ABSTRACT
The high transmissibility and the broad spectrum of clinical manifestations of COVID-19 are in part due to the high affinity of SARS-CoV-2 for its receptor, Angiotensin Converting Enzyme 2 (ACE2). The depletion of the biological functions of ACE2, due to the internalization of the receptor along with SARS-CoV-2, leads to impairment of Renin Angiotensin System (RAS), which can contribute to COVID-19 pathogenesis. In addition, genetic differences in RAS may be associated with more severe symptoms and complications observed in COVID-19 patients. This study aims to perform a comparative analysis between COVID-19 positive patients and uninfected individuals, to correlate such disease profiles with ACE I/D (Insertion/Deletion) and ACE2 G8790A polymorphisms, and their enzymatic activities. The anthropometric, demographic, clinical and cardiovascular parameters of 764 individuals from Ipaussu/SP (Brazil) were evaluated. ACE and ACE2 activities were measured by fluorometric assays, and assessment of both enzymes polymorphisms was performed by PCR. In this cohort, 35,2% (269 of 764) the volunteers were positive for COVID-19. The prevalence of COVID-19 was higher among women (67%) and individuals aged between 18 and 49 years. Also, comorbidities as obesity and arterial hypertension were more frequent in the positive group, when considered individuals under 60 years old. Higher ACE and ACE2 enzymatic activities were observed in positive group (46.4 vs 41.6 and 11.3 vs 8.5, respectively). Individuals with ID genotype in the positive group presented higher ACE activity compared to individuals with same genotype in control group (46.9 vs 41.7). In the positive group, ACE activity was increased in the DD (54.5) when compared to ID (46.9) and II (37.9) genotypes. No significant differences related to ACE2 activity and polymorphism were observed. ACE/ACE2 activity ratio was higher in the COVID-19 negative group (4.7 vs 3.7). The increased ACE activity for the DD genotype was in line with the literature data for hypertension and cardiovascular diseases. We can suggest a synergic effect between ACE DD genotype and COVID-19 infection enhancing ACE activity, what may contribute to pro-inflammatory phenotype and more severe symptoms of COVID-19.
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Purpose: Compared to azathioprine (AZA), mycophenolate (MPA) is implicated in an increased risk of several viral infections. Contrariwise, mTOR inhibitors (mTORi) are protective. Therefore, the study proposal is to evaluate the Covid-19 outcomes among kidney transplants (KT) patients under different maintenance immunosuppressive regimens. Method(s): We analyzed 90-day outcomes after Covid-19 infection using nationalwide Brazilian cohort data. RT-PCR positive patients tested between Mar/20 and Apr/21 (before immunization) were included. Patients using calcineurin-inhibitors (CNI)-free regimens were excluded. Result(s): 1,833 patients from 44 centers were analyzed, divided into three groups: CNI-AZA (n=389), CNI-MPA (n=1,258), and CNI-mTORi (n=186). Except for donor source, time after KT, and diabetes, demographics were similar among groups (Table1). The main outcomes are shown in Table 1. Considering CNI-AZA as the reference group, center-adjusted multivariable Cox regression showed that the CNIMPA group was associated with higher 30-day fatality (HR 1.65, 95% CI 1.17-2.33, p=0.004), effected also demonstrated in 90-day fatality (HR 1.43, 95%CI 1.06-1.93, p=0.020). CNI-mTORi was neutral for the 30-day fatality (HR 0.75, 95%CI 0.43- 1.29, p=0.296), but protective for the 90-day (HR 0.56, 95%CI 0.34-0.94, p=0.027). Conclusion(s): This data suggests that maintenance immunosuppressive drugs impact Covid-19 outcomes in kidney transplant patients. While MPA is associated with poor prognosis, mTORi seems to be protective. (Figure Presented).
ABSTRACT
Purpose: To evaluate the seroconversion rate in kidney transplant recipients (KTR), compared to two non-transplanted groups of patients, and identify predictors of seroconversion in COVID-19 convalescent patients. Method(s): A retrospective cohort study enrolled RT-PCR COVID-19 diagnosed patients (Mar/20 and Oct/2020) of three groups: 601 KTR, 211 health care workers (HCW), and 170 non-transplanted inhabitants (INH) in a countryside city in the state of Sao Paulo - Brazil. At least 14 days after diagnosis, all survivors underwent antibody testing by chemiluminescent microparticle immunoassay (titter expressed in RLU). The primary outcome was seroconversion. The group-adjusted multivariable model for the probability of seroconversion was built by generalized linear mixed models with binary logistic regression and the discrimination performance by AUC-ROC. Result(s): Several differences were observed among groups regarding demographic data and COVID-19 clinical presentation. Of note, KTR were older (54.0 years old vs. 37.0 in HCW vs. 42.0 in INH, P<0.001), more frequently had comorbidities (P<0.001), and severe COVID-19 (P<0.001). Compared to HCW and INH, respectively, admission to ICU (44.9% vs. 0% vs. 1.8%), MV requirement (32.3% vs. 0% vs. 1.8%), and death (28.8% vs. 0% vs. 1.2%) were significantly more frequent in KTR (P<0.001). On the other hand, the seroconversion rate was not different among survivors: 76.2% for KTR, 74.9% for HCW, and 82.2% for INH (P=0.35). The IgG anti-SARS-CoV-2 was slightly higher among INH: 5.8 RLU vs. 5.4 for KTR and 4.4 for HCW (P=0.009). Seroconversion was associated with a shorter time between infection and blood sample collection (OR for each day= 0.986;P<0.001) and increased by 64% if the fever was a COVID-19 symptom (OR=1.737;P=0.017), 78% if the cough was present (OR=1.785;P=0.005) and 98% if the ventilatory support was required (OR=1.981;P=0.017). This predictive model achieved an AU-ROC of 0.730 (P<0.001). Conclusion(s): As expected, the rates of clinical deterioration to ICU admission, MV requirement, and death were significantly higher among KTR. However, among the survivors, KTR had a similar rate of seroconversion, associated with clinical severity parameters and a shorter time of blood sample collection.
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Purpose: A high number of comorbidities associated with the severity of the disease caused by SARS-CoV-2 (COVID-19) has been reported, such as systemic arterial hypertension (SAH), diabetes mellitus (DM), cerebrovascular and cardiovascular diseases, obesity, chronic kidney disease, among others. Importantly, poor glycemic control in diabetic individuals and hyperglycemia at admission are associated to COVID-19 progression. To evaluate whether kidney transplant recipients with DM have worse outcomes in COVID-19 setting when compared to non-diabetics, as well as to verify whether the poor glycemic control contributes to COVID-19 progression. Methods: Retrospective analyses of 590 kidney transplant recipients who were diagnosed with COVID-19 at one single Brazilian center. We used DM, SAH and poor glycemic control as dependent variables in univariate analyses to determinant the risk factors for COVID-19 progression. Results: 60% male, 64.4% white, average age 51.6 years-old, 192 (32.6%) DM and 158 (26.8%) SAH. COVID-19-related symptoms included: fever (63.4%), chills (63.4%), cough (60.3%), dyspnea (49.3%), myalgia (46.3 %), diarrhea (32.4%), anosmia (31.2%), headache (23.7%) and runny nose (21.7%). DM was associated with acute respiratory distress syndrome (ARDS) (P=0.0001), use of supplemental oxygen (P=0.001), intensive care unit (ICU) admission (P=0.0001), mechanical ventilation (MV) (P=0.001), acute graft dysfunction (P=0.0001), hemodialysis (P=0.009), and death (P=0.0001). Fasting blood glucose prior to hospitalization was related to the risk of death (130 vs 112 mg/dL, P=0.002), MV (130 vs 119 mg/ dl, P=0.0001) and ICU admission (127 vs 109 mg/dl, P=0.0001). HbA1c values were associated with the risk of MV (7.2 vs 6.9%, P =0.031) and ICU admission (7.1 vs 6.6%, P=0.025). SAH was associated with ARDS (P=0.044), ICU admission (P=0.028), MV (P=0.018), graft dysfunction (P=0.006), HD (P=0.007) and death (P=0.037). ACE inhibitors or ARBs were not associated with the risk of death (P=0.792 and P=0.138, respectively). Conclusions: DM and poor glycemic control, as well as SAH were associated with worse outcomes in COVID-19. These findings highlight the importance of adequate management of comorbidities in transplant patients, especially in relation to DM, since poor glycemic control contributes to the worst outcomes in COVID-19. ACE inhibitors and ARBs should not be discontinued during COVID-19 pandemic, as they do not increase the risk of death.
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INTRODUCTION: The unprecedented coronavirus disease 2019 (COVID-19) pandemic has affected kidney transplant (KT) recipients, with worldwide fatality rates around 25%. Considering the well-known Brazilian socio-demographic disparities, this report describes for the first time the main outcomes of COVID-19 in KT recipients according to Brazilian geographic regions. METHODS: This multicenter national retrospective analysis included data from KT recipients with confirmed COVID-19 between March and November 2020. RESULTS: Thirty-five of the 81 centers (57% of KT activity in Brazil) reported 1,680 patients with COVID-19. The Northeast was the first to reach the peak in the number of infections. The Southeast, due to its population density, contributed with the largest number of patients. Patients had a median age of 52 years, 76% had hypertension and 34% diabetes, 75% were recipients of a deceased donor, and the time interval between diagnosis and transplantation was 5.9 years. In 53% of patients, immunosuppression was adjusted, and clinical support varied according to geographic region. Hospitalization was required for 65% of the patients, 35% of them needed intensive care, 25% mechanical ventilation, and 23% renal replacement therapy. The 90-day overall fatality was 21%, being 23% in the Southeast, 16% in the Northeast, and 19% in the Central-west and South regions. CONCLUSION: The migratory pattern of the pandemic among KT recipients followed that of the general population and the outcomes were influenced by regional features. COVID-19 in KT recipients was associated with high utilization of health-care resources and higher fatality rates than those reported in the general population.