COVID-19 infection originated in Wuhan city in Hubei province of China in November 2019. It was declared a pandemic by the WHO on March 11, 2020. It can have a diverse outcome in patients, particularly in renal transplant recipients, owing to their underlying immunocompromised state. Most of them have preexisting comorbidities which add to their risks. We attempted to study the clinical course and outcomes of renal transplant recipients with a functioning graft, who attended our hospital for COVID-19 infection.
MATERIALS AND METHODS
All adult renal transplant recipients who attended our center for COVID-19 infection were included in the study, irrespective of the place or time of renal transplantation. Patients who had graft failure before COVID infection were excluded from the study.
COVID-19 infection was defined as mild, moderate, or severe based on the guidelines issued by the Ministry of Health and Family Welfare, Government of India. Mild cases were defined as those with mild symptoms of uncomplicated upper respiratory tract infection who were not hypoxic. Moderate cases were defined as those with an oxygen saturation of 90%–94% on room air, respiratory rate between 24 and 30/min, and mild-to-moderate pneumonia. Severe cases were defined as those with a respiratory rate of more than 30/min, whose oxygen saturation was <90%, or with adult respiratory distress syndrome (ARDS) or septic shock. Critical cases were those with rapid deterioration of respiratory symptoms and ARDS.
Criteria for hospitalization
The moderate and severe categories of COVID-19 infection were hospitalized. The discharge criteria were according to the guidelines laid by the Ministry of Health, Government of India. The mild cases were offered hospitalization for the purpose of observation, monitoring, and prevention of transmission of infection. If they chose to be on home isolation, they were asked to monitor their symptoms and oxygen saturation and follow up by video consultation with the nephrologist and COVID physician.
As part of the protocol followed for COVID-infected patients, investigations done at presentation included a complete hemogram, renal and liver panel, sugars, chest X-ray, inflammatory markers (D-dimer, ferritin, lactate dehydrogenase, and C-reactive protein), and Trop I. The decision to do a computed tomography [CT] scan of the chest at baseline was decided based on the symptoms at presentation.
This was a descriptive data of the spectrum of clinical manifestations and outcomes of renal transplant recipients with varying degrees of covid 19 infections. Simple statistical tests like mean, median and percentages were applied.
Declaration of patient consent
The patient consent has been taken for participation in the study and for the 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.
The study was performed according to the guidelines in Declaration of Helsinki.
The study has been approved by Institutional ethics committee of approved by the ethics committee of Manipal hospitals (ECR/34/Inst/KA/2013/RR-19).
There were a total of 18 patients and 19 episodes of COVID-19 infection (one reinfection), of whom 14 were males and 4 were females. The mean age was 42.67 years. One was a recipient of a second transplant while the rest were recipients of a first renal transplant. The median time of COVID infection after transplant was 38.95 months (range: 8 days to 22 years). Fourteen patients were recipients of a live donor and four were recipients of a deceased donor. The baseline characteristics of the patients are shown in Table 1. Of the 19 episodes, 3 occurred in the first wave of COVID, 7 in the second wave, and 9 in the third wave (including reinfection in the same patient of the 2nd wave, which was incidentally detected). None of the infected patients in the first or second wave had received any vaccination (due to unavailability at that time). Of the nine episodes in the third wave, eight had received two doses of the vaccine and one was not vaccinated.
Clinical features at onset of COVID infection
Twelve patients had mild infection (13 episodes, including an incidentally detected reinfection in 1 patient, which was not counted separately), two patients were of moderate category, and four patients had severe COVID pneumonia. Of the severe cases of COVID pneumonia, two survived and two died. Of the surviving patients, one had normal allograft functions and one had graft failure.
Earliest COVID-19 infection reported in our study was 8 days after a successful renal transplant.
Fever was the most common presenting symptom, followed by myalgia, cough, dyspnea, and anosmia [Figure 1].
One of the cases of severe COVID pneumonia [Case 11, Table 2] was a 41-year-old diabetic gentleman who received a single haplotype-matched kidney from his mother 8 days back. The baseline characteristics of the patients are shown in Table 1. The COVID reverse transcriptase–polymerase chain reaction (RT-PCR) of both donor and recipient were negative before surgery. Two doses of the COVID vaccine were taken before the transplant. He had received an injection of antithymocyte globulin (ATG), (rabbit ATG - Grafalon) for induction (a total of 300 mg) along with methylprednisone. Immediate graft function was good and improved over the next 7 days to a creatinine level of 0.9 mg/dl. Tacrolimus trough level was 4.4 ng/ml on day 5 of transplant. Mycophenolate mofetil was at 1500 mg a day, and oral prednisone was ongoing. On day 8 of the transplant, he had an acute onset of respiratory distress. The hypoxia rapidly worsened, requiring mechanical ventilation. CT scan showed ground-glass opacities in both lung bases. Rapid antigen test for COVID-19 was positive. He continued to need a high FiO2, and was given prone ventilation but succumbed within 6 h of the onset of tachypnea, despite all efforts. He had also received antibody cocktail therapy (600 mg of casirivimab and 600 mg of Imdevimab) as the antibody to SARS-CoV-2 was negative.
Another 58-year-old gentleman [Case 1, Table 2] presented with severe disease needing ventilatory support, had morbid obesity, obstructive sleep apnea syndrome (OSAS), hypertension, and was a recipient of a second transplant. The immunosuppression modification done was complete stoppage of azathioprine, reduction of cyclosporin by 75% to a dose of 25 mg/day, and oral prednisone was changed to methylprednisone. The time of COVID infection from the transplant was 17 years from the second transplant (the first transplant was 25 years ago). He had an intensive care unit stay of 21 days and was discharged from the hospital after 27 days of hospitalization with allograft functions that had returned to his baseline. The peak serum creatinine was 2.1 mg/dl, and at discharge, it was 0.98 mg/dl.
The other two severe cases of COVID pneumonia-one had graft failure but survived, and the other had a functioning graft except terminally when he was in septic shock.
The calcineurin inhibitor (CNI) was reduced by 25% in 2/12 mild cases and was continued at the same dose in 10/12 mild cases. CNI was reduced by 25% in both the moderate cases [Cases 3 and 9, Table 2]. Of the severe cases, one [Case 1, Table 2] was on a low-dose cyclosporin (dose reduction of 75%) and in the other three patients of severe category, the CNI was reduced and stopped. The immunosuppression modification done is shown in Table 2.
Tacrolimus trough level was available in 5/12 mild cases. The mean level was 5.87 ng/ml. The time to COVID infection after transplant in these five patients was 6 years, 6 months, 9 months, 9 months, and 6.5 months. Tacrolimus level was not available in any of the moderate cases. Of the four severe cases, tacrolimus level was available in two patients. One of them [case 8, Table 2] had a level of 7.4 ng/ml on day 4 of the illness and 2.9 ng/ml on day 10 of the illness. Tacrolimus was reduced by 75% and then stopped. His antiproliferative medication was stopped. He survived the infection but lost the graft. Another patient with severe disease and renal transplant 1 week back [case 11, Table 2], had a tacrolimus level of 4.4 ng/ml on day 5 of the transplant.
The antiproliferative medication was stopped in all the cases of severe COVID pneumonia (4/4) and reduced in 1 of the moderate cases by 50% [Case 9, Table 2]. The other moderate COVID pneumonia [Case 3, Table 2] was on leflunomide for BK virus nephropathy and that was continued at the same dose.
The antiproliferative medication was continued at the same dosage in 8/12 mild cases and reduced by 25% in 4/12 mild cases. The modification of immunosuppressant medication was done at the discretion of the treating nephrologist based on the severity of the infection.
The steroid dosages were increased in all severe and moderate cases, and 2/12 in mild cases. The remaining 10/12 mild cases were continued on the same dosage as earlier. The dosage and continuation were based on the markers, especially the C-reactive protein.
Treatment and outcomes
Antivirals given were given in six patients altogether. Of the mild cases, 1/12 received favipiravir while 11/12 did not receive any antiviral therapy.
Both the moderate cases received remdesivir. They were on 4 L and 6 L of oxygen, respectively, with ground-glass opacities typical of COVID pneumonia on CT chest. One of them [Case 3, Table 2] had acute kidney injury (AKI) during this episode. He also had a background of BK virus infection for which he was on leflunomide. Injection remdesivir was administered on alternate days in view of AKI. The other patient [Case 9, Table 2] was on remdesivir daily, and his allograft functions remained stable. At discharge, he was saturating on room air and allograft functions were stable. The steroid used was injectable dexamethasone in mild and moderate cases and injection methylprednisone in severe cases. The patients were continued on oral steroids at discharge for 2 weeks (oral dexamethasone or prednisone at the discretion of the physician) or longer if the inflammatory markers warranted an extension in the course of steroids.
One of the severe cases of COVID pneumonia who survived, had not received any antiviral therapy, 1 received remdesivir only, and another received remdesivir and tocilizumab. One patient (who developed COVID-19 pneumonia on day 8 of a successful transplant) had received the antibody cocktail (600 mg of casirivimab and 600 mg of Imdevimab).
Anticoagulants were given according to the D-dimer levels.
AKI occurred in four patients, graft loss in one patient, and death in two patients. There was no graft loss in the two patients who did not survive. Of the 16 surviving patients, all have recovered to their baseline creatinine at a mean follow-up of 17.43 days (median follow-up: 14.5 days and range: 0–44 days), except for one who progressed to graft failure.
In this case series, we describe our experience of 18 renal transplant recipients (19 episodes) who had varying degrees of COVID-19 infection. The shortest time of COVID after a transplant was 8 days in our series while the earliest time that COVID infection has been reported in the literature after a transplant is 5 days.
Although it is well known that immunosuppression has to be reduced in the face of an infection, there is no consensus on the practices. The modification of the immunosuppression in our study, particularly in the mild case, had an approach that was similar to that of Oto et al. where mild cases had minimal or no change in their immunosuppression.
The unexpected rapid deterioration of this patient 11 in our series suggests that he may have been in the incubation period during surgery though the pretransplant COVID test by RT-PCR was negative. The Brazilian study as well as other studies in the nontransplant population suggest that patients who underwent elective surgeries in the incubation period may have higher mortality early in the postoperative period.[1,3,4]
The survival of case 1, despite the severity of pneumonia and several comorbidities including OSAS and being a recipient of a second renal transplant, suggests that the choice of CNI may have a role. Cyclosporin may have an inhibitory effect on the proliferation of coronavirus and hepatitis C in vitro. Banerjee et al., in their study, suggested that cyclosporin has an effect on cyclophilin A and B which may inhibit the replication of coronavirus. This was not true for tacrolimus. Genetic backgrounds such as human leukocyte antigens (HLA) polymorphism or angiotensin-converting enzyme polymorphism could also be implicated in individual response to infection, as suggested by the Belgian study and others. The HLA type may predict vulnerability and individual genetic variability in the immune response to COVID infection.[6,7]
The above two cases deserve a mention as a young transplant recipient with good graft functions, planned for discharge took an unpredictable turn, whereas a morbidly obese recipient of a second transplant with multiple comorbidities and a stormy course in the critical care unit, was discharged uneventfully with a functioning graft.
The infection rate and mortality rate in our study are difficult to calculate as we included all COVID-19 infections in renal transplant recipients who attended our hospital irrespective of when and where they had undergone renal transplants. Our hospital is a 5-year-old tertiary care center, our transplant program being 2.5 years old. The number of renal transplants performed at our center between July 2020 and January 2022 was 24. Of the patients transplanted during this period, seven patients had COVID infection (29.16%) at a median time of 8.9 months from the time of transplant (Range: 8 days to 15 months). The European study conducted by ERA-EDTA yielded an average infection rate of 14/1000 transplants (Spanish Registry 17.7/1000, French Registry 9.5/1000, and Dutch Registry 14/1000).[8–12]
In our study, the mortality rate related to COVID for the patients transplanted during the above period was 1/24 (42 per 1000). However, the sample size was too small to compute a mortality rate. The mortality rates in other studies were diverse. Oto et al. reported a mortality of 12.8% in their registry whereas in others the mortality rate ranged from 24% to 30%.[13–16]
The incidence of AKI in COVID is variable. In our study, AKI occurred in 22.22% (n = 4). In Muhammed’s study of eight patients, two had AKI of whom one needed continuous venovenous hemofiltration. Earlier studies report an AKI incidence of 3%–9% in COVID infection in transplant recipients whereas the AKI incidence in COVID in the general population is 15%.[18–21]
The most common presenting symptom was fever in our study, which is similar to the general population and to other studies of COVID infection in renal transplant recipients. Interestingly, none of our patients presented with diarrhea, which is a striking contrast to the findings of the Brazilian study that found diarrhea as the presenting symptom in 30% of the patients.
The most common comorbidity in our study was hypertension, which was similar to the study by Elhadedy et al., that included 8 renal transplant recipients with COVID infection.
Although there is an undisputable consensus of reducing or stopping immunosuppression in the face of a severe infection, the decision to reduce or completely stop the immunosuppression and the timing of doing so weighs heavily on the nephrologist and the patient, considering the high chance of graft loss. The benefit of treating a life-threatening infection undoubtedly outweighs the risk of graft loss. The general consensus is to stop the antiproliferative medication first, then tacrolimus and, steroids remain unchanged or the dose may be increased for the underlying respiratory disease. A standard protocol of immunosuppression reduction was not adopted in our study. Contrariwise, the Belgium study had adopted a standard strategy of immunosuppression minimization and treatment. Another series of eight patients reported by Elhadedy et al., also universally adopted a strategy of discontinuing the antiproliferative medication in all their patients.
There is also no consensus on when to reintroduce or increase the immunosuppressants after recovery from COVID-19 infection.
The risk of infection in the early days of transplantation cannot be overlooked. This concern of an asymptomatic infected patient being in the preclinical phase with normal radiological findings and negative RT-PCR has been highlighted in the Brazilian study. The subclinical infection can reactivate in the posttransplant phase which unfortunately turned disastrous in our patient [case 11]. Kidney transplant recipients experience high mortality, especially in the early period, after the transplant. The role of potential donor transmission is unestablished. Elective surgery during the incubation period carries a high risk of mortality in the postoperative period.[1,3,4] Other than nosocomial transmission, the possibility of the patient being in the incubation period of an asymptomatic infection before the transplant can be considered. Such a scenario is associated with high mortality as suggested in the analysis of Sharma et al.
In most of the studies, community-acquired COVID-19 infection was the most common (92% in the Brazilian study). Our study also had predominantly a community-acquired source, except for one infection that was considered to be nosocomial.
Transplant recipients have high morbidity and mortality owing to their immunocompromised state, underlying chronic kidney disease, and many shared comorbidities such as hypertension and diabetes.
Renal transplant recipients may have diverse manifestations of COVID-19 infection. Our study, although small in size, has thrown light on this diversity, the varied presentations, course, and unpredictable outcomes in some patients. The unexpected trajectory of recovery taken by one of the most severe cases and the unprecedented rapid worsening of one of seemingly stable recipients early after transplant, make the scenario an area of uncertainty.
A possible genetic predisposition determining outcomes cannot be ruled out, and studies inclusive of genetic analysis would add key information to this group of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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