipients, only 3 were aged below 18 years; the proportion of female recipients was 20.3%. Five recipients were sensitized, with substantial titers present in class I, class II, and both classes in 2, 1, and 2 cases, respectively. Six recipients (9.3%) had ABO-incompatible transplants. The blood group distribution was A, B, AB, and O in 22, 13, 8, and 21 recipients, respectively. Fifteen of the 64 recipients had a moderate to severe COVID-19 course. Number of days from SARS-CoV-2 RT-PCR positive test to first documented negative test in recipients was 13 ± 0.9 (7.37) days. Almost half of the recipient cohort had thymoglobulin as induction with no difference between recipients with mild versus moderate-severe COVID-19 (51.6% vs 51.0%; P = .55; OR = 0.93 [95% CI, 0.38-2.26]). No induction was given in 28.1% of the recipients, with a greater amount in those with mild disease compared with moderate-severe disease (34.7% vs 7.6%; P = .03; OR = 5.4 [95% CI, 0.77-38.6]). The total number of documented RT-PCR tests done was 2, 3, and ≥4 in 12, 19, and 33 recipients, respectively. For recipients, the total follow-up days from SARS-CoV-2 RT-PCR positive test to last follow-up was 318 ± 14 (112) days.
The minimum follow-up time was 90 days, and the maximum time was 502 days. The median follow-up was 351 days (IQR, 220-410 days). There were 8 acute rejection episodes (12.5%), with biopsy-confirmed acute rejection in 6 cases (9.3%). The biopsy-proven acute rejection was divided into 3 with cellular rejections and 3 with antibody-mediated rejections. There was no difference in frequency of acute rejection between the 2 groups of recipients divided based on the requirement of oxygen during the COVID-19 stay. The number of days to acute rejection was 192 ± 15.9 (127.2) days. The median (IQR) range for time to acute rejection was 189 (76.5-299) days. The minimum number of days from transplant to rejection episode was 2 days, and the maximum was 398 days.
No deaths in either donors or recipients were reported. No recipients in the study became flow or cross-match positive after COVID-19 infection pretransplant. There were no new donor-specific antibody levels after infection and during follow-up. No graft losses were reported. The trajectory of serum creatinine levels in the donor-recipient pairs with follow-up is shown in Figure 1 and Figure 2 . Figure 3 illustrates the relation between wait time and number of RT-PCR tests in donors and recipients. Figure 4 outlines the wait time for donor-recipient pairs after first RT-PCR negative test. Overall, most cases had at least 2 negative RT-PCR tests, and the number of RT-PCR tests done increased with wait time, as expected. No new episodes of hypertension or hematuria/proteinuria were detected in either donors or recipients.
To our knowledge, our report includes the largest cohort of LDKT where both the donor and recipient pair had a prior history of COVID-19. Transplant in these situations has numerous challenges, including selecting the induction and maintenance immuno-suppression regimen and determining wait time from recovery to transplant and wait time from recovery to nephrectomy. The theoretical concerns of adverse outcomes in both donors and recipients are worrisome for transplant centers. Our data addressed the majority of the challenges and concerns related to this complex area of transplantation.
The donor-recipient pairs in our study had at close and dedicated follow-up through in-person/telecommunication for any possible problems. In a recent meta-analysis of transplant recipients with COVID-19, kidney outcome data were sparse. We have assessed the renal functions in donors and recipients in our longitudinal follow-up, and results were satisfactory, with organs not affected by the wait time from COVID-19 positive test to surgery in donors or recipients. We have also investigated donor-specific antibodies at the individual centers as per standard practice; in no cases were donor-specific antibodies detected during follow-up. There was also no graft loss reported. Furthermore, there were no deaths reported in either donors or recipients. There were no new episodes of hypertension or hematuria in either donors or recipients. There was no report of pulmonary fibrosis or any cardiac event in our study cohort.
The excellent outcomes and follow-up for donor-recipient pairs without any theorized COVID-19 sequelae is a weighty achievement for the participating transplant centers in this study and is a source of encouragement for transplant professionals across the world. With organ shortages mounting and consistent evidence of suboptimal outcomes for patients on wait lists compared with those who receive transplants, the decision of delaying transplant is not justified. Even those who are infected with SARS-CoV-2 can be considered as donors with a low risk of eventful outcomes in emergency circumstances, when low cycle threshold value of RT-PCR, long duration from first symptoms of COVID-19 to donation, normalization of laboratory markers, and radiology findings are considered.10 The aforementioned risk cannot be applied to nonemergent living donation, where the health status of donors is at stake. Still, the available literature has not shown any major risks for donor-derived COVID-19 during transplant surgery. We documented no donor-derived COVID-19 infections in our study cohort, with no cases of SARS-CoV-2 reinfection or reactivation after surgeries. Although most of our patients were unvaccinated, recent studies have shown attenuated response after partial vaccination11 and conversely a heightened immune response after complete vaccination.12 Thus, a complete vaccine regimen would be ideal before surgery.
The choice of induction is extremely crucial in these situations. There are no proper universal guidelines that could be applicable in this context, and real-world practices may differ and are often individualized. A few real-world data reports13-15 have shown a policy of tailored immunosuppression during the pandemic. However, we found no difference in the choice of induction, tailoring of induction dose, or maintenance immunosuppression in our study cohort compared with regimens before the pandemic. All centers have a uniform policy of induction agents as per the KDIGO guidelines.16 We did not compare our outcomes with a control group. However, in a recent Indian multicenter report17 of renal transplants conducted during the pandemic, the induction chosen was antithymocyte globulin (1.5-3 mg/kg), and interleukin 2 and no induction in 57.5% and 14.8%, which is similar to our report of 51.6% and 17.2%. In their report, the patient and graft survival rates were 95.3% and 97.6%, which was even improved upon in our report. In our report, rather than an expected decline in induction for moderate and severe cases, we reported that 93.3% of those with moderate-severe COVID-19 received induction compared with 67.3% of those with mild severity of COVID-19, with this difference reaching statistical significance. These findings further support our policy of no new amendments in patients who have recovered from COVID-19 regarding the induction regimen.
Strengths and limitations
The available literature18 pertinent to transplant from donors with active/past COVID-19 is mainly case reports and case series, with limited follow-up data. Our report is strong because we included both donors and recipients who recovered from COVID-19 infection. The other major strength was capturing high-quality data in this rare subject. The long-term follow-up of the cohort was an added strength of the study along with the significant number of cases.
The limitations of our study involve the diversity in the protocol for managing COVID-19 in various centers and at different time lines, but this was understandable as there was no definitive therapy available. It is worth mentioning that the number of donors with oxygen requirements during COVID-19 was substantially small in our study. Because we included only kidney transplant, the applicability and outcomes would slightly differ in other organ transplant procedures, especially with lung19 and liver transplant.20 The minimum number of RT-PCR tests performed before nephrectomy or transplant was more than 3 in many cases, which shows the reluctance, regional variation in COVID-19 transmission, possible burdens on hospital capacity and infrastructure, and perhaps legislations involved before transplant. It also was thus possible to extract the exact and minimum number of RT-PCR negative tests required and the exact days required to wait before surgery. Still, with a diverse range of wait times and good outcomes in the donor-recipient pair, our report provides a safe margin. Only 5 recipients were partially vaccinated with the COVID-19 vaccine before transplant surgery, and none were completely immunized. Although not relevant to the outcomes of our study, if there were a surge of COVID-19 cases over potential upcoming waves, immunization of patients on wait lists as a high-risk priority before transplant could help to avoid this complex scenario. With reports21 of low immunogenicity of COVID-19 vaccine and emerging need of a booster dose,22,23 the policy of tailoring induction or maintenance immunosuppression is a matter of future research.
We reported excellent outcomes of transplant when both the donor and recipient pair recovered from COVID-19. We reported no change in induction or immunosuppression regimens for conducting such transplants. To date and to our knowledge, this remains the first and the largest study of LDKT when the donor-recipient pair had prior COVID-19. This study could provide useful insights for transplant communities and could help in better pandemic preparedness.
Volume : 20
Issue : 10
Pages : 908 - 916
DOI : 10.6002/ect.2022.0205
From the 1Department of Nephrology, Institute of Kidney Diseases and Research Centre,
Dr. HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India; the 2Department of Nephrology, IQRAA International Hospital, and Research Centre Calicut, Kozhikode, Kerala, India; the 3Department of Nephrology, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India; the 4Department of Nephrology, Rabindranath Tagore International Institute of Cardiac Sciences, Kolkata, West Bengal, India.; the 5Department of Nephrology, VPS Lakeshore Hospital, Kochi, India; the 6Department of Nephrology, Manipal Hospital, Bangalore, India; and the 7Department of Nephrology, Muljibhai Patel Urological Hospital, Nadiad, Gujarat, India
Acknowledgements: The ISOTSTUDY group included G. Swarnalatha (Department of Nephrology, Nizam’s Institute of Medical Sciences Panjagutta, Hyderabad, India), B. T. Anil Kumar (Department of Nephrology, BGS Global Hospital, Bengaluru, Karnataka, India), Ashish Sharma (Department of Renal Transplant Surgery; Postgraduate Institute of Medical Education and Research, Chandigarh, India), Prakash Khetan (Department of Nephrology, Kingsway Hospitals, Nagpur, Maharashtra, India), and Sanjeev Gulati (Department of Nephrology Fortis Group of Hospitals, New Delhi). 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 interest.
Corresponding author: Vivek B. Kute, Department of Nephrology, Institute of Kidney Diseases and Research Centre, Dr. HL Trivedi Institute of Transplantation Sciences, Ahmedabad, Gujarat, India, IKDRC
Phone: +91 7999514306
Table 1. Donor Baseline Status and COVID-19 Brief History
Table 2. Recipient Baseline Data, COVID-19 Course, and Induction Regimen
Figure 1. Serum Creatinine Trends in Recipients From Nadir After Surgery to 1 Year Correlated With Waiting Time From COVID-19 Infection to Surgery in Recipients
Figure 2. Serum Creatinine Trends in Donors (right) and Recipients (left) From Nadir After Nephrectomy to 1 Year Correlated With Wait Time From COVID-19 Infection to Nephrectomy in Donors
Figure 3. Number of Tests With Wait Time From First Documented RT-PCR to Surgery in Recipient (right) and Donor (left)
Figure 4. Timeline the Wait Time for Donor-Recipient Pair After First Documented RT-PCR Test