key: cord-0702286-hgjalayz
authors: Elec, Alina Daciana; Oltean, Mihai; Goldis, Patricia; Cismaru, Cristina; Lupse, Mihaela; Muntean, Adriana; Elec, Florin Ioan
title: COVID-19 after kidney transplantation: Early outcome and renal function following antiviral treatment
date: 2021-01-13
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.01.023
sha: 6ec2c144cf0c655263247f2213312210397f7e24
doc_id: 702286
cord_uid: hgjalayz

Objectives The lack of effective COVID-19 treatments mandated the repurposing of several drugs, including antiretrovirals (ARV) and remdesivir (RDV). These compounds may induce acute kidney injuries and are not recommended in patients with poor renal function, such as kidney transplant recipients (KTx). Methods We reviewed the records of 42 KTx with COVID-19, some of them receiving ARV (n = 10) or RDV (n = 8) as part of the COVID-19 management. Most patients were male (71%) with a median age of 52 years and median GFR 56 mL/min and had mild (36%), moderate (19%), severe (31%), and critical (12%) disease. Subgroups (patients receiving ARV, RDV, or no antivirals) were comparable regarding patient age, comorbidities or immunosuppression. Results: Seven patients (16,6%) died during hospitalization. Acute kidney injury was found in 24% KTx at admission. Upon discharge, eGFR increased in 32% and decreased in 39% of the KTx compared with the admission. The decrease was more prevalent in the RDV group (80%) compared with KTx without any antiviral treatment (29%) (p < 0.05). Most patients (62%) returned to baseline eGFR values within one month from discharge. The proportion was similar between the patients receiving antiviral treatment or not. Conclusions KTx run a high risk of COVID-19-related renal impairment. Antivirals appear safe for use without major risks for kidney injury.

The ongoing COVID-19 pandemic continues to ravage the world and claim the lives of thousands of individuals each day. COVID-19 patients may develop different degrees of disease severity, varying from mild forms to critical disease evolving with acute respiratory distress syndrome, sepsis, and multiorgan failure (Cummings et al. 2020; Karagiannidis et al. 2020 ). Severe forms result from a combination between the ensuing cytokine storm, the procoagulant state, and the direct viral tropism for various organs. Advanced age, the presence of multiple comorbidities, or certain medications have been repeatedly confirmed as risk factors for critical disease and negative outcome (Cummings et al; Zhou et al. 2020) .

Organ transplant recipients usually present concurrent comorbidities and increased frailty J o u r n a l P r e -p r o o f and receive a long-term immunosuppressive medication, placing them at much higher risk for an unfavorable outcome (Kates et al. 2020; Ravanan et al. 2020; Oltean et al. 2020 ).

The lack of specific antiviral medication against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the rapid repurposing of several drugs, including several retrovirals (darunavir and lopinavir). Antiretrovirals are generally prescribed along with a pharmacokinetic booster (ritonavir or cobicistat) aimed at blocking their CYP3Amediated metabolism and prolonging their lifetime (Dhampalwar et al. 2020) . Anti retroviral therapies have been previously associated with acute kidney injuries, particularly interstitial nephritis and proximal tubular injury (Parkhie et al., 2010) . Likewise, several randomized controlled trials reported a significantly higher frequency of renal severe adverse events in the COVID-19 patients receiving the lopinavir/ritonavir combination, particularly in intensive care patients (Dhampalwar et al., 2020; Cao et al., 2020) .

Initially developed as an investigational agent for Ebola, Remdesivir is a nucleotide analog that inhibits viral RNA-dependent RNA polymerase and interferes with viral RNA replication.

Remdesivir is not recommended in patients with eGFR less than 30 mL per minute unless the potential benefit outweighs the potential risk (Adamsick et al., 2020) . Although there are concerns about its potential toxicity in patients with kidney disease, data from randomized, controlled trials in COVID-19 in patients with normal kidney function did not demonstrate an increased risk of renal adverse events Beigel et al., 2020) and some centres have lifted estimated glomerular filtration rate restrictions on remdesivir, although safety data is scarce and more information is needed, (Adamsick et al ., 2020) .

J o u r n a l P r e -p r o o f 6 Calcineurin inhibitors (CNI) cyclosporin A and tacrolimus form the mainstay of immunosuppression in organ transplantation. Both drugs are metabolized by cytochrome P450 3A (CYP3A) in the liver and the intestine and are nephrotoxic at higher concentrations (Gregoire et al., 2020) . As the boosters ritonavir and cobicistat can inhibit CYP3A, it has been expected that CNI would increase (Elens et al., 2020) . Although one of the critical steps in managing transplanted patients has been lowering the immunosuppression (Oltean et al., 2020; Maggiore et al., 2020) , there has been increasing concern about supratherapeutic CNI levels that may negatively impact renal function. Moreover, this could raise confusion with other causes of renal dysfunction, most notably acute rejection.

An analysis of the renal function in transplant recipients with COVID-19 receiving different antivirals has not been performed so far. As this patient group usually has impaired kidney function and prolonged use of nephrotoxic drugs, we set out to analy ze the short-term effects of two different types of antiviral drugs in a cohort of renal transplant recipients.

We performed a retrospective review of all patients who underwent kidney transplantation at the Clinical Institute of Urology and Renal Transplantation in Cluj-Napoca, Romania, alive on April 1 st , 2020 and got sick with COVID-19 between April 1 st and October 10th th , 2020.

COVID-19 positivity was defined as a positive result for SARS-CoV-2 RNA on real-time polymerase chain reaction (PCR) assay of nasopharyngeal swab as well as typical symptoms such as temperature >38˚C, respiratory, gastrointestinal, neurological, or general symptoms.

In the first part of the study period (April-July, 2020), the COVID-19 treatment protocol recommended in Romania was based on Hydroxychloroquine (HCQ, Plaquenil ®, Sanofi).

HCQ was started with a loading dose of 400 mg orally twice daily for one day, then continued at 200 mg orally twice daily for 7-10 days. Caution was taken in individuals with pre-existing QT prolongation or those at risk for QT prolongation. Lopinavir/ritonavir (LPV/R, Kaletra ® AbbVie, Ludwigshafen, Germany), darunavir/ritonavir (DRV/r, Prezista ®, Janssen -Cilag SpA, Latina, Italy) or darunavir/cobicistat (DRV/c, Rezolsta ®, Janssen-Cilag) were generally added in those with mild and moderate forms with adequate renal function (GFR >30 mL/min). LPV/r was given at a dose of 400/100 mg twice daily for 7-10 days. From mid-July 2020, remdesivir was added to the treatment protocol in more severe cases, whereas retrovirals were phased out. When available, remdesivir was administered at a dose of 200 mg/day on the first day, followed by 100 mg/day over the next four days, given as an intravenous infusion. Dexamethasone and antibiotics were also given at the discretion of the medical teams attending the patients. The use of anticoagulation using low molecular weight heparin (LMWH) was recommended in hospitalized patients.

Immunosuppression was reduced by holding the antimetabolite (mycophenolate mofetil MMF or mycophenolic acid MPA) with or without adjustment of calcineurin inhibitors.

Tacrolimus was withdrawn in patients receiving antiretrovirals and adjusted to maintain a trough level of 4-6 ng/mL in the other patients. Steroids were either kept at the maintenance dose or converted to IV for stress dosing.

Three subgroups were defined within the patient cohort: patients receiving antiretrovirals (ARV), patients receiving remdesivir (RDV), and patients receiving neither. All availabl e medical records of the patients were reviewed, and data on demographics, medical history, J o u r n a l P r e -p r o o f comorbidities, therapeutic interventions (antivirals, antibiotics, changes in immunosuppression, corticosteroid therapies, respiratory support), and outcomes were collected and analyzed. Disease severity was classified from mild to critical (COVID-19 Treatment Guidelines Panel, 2020). The comorbidity assessment was performed using the age-adjusted Charlson comorbidity index (CCI) (Oltean et al ., 2012) . CCI includes 19 different medical conditions, and each comorbid disorder is ranged from 1 to 6 points to sum an index score. Additional points were added for age, and each decade over the age of 40 years was assigned a comorbidity score of 1. Renal function was assessed on data collected one to two months before COVID-19, at admission, at discharge, and one month after hospital discharge (or the resolution of symptoms) using the CKD-EPI formula. Acute kidney injury was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria as an increase in baseline serum creatinine by ≥0.3 mg/dL within 48 hours or a 1.5-1.9 times increase in serum creatinine from baseline within seven days (Thomas et al ., 2015) . The study was approved by the institutional review board of the Clinical Institute of Urology and Renal Transplantation (4/2020).

Discrete data are described by their frequency expressed as a percentage. Continuous data are expressed as median and range unless otherwise stated. Given the small group size and data distribution, the Kruskal-Wallis test and Mann-Whitney U test were used for data analysis. Fisher's exact test was employed for analyses of contingency tables. A p -value < 0.05 was considered significant.

One thousand four hundred sixty-seven KTx recipients were in follow-up with a functioning graft at our centre and 42 of these got COVID-19 during the study period, corresponding to a prevalence of 2,86%. The characteristics of all 42 SARS-CoV-2-positive kidney transplant recipients are presented in Table 1 both as a single patient cohort and separately for the three subgroups according to the antiviral treatment received (ARV, RDV, and no antivirals ).

Overall, the median patient age was 52 years (range 20-72), and males represented 71% of the entire cohort. Median baseline eGFR for the entire cohort was 50 ml/min (range 20-120), whereas median CCI was 3 (range 2-8). Four patients (9,5%) received their transplants in the year preceding the COVID-19 infection. Disease severity was mild in 16 cases (38%), moderate in 8 (19%), severe in 13 (31%), and critical in five (12%).

The three subgroups (i.e., patients receiving ARV, RDV, or no antivirals) did not differ in terms of patient age, comorbidities (as reflected by CCI), or baseline immunosuppression.

Patients receiving antiretrovirals had significantly higher baseline eGFR than those receiving remdesivir (70 ± 26 vs. 42 ± 14 ml/min, p<0.05). KTx not receiving antivirals had significantly more mild and moderate disease forms (p<0.001).

Details on patient management are presented in Table 2 . Eighteen patients (43%) required supplemental oxygen, and eight patients (19%) were admitted to the intensive care unit. All but two patients had their immunosuppression lowered: the antimetabolite was discontinued in 36 (86%) and reduced in the remaining 6. Tacrolimus was withdrawn in J o u r n a l P r e -p r o o f eleven 11 cases (26%) and reduced in 14 (33%). Thirty-six patients (86%) received anticoagulation with LMWH or NOAC.

In the ARV group, all patients had the antimetabolite (mycophenolate mofetil) discontinued. Also, Tacrolimus was temporarily withheld in six (60%) patients and reduced in the remaining four due to the risk of supratherapeutic concentrations secondary to pharmacologic interactions. In the RDV group, the antimetabolite was suspended in all patients, whereas tacrolimus was discontinued in half of the patients and reduced in a further two (25%). Twenty-one of the patients (88%) Two patients (20%) in the ARV group, three in the RDV group (37,5%) , and two in the group receiving no antivirals (8%) expired during the initial hospitalization. The remaining patients were discharged at home and had at least one month of follow-up. No rejection episodes have been recorded so far.

Baseline eGFR for the entire patient cohort, and the three subgroups are shown in Table 1 .

Patients receiving ARV had a higher mean baseline eGFR than dose receiving RDV. Nineteen J o u r n a l P r e -p r o o f patients (33%) had signs of impaired kidney function upon admission, as reflected by increased creatinine or a lower eGFR compared to pre-COVID-19 values (Figure 1 ). Patients who ultimately did not survive had lower mean baseline eGFR compared with survivors (41 ± 19 vs. 60 ± 24, p=0.03). The proportion of patients presenting with worsening of the kidney function was similar between the three groups (40%, 37,5%, and 54% in ARV, RDV, and no antivirals groups, respectively).

Upon admission, acute kidney injury (as defined by KDIGO) was present in ten patients (24%), showing mild (2 patients), moderate (4 patients), severe (3 patients), and critical (one case) COVID-19 severity. Two patients (one in ARV and one in RDV group) received continuous renal replacement therapy during hospitalization, both of which ultimately died.

Upon discharge, eGFR was higher (> 2 mL/min) than the value at admission in 32% of the patients and lower in 39% of the patients. The latter proportion appeared significantly higher in the group receiving RDV (80%) compared with the patients without antiviral treatment (29%) (p<0.05). The proportion of patients showing a decrease in eGFR in the groups receiving ARV did not differ when compared with the patients without antiviral treatment (33% and 29%, respectively). The changes in eGFR in each group are shown in Fig.1 B. Most patients (62%) returned to baseline eGFR values within one month after discharge (Fig.1C) . The proportion was similar between the patients receiving antiviral treatment or not.

This analysis confirms the unfavourable outcome and the high mortality of kidney transplant recipients following SARS-CoV-2 infection. In addition, the current results suggest that kidney transplant recipients with COVID-19 do not have significantly poorer early renal outcomes after receiving two different antiviral regimens compared with kidney transplant recipients not receiving antiviral treatment.

Kidney injury has been reported during COVID-19 infection, likely due to a synergistic effect of virus-induced direct cytotropic effect, dehydration secondary to fever and diarrhea, cytokine-mediated inflammatory injury, and hemodynamic instability in severe cases (Argenziano et al. 2020) . To these factors it may add the known nephrotoxic effect of several drugs and drug-drug interactions. The current findings indicate that renal dysfunction was more frequent than in the non-transplanted population (Yang et al, 2020) , likely due to the reduced nephron mass of the transplanted kidneys. However, the dysfunction was mild in most of the cases and not requiring renal replacement therapy. A certain recovery was noted already at discharge, yet a worse kidney function than the baseline persisted in the early post-infection period in almost half of the patients.

Apart from COVID-19 itself, several drugs used during the course of the disease may have negatively influenced kidney graft function. The potential nephrotoxicity of Lopinavir/ritonavir and its interactions with a number of other nephrotoxic drugs, particularly tacrolimus, are likely contributors. A small series of non-transplanted COVID-19 patients, found almost four times higher lopinavir concentrations compared with HIVinfected patients receiving a similar dosage and suggested that the down-regulation of cytochrome P450 by active infection and inflammation is responsible for the decreased metabolism of the ARV (Gregoire et al. 2020) . This phenomenon will likely impact the J o u r n a l P r e -p r o o f pharmacokinetics of several drugs with nephrotoxic potential, particularly antibiotics, despite Tacrolimus being reduced or withdrawn early in the treatment.

The exclusion of patients with eGFR < 30mL/min/1.73m2 (i.e., stage 4 chronic kidney disease, CKD) from the clinical trials using RDV has generated a significant knowledge gap in safety data for remdesivir as up to 15% of the KTx have CKD stage 4 and 5 five years after transplantation (Marcén et al., 2010) . Moreover, acute kidney injury (AKI), chronic kidney disease (CKD), and end-stage renal disease (ESRD) are frequently found in patients with COVID-19 (Bowe et al., 2020) , further underscoring the need for additional safety data.

Although the data needs to be interpreted cautiously, we have to stress that two out of the four (9,5%) patients with CKD stage 4 in this cohort, both receiving RDV, did not survive.

The patient group detailed herein presents a dynamic, evolutionary experience following the changing treatment guidelines during 2020 (Maggiore et al., 2020; Dagens et al., 2020) .

Although the median age of the patients appears slightly lower than in other reports, the overall patient profile in terms of comorbidities and gender distribution appears similar to other reports (Felldin et al., 2021; Lubetzky et al., 2020) . The overall outcome of this first Eastern European cohort of transplant patients is comparable with that from other singlecenter reports or registry analysis, and further suggests the existence of yet unidentified risk factors particular to this patient group (Caillard et al., 2020; Felldin et al., 2021; Hoek et al., 2020; Hillbrands et al., 2020 , Kute et al., 2020 , Nair et al., 2020 .

The use of antiretrovirals in KTx with COVID-19 was widespread in the first months of the pandemic (Alberici et al, 2020; Oltean et al, 2020) as LPV/r has been recommended as a first-line or second-line in many countries (Dagens et al., 2020) . Recent data from Solidarity Trial found that neither RDV, hydroxychloroquine, LPV/r, nor interferon affected overall J o u r n a l P r e -p r o o f mortality and hospital stay in hospitalized patients (World Health Organization Solidarity trial, 2020). The earlier results from the RECOVERY trial showing that lopinavir-ritonavir monotherapy was not an effective treatment for hospitalized COVID-19 patients had already led to a change of practice and lower use of antiretrovirals.

Creatinine increase is a hallmark for kidney allograft rejection, albeit rather unspecific.

Considering the universal immunosuppression lowering in KTx with COVID-19 and the resulting increased rejection risk, it is imperative to identify and understand other potential causes of kidney injury, including any antiviral treatments, which may lead to creatinine increase. We speculate that the prompt creatinine lowering and function recovery observed after the COVID-19 episode has been partly due to the reduction or suspension of calcineurin inhibitors. In line with other reports, we did not record any suspicion of allograft rejection in spite of the significant immunosuppression lowering and we believe that the COVID-19 associated lymphocytopenia may safely allow for a temporary "drug holiday" for up to two weeks.

Although it would be tempting to speculate on the efficiency of either treatments, the small size of the patient cohort and its heterogeneity in terms of disease severity and individual medications precludes any solid conclusions on the impact of the antiviral drugs on the outcome of COVID-19. Whereas the current results suggest that RDV use may result in worse kidney function than KTx not receiving antivirals, the proportion of mild and moderate disease was significantly higher in the group not receiving antivirals. However, it is possible that this finding may have been dependent on the disease severity, not disease treatment. Nonetheless, the present study provides further data and allows a glimpse into the potential renal side effects and safety profile of antivirals in this particularly vulnerable patient population and the time course of renal dysfunction in this risk group.

Another limitation is given by the assessment of kidney injury by serum creatinine only, which is a rather coarse parameter, whereas no specific assessments of the glomerular or tubular injury were consistently available. However, considering the particularities of th e kidney in KTx population (immune and non-immune graft injury, recurrence of the initial renal disease on the grafted kidney), it would have been difficult to interpret such data correctly in the actual context of superimposing COVID-19 and antivirals. Moreover, the data adds to the limited literature on antivirals in transplanted patients and will hopefully contribute to comparisons and benchmarking of renal effects of other emerging treatment strategies such as favipiravir, nitazoxanide, or nelfinavir (Zhao et al 2020; Gavriatopoulou et al., 2020) .

In conclusion, this analysis shows that two different types of antivirals do not lead to significant and protracted kidney impairment in KTx with COVID-19. More extensive studies or meta-analyses are required further to explore this hypothesis in this vulnerable patient population.

There is no funding source to be reported.

J o u r n a l P r e -p r o o f 16 The study was reviewed and approved by the Ethical Review Committee of the Clinical Institute for Urology and Renal Transplantation (04/2020).

The authors do not report any conflicts of interest. Table 1 Patient demographics and baseline immunosuppression. CCI -Charlson comorbidity index, eGFR -estimated glomerular filtration rate; Table 2 Disease severity, management and outcome CNI -calcineurin inhibitors, HCQ -hydroxychloroquine, LMWH -low molecular weight heparin, MMF -mycophenolate mofetil, NOAC -Non-Vitamin K antagonist oral anticoagulants¨. Data are presented as number/total number of available observations or (percent).

Patient demographics, management and outcome in the 42 kidney recipients with COVID-19. BMI -body mass index, CCI -Charlson comorbidity index, CyA-cyclosporine A, Dexa -dexamethasone, DRV/c -Darunavir/cobicistat, DRV/r -Darunavir/ritonavir, eGRF -estimated glomerular filtration rate, MMF-mycophenolate mofetil, HCQ -hydroxychloroquine, KTx-kidney transplant, LPV/r -lopinavir/ritonavir, LMWH -low molecular weight heparin, NOAC -Non-Vitamin K antagonist oral anticoagulants, Pred-prednisolone, RDV -remdesivir, Tac-tacrolimus, 

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