Key words : Coronavirus disease 19, Disability, Kidney transplant recipients

Introduction

The COVID-19 pandemic has caused great distress to the community,¹ and renal transplant recipients (RTRs) are no exception to this.^2-4 There is wide variability in patient clinical presentations and outcomes of COVID-19 in the literature because of the varied preparedness and health infrastructure in different countries to cope with the sudden surge of patients with COVID-19.⁵ Renal transplant recipients are at high risk of acquiring infection, severe COVID-19, hospitalization, and mortality because of the immunosuppressed state and inherent morbidities associated with renal transplant. Studies conducted in 2020 reported mortality rates that varied from 10% and 40%.^6-8 An Indian multicenter study reported an overall patient mortality rate of 11.6%, hospitalization rate of 14.5%, intensive care unit (ICU) rate of 47%, and ventilation rate of 96.7%.⁶

Renal transplant recipients are prone to multifac-torial acute graft dysfunction directly induced by SARS-CoV-2 cytotoxicity, cytokine storms, antiviral drugs, and dehydration.^2-4 Alterations in immunosup-pression during COVID-19 illness can increase the risk of rejection, which requires readmission and graft kidney biopsies.^6,9-11 The post-COVID-19 sequelae have been increasingly reported in the literature, with many of these complications requiring rehabilitation.^12,13 The incidence of post-COVID-19 sequalae among those who survive is unclear in RTRs. There are insufficient data on outcomes of COVID-19 in RTRs from the northern part of India. Data are also limited on whether survivors develop residual disabilities, have graft rejections, or develop opportunistic infections on follow-up.

Recent systematic and meta-analysis reports from the developed world have also shown varying outcomes.^14,15 One meta-analysis showed a mortality rate of 23% and acute kidney injury of 50% in RTRs.¹⁴ A systematic review¹⁶ also showed varying mortality, from 18% in New York City¹⁷ to 46% in Spanish national registry data.¹⁸ However, these studies revealed heterogeneity and suboptimal data reporting. The authors called for consistency and uniformity in reporting outcomes of RTRs with COVID-19 with regard to anthropometric characteristics, kidney function at baseline and discharge, immunosup-pressive therapy, acute kidney injury, and renal outcomes.^14-16 As shown in the reports, renal transplant recipients are prone to SARS-CoV-2 infection and can have higher rates of early mortality; however, medium- and longer-term outcomes remain uncertain and merit careful investigation. The varying outcomes may also be because of different health infrastructures to manage the pandemic in different countries. Data on quality of life after recovery from COVID-19 in RTRs are not yet available. Knowing the health care requirements and resource utilization for high-risk RTRs can help in planning resource allocation for comprehensive care on future surges of COVID-19. Here, we analyzed the outcomes of RTRs with COVID-19 and the post-COVID-19 sequelae and quality of life scores among survivors after the first wave of COVID-19.

Materials and Methods

We conducted a prospective observational cohort study of consecutive RTRs who developed reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection-induced COVID-19 disease between April 1, 2020, and December 31, 2020, at our tertiary care institute. Patients with allograft failure on maintenance dialysis were excluded. Cases were categorized as mild, moderate, and severe as per the Revised Guidelines on Clinical Management of COVID-19, Ministry of Health and Family Welfare, the Government of India. COVID-19 disease was classified as mild when symptoms were present without features of viral pneumonia on imaging (chest radiography or high-resolution computed tomography [HRCT] scans), moderate if manifestations were present, and severe if hypoxia was present.¹⁹

The clinical characteristics and laboratory variables were recorded. Transplant-related data were obtained from the electronic records of our hospital information system. All comorbidities (diabetes mellitus, hypertension, chronic obstructive airway disease, cardiovascular disease, and cancer) were noted. All laboratory tests were performed according to the clinical care needs of the patient. Laboratory assessments consisted of complete blood counts, blood chemical analyses, coagulation testing, assessments of liver function, and measurements of electrolytes. Levels of C-reactive protein, serum ferritin, and interleukin 6 were measured as per the physician decision and availability of the test. Thorax HRCT scans were first conducted to assess for any typical findings of COVID-19 pneumonia (bilateral, multilobe, posterior peripheral ground-glass opacities) as defined previously.²⁰ Severity was assessed using a previously reported scoring system, which depends on visual assessments of each lobe involved.^21,22 These tests were performed for all hospitalized patients; for patients isolated at home, tests depended on their availability and clinical decisions. Patients were managed as per our institute’s COVID-19 management protocol and the best available evidence at patient presentation.

As per the Indian Council of Medical Research guideline, all organ recipients with COVID-19 should be hospitalized. However, decisions to admit or advise home isolation were made as per our institute’s protocol. Our infrastructure did not allow all patients to be admitted, and only patients with moderate to severe disease were admitted. Patients isolated at home were instructed to monitor for oxygen saturation and temperature every 6 hours; those who had saturation lower than 95% were asked to report for hospitalization. Patients were followed during their hospital course and by telephone daily if they were in home isolation. Immunosuppressive agents were modified with an increase in steroids and reduction of antimetabolites to half in patients with mild-moderate disease and stopping in patients with severe disease. Calcineurin inhibitors (CNIs) were reduced to half in patients with severe disease, and all patients were given remdesivir.²³ Trough levels of tacrolimus were targeted toward lower levels of the recommended amount (between 3 and 5 ng/mL if beyond 6 months posttransplant and between 6 and 8 ng/mL if within 6 months posttransplant). Patients underwent follow up every 2 weeks after discharge through our institute’s telemedicine facilities for a minimum of 12 weeks and were seen at our facility if further evaluations and graft kidney biopsy were needed.

Outcome measures
Mortality, readmissions, reinfection, graft dysfunction, and rejection episodes were evaluated. Scores for health-related quality of life were obtained using the EQ-5D survey (Hindi version), which was given to hospitalized patients and sent electronically to all home-isolated patients with instructions to complete and return to the investigator. One investigator assisted in completion of the questionnaire for any patient who could not complete it on their own. The EQ-5D survey is a standardized measure of health status developed by the EuroQol group to provide a simple, generic health measure. It has 5 components covering 5 dimensions to describe the health-related quality of life: mobility, anxiety, self-care, pain/discomfort, and usual activities.²⁴ Each variable in the score was assigned a score between 0 and 100. A total average of all 5 variables was calculated for a maximum score of 100. The EQ-5D survey has been validated as a reliable measure of health status in renal transplant recipients.²⁵ Permission to use the EQ-5D survey was obtained from the developer of the EuroQol group. Our ethics committee approved the study.

Statistical analyses
Continuous variables are shown as means ± standard deviations. Categorical values are shown as numbers and percentages in parentheses. We used the t test to analyze mean differences in values, and the Fisher exact test or the chi-square tests as needed to compare categorical values between the groups. P < .05 was considered significant. We used the SPSS program (version 25) for data analysis.

Results

Of the 3100 RTRs who were followed up at our institute, 128 patients were shown to have SARS-CoV-2 infection between April 1, 2020, and December 31, 2020. After patients with chronic kidney disease (n = 19), patients with deceased donor transplant (n = 3), and patients who had 1 rapid test positive but 2 RT-PCR negative tests and those lost to follow-up (n = 1 each) were excluded, 104 patients (92.3% ABO compatible and 7.7% ABO incompatible) were included in the study. These patients had a minimum of 12 weeks of follow-up (mean follow-up of 13.72 ± 1.9 weeks). All had living-related kidney donor transplant procedures. Donor details are shown in Table 1; most donors were spouses (63.5%) followed by a parent (32.7%) or a sibling (3.8%).

Table 1 shows the baseline clinical characteristics of patients (results at first presentation). Among 104 patients, 75 (72.1%) had mild to moderate disease and 29 (27.9%) had severe disease. Mean age of RTRs was 44.09 ± 12.84 years; patients with severe COVID were significantly older than those who had mild-moderate COVID-19 disease (49.86 ± 12.78 vs 41.85 ± 12.2 years, P = .04). Median time since transplant to COVID-19 disease was 64 ± 48 months (range, 2-280 mo); these results were similar between those with mild to moderate disease (62.84 ± 47.73 mo) and those with severe disease (68.17 ± 49.79 mo). The most common comorbidity was hypertension in 73 patients (70.2%) followed by diabetes in 36 patients (34.6%). The proportion of patients with diabetes was higher in the severe COVID-19 group (55.2%) than in the mild-moderate COVID-19 group (26.7%; P = .007). Coexistent mycobacterium tuberculosis infection of the lung on antituberculous medicine was noted in 12.5% of patients, and coronary artery disease was noted in 6.7% of patients. Among hospitalized patients, serum C-reactive protein levels (143.4 ± 22.1 vs 34.1 ± 6.22 mg/L; P < .001) and procalcitonin levels (11.13 ± 4.62 vs 0.99 ± 0.76 ng/mL; P = .03) were significantly higher in patients with severe than in patients with mild-moderate COVID-19. Basiliximab induction was given in 48 patients (46.2%), and antithymocyte globulin was given in 28 patients (26.9%) with no difference in COVID-19 severity between the groups. Maintenance immuno-suppression of triple-drug immunosuppression (tacrolimus/cyclosporine, mycophenolate, and an oral corticosteroid) was similar between the groups (Table 1).

Symptoms, laboratory parameters, and treatment details are shown in Table 2. Fever was the most common presenting feature in 94 patients (90.4%). Patients with severe COVID-19 had a higher incidence of cough, fatigue, diarrhea, dyspnea, and oliguria. Of all patients, 78 patients (75%) were hospitalized, with 43 (41.3%) admitted to the ICU dedicated to COVID-19 care. All admitted patients underwent thorax HRCT for evaluation, with determination of severity score. The average severity score (maximum of 25) was 11.59 ± 5.2 and 7.4 ± 5.3 versus 15.4 ± 3.9 in those with mild to moderate disease versus severe disease. Home isolation with telephone follow-up was done in 26 patients (25%). Mechanical ventilation was required in 13 patients (12.5%), with only 1 patient who was extubated. The remaining patients in the ICU were treated with high-flow nasal cannula or bilevel positive airway pressure ventilation.

Treatment and patient survival
Thirteen of 104 patients (12.5%) died; all 13 were in the severe COVID-19 group. The relative risk of mortality was determined to be 51.3% (95% CI, 3.1-840.6; P = .006) higher in those with severe COVID-19 than in those with mild-moderate COVID-19. All of these patients died in the hospital. The mean duration of hospitalization before death was 18 ± 3 days. Causes of death were acute respiratory distress syndrome (ARDS) in 9 patients, ARDS with septic shock in 2 patients, and cardiovascular death in 2 patients.

Association of remdesivir use with mortality
Remdesivir was used in 46 of the 78 hospitalized patients (58.9%; 20 in the severe group and 26 in the mild-moderate group). None of the patients with mild-moderate COVID-19 died irrespective of the status of whether they received remdesivir or not. Of the 29 patients with severe COVID-19 patients, 20 (68.9%) patients received remdesivir and 9 (31%) did not (5 because of unavailability and 4 did not consent for remdesivir). Of the 16 patients with severe COVID-19 who survived, 13 (81.25%) received and 3 did not receive remdesivir (18.8%). Of the 13 who received remdesivir, 12 had been started on remdesivir within the first week (mean 6 ± 1.5 days), and only 1 had been started on day 10 after onset of COVID-19 symptoms.

Of the 13 patients with severe COVID-19 who did not survive, 7 (53.8%) received and 6 (46.2%) did not receive remdesivir. However, all 7 patients who died on remdesivir in the severe group had started remdesivir at least 10 days (mean 12 ± 2.3 days) after symptom onset. The mortality rate for those with severe COVID-19 who received and did not receive remdesivir was 15.2% and 18.8% , respectively (P = .680) (Table 2). Convalescent plasma therapy and tocilizumab were used in 1 patient each; however, both patients died. Azithromycin was used in 87.5% and ivermectin in 85.6% of patients.

Rehospitalization and reinfection after recovery from COVID-19
At end of follow-up, 16 of 91 survivors (17.5%), 13 from the mild-moderate group (17.3%) and 3 from the severe group (18.8%; P = .121), were readmitted in a non-COVID-19 setting after discharge (Table 3). The most common reason for readmission was opportunistic infection (7/16, 44%) followed by acute graft dysfunction (6/16, 38%). Two were admitted with pulmonary sequelae and 1 with angina-like symptoms. Among 7 with an opportunistic infection, 3 had bacterial urinary tract infections, 2 had fungal pneumonia, 1 had BK virus nephropathy with BK viremia, and 1 had cytomegalovirus disease.

In addition, 3 of the patients (2 from the mild-moderate group, with 1 after 10 weeks and 1 after 8 weeks of discharge) were readmitted with reinfection with new onset of fever and cough. The other patient (from the severe group) also had readmission at 11 weeks after discharge from the first admission with new onset of fever and cough. All 3 patients had been discharged from COVID-19 care after 2 negative RT-PCR tests per our protocol during the first admission. All 3 had reinfection confirmed with RT-PCR. However, the sequencing could not be done during either first admission or readmission; therefore, an infection that happened with the same or different variant of SARS-CoV-2 could not be confirmed. However, all 3 recovered. Two patients were admitted for management of COVID-19-related pulmonary sequelae for rehabilitation. Follow-up HRCT scans in patients showed evidence of persistent injury and onset of fibrosis and chronicity in 2 patients with persistent pulmonary sequelae (Figure 1).

Graft dysfunction after COVID-19
The mean baseline serum creatinine value was significantly higher in the severe COVID-19 group (1.79 ± 0.14 mg/dL) than in the mild-moderate COVID-19 group (1.27 ± 0.4 mg/dL). Acute graft dysfunction was noted in 54 of 104 patients (51.9%) (29/75 [38.6%] with mild-moderate COVID-19 and 26/29 [86.2%] with severe COVID-19; P = .01). Graft dysfunction was transient in 49 patients, which gradually recovered on follow-up. Seven patients (6.7%) required dialysis support during hospitalization (all in the severe group). Of 91 surviving patients, 6 patients (6.59%) (5 [18.6%] from the severe group and 1/75 (1.33%) from the mild-moderate group; P = .04) had persistent graft dysfunction; all remaining patients recovered. Six patients with persistent graft dysfunction were evaluated with graft kidney biopsy. Biopsy-proven rejection was observed in 3 patients. Two had acute antibody-mediated rejection (with 1 having peritubular capillaritis 2+, glomerulitis 1+, and C4d positive and 1 having peritubular capillaritis 2+ and C4d positive) and 1 had T-cell mediated rejection (tubulitis 1, and interstitial inflammation 2). Two patients had recovering acute tubular necrosis and 1 patients had transplant glomerulopathy changes with duplication and multilayering of glomerular basement membrane, C4d less than 10% positivity, and class II antibody mean fluorescence intensity of 2400.

Quality of life score at the end of follow-up
Table 4 presents the exact EQ-5D scores for the different categories of COVID-19 disease. The baseline EQ-5D scores were not different between mild-moderate and severe COVID-19 groups. Overall, the total EQ-5D score was significantly affected by COVID-19 disease compared with baseline results, with significant differences mainly observed for pain (P = .021) and anxiety/depression scores (P = .001). Usual activities, mobility, and self-care scores were not different (Figure 2A). Similar observations were found in the mild-moderate COVID-19 group (Figure 2B). However, the total EQ-5D score and every component of the score were significantly affected in the severe COVID-19 group on follow-up (Figure 2B).

Discussion

To the best of our knowledge, this is the only study to evaluate the effects to quality of life caused by severe COVID-19 illness in a large cohort of RTRs on longitudinal follow-up. This study observed that severe COVID-19 significantly affected patient quality of life as shown by EQ-5D score. We also observed that mortality rate (12.5%) among those with severe COVID-19 was higher than among those with mild-moderate COVID-19, which is approximately 6 times higher than the general population with COVID-19 in Uttar Pradesh, India, during the same period.²⁶ The mortality rate of RTRs with COVID-19 was either comparable or lower than other centers that reported mortality of RTRs with COVID-19 during the first wave of COVID-19.^23,27 Elevated C-reactive protein and procalcitonin were associated with severe COVID-19 disease and more unsatisfactory outcomes. In agreement with the TANGO study group and the French cohort, we found that diabetes mellitus was associated with a high incidence of severe disease.²⁸

A critical observation in our study was the home isolation of RTRs with COVID-19. A significant challenge during the COVID-19 pandemic was bed availability for hospitalizations. Despite recom-mendations to hospitalize all transplant recipients by the Ministry of Health and Family Welfare, the Government of India, 25% of our patients were successfully managed with in-home isolation and daily monitoring without any mortality. Thus, with the lack of available hospital beds, we found that RTRs with mild-moderate COVID-19 could be successfully treated at home. Modifications of immunosuppressants also played a vital role.^29,30 We suggest that reducing the dose of antimetabolites to half in patients with mild-moderate disease or stopping medications in those with severe disease and simultaneously doubling prednisolone maintenance dose from 7.5 mg to 15 mg and from 10 mg of baseline to 20 mg may be an important factor for successful outcomes in all patients treated at home. In patients with severe COVID-19, prednisolone was changed to dexamethasone or methylprednisolone.

The RECOVERY trial established the role of steroids in the management of hypoxia in COVID-19 patients.³¹ Corticosteroids seem to be also valuable in transplant patients who are already on low-dose steroids to prevent rejection. Steroid doses (6 mg dexamethasone or equivalent) higher than recom-mended in the RECOVERY trial have not been clearly defined, and the long-term effects of such practice in transplant recipients are mainly unknown. In vitro studies have shown that tacrolimus and cyclosporine have antiviral activities against beta coronaviruses.³² Among our patients, CNI doses were only reduced in those with severe disease to avoid net immunosup-pression as simultaneously steroids were being increased. Dose modifications of immunosuppression are not well defined and are determined by the treating clinicians depending on disease severity. Tailoring of immunosuppression resulted in rejection to 3 of our patients, which was alarming. The definite setpoint of immunosuppression and the ideal time of reintroduction of immunosuppression remain controversial. For our patients, we reintroduce immunosuppression as soon as infection has cleared.

One significant difference from other centers in the treatment of COVID-19 was the use of the antiparasitic ivermectin, which carries antiviral properties.³³ It was used in 89 patients (85.6%), and azithromycin, a macrolide antibiotic, was used in 91 patients (87.5%). The government supplied these medicines to patients at home as soon as SARS-COV-2 infection was detected. However, the role of these medicines as anti-COVID-19 therapy remains controversial.³⁴ The use of remdesivir is also controversial; the largest trial showed no mortality benefit in patients with severe COVID-19, although duration of recovery was reduced.^35,36 Our study also did not find any mortality benefit in those with severe COVID-19, as mortality in the severe group was similar between those who received and did not receive remdesivir. However, it was noticeably clear that patients who survived severe COVID-19 received remdesivir early, mainly during the first week of illness. Those who received remdesivir early had a better chance of recovery. As per protocol, remdesivir did not affect the tacrolimus level as most patients received lower doses of CNIs. We observed no deaths in patients with moderate COVID-19 who received remdesivir, suggesting that the early use of remdesivir in the course of the disease may be associated with benefit in mortality.

Even after recovery from COVID-19, some patients required rehospitalization with graft dysfunction, acute rejection, and opportunistic infections, irrespective of the severity of COVID-19. A possible reason for graft rejection in 3 patients may have been the modifications in immunosuppressive agents. Many patients had reduced CNI doses and stopped antimetabolite doses. Another possible reason for graft dysfunction could be the immuno-modulating effects of the SARS-CoV-2 per se.^37,38 The virus attacks the kidney, and the presence of viral particles on ultrastructural changes supports the hypothesis of direct cytotoxicity.39 However, the viral particle-like changes were not seen in any of the patient graft biopsies, even on electron microscopy. Admission with infection in these patients may be associated with a high dose of corticosteroids in the management of the COVID-19 cytokine storm. Only 2 patients were admitted for COVID-19-related pulmonary sequelae, with some evidence of pulmonary fibrosis, which can be a sign of severe pulmonary damage.^40,41 The pattern of readmission suggests that patients might have had a loss of balance between rejection and infection due to adjustment of immunosuppression during the treatment of COVID-19 disease.

In this study, we found that patient-related outcomes could be measured in transplant recipients with the EQ-5D survey, a validated outcome measure of quality of life.²⁵ We found that patient-related quality of life and functional disability in RTRs with severe COVID-19 were similar to sequelae observed in non-RTRs with COVID-19.⁴² Anxiety/depression was a strongly affected component. Thus, the mental well-being of patients with severe COVID-19 disease should be considered. Similarly, RTRs should also be assessed for physical rehabilitative measures as performed for nontransplant recipients.⁴² Post-COVID-19 sequelae have been reported in non-RTRs at follow-up of up to 1 year and showed that most patients who recovered from severe COVID-19 had improved dyspnea scores and exercise capacity over time; however, physiological and radiographic changes persisted in a subgroup of patients at 12 months.⁴³

At 7 months of follow-up,⁴⁴ multisystem involve-ment with COVID-19 was demonstrated, showing that many systemic and neurological/cognitive symptoms did not return to previous levels and nontransplant patients continued to experience significant symptom burden at the end of follow-up. To observe whether persistence occurred in our patients, a longer period of follow up is required. It is clear that RTRs are more vulnerable to risk of severe COVID-19 disease and high mortality associated with COVID-19.^45,46 However, in a study from Turkey, no mortality was shown in RTRs with COVID-19 in the early pandemic period.⁴⁷ In another paper from the same center, kidney and liver transplant procedures were safely performed during the pandemic period, as long as adequate precautions were taken; patients did not have much change in immunosuppressive therapy or mortality.⁴⁸ Indeed, increased time on the wait list could increase risk of death in patients awaiting transplant. In an editorial, Haberal emphasized that transplant centers should follow guidelines on how to manage further anticipated onslaughts of COVID-19 cases together with care of patients with chronic diseases in their hospitals and countries.⁴⁹ However, COVID-19-related outcomes depend on the health infrastructures of the country and their ability to handle any surges of severe cases. With these considerations, there are varying outcomes of COVID-19 in organ transplant recipients from different countries.^45,46 In the absence of an effective treatment for severe COVID-19, rapid vaccinations to these vulnerable RTRs are warranted to prevent severe COVID-19 and its associated mortality.⁵⁰

Strength and limitations
The present study highlights the progress in care of COVID-19 over the year along with usual treatment to post-COVID-19 rehabilitative effors.^41,42 The meticulous prospective follow-up in RTRs with COVID-19 and use of quality-of-life measurements are the study’s strengths. However, there is a possibility of some recall bias in some of the patients with regard to the questionnaire.

Conclusions

Renal transplant recipients with severe COVID-19 are more likely to experience post-COVID-19 sequelae in terms of lower EQ-5D score and pulmonary complications. We found that those with severe COVID-19 had a higher risk of mortality than those with mild-moderate COVID-19. Transient acute graft dysfunction is common; however, persistent graft dysfunction may warrant hospitalization and graft biopsy. This is a preliminary report on quality of life in the short term after diagnosis with COVID-19. An extended follow-up study is required to determine any long-term persistence of disabilities and other sequelae. The high mortality rate in RTRs warrants a call for rapid vaccination to these patients to prevent severe COVID-19.

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