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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 14  |  Issue : 4  |  Page : 288-292

Clinical profile of SARS-CoV-2 infection in kidney transplant patients - A single centre observational study


Department of Nephrology, Madras Medical Mission Hospital, Chennai, Tamil Nadu, India

Date of Submission09-Nov-2020
Date of Acceptance05-Dec-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. Georgi Abraham
Madras Medical Mission Hospital, Chennai - 600 037, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_140_20

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  Abstract 


Background: In India, 8.27 million documented cases of COVID 19 and a total of 123K deaths have been reported till October 2020. We were able to estimate the clinical consequences of SARS CoV 2 in 16 patients over a period of 5 months. The disease prevalence and mortality rate observed in transplant recipients were found to be higher than in the general population. Aims and Objectives: A retrospective analysis of COVID 19 infections in kidney transplant recipients and the outcome. Materials and Methods: A single centre observational study of all patients who have undergone kidney transplant between March 2001 and December 2019 and documented evidence of SARS CoV 2 infection between March 2020 and October 2020. From a large cohort of 720 kidney transplant recipients, 16 recipients who developed COVID 19 infection were studied. They were all on maintenance immunosuppression in varying doses. None of the patients in this cohort had any recent episodes of cellular rejection requiring heightened immunosuppression. The vintage of the transplant varied from 9 to 192 months. Results: Acute kidney injury was identified in two patients. Eight patients were home quarantined and eight patients were hospitalized. All patients had a reduction in immunosuppression during the covid 19 infection dosage based on the severity of the disease. Out of the hospitalized patients, three died, two of whom had stable functioning grafts and the cause of death was identified as acute lung injury 1 patient had post covid ACR which was treated with Injection. Methyl Prednisolone. Conclusions: In our study, 2.22% developed COVID-19 disease and the mortality rate was 18.75% among those who developed COVID-19. The disease prevalence and mortality rate observed in transplant recipients were found to be higher than in the general population. Obesity, diabetes mellitus, and systemic hypertension were identified as independent risk factors.

Keywords: COVID-19 infection, immunosuppression, kidney transplantation


How to cite this article:
Kumaresan M, Babu M, Parthasarathy R, Matthew M, Kathir C, Rohit A, Abraham G. Clinical profile of SARS-CoV-2 infection in kidney transplant patients - A single centre observational study. Indian J Transplant 2020;14:288-92

How to cite this URL:
Kumaresan M, Babu M, Parthasarathy R, Matthew M, Kathir C, Rohit A, Abraham G. Clinical profile of SARS-CoV-2 infection in kidney transplant patients - A single centre observational study. Indian J Transplant [serial online] 2020 [cited 2021 Jan 23];14:288-92. Available from: https://www.ijtonline.in/text.asp?2020/14/4/288/305422




  Introduction Top


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), declared as a global pandemic in March 2020, has spread rapidly around the world and affected >40 million people by October 2020. In a large cohort study of 5449 patients hospitalized with COVID-19, the proportion of patients with acute kidney injury (AKI) at any stage was found to be 31.1%.[1] The Centers for Disease Control and Prevention listed kidney transplant recipients on immunosuppression under the high-risk category requiring intensive care admission due to long-term immunosuppression resulting in impaired immunological response to pathogens, associated comorbidities, and residual kidney disease. Emerging evidence suggests tenfold higher increase rate of early case fatality rate in transplanted patients compared to the general population.[2] A systematic review report on 420 adult kidney transplant recipients (mean age of presentation: 55 ± 15 years) with confirmed COVID-19 demonstrated male predominance (67%). Majority were deceased donor recipients 74%, 23% recently transplanted (<1 year), patients with at least one comorbidity (88%). 90% of the patients were hospitalized, 30% admitted to the intensive care unit (ICU), 45% developed acute respiratory distress syndrome, and 44% had AKI with 23% requiring renal replacement therapy and 22% of the total hospitalized patients were deceased.[2] Among the 720 renal transplant recipients from 2001 in our center, 16 patients developed SARS-CoV-2 infection. Here, we describe the management and outcome of our kidney transplant recipients.


  Materials and Methods Top


Inclusion criteria

This is a single-center observational study of all patients who have undergone kidney transplant between March 2001 and December 2019 and documented evidence of SARS-CoV-2 infection between March 2020 and October 2020.

Exclusion criteria

Those unwilling to give informed consent were excluded the demographic, clinical, and radiological variables of the infected 16 patients (transplantation live – 14 and deceased – 2) are given in [Table 1] and [Table 2]. All infected patients were on maintenance immunosuppression which included prednisolone 2.5–5 mg OD, tacrolimus 0.5 mg BD–3 mg BD, mycophenolate mofetil 250 mg OD–500 mg BD, sirolimus 2 mg OD, azathioprine 25–100 mg OD, and cyclosporine 75 mg BD. Hypertension in these patients was treated with calcium channel blockers, beta blocker, and diuretics. None of the patients were on Angiotensin converting enzyme inhibitors or Angiotensin receptor blockers. Furthermore, none of the patients in this cohort had any recent episodes of cellular rejection requiring heightened immunosuppression. The vintage of the transplant varied from 9 to 192 months. All hospitalized patients were started on prophylactic low-molecular weight heparin therapy.
Table 1: Patient demographic status

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Table 2: Clinical features

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Statistical analysis

Variables were presented as mean and stan-dard deviation or as frequencies (percentage). Continuous variables were analyzed using Student's t-test or ANOVA. Kolmogorov– Smirnov test was used for testing normality. Nonparametric variables were compared using Mann–Whitney U or Kruskal–Wallis tests as appropriate. The Pearson's χ2 test or Fisher's exact test was used for categorical variables. P < 0.05 was considered to indicate a statistically significant difference. The statistical analysis was performed using Epi infoTM Version 7.1, Division of Health informatixs and surveillance, Center for Disease Control, Atlanta, USA.ext.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Indian Council of Medical Research/Good Clinical Practice guidelines were followed as per Institutional ethics committee (EC number ECR/140/INST/TN/2013/RR-20). Study was carried out as per Declaration of Helsinki.


  Results Top


Among the 16 patients who developed COVID-19, 3 died (18.75%, 2 males and 1 female). There were 10 diabetics and 14 hypertensive patients. Nine males and seven females were present in this cohort and their age varied from 38 to 64 years. The mean body mass index (BMI) of the population was 25.66 kg/m2. As per the blood group, COVID-19 infection was seen in ten B +ve, three O +ve, two A +ve, and one O −ve. Out of the hospitalized patients, 18.75% required O2 via nasal prongs and 18.75% of patients required mechanical ventilation and ICU care [Table 3]. Eight out of the sixteen patients were home quarantined and were advised to take vitamin supplements, oral antibiotics, and monitor saturation via a pulse oximeter. They were asked to report to the hospital in case of SpO2 <95% or worsening symptoms. A 38-year-old hypertensive female who previously had IgA nephropathy and acute cellular rejection in the allograft in March 2020 was home quarantined and sodium salt of MMF was reduced to 360 mg OD and she continued tacrolimus 1.5 mg BD and prednisolone 5 mg OD. After the resolution of COVID-19, her baseline creatinine increased from 1.73 to 2.18 mg/dl, and hence, an allograft biopsy was done [Figure 1]. This showed scattered interstitial mononuclear infiltrate and acute tubular injury with negative C4D staining and BK virus. She received two doses of IV methylprednisolone 500 mg and 250 mg and her serum creatinine came down to 1.95 mg/dl. Except one 45-year-old hypertensive female patient who became COVID-19 negative and developed severe lung injury with septicemia and AKI requiring hemodialysis and mechanical ventilation, all others had functioning grafts. Of the total 167 patients on maintenance hemodialysis in our center, 19 developed COVID-19 infection. The mortality rate of 10.5% was observed in this cohort. Out of 59 patients on home peritoneal dialysis, 5 patients developed COVID-19 infection. The mean age of infected patients was 60 years and 2 out of 5 patients were diabetic. There was no mortality observed in this cohort. A 57-year-old diabetic male with sibling kidney transplant developed COVID-19 lung [Figure 2] with increased inflammatory markers – D-dimer 1163 ng/ml (<500 ng/ml), lactate dehydrogenase (LDH) –34 IU/L, C-reactive protein (CRP) –80 mg/L(<10 mg/L), and SpO2 90%, requiring 2 l O2 via nasal prongs and he recovered. Regarding the contact tracing of the patients, we have information of six recipients who developed COVID-19. Close family members were the index cases including spouses and household help from outside.
Table 3: Treatment and outcome

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Figure 1: (a and b) Allograft biopsy showing tubular injury and scattered mononuclear interstitial inflammation. UHID 20130810990

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Figure 2: Computed tomography of a COVID-19 lung with bilateral ground-glass opacities

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  Discussion Top


The epicenter of the COVID-19 pandemic shifted from the Wuhan province, China, in 2019 to the US and India in mid-2020. The global mortality rate declared by the World Health Organization was 3.4% as of March 2020. In India, 8.27 million documented cases of COVID-19 and a total of 123K deaths have been reported till October 2020. The TANGO International registry demonstrated a high early mortality rate of 32% in hospitalized kidney transplant recipients with COVID-19.[3]

With a total number of 720 kidney transplant recipients in our center, we were able to estimate the clinical consequences of SARS-CoV-2 in 16 patients over a period of 5 months. In our study, 2.22% developed COVID-19 disease and the mortality rate was 18.75% among those who developed COVID-19. The disease prevalence and mortality rate observed in transplant recipients were found to be higher than in the general population.

The median age of presentation was 55 years, with 56.25% male predominance. In this cohort, 62.5% of the patients were found to have B +ve blood group, 18.75% of the patients belonged to O +ve, and 12.5% belonged to A +ve blood group. Twenty-five percent of the population was recently transplanted (≤1 year) and 87.5% were live donor transplants. The mean BMI for the population was found to be 25.66 kg/m2 which falls under the obese category in the Asia-Pacific region.[4] All patients had at least one comorbidity, 62.5% of the population was diabetic, 87.5% had systemic hypertension, 12.5% had coronary artery disease (CAD), 12.5% were found to be asthmatics, and 6.25% had hypothyroidism. As in the general population, our study identified obesity, diabetes mellitus, hypertension, bronchial asthma, and CAD as factors independently associated with COVID-19 disease in patients with kidney transplantation. However, in comparison to other studies, sex, age, and ABO blood group played no specific role.[5],[6]

The most common symptoms at presentation were fever and cough –68.75%, followed by fatigue and myalgia –56.25%, 12.5% were found to be asymptomatic, and among the 56.25% of the hospitalized patients, three required ICU admission. Computed tomography changes of lung parenchymal involvement were present in 37.5% of patients. Radiological profile of this cohort was found to be similar to the general population with bilateral perihilar ground-glass opacities. In a 32-year-old female, the symptoms were bilateral eye pain, giddiness, and low-grade fever which responded within 36 h following injection remdesivir 200 mg stat, followed by 100 mg OD.

Inflammatory markers (D-dimer, CRP, serum ferritin, and LDH) were raised in 56.25% of the population. Interestingly, 12.5% (2/16) of the patients had AKI 1 week post recovery from COVID-19 – one patient had a significant rise in serum creatinine and underwent biopsy. Another patient had acute lung injury with raised creatinine and reduced urine output. She underwent SLED but progressed to septicemia and died.

All hospitalized patients were given injection remdesivir and were started on prophylactic low-molecular weight heparin therapy. All the transplant patients were on a maintenance immunosuppression with tacrolimus, sirolimus, cyclosporine-A, azathioprine, prednisolone, and MMF in varying dosages. There is no consensus guideline about immunosuppression dose tailoring in COVID-19 kidney transplant recipients. While immunosuppression may prevent an effective anti-SARS-CoV-2 T-cell response, it may also help in controlling the cytokine storm that is, at least in part, responsible for COVID-19 mortality.[7] Studies have shown that COVID-19 nonstructural protein-1 induced the expression of interleukin-2 (IL-2) via the nuclear factor of activated T-cell (NF-AT) activation, which might trigger the cytokine storm seen in patients with severe infection.[8] Cyclosporine was found to exert its immunosuppressive and anti-inflammatory effect by binding to cyclophilin-A which prevents the activation of the NF-AT and the transcription of genes required for T-cell proliferation like IL-2.[8] At our center, MMF and azathioprine dosage was reduced by half in patients with milder disease and discontinued temporarily in those who required hospitalization. Any infection in transplant recipients can upregulate Class II HLA antigens leading to acute rejection, and hence, these patients should be carefully monitored as in the case of one of our female patients who was given injection methylprednisolone following biopsy due to clinical and histological evidence of mild cellular rejection.

During a median follow-up of 7 days, three patients required O2 via nasal prongs (18.75%), three patients required mechanical ventilation (18.75%), and three patients had died, totaling to 18.75% mortality in this cohort. Two deaths were observed to be a result of acute lung-related injury with functioning allografts. The 43-year old female patient who expired had AKI along with acute lung injury. The median time from illness onset to resolution was 20 days, whereas the median time to death was 15 days.

There is an ongoing debate in literature on the detection of the virus in the podocytes and tubular cells, suggesting a direct injury. Studies around the world have reported the presence of spherical viral particles and viral ribonucleic acid in the glomerular cells of the kidney.[9] In addition, viral entry via angiotensin-converting enzyme-2 expressed on proximal tubular cells in the kidney supports the mechanism of AKI. Other hypothesis surrounding kidney injury includes angiotensin dysregulation, hypercoagulable states, and innate and adaptive immune pathway activation. One of our patients underwent allograft biopsy which helped us in tailoring the treatment for graft dysfunction.

Limitation of the study

We were not able to measure the COVID antibody level to look at their immune status. We did not do electron microscopy in our 14 patients to look at viral particles in tubules or podocytes.

In conclusion, we report our experience with COVID-19 infection in our kidney transplant recipients and the cause of mortality was found to be serious lung injury and majority of the patients did not require hospitalization but a reduction in immunosuppressive therapy (MMF and azathioprine). We were not able to measure the COVID antibody level to look at their immune status. We did not do electron microscopy in our patients to look at viral particles in tubules or podocytes. We are following up with the 12 recovered patients for long-term risk progression and residual kidney function and watching out for any immune-mediated pathology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Farouk SS, Fiaccadori E, Cravedi P, Campbell KN. COVID-19 and the kidney: what we think we know so far and what we don't. J Nephrol 2020;20:1-6.  Back to cited text no. 1
    
2.
Marinaki S, Tsiakas S, Korogiannou M, Grigorakos K, Papalois V, Boletis I. A systematic review of COVID-19 infection in kidney transplant recipients: A universal effort to preserve patients' lives and allografts. J Clin Med 2020;9:2986.  Back to cited text no. 2
    
3.
Kant S, Menez SP, Hanouneh M, Fine DM, Crews DC, Brennan DC, et al. The COVID-19 nephrology compendium: AKI, CKD, ESKD and transplantation. BMC Nephrol 2020;21:449. https://doi.org/10.1186/s12882-020-02112-0.  Back to cited text no. 3
    
4.
Mahajan K, Batra A. Obesity in adult Asian Indians-the ideal BMI cut-off. Indian Heart J 2018;70:195.  Back to cited text no. 4
    
5.
Hoiland RL, Fergusson NA, Mitra AR, Griesdale DE, Devine DV, Stukas S, et al. The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19. Blood Adv 2020;4:4981-9.  Back to cited text no. 5
    
6.
Palaiodimos L, Kokkinidis DG, Li W, Karamanis D, Ognibene J, Arora S, et al. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York. Metabolism 2020;108:154262.  Back to cited text no. 6
    
7.
Johnson KM, Belfer JJ, Peterson GR, Boelkins MR, Dumkow LE. Managing COVID-19 in renal transplant recipients: A review of recent literature and case supporting corticosteroid-sparing immunosuppression. Pharmacotherapy 2020;40:517-24.  Back to cited text no. 7
    
8.
Cour M, Ovize M, Argaud L. Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure? Crit Care 2020;24:276.  Back to cited text no. 8
    
9.
Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int 2020;98:219-27.  Back to cited text no. 9
    


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  [Table 1], [Table 2], [Table 3]



 

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