key: cord-1001535-e7k4932k
authors: Caillard, Sophie; Chavarot, Nathalie; Francois, Hélène; Matignon, Marie; Greze, Clarisse; Kamar, Nassim; Gatault, Philippe; Thaunat, Olivier; Legris, Tristan; Frimat, Luc; Westeel, Pierre Francois; Goutaudier, Valentin; Snanoudj, Renaud; Colosio, Charlotte; Sicard, Antoine; Bertrand, Dominique; Mousson, Christiane; Bamoulid, Jamal; Masset, Christophe; Thierry, Antoine; Couzi, Lionel; Chemouny, Jonathan M.; Duveau, Agnes; Moal, Valerie; Blancho, Gilles; Grimbert, Philippe; Durrbach, Antoine; Moulin, Bruno; Anglicheau, Dany; Ruch, Yvon; Kaeuffer, Charlotte; Benotmane, Ilies; Solis, Morgane; Le Meur, Yannick; Hazzan, Marc; Danion, Francois
title: Is Covid‐19 infection more severe in kidney transplant recipients?
date: 2020-12-01
journal: Am J Transplant
DOI: 10.1111/ajt.16424
sha: 548385a6a51b904cbc609d8d361768793604e0ae
doc_id: 1001535
cord_uid: e7k4932k

There are no studies which have compared the risk of severe Covid‐19 and related mortality between transplant recipients and non‐transplant patients. We enrolled two groups of patients hospitalized for Covid‐19, i.e., kidney transplant recipients from the French Registry of Solid Organ Transplant (n=306) and a single‐center cohort of non‐transplant patients (n=795). An analysis was performed among subgroups matched for age and risk factors for severe Covid‐19 or mortality. Severe Covid‐19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death.Transplant recipients were younger and had more comorbidities compared to non‐transplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30‐day cumulative incidence of severe Covid‐19 did not differ between KTR and non‐transplant patients; however, 30‐day Covid‐19‐related mortality was significantly higher in KTR (17.9% versus 11.4%, respectively, p=0.038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C‐reactive protein (CRP) were associated with severe Covid‐19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR=1.55), and creatinine level >115 µmol/L (HR=2.32) were associated with Covid‐19‐related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. Kidney transplant recipients had a higher Covid‐19‐related mortality compared to non‐transplant hospitalized patients.

Prior experience with respiratory viruses in patients who had undergone solid organ transplantation revealed how recipients have greater susceptibility, more rapid progression to pneumonia, greater disease severity, and prolonged viral shedding compared with non-transplant hosts. In light of past coronavirus outbreaks, 1, 2 Covid-19 poses a significant threat for immunocompromised patients, and transplant physicians are particularly concerned about the impact of this new infection on this frail population. Single-center studies have reported a high mortality rate in kidney transplant recipients (KTR) with Covid-19. [3] [4] [5] There is also evidence that at least part of Covid-19's severity is linked to the "cytokine storm", which is a disproportionate hyperinflammatory reaction occurring in infected patients. 6 In this scenario, immunosuppressive drugs may be clinically useful in reducing this dysfunctional immune response by attenuating the positive feedback loop typical of the cytokine release syndrome (CRS) . Nonetheless, the question as to whether KTR would actually exhibit a higher risk of severe Covid-19 or -alternativelyimmunosuppression would protect them from CRS and critical forms of the disease remains unanswered.

Chronic kidney disease and acute kidney injury (AKI) have been reported to affect the prognosis of patients hospitalized for Covid-19. 7 Notably, KTR are in an immunosuppressed state with concurrent chronic kidney disease and are particularly susceptible to AKI. Starting from these premises, this research was undertaken to determine how these factors may influence the clinical outcomes of KTR with Covid-19. We also compared the prognosis of Covid-19 in KTR and nontransplant patients by using data from a French nationwide registry. 

This article is protected by copyright. All rights reserved syndrome coronavirus-2 (SARS-CoV-2) infection determined by reverse transcriptase-polymerase chain reaction (RT-PCR) testing of nasopharyngeal swab specimens, or 2) presence of typical respiratory symptoms associated with evocative pulmonary lesions on low-dose chest computed tomography (CT) when RT-PCR yielded negative results. AKI was defined according to the Kidney Disease Improving Global Outcomes guidelines. Severe Covid-19 was defined as admission (or transfer) to an intensive care unit (ICU), need for mechanical ventilation, or death.

All other patients were considered as non-severe cases. Ethical approval for the creation of the French SOT COVID Registry was obtained from the Institutional Review Board of the Strasbourg University (approval number 02.26). The study was registered at clinicaltrials.gov (NCT04360707). While the requirement for informed consent was waived, all patients were informed about their inclusion in the registry. The study protocol for non-transplant patients was approved by the Human Investigation Review Committee of the Strasbourg University Hospital (approval number CE-2020-51). Patients who declined to participate were deemed ineligible.

Discrete variables are presented as counts and percentages, whereas continuous data are summarized as medians and interquartile ranges (IQRs) upon verification of their skewed distribution. The composite endpoint of severe COVID-19 was considered as a time-dependent variable since the onset of the symptoms. Cumulative event curves (for severe Covid-19 or Covid-19-related mortality) of transplant recipients and non-transplant patients were plotted with the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards univariable and multivariable models were constructed using a backward-conditional selection procedure to identify predictors of the study endpoints. The optimal model was selected according to the highest concordance (Harrel's C statistic) value. Results are expressed as hazard ratios (HRs) with their 95% confidence intervals (CIs). Matching was performed by selection of nearest neighbor best control matches for each individual in the KTR group. 8 Patients were matched in a 1:1 ratio using the logit of the estimated propensity of being in the transplant group as the distance metric.

Age, BMI, cardiovascular and respiratory diseases, cancer, and diabetes were included as covariates in the propensity score model because these variables are the main risk factors for COVID-19. 9, 10, 11 A caliper (0.3) was set for age only. There were 33 transplant recipients who could not be matched to a non-transplant patient. Tabular data for matched cohorts are reported as standardized mean differences with their 95% CIs. All analyses were undertaken in the R

This article is protected by copyright. All rights reserved environment (R Foundation for Statistical Computing, Vienna, Austria). A value of P <0.05 (twotailed) was considered statistically significant.

A total of 306 KTR were included in the SOT COVID Registry at the time of this analysis. The median recipient age was 62 years (IQR: 52−69 years) and 67.6% were men. The median time between transplantation and Covid-19 diagnosis was 74.6 months (IQR: 27.8−140.6 months), and only 12% of all KTR were in the first post-transplant year at the time of Covid-19 diagnosis.

Immunosuppressive drugs used at baseline and management of immunosuppression at the time of The characteristics of the two study groups are reported in Supplementary Table 2 . KTR were younger, more commonly male, and had lower body mass index (BMI) but had more comorbidities (hypertension, cardiovascular diseases, respiratory diseases, and diabetes). They less frequently exhibited dyspnea during admission for Covid-19, but more commonly had fever and diarrhea than non-transplant patients. Of note, the median time from symptom onset to admission was shorter among KTR than non-transplant patients (5 versus 7 days, respectively, p=0.006).

KTR displayed a less severe inflammatory syndrome, a more profound lymphopenia, and a higher creatinine level at admission (176 µmol/L versus 75 µmol/L, respectively, p<0.001). Infection management was slightly different, with antibiotics and azithromycin more frequently used in non-transplant patients, in contrast to more antifungal drugs (4.6% versus 2.1%, respectively, p=0.028), fewer specific antivirals (lopinavir/ritonavir 5.2% versus 21.8%, respectively, p<0.01), and more frequent tocilizumab (5.6% versus 1%, respectively, p<0.001) in KTR. Moreover, KTR were less frequently in need of vasopressor support but were significantly more likely to develop AKI (46.1% versus 11.2%, respectively, p<0.001) that would require dialysis ( Owing to the significant differences in age and comorbidities, a further analysis was performed on 

This article is protected by copyright. All rights reserved transplant patients, respectively. The characteristics and outcomes of the matched groups are shown in Table 1 . The univariable analysis showed that the 30-day cumulative incidence of severe disease was similar in both groups ( Figure 1A ; 42.2% versus 42.1% in KTR and non-transplant patients, respectively; p=0.6), whereas the 30-day mortality was significantly higher among KTR ( Figure 1B; 17 .9% versus 11.4%, respectively; p=0.038). Risk factors for severe COVID-19 were age> 60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein >60 mg/L (Table 2) . Furthermore, age >60 years, hypertension, cardiovascular disease, diabetes, lymphopenia, being a KTR (HR=1.55, 1.02−2.35), and having a creatinine level >115 µmol/L (HR=2.32, 1.45−3.70) were associated with mortality (Table 3 ). In multivariable analysis, cardiovascular disease, dyspnea, and fever were independent risk factors for severe disease. Age >60 years, cardiovascular disease, having dyspnea and fever at admission, and a serum creatinine >115 µmol/L were also independently associated with mortality, whereas being a kidney transplant recipient was not (Table 4 ). Because the two matched groups were not well balanced in terms of hypertension, we constructed a different model in which this variable was included for matching. However, the results of multivariable analysis were entirely consistent with those reported in the model that did not include hypertension as a matching variable (data not shown).

The present study compared for the first time hospitalized KTR with Covid-19 to a cohort of hospitalized non-transplant patients in order to determine if they would have different outcomes and a higher mortality rate. First, we demonstrated that the entire cohort of KTR hospitalized for Covid-19 exhibited significant differences compared to the non-transplant cohort. Accordingly, KTR were younger (by 7 years) and had a higher burden of comorbidities. As expected, nontransplant patients had a better renal function at admission. This could reflect either the presence of a preexisting chronic kidney disease or an AKI in KTR -who were frequently admitted with diarrhea and high fever. Moreover, subsequent AKI and renal replacement therapy occurred more frequently among KTR than in non-transplant patients (46.1% and 11.2%, respectively) during hospitalization. AKI was observed in 5.1% of patients hospitalized with Covid-19 in Cheng et al's report 7 , and 4.5% of patients in the meta-analysis published by Yang et al. 12 The etiology of AKI during Covid-19 is multifactorial. In addition to SARS-CoV-2's direct attack of tubular cells via ACE2 receptors, other factors that may contribute to kidney injury include hypoxia, CRS, and a

This article is protected by copyright. All rights reserved hypercoagulable state. 13 The susceptibility of KTR to dehydration, nephrotoxic drugs, and hemodynamic instability can also explain the high frequency of renal dysfunction in this cohort.

Given the differences between the transplant and non-transplant cohorts' baseline characteristics, we performed a matched analysis after adjusting for known risk factors of severe Covid-19 and Covid-19-related death 9, 10, 11 (i.e., age, BMI, cardiovascular and respiratory diseases, cancer and diabetes) to minimize the effects of potential confounders. Our results validate the findings from previous studies in non-transplant patients with respect to known risk factors for severe and Covid-19-related death. 14, 15 However, being a KTR was not associated with a more frequent need for ICU admission in our study. This could be explained by the shorter time from symptom onset to hospitalization (5 versus 7 days in KTR and non-transplant patients, respectively) and the lower incidence of pulmonary involvement at admission (dyspnea: 45.1 versus 63.7% in KTR and non-transplant patients, respectively).

However, the comparison of matched cohorts also showed that KTR had a two-fold higher risk of Covid-19-related death compared to non-transplant patients after adjustment for age, BMI, and major comorbidities. While previous studies have shown that transplantation is a risk factor for mortality, a direct matched comparison between transplanted and non-transplant patients had never been performed. Data from a very large cohort of 17 million patients indicated that organ transplant recipients had an adjusted 3.55-fold higher risk of death, whereas those with glomerular filtration rates below 30 mL/min had a 2.5-fold increased risk. 16 In Cheng et al's cohort, 7 the incidence of in-hospital death in patients with increased baseline serum creatinine was 33.7%, which was higher than in those with normal creatinine levels (13.2%). Notably, this difference persisted after adjusting for age and comorbidities. In prior studies focusing on respiratory viruses (H1N1, SARS, and MERS-CoV), 17, 18 kidney injury was also associated with an increased risk of death. It remains uncertain whether the higher mortality rate observed in KTR is caused by immunosuppression and/or the increased rate of renal dysfunction. Multivariable analysis revealed that being a KTR was not independently associated with mortality, whereas a serum creatinine >115 µmol/L was retained in the model as an independent risk factor for death. These results indicate a prominent role for renal failure as a driver of Covid-19-related mortality.

Our findings need to be interpreted in the context of some limitations. First, one may argue that the comparability between a multicenter French nationwide transplant cohort and a single-center control group is low. Nevertheless, the single-center control group was large and representative of a different range of settings (i.e., medical, surgical and ICU departments). Second, we are aware

This article is protected by copyright. All rights reserved that KTR and control patients were managed differently -which can represent a potential source of confounding when their clinical outcomes are analyzed. While baseline lymphocyte count and creatinine concentrations were available for KTR, the majority of non-transplant patients had a negative clinical history before the onset of Covid-19. Therefore, we were unable to provide data on these parameters in non-transplant patients. Finally, all of the study patients were hospitalized.

Thus, the question as to whether our findings are generalizable to an outpatient setting remains answered. These caveats notwithstanding, this study is the largest to date to comprehensively compare the clinical features and outcomes of Covid-19 in KTR with respect to non-transplant patients.

In summary, our study shows that, after adjustment for potential confounders, KTR with Covid-19 had a higher mortality rate than non-transplant patients, despite a similar occurrence of severe disease. While preexistent chronic kidney disease or AKI might have a greater prognostic impact than the immunosuppression state, further research is needed to shed more light on this issue. 

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