Clinical profile and outcome of coronavirus disease-2019 in kidney transplant recipients admitted to a tertiary care center: A retrospective study

Deepak Kumar Panigrahi; Sahil Bagai; Kamakshi Narula Singh; Kunal Raj Gandhi; Pallavi Prasad; Gagan Deep Chhabra; Rahul Grover; Dinesh Khullar

doi:10.4103/injms.injms_112_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 13 | Issue : 1 | Page : 45-50

Clinical profile and outcome of coronavirus disease-2019 in kidney transplant recipients admitted to a tertiary care center: A retrospective study

Deepak Kumar Panigrahi, Sahil Bagai, Kamakshi Narula Singh, Kunal Raj Gandhi, Pallavi Prasad, Gagan Deep Chhabra, Rahul Grover, Dinesh Khullar
Department of Nephrology, Max Super Speciality Hospital, New Delhi, India

Date of Submission	04-Oct-2021
Date of Decision	20-Oct-2021
Date of Acceptance	21-Oct-2021
Date of Web Publication	24-Jan-2022

Correspondence Address:
Dr. Deepak Kumar Panigrahi
Flat A21, Shree Balaji Apartment, Sector 6, Dwarka, New Delhi - 110 075
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_112_21

Abstract

Background: The mortality of kidney transplant recipients (KTR) affected with coronavirus disease-2019 (COVID-19) is reported to be higher than the general population. There is a scarcity of data on the pattern and outcome of COVID-19 in KTRs in developing country like India. Materials and Methods: It was a retrospective study conducted in a tertiary care center in North India. The detailed data on the Covid-19 affected KTR admitted to our center from March 2020 to March 2021 was obtained from computerized records. Clinical and biochemical characteristics of the survivors and nonsurvivors were studied. The factors affecting the mortality in this cohort were analyzed. Results: Of the 35 participants, 25 (71.4%) were males. The mean age was 53.06 ± 11.84 years. Overall, mortality was 17.1% (Six out of 35). There was a significant difference in the oxygen saturation at presentation, computed tomography severity scores, level of inflammatory markers, level of serum albumin, and the absolute lymphocyte count (ALC) between the survivors and nonsurvivors (P < 0.05). On univariate regression analysis, serum C-reactive protein, ferritin, albumin, and ALC were found to be significantly predicting mortality in COVID-19 affected KTR. Conclusions: Mortality rate in COVID-19 affected KTR is higher than in the general population. Clinical, biochemical, and radiological parameters can be helpful in predicting the adverse outcome.

Keywords: Coronavirus disease-2019, kidney transplant recipients, mortality, retrospective study

How to cite this article:
Panigrahi DK, Bagai S, Singh KN, Gandhi KR, Prasad P, Chhabra GD, Grover R, Khullar D. Clinical profile and outcome of coronavirus disease-2019 in kidney transplant recipients admitted to a tertiary care center: A retrospective study. Indian J Med Spec 2022;13:45-50

How to cite this URL:
Panigrahi DK, Bagai S, Singh KN, Gandhi KR, Prasad P, Chhabra GD, Grover R, Khullar D. Clinical profile and outcome of coronavirus disease-2019 in kidney transplant recipients admitted to a tertiary care center: A retrospective study. Indian J Med Spec [serial online] 2022 [cited 2023 Jun 9];13:45-50. Available from: http://www.ijms.in/text.asp?2022/13/1/45/336425

Introduction

The severe acute respiratory syndrome coronavirus 2 infection started in China in December 2019 and soon had to be declared as a pandemic by the World Health Organization in March 2020. It has had a huge impact on the health care system of almost all the countries across the globe. The impact of coronavirus disease-2019 (COVID-19) on all aspects of life has been devastating. Healthcare system in a developing country like India has crippled. As of April 2021, the total number of COVID-19 cases has crossed 13.6 million marks in India. Approximately 20% of Covid-19 affected patients have been reported to have moderate to severe clinical manifestations and 5% progressed to critical illness requiring life support.^[1] Older age, diabetes mellitus (DM), hypertension, chronic kidney disease, morbid obesity, coronary artery disease (CAD) have been implicated as risk factors for severe disease.^[2] Kidney transplant recipients (KTR) are at an increased risk of complications from COVID-19 due to chronic immune suppression. They also have multiple associated co-morbidities which contribute to the poor outcome. A number of studies have reported the pattern of COVID-19 in KTR especially in the developed world. However, in India, due to lack of kidney transplant registry we do not have any robust data that can effectively guide us and help analyzing clinical profile of patients. We, herein aimed to retrospectively study the clinical profile and outcome of KTR affected with COVID-19 and being admitted to a tertiary care center in North India.

Materials and Methods

This was single-center retrospective cohort study. The clinical study was approved by the institute ethics committee. The primary objective was to study the clinical profile and outcome of COVID-19 in KTR. Secondary objective was to assess the factors associated with mortality in this population. The primary outcome was mortality of the admitted COVID-19 affected KTR. The study population comprised of KTR aged 18 years and above irrespective of the duration of transplant who were being admitted in our hospital in between March 2020 and March 2021. The key exclusion criterion was estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m², history of any chronic lung disease such as chronic obstructive airway disease, interstitial lung disease, or pregnancy or death within 24 h of admission. Permission was obtained from the Institutional Review Board of the hospital. The informed consent requirement was waived off as the research was conducted retrospectively on patient's data. The study was carried out in accordance with the declaration of Helsinki. Clinical characteristics and treatment details were collected from the patient's medical records. The diagnosis of Covid-19 was confirmed by real-time reverse transcription-polymerase chain reaction from nasopharyngeal (nasal) and oropharyngeal (throat) swab. The data of all the KTR studied were noted from the computerized case files. At presentation to the hospital, all the patients were thoroughly evaluated with proper history and clinical examination. The population was divided as per clinical severity and other parameters into three categories.^[3]

Mild: KTR presented with mild symptoms including fever, cough, without shortness of breath or hypoxia, and uncomplicated upper respiratory tract infections.
Moderate: Patients demonstrated clinical features of pneumonia including fever, cough, dyspnoea, hypoxia with oxygen saturation (SpO2) <94% (range 90%–94%) on room air, and respiratory rates of 24–30/min.
Severe: Patients had advanced signs of clinical pneumonia plus 1 of the following clinical criteria: Respiratory rate >30/min, severe respiratory distress, and SpO2 <90% on room air.

All the necessary blood investigations including complete blood count, renal function tests, liver function test at presentation were noted. The peak level of inflammatory markers (interleukin-6, c-reactive protein, ferritin, D-dimer) was noted. The lowest absolute lymphocyte count (ALC) during hospitalization was also noted. Computed tomography (CT) scan findings along with CT severity scores (CTSS) were noted.

Patients were managed according to the severity of disease. Supplemental oxygen was given to maintain a target oxygen saturation of ≥94%. Patients were shifted to intensive care units if any sign of respiratory failure was seen. All of our admitted patients were on triple-drug immunosuppression with tacrolimus, antiproliferative (mycophenolate mofetil or azathioprine), and steroids. On presentation to the hospital antiproliferative agent was stopped. Tacrolimus was continued with a target trough level of 5–7 ng/dl if the transplant was more than 1 year and 7–10 mg/dl if <1 year duration. In moderate and severe disease, prednisolone was replaced with intravenous methyl-prednisolone or dexamethasone. Prophylactic anticoagulation was done in moderate and severe disease with unfractionated or low molecular weight heparin. Favipiravir was given only in minority of cases with mild disease if presented early in the course. Intravenous remdesivir was given in moderate and severe cases with eGFR >30 ml/min/1.73 m². A loading dose of 200 mg was given on day 1 followed by 100 mg once daily for 5–7 days. Convalescent plasma was considered in patients with moderate and severe disease in the absence of clinical improvement to other therapy. The volume of convalescent plasma ranged from 4 to 13 mL/kg. The interleukin-6 (IL-6) receptor antibody tocilizumab was used in selected cases with moderate to severe disease, with progressively worsening status especially in mechanically ventilated patients with significantly raised inflammatory parameters. Antibiotics were prescribed as per the hospital antibiotic policy whenever there was strong suspicion of bacterial infections.

Data were analyzed by SPSS and presented as mean (standard deviation), median (interquartile range) and frequency (percentage). Categorical variables were compared in two groups by using Chi-square/Fisher's exact test as applicable. Continuous variables were compared by independent t-test (following normal distribution) or Wilcoxon rank-sum test (for skewed data) as applicable. Univariable and multivariable logistic regression analysis was applied to assess risk factors for mortality and unadjusted and adjusted Odds ratio was calculated. P < 0.05 was considered statistically significant.

Results

It was a retrospective cohort study. Thirty-five KTR met the inclusion criteria and were included in the analysis. Twenty-five of them were males (71.4%). The mean age of the population was 53.06 ± 11.84 years. The other baseline characteristics of the cohort are represented in [Table 1].

Table 1: Baseline characteristics of the cohort

Click here to view

The overall mortality in the cohort was 17.1% (6 out of 35). M:F was 1:1 in terms of the mortality. There was no significant difference in age, sex, BMI or associated co-morbidities between the survivors and nonsurvivors. The oxygen saturation on presentation to hospital was lower in the nonsurvivors (P < 0.05). The levels of the inflammatory markers (IL-6, D-dimer, serum procalcitonin [PCT], and ferritin) were significantly higher in the nonsurvivors (P < 0.05). Similarly, the levels of ALC, serum albumin were lower in the nonsurvivors (P < 0.05). CTSS was higher in the nonsurvivors (P < 0.05) [Table 2].

Table 2: Comparison of variables between nonsurvivors and survivors

Click here to view

The correlation between the CT severity score and various other parameters was analyzed. A significant negative correlation was found between CTSS and serum albumin level (P < 0.05). Similar was the finding for ALC. A significant positive correlation was found for CTSS and the level of inflammatory markers (P < 0.05) [Table 3].

Table 3: Correlation of parameters with computed tomography severity scores

Click here to view

The area under the receiver operating characteristic curve for the parameters listed in [Table 4] in predicting mortality was found to be significant with P < 0.05. The sensitivity and specificity of the cut off values of the parameters are shown in [Table 4].

Table 4: Sensitivity, specificity, positive predictive value and negative predictive value of the parameters in predicting mortality

Click here to view

On univariate regression analysis, serum C-reactive protein (CRP), ferritin, albumin, and ALC were found to be significantly predicting mortality in Covid-19 affected KTR [Table 5]. However, in multivariable binary logistic regression analysis, after controlling other factors none of the above were found to be significantly predicting outcome.

Table 5: Univariate binary logistic regression analysis for mortality prediction

Click here to view

Discussion

This retrospective study provides a comprehensive insight into COVID-19 disease in the KTR cohort in a tertiary care center in a developing country. The overall mortality in our cohort was 17.1% which was much higher than that found in general population in India. In previously published reports the overall mortality in solid organ transplant recipients was 10%–28%.^{[4],[5],[6],[7]} More specifically in KTR cohort the overall mortality varies from 6% to 28% in various studies.^[8],[9],[10] In a previous Indian study, the overall mortality was 11.8%.^[11] This was slightly lower than what we had in the present study. Higher mortality amongst our cohort was possibly due to the higher mean age of our cohort (53 vs. 43 years). Furthermore, in our study, the proportion of KTR with comorbidities like type 2 DM (40% vs. 32%) and CAD (17.1% vs. 12%) were higher.

There was a significant difference in oxygen saturation at presentation and CTSS between the survivors and the nonsurvivors. SpO2 was lower and CTSS was higher in the KTR with severe disease, thereby, correlating with the mortality. In a case series, the mortality among the KTR with Covid-19 infection was higher in those with greater involvement of lung parenchyma in the CT imaging.^[12] There is no such Indian study correlating the CTSS with the mortality in Covid infected KTR cohort. The peak level of inflammatory markers namely IL-6, ferritin, D-Dimer were significantly higher in the nonsurvivors indicating a severe cytokine storm. Similar was the finding in a study by Azzi et al.^[13] After the viraemic phase there occurs a stage of systemic hyperinflammation. A significant elevation of the inflammatory cytokines and biomarkers, such as interleukins (IL-2, IL-6, IL-7), CRP, ferritin, PCT, and D-dimer is seen.^[14] Severe cytokine storm may lead to cardiopulmonary collapse and multi-organ failure.^[15],[16] Like other studies,^[11],[13] IL-6, D-dimer, PCT, CRP, and ferritin levels were found to be significantly different between the groups. Lymphopenia is a common finding in the clinical course of COVID-19 in both the general population and SOT recipients, and several studies in past have shown an association between disease severity (need for intensive care and mortality) and lymphopenia.^{[17],[18],[19],[20],[21]} Our findings are in line with these previous reports. The ALC was significantly lower in the nonsurvivors in our cohort indicating a reduced immune competency in them which could be correlated with the mortality. In the above and various other studies,^[22],[23] higher age, associated comorbid conditions, type of induction regimen, and treatment of rejections have been found to be predicting severe disease and mortality in KTR. However, in our study, none of the above factors were significantly different between the survivors and nonsurvivors. It could be due to the overall higher mean age (53.06 ± 11.84 years) of the cohort. The comorbid conditions were almost similar in both survivors and nonsurvivors. The mean duration of acquiring infection posttransplant was 72 months in our study, so, the factors like the type of induction regimen or any peri-operative event or early rejections did not bear any direct/indirect influence on the mortality in our population.

On univariate binary logistic regression analysis, factors such as level of CRP, ferritin, albumin, and ALC were found to be significantly predicting mortality. However, on multivariate regression analysis, after controlling the confounding factors, none of the factors studied were found to be significantly predicting mortality. It might be due to the fact that the above parameters are highly correlated among themselves. In a previous study by Oto et al.^[21] ischemic heart disease and poor graft function were found to be significantly predicting mortality in KTR with covid infection. However, in the Indian study by Kute et al.,^[11] none of the factors mentioned above were significantly predicting the outcome on multivariate analysis. In our study group, a smaller sample size and higher variability of the values could possibly have affected the statistical results. Nonetheless, factors such as oxygen saturation at presentation, CTSS, peak values of inflammatory markers, ALC were found to be significantly different between the survivors and nonsurvivors.

Our study has got some limitations. It was a single-center retrospective study with a limited sample size. Since our center is a tertiary referral center, selection bias could not be completely avoided. Hence, the results cannot be generalized to all the transplant population. In addition, the treatment given was nonuniform and it kept evolving as per the national guidelines. Therefore, the changes in treatment algorithms during the patient recruitment phase made it difficult to evaluate the results. So, the association of the parameters could not reciprocate into a causal relationship with the mortality.

Conclusions

Covid-19 in KTR has got a higher mortality rate than in general population. Clinical, radiological, and biochemical parameters do influence the outcome. Early supportive therapy along with careful titration of immunosuppression by an expert is necessary.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

References

1.	Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese centre for disease control and prevention. JAMA 2020;323:1239-42.
2.	Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID- 19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.
3.	Clinical Management Protocol: COVID-19. Available from: https://www.mohfw.gov.in/pdf/clinical management protocol for covid19.pdf. [Last accessed on 2021 Jun 26].
4.	Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant 2020;20:1800-8.
5.	Caillard S, Anglicheau D, Matignon M, Durrbach A, Greze C, Frimat L, et al. An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants. Kidney Int 2020;98:1549-58.
6.	Fernández-Ruiz M, Andrés A, Loinaz C, Delgado JF, López-Medrano F, San Juan R, et al. COVID-19 in solid organ transplant recipients: A single-center case series from Spain. Am J Transplant 2020;20:1849-58.
7.	Akalin E, Azzi Y, Bartash R, Seethamraju H, Parides M, Hemmige V, et al. Covid-19 and kidney transplantation. N Engl J Med 2020;382:2475-7.
8.	Alberici F, Delbarba E, Manenti C, Econimo L, Valerio F, Pola A, et al. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int 2020;97:1083-8.
9.	Crespo M, Pérez-Sáez MJ, Redondo-Pachón D, Llinàs-Mallol L, Montero MM, Villar-García J, et al. COVID-19 in elderly kidney transplant recipients. Am J Transplant 2020;20:2883-9.
10.	Hilbrands LB, Duivenvoorden R, Vart P, Franssen CF, Hemmelder MH, Jager KJ, et al. COVID-19-related mortality in kidney transplant and dialysis patients: Results of the ERACODA collaboration. Nephrol Dial Transplant 2020;35:1973-83.
11.	Kute VB, Bhalla AK, Guleria S, Ray DS, Bahadur MM, Shingare A, et al. Clinical profile and outcome of COVID-19 in 250 kidney transplant recipients: A multicenter cohort study from India. Transplantation 2021;105:851-60.
12.	Abrishami A, Samavat S, Behnam B, Arab-Ahmadi M, Nafar M, Taheri MS. Clinical Course, imaging features, and outcomes of COVID-19 in kidney transplant recipients. Eur Urol 2020;78:281-6.
13.	Azzi Y, Parides M, Alani O, Loarte-Campos P, Bartash R, Forest S, et al. COVID-19 infection in kidney transplant recipients at the epicenter of pandemics. Kidney Int 2020;98:1559-7.
14.	Huang I, Pranata R, Lim MA, Oehadian A, Alisjahbana B. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: A meta-analysis. Ther Adv Respir Dis 2020;14:1753466620937175.
15.	Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39:405-7.
16.	Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China. Clin Immunol 2020;214:1083-93.
17.	Chaudhry ZS, Williams JD, Vahia A, Fadel R, Parraga Acosta T, et al. Clinical characteristics and outcomes of COVID-19 in solid organ transplant recipients: A cohort study. Am J Transplant 2020;20:3051-60.
18.	Kates OS, Haydel BM, Florman SS, Rana MM, Chaudhry ZS, Ramesh MS, et al. COVID-19 in solid organ transplant: A multi-center cohort study. Clin Infect Dis 2020;73:e4090-e4099.
19.	Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020;46:846-8.
20.	Huang I, Pranata R. Lymphopenia in severe coronavirus disease-2019 (COVID-19): Systematic review and meta-analysis. J Intensive Care 2020;8:1-10.
21.	Oto OA, Ozturk S, Turgutalp K, Arici M, Alpay N, Merhametsiz O, et al. Predicting the outcome of COVID-19 infection in kidney transplant recipients. BMC Nephrol 2021;22:100.
22.	Hasan I, Rashid T, Suliman S, Amer H, Chirila RM, Mai ML, et al. Predictors of disease severity and outcome of hospitalized renal transplant recipients with COVID-19 infection: A systematic review of a globally representative sample. Rom J Intern Med 2021;59:10-42.
23.	Benotmane I, Perrin P, Vargas GG, Bassand X, Keller N, Lavaux T, et al. Biomarkers of cytokine release syndrome predict disease severity and mortality from COVID-19 in kidney transplant recipients. Transplantation 2021;105:158-69.