COVID-19 has affected all aspects of a transplantation program, from donor selection to transplantation. The death to case ratio of 13.8% in KTR with COVID-19 infection at the study centre is similar (11.6%) to the reported multicentric study from India but much higher than the general Indian population (< 1.5%) [5, 6]. The reported mortality rate across the globe has been quite variable with a range of 12 to 32% amongst studies included in a recent meta-analysis of KTR . The reasons for this wide variability are not clear. However, they might be related to differences in population demographics like the majority of KTR included in the meta-analysis were elderly, a higher prevalence of medical comorbidities like diabetes and quality of care received during the evolving pandemic. Among developing nations, KTR with COVID-19 infection has been reported to have a varying mortality rate of 9.5–11.6% in India and 21% in Brazil, possibly due to the higher median age of KTR in the Brazilian study group as compared current study group (51.3 vs 41 years, respectively) [7, 8]. Older age is a well-established risk factor for death among both KTR and the general population [16, 17].
The present study analyzed various risk factors contributing to mortality in KTR affected by COVID- 19 infection. Coinfection was an independent risk factor for mortality in the present study. This finding concords with a recent meta-analysis concerning coinfection with COVID-19, which showed a high prevalence (upto10%) of viral co-infections, which is associated with poor outcomes and further supports the need for diagnostic testing and treatment of associated infections . In the present study group, cytomegalovirus infection was the commonest co-infection, and its presence has been associated with increased mortality amongst Iranian KTR with COVID-19 [19, 20]. CMV has a high prevalence (> 80%) in India amongst the adult population . Reactivation of latent CMV infection occurs in > 30% of the seropositive patients receiving immunosuppression after kidney transplantation [22, 23]. Low absolute lymphocyte count is a known independent predictor of recurrent CMV disease in solid organ transplant recipients . Lymphopenia at presentation among KTR with COVID-19 infection has been associated with increased mortality in the TANGO consortium . It is possible that lymphocytopenia during severe SARS-CoV-2 infection might lead to cellular immune system deficiencies resulting in reactivation of CMV. CMV reactivation has also been reported in critically ill COVID-19 infected patients. CMV has been shown to increase the length of hospital stay among mechanically ventilated non-transplant patients in ICU and predispose them to other secondary infections [24, 26,27,28]. Routine screening of patients with severe or persistent lymphopenia for the presence of CMV infection might help in early diagnosis and timely intervention.
In the present study, monitoring of CMV in selected high-risk COVID-19 KTR helped us diagnose the disease early during the second wave. This strategy helped in the timely diagnosis and treatment of three KTR with CMV co-infection during the second COVID-19 wave. However, CMV testing was not done in the majority of the cases due to logistic issues during the lockdown when the medical and societal resources were overwhelmed. The clinical features of CMV like graft dysfunction, interstitial pneumonia with persistent lymphopenia, and diarrhoea are also present in COVID-19 infection.
The clinical spectrum of COVID-19 infection is broad. Therefore, it would be beneficial to understand any particular presentation with the risk of severe illness. Diarrhea at presentation was an independent risk factor for death amongst affected KTR in the present study and has been reported as a predictor for hospitalization but not for death among the Brazilian cohort of 1,680 KTR . Several meta-analyses in patients with COVID-19 infection among non-transplant patients with gastrointestinal manifestations have reported that patients with diarrhoea were at much higher odds of increased disease severity and worse prognosis, and prolonged viral shedding in the GI tract has been shown in (> 20%-40%) of patients even after having a negative respiratory sample [29,30,31,32,33]. However, conflicting reports of diarrhea associated with lower mortality were observed in a meta-analysis of 4,440 KTR; the reason for this is not apparent . Diarrhea in COVID-19 KTR has been proposed to result from direct infection of SARS-CoV-2 in the intestinal epithelium cells via angiotensin-converting enzyme 2 (ACE2) receptors, resulting in cytokine storm through direct cytopathic effects of SARS-CoV-2 contributing to gut dysbiosis and aberrant immune response resulting in increased intestinal permeability, which further exacerbates existing symptoms and worsen prognosis [34, 35]. Gastrointestinal SARS-CoV-2 infection has important epidemiological significance as diarrheal diseases are more common in developing nations, and SARS-CoV-2 in the faeces may facilitate the spread of COVID-19 through the faecal-oral transmission and contamination of surroundings . Gut-lung axis and GI dysbiosis in COVID-19 have been postulated as contributory factors for the severity of SARS-CoV-2 illness [37, 38]. Due to limited healthcare resources, the present study group did not test for faecal samples among KTR with COVID-19 infection.
No differences in patient survival were found depending on the time after kidney transplantation among 138 hospitalized KTR with COVID-19, suggesting that continuing transplant activity may not put transplant patients in the early postop period with additional risk . In contrast, higher mortality in the early post-transplant period (< 60 days) was observed among KTR from Spain in the early phase of the pandemic conceivably due to the inclusion of elderly KTR (> 60 years) . Modification in induction immunosuppression regimens was performed during the COVID-19 pandemic at many centres, with some initial success in kidney transplantation, while the standard ATG induction therapy was associated with the risk of severe COVID-19 illness [41,42,43]. The study centre used a low dose induction therapy with doses up to 3 mg/kg, and this was not associated with increased mortality among KTR during the COVID-19 pandemic. A similar finding was observed in a retrospective study from Poland regarding the safe usage of standard dosage of ATG in KTR both as induction and antirejection therapy during the COVID-19 pandemic . However, antirejection therapy during the last three months before acquiring COVID-19 infection was associated with worse outcomes on univariate analysis in the present study, in agreement with a multicentric study from India . Ongoing graft rejection during the COVID-19 infection was another risk factor for death among KTRs on univariate analysis, possibly related to the intensification of immunosuppression in the presence of graft dysfunction.
Furthermore, Calcineurin inhibitor (CNI) withdrawal during the hospital stay was a risk factor for mortality on univariate analysis in the study cohort, and continued use of tacrolimus has been associated with better survival amongst liver transplant recipients requiring hospitalization in the ELITA/ELTR multicentre European study . Withdrawal of tacrolimus is an integral part of managing sick KTR, and the benefits of continuing it in KTR with severe COVID-19 infection need to be confirmed in future studies as patients with COVID-19 infection have also been associated with cytokine storm during the immuno-inflammatory phase that is more likely to happen if the immunosuppression is suddenly lowered .
COVID-19 related mortality in this study is also attributed to the difficulty accessing healthcare facilities during the pandemic. The study centre caters to patients with limited health care resources, thereby attracting transplant recipients from far-flung regions. The lockdowns resulted in the discontinuation of routine outpatient services. Markedly reduced public transport options made it further difficult for those patients who cannot afford private health care facilities .
Our data does not show any influence of hypertension as comorbidity, type of transplantation (living versus deceased donor) and delayed graft function on mortality figures mainly due to the younger age group and typically shorter cold ischemia time in recipients of deceased donor kidneys at the study centre, but this could be a type 2 error because of too much scattering of data or inadequate sample size. Inferior allograft function among the deceased donor KTR than living donors KTR has been associated with an increased risk of severe COVID-19 infection in a recent meta-analysis .
Other well-established risk factors for mortality in KTR due to COVID-19 infection were also significant in univariate analysis in the present study, i.e. elderly KTR, diabetes as comorbidity, dyspnea, acute kidney injury, lymphopenia, the requirement of renal replacement therapy and are in accord with already published literature [2, 3, 6, 8, 16, 25].
Limitations of study
Limited laboratory tests for inflammatory biomarkers (interleukin-6, C-reactive protein) have been available due to logistic issues during the pandemic. This study presumes that the distribution of the risk of exposure was the same in both groups, i.e. survivors vs non-survivors. In addition, this study presumes that the promptness and economic factors that play a role in access to health care, especially when the health care systems are overstretched during the pandemic, were similar in both groups. It is impossible to eliminate or mitigate against three types of biases in a retrospective study, i.e., selection, recall, and observer bias.
Strengths of study
The study is endowed with many positive features such as matched study design with extensive workup, regular and comprehensive follow-up, a robust data extraction facility and a finely monitored data collection process that is regularly cross-checked by a dedicated team of residents in-charge of COVID-19 team who ensured that missing data was kept to a minimum. The quality of information is reliable and reproducible.