key: cord-0939397-ad9f8l7n
authors: Kędzierska-Kapuza, Prof. Karolina; Zielińska, Mrs Dorota; Matejak-Górska, Marta; Durlik, Prof. Marek
title: The course of SARS-CoV-2 in a patient after a recent kidney transplantation – a literature review on COVID-19 therapy
date: 2021-03-15
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.03.008
sha: 446350dafcbbb4f22bb03a2aea3a65c64c4e60b6
doc_id: 939397
cord_uid: ad9f8l7n

Introduction Kidney transplant recipients are at high risk of severe complications and death due to coronavirus disease (COVID-19). Methods First part of the paper describes a case of COVID-19 in our patient after recent kidney transplantation. Second and third part of the paper is an outcome of literature search from multiple resources from April 2020 till March 2021. Abstracts were screened, followed by full-text review with data extraction. Part two discusses current treatment options of COVID-19 and part three refers to this treatment application in patients after solid organ transplantation. Results We have summarized 45 studies from China, France, Italy, Spain, United Kingdom, and United States. Mortality rates from published studies were variable. Based on early data early from Spain, 42% of patients who developed COVID-19 within 60 days of transplantation died. According to results of the ERACODA collaboration group the 28-day COVID-19-related mortality is 21.3% in kidney transplant which is still markedly higher than what is observed in other populations. Acute kidney injury was common, and mycophenolate mofetil and mTOR were discontinued in most patients. Conclusion Effective therapy has been sought since the outbreak of the pandemic, and at the same time intensive work has been underway to produce a vaccine that could effectively protect against the disease. Summing up the efforts of numerous groups of researchers from around the world that have been continued since the beginning of 2020, we may assume the following: -We still do not have causal drugs that would reduce SARS-CoV-2 replication and allow its complete elimination, but anti-spike monoclonal antibodies against SARS-CoV-2 seem to be very promising. -The withdrawal of antiproliferative and antimetabolic drugs and the continuation of steroids and CNI inhibitors is nowadays a commonly accepted approach in patients after an organ transplantation.

Since March 4, 2020, untill March 8, 2021 the total number of cases in Poland reached over 1.8 million (1.801.083). According to the Polish Ministry of Health, over 45 thousand infected patients died (45.317) , and most of them had been suffering from concurrent diseases i . Mortality rate in Polish population is ~ 2,5%.

In 2020 significant drop in solid organ transplantation occured in Poland and worldwide. In 2020 in Poland a total number of 1180 organ transplantation was performed compared to 1473 in 2019 (-20%). Transplantation Coordinating Center (Poltransplant) database ii . It was probably caused by high mortality of patiens on waiting list due to or the lack of current tests qualifying for transplantation and the inability to perform them, due to the situation of hospitals/outpatient clinics related to COVID-19. This resulted in patients dropping out of the active waiting list for transplantation (no data available).

There are no current official and published data on the mortality of patients after solid organ transplants in Poland. This data is still being collected in Poltransplant database and may be published at the end of 2021 in the annual newsletter. According to results of the ERACODA collaboration group including data of 22 pts from Poland the 28-day COVID-19-related mortality is 21.3% in kidney transplant and 25.0% in dialysis patients, which is markedly higher than what is observed in other populations iii .

First part of the paper describes a case of COVID-19 in our patient after recent kidney transplantation.

Second part of the paper is an outcome of literature search from multiple resources from April 2020 till March 2021. Abstracts were screened, followed by full-text review with data extraction. Part two discusses current treatment options of COVID-19 and refers to this treatment application in patients after solid organ transplantation. We have summarized 45 studies from China, France, Italy, Spain, United Kingdom, and United States.

A 54-year-old patient with autosomal dominant polycystic kidney disease (ADPKD) after leftsided nephrectomy had been on dialysis therapy through an arteriovenous fistula since 2017. The patient had a history of hypertension, a neurosurgery due to hemorrhage following a ruptured brain aneurysm, which was sealed with a vascular clamp in 2001. He received a transplant (Tx) from a deceased donor with a simultaneous implantation of a JJ stent into the transplanted kidney (08.10.2020).

The donor, 57, male, died due to an intracranial trauma. His last creatinine record was 0.58 mg/dl (on the day of harvesting). He was obese (114 kg), his height was 180 cm, BMI 35.1. He had been receiving low doses of levonor at 0.07 ug/kg/min. The cultures were negative and the diuresis was 140 ml/hour (2300 ml daily). Donor was COVID-19 negative, staying in the "clean" part of ICU.

The recommendations of the Polish Transplant Society issued in April 2020 prohibit organ donation from Covid-19 + patients. (Table 1 ). The harvested kidney was perfused on a pump. CIT was 32 hrs 20 min, WIT 20 min, with 5 HLA mismatches. The selection of a recipient with low-HLA compatibility (2 pts) was due to the fact that patients with higher scores did not consent to undergo a surgery because of the epidemic situation, 2 persons had an infection and 1 person was waiting for a transplant from a living consanguineous donor. Prior to the transplantation the patient underwent a protocol ruling out a SARS-CoV-2 infection, and a complete epidemiological history. He had a negative nasopharyngeal swab based on PCR. The chest radiograph excluded pneumonia and other pulmonary pathologies. Cold ischemia time (CIT) was prolonged, as it was impossible to harvest lymph nodes for typing in the donor's hospital (the surgical team was quarantined) and it took a long time to obtain the PCR SARS-CoV-2 result of the recipient. On 9 th October 2020 the provincial governor decided to change the whole Hospital of the Ministry of the Interior and Administration into a tertiary hospital which provided services only to COVID-19 patients. Therefore, the patient was Inferiorly and dorsally, the lesions were continuous with more consolidated streaky opacities which were estimated to affect approx. 40% of the volume of both lungs. The patient's MEWS score was 1 point. MEWS score assesses: age=54, O2 saturation=95%, oxygen use-no, respiratory rate-12/min, heart rate 76/min, systolic blood pressure 130 mmHg, body temperature 37,1, consciousness-yes. Due to a tender, palpable fluid collection around the postoperative wound, two incisions were performed in the area, and a partially hemolyzed hematoma (clots and liquid matter) were evacuated.

MMF was discontinued, the dose of tacrolimus was reduced to obtain the level of 8.6 ng/ml. The following treatment was introduced: Dexaven 1x6 mg intravenously, broad spectrum antibioticspiperacillin/tazobactam 3x4.5g intravenously. Subsequently, due to the fact that the cultures sampled from the collection were positive for Enterococcus faecium HLAR+ VRE it was changed into Vankocin 2x1 g intravenously with the monitoring of vancomycin level in blood serum. Moreover, the patient was administered low molecular weight heparin as prophylaxis, valganciclovir, trimethoprim/sulfamethoxazole. Hypertension was controlled with one drugamlodipine. The patient was not administered Remdesivir nor Tocilizumab, because Tocilizumab is recommended only in individuals with severe course and cytokine storm phase with marked elevation of inflammatory cytokines and other markers (CRP, PCT, IL-6, d-dimers, LDH, ferritin, troponin, NT-pro BNP).

According to our clinical and laboratory asessment ( Table 2 figure 2) patien's condition was fair and he did not fell into cytokine storm phase of the COVID-19 disease. His newly-diagnosed druginduced diabetes was treated with insulin followed by sulfonylurea derivatives 1x1 orally. During the whole hospitalization in the Department the patient was respiratorily and cardiovascularly stable, he received passive oxygen therapy via a nasal cannula. He was discharged on day 40 after transplantation with nadir creatinine at 0.94 mg/dl (Table 2) .

Whether the patient underwent an organ transplantation or not, the course of SARS-CoV-2 infection is relatively similar with clinical and therapeutic implications as presented in Figure 1 modified from Siddiqi et al. iv

a. Baricitinib, a JAK-kinase inhibitor, has 2 targets: it inhibits SARS-CoV-2 virus entry into the cell and the cytokine storm phase. Adaptive Covid-19 Treatment (ACCT-2) study v , which included the co-treatment with Remdesivir or Remdesivir alone was conducted in over 1000 patients. Convalescence was obtained 1 day earlier in case of the baricitinib arm. However, complete results of the study are still unknown. A small randomized study (Italy, 24 participants) demonstrated the effectiveness of baricitinib/kaletra. vi b. Nafamostat mesylate: SARS-Cov-2 enters the lung cells via binding to ACE-2 and the activation of TMPRSS2 protease. Therefore, it may be the target of antiviral treatment.

TMPRSS2 inhibitors prevented SARS-CoV-2 entry into cells in vitro. Nafamostat, being the strongest of those inhibitors, is used as an antithrombotic and anti-pancreatitis agent. It was approved in the treatment of cystic fibrosis, as its mucolytic properties may prevent the deterioration of pulmonary function via inhibiting respiratory infections. The RACONA study is going to test a hypothesis that nafamostat is useful in COVID-19-related pulmonary involvement, as COVID-19 is associated with the activation of the coagulation cascade, pulmonary embolism and bacterial superinfections. vii c. Convalescent plasma: plasma collected from successfully cured patients provides neutralizing antibodies against SARS-CoV-2. The effectiveness was proved and the therapy was accepted by the FDA (August 2020). viii Over 35,000 patients were examined with no significant complications reported (also by the Polish Society of Epidemiologists and Contagious Disease Specialists). The research is scarce. A Chinese observational study from April 2020 included 6 patients in whom the use of plasma was beneficial. ix Another randomized study from China was discontinued. The authors included 103 patients, but a positive effect of plasma was not confirmed in severely ill patients. x A randomized Dutch study was conducted in July 2020. It included 86 individuals. However, it was discontinued, as prior to plasma administration the patient had had their own neutralizing antibodies. xi The latest study (PLACID) showed no beneficial effects associated with the use of convalescent plasma. It was a "real world" study which also qualified individuals with concomitant diseases. A very interesting editorial comment on the publication drew attention to the fact that the procoagulatory activity of the serum removed the beneficial influence of antibodies neutralizing the virus. xii Another randomized placebo-controlled study published in November 2020 in NEJM demonstrated that convalescent plasma did not protect COVID-19 patients and those with COVID-19related pneumonia from death. Furthermore, it did not alleviate the course of the disease. xiii b. Dexamethasone has multidirectional properties such as the suppression of proinflammatory cytokine formation. According to recommendations it was effective, which was shown in the Recovery studyinvolving its use for 10 days at a dose of 6 mg intravenously in patients requiring oxygen therapy and mechanical ventilation. xxx c. Heparinits role is to lower blood clotting in severe cases of COVID-19. Antimetabolite drugs were discontinued in all ICU patients. Tacrolimus (4-6 ng/ml) or CsA (400-600 ng/ml) and prednisone were continued. CNI was discontinued in only 2 recipients.

Immunosuppression was completely withdrawn in only 2 severely ill patients [36] . "ground-glass opacity" located mainly in peripheral regions. Inferiorly and dorsally, the lesions were continuous with more consolidated streaky opacities which were estimated to affect approx. 40% of the volume of both lungs. We lowered the dose of tacrolimus administered to the patient. The level of the drug was monitored until 8.6 ng/ml was reached. At discharge the level was 3.8 ng/ml. The definitive dose of tacrolimus was increased to 2x1.5 mg.

Other authors described a patient with a recent kidney transplantation and a severe course of COVID- Anti-spike monoclonal antibodies against SARS-CoV-2 seem to be very promising therapy especially in immunocompromised patients. One must remember, that treatment with anti SARS-Cov-2 monoclonal antibodies recently approved by FDA has several limitations. The FDA EUAs allow for the use of bamlanivimab plus etesevimab or casirivimab plus imdevimab for the treatment of mild to moderate COVID-19 in nonhospitalized adults and children and who are at high risk for progressing to severe COVID-19 and/or hospitalization. High-risk criteria specified in the EUA are: body mass index (BMI) ≥35, chronic kidney disease, diabetes mellitus, immunocompromising condition, currently receiving immunosuppressive treatment, aged ≥65 years or aged ≥55 years, and having cardiovascular disease, or hypertension, or chronic obstructive pulmonary disease or another chronic respiratory disease. In the studies described above (14-15), the number of participants was small, and only a limited number of clinical events (e.g., hospitalizations or emergency department visits) were reported. Given the low number of clinical events, it is difficult to draw definitive conclusions about the efficacy of these anti-SARS-CoV-2 antibodies. Additional clinical trial data are needed to provide further evidence on the safety and efficacy of these agents and to identify the populations (dialysis pts with end stage renal disease? patients after organ or bone marrow transplantation??) in which the potential benefit will be the greatest.

Some questions still remain unanswered: When should antimetabolite or antiproliferative drugs be reintroduced in convalescents? What CNI dose should be used in such patients? Is two-drug (e.g. steroids and CNI) therapy sufficient? Hopefully, answers to those questions will be available in the literature soon.

• discontinue MMF, discontinue mTOR,

• a recent transplantation  dexamethasone max 12 mg for 10 days, tacrolimus at a dose adjusted to the level of the drug (6-8 ng/ml),

• a non-recent transplantation (e.g. a kidney transplanted a year or longer before)  dexamethasone 1x6 mg for 10 days, tacrolimus at a dose adjusted to the level of the drug (6-8 ng/ml), 6 mg of dexamethasone = 40 mg of prednisolone,

• enoxaparin sodium at a dose of 0.4-0.6 ml subcutaneously or nadroparin calcium 0.3-0.5 ml subcutaneously; to be controlledif D-dimers increase the patient should receive a therapeutic dose,

• antibiotic therapy (in case of a high risk of a superinfection): ceftriaxone 1x2 g intravenously once a day and azithromycin 500 mg orally for 6 days,

• good hydration of the patientminimum 3000-3500 ml orally and/or intravenously (in total),

• the administration of Remdesivir is justified only during the viremic phase (the first week after the infection was confirmed during the viral replication phase): the dose of 200 mg on day 1, then 100 mg for 4 days; if GFR <30 ml/min/1.73 m2it should be discontinued,

• tocilizumab in individuals with an increased level of IL-6 (to be administered in the severe course, cytokine storm phase): intravenously 8 mg/kgadministration via an IV pump for 1 hour; the second dose may be administered during 2 days; the patient should be observed, administration only after ruling out an active bacterial and viral infection, IL-6 should be monitored (a characteristic increase even >600 ng/mlreceptor blockade),

• plasma -no data in patients with KTx, "an act of despair" in patients with chronic diseases, e.g. chronic kidney disease, without anti-SARS-CoC-2 antibodies produced.

• Anti-spike monoclonal antibodies against SARS-CoV-2 seem to be very promising therapy,

Additionally it is possible to:

• Measure the level of vitamin 25(OH) D3 or 1.25 OG D3  vitamin D3 supplementation or alfacalcidol 1x1.0 ug orally,

• Vitamin C 2x1 g intravenously,

• Zinc -70 mg daily in divided doses, orally.

Effective therapy has been sought since the outbreak of the pandemic, and at the same time intensive work has been underway to produce a vaccine that could effectively protect against the disease.

Summing up the efforts of numerous groups of researchers from around the world that have been continued since the beginning of 2020, we may assume the following:

-We still do not have causal drugs that would reduce SARS-CoV-2 replication and allow its complete elimination, but anti-spike monoclonal antibodies against SARS-CoV-2 seem to be very promising.

-The withdrawal of antiproliferative and antimetabolic drugs and the continuation of steroids and CNI inhibitors is nowadays a commonly accepted approach in patients after an organ transplantation.

Conflict of interest statement: the results presented in this paper have not been published previously in whole or part, except in abstract format. 

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