Acute Kidney Injury in Non-Intensive Care Unit (ICU) Hospitalizations for Coronavirus Disease (COVID-19).

BACKGROUND: Acute kidney injury (AKI) is a common complication among SARS-CoV-2-positive patients who undergo hospitalization. Abundant evidence exists concerning the epidemiology of AKI in patients hospitalized in the ICU for COVID-19 but limited data are available about the occurrence of AKI in SARS-CoV-2-positive patients being hospitalized in a non-ICU setting. AIM AND METHODS: We have carried out a retrospective study to evaluate frequency and risk factors for AKI among patients consecutively admitted at a third-level university hospital starting from February 2020 (the beginning of the first wave of the SARS-CoV-2 pandemic); all patients were hospitalized outside the ICU. RESULTS: A total of 387 SARS-CoV-2-positive patients were included in the current study; 372 (96.1%) had SARS-CoV-2-related pneumonia. In-hospital AKI onset was recorded in 119 (30.7%) patients, mainly with AKI stage 1 (n = 74, 62.2%); eighteen (4.6%) patients reported AKI stage 3 and six (1.5%) patients had HD-dependent AKI. There were 235 (60.7%) patients with severe COVID-19, and this was more common in patients developing AKI, 94.5% (86/119) vs. 86.1% (149/268), p = 0.02. Multivariate regression model (n = 144 patients) reported an independent and significant relationship between AKI occurrence and greater levels of ferritin (p = 0.036), IL-6 (p = 0.032), and azotemia at admission (p = 0.0001). A total of 69 (17.8%) SARS-CoV-2-positive patients died and strong predictors of in-hospital death resulted from age (p < 0.0001), serum ferritin (p < 0.0001) and white blood cells (p < 0.001). According to multivariable analysis (n = 163 patients), there was a consistent link between in-hospital death and AKI stage (1) (p = 0.021) and -stage (2) (p = 0.009). Our results support the notion that AKI occurs frequently among hospitalized COVID-19 patients even in a non-ICU setting and plays a pivotal role in the mortality of this population. Further studies are ongoing in order to clearly establish the frequency of AKI in patients with COVID-19; the mechanisms underlying kidney injury in this population are an area of active investigation. These data provide solid evidence to support close monitoring of COVID-19 patients for the development of AKI and measures taken to prevent this.

Vitamin D Status and Sars-Cov-2 Infection in A Cohort of Renal Transplanted Patients

BACKGROUND AND AIMS Immunomodulatory and anti-inflammatory properties have been hypothesized for native vitamin D (nVD). Very little is reported about nVD and risk of Sars-CoV-2 infection (COV) in renal transplant (RTx). In a cohort of renal transplanted patients (RTxp) we retrospectively evaluated: (i) nVD status in patients with (COV+) and without (COV-) COV infection;(ii) the impact of nVD status on severity of COV. METHOD The study includes 61 COV + in whom nVD status was available in the year before the infection, and 122 COV- matched 1:2 for age (53[45–64]years), gender (M = 60.7%), RTx vintage (7[2–15] years), presence of diabetes (18%), arterial hypertension (85%) and cardiac symptomatic disease (3%). Renal function, 24-h proteinuria and mineral metabolism (MM) parameters were evaluated at 1, 6 and 12 months before COV whereas nVD status was considered as the mean 25-OH-VD levels at the same timepoints. Severity of COV was based on the need for hospitalization (HOSP+: 27/61, 44.3%) and death (D+: 6/61, 9.8%). RESULTS (i) nVD levels were significantly lower in COV + than in COV- (19[12–26] ng/mL and 23[16–30] ng/mL, respectively, P = 0.01). No differences in the other biochemical parameters were found. The COV discriminative power of nVD status was evaluated by ROC curve (AUC 0.61, 95% CI: 0.54–0.68, P = 0.01), with a value of 25-OHVD 23.9 ng/mL showing the best discriminative power (sensibility 72%, specificity 47%). (ii) nVD levels showed a trend towards lower values in HOSP + COV + than HOSP-COV+ (17[8–25] ng/mL versus 20[14–26] ng/mL) and in D + COV + than D-COV+ (13[6–23] ng/mL versus 20[13–26] ng/mL), although these differences did not reach the statistical significance (P = 0.1 and P = 0.2, respectively). CONCLUSION With the limitations of the retrospective nature of the study and the small sample size, our data report that: COV + showed lower nVD levels in the year preceding the infection compared with controls with similar main demographic features and comorbid conditions No differences were found in renal function, proteinuria and other MM parameters between the two groups. No association was found between nVD levels in the year preceding the infection and COV severity.

Covid-19 Vaccine in Kidney Transplanted Patients. is There A Clinical Relevance? An Italian Single Center Experience

BACKGROUND AND AIMS COVID-19 is a life-threatening infection among elderly, comorbid patients or transplanted patients. In our recently published paper (Campise, M.;Alfieri, C.M.;et al. Pathogens 2021, 10, 964), we described our single Centre experience with 82 adult kidney-transplant patients (KTxp) with COVID-19 infection during the previous two pandemic outbreaks: 27 KTxp (first outbreak) and 65 (second). We observed a relatively low and possibly underestimated incidence of infection (5.1%) with a incidence of death almost four times higher than in general population (13%). The availability of COVID-19 vaccines has undoubtedly changed the outcome of the infection in both immunocompetent and immunosuppressed patients. Aim of this second ongoing observational and descriptive study, is to evaluate if the vaccination performed extensively among our KTxp, has modified the incidence and gravity of COVID-19 infection. METHOD Data on KTxp with COVID-19 infection (COV+) from the 29 October 2021 to 31 December 2021 were collected. Particularly, we focused our anthropometric, clinical and therapeutic aspects. In the statistical analyses, continuous variables were expressed as median and interquartile range (25%–75%), and nominal variables were reported as percentage of cases. RESULTS From the 29 October 2021 to the 31 December 2021, 33 KTxp developed COVID-19 infection, 60% were male. Median age was 50[29–58] years. Transplant vintage was 57[27–163] months. Median serum creatinine was 1.30[1.0–1.9] mg/dL and body mass index was 23[21–28] kg/m2. Immunosuppressive schedule included: CNI inhibitors, steroids and mycophenolate (MMF) in 97–90 and 70% of COV + respectively. In 50% of cases native vitamin D supplementation was present, whereas only 30% of cases were treated with renin-angiotensin inhibitors. Only one had insulin dependent diabetes. At the moment of nasopharyngeal swab positivity 64% of COV + had already received three doses of vaccine (Comirnaty (BNT162b2)®) and 30% 2 doses. Only 3% of pts had received a single dose. One patient had refused vaccination for personal reasons. Antigenic nasopharyngeal swab was performed in 70% of COV + and molecular swab in 60%. Thirty-five % of COV + were tested with both methods. The most frequent symptoms were: fever (70%), cough (75%) and headache (40%). In the previous outbreaks dyspnea was present in 33% of cases dropping to 13% in this cohort. Smell and taste alteration were present in 25% and 28% respectively. We did not perform the COVID-19 sequence. But, on the base of the symptoms referred, we are confident that 17 patients had delta variant and remaining had omicron. The first therapeutic approaches were the increase of the daily steroid dosage up to 25 mg (60% of cases) together with MMF temporarily withdrawing in 70% of cases and halving in 10%. Forty % of pts were also treated with monoclonal antibodies (Ronapreve ®) upon infectious disease specialist evaluation. During the first two outbreaks, hospitalization was necessary in 45% of cases, and 13% of pts died. In the present cohort only 10% of patients required oxygen support and hospitalization. Nobody died. CONCLUSION Although very preliminary, our results indicate that the vaccination campaign has noticeably ameliorated the incidence, the clinical presentation and the outcome of COVID-19 in KTxp. This comforting data should further sensitize the medical community on vaccination counseling in KTxp as soon as possible. Study with higher number of patients are needed to further clarify the individual response on antibody production and sensitivity to this still life-threatening infection.

A Recombinant BIO-HDL (CER-001) Can Prevent SARS-COV2-Induced Renal Dysfunction by Restoring SR-BI Signalling

BACKGROUND AND AIMS Replication of the enveloped SARS-COV2 virus can alter lipidomic composition and metabolism of infected cells [1]. These alterations commonly result in a decline in HDL, total cholesterol and LDL, and an increase in triglyceride levels in COVID-19 patients. Furthermore, the ‘cytokine storm’ subsequent to release of inflammatory cytokines can severely impair lipid homeostasis. Importantly, decreased HDL-cholesterol correlates with severity of COVID-19 infection and represents a significant prognostic factor in predicting poor clinical outcomes [2]. Similarly, it has been observed that COVID-19 patients’ recovery is accompanied by a rise in serum HDL levels. Pharmacological intervention that aims to restore ApoA-1 or functional HDL particles may have beneficial roles for clinical outcome of COVID-19 patients and has recently been approved for compassionate use [3]. SARS-CoV 2 spike proteins S1 and S2 can bind free cholesterol and HDL-bound cholesterol, facilitating virus entry by binding the ACE2 co-receptor Scavenger Receptor-BI (SR-BI) [4]. When activated at the trans-membrane level, SR-BI signalling culminates in Ser1173-eNOS phosphorylation with both anti-inflammatory and anti-apoptotic effect. We hypothesized that SARS-COV2 binding promoted SR-BI internalization, so that it could not exert its essential protective function. Therefore, the aim of this study is to evaluate the effects of CER-001, a mimetic HDL, in antagonizing this process. METHOD Endothelial and tubular (RPTEC) cells were exposed to S1, S2 and S1 + S2 (50–250 nM) with or without CER-001 (CER-001 50–500 ug/mL) and cholesterol (10–50 uM). Apoptosis tests (MTT and AnnV/PI) were performed. Internalization of SR-BI, ACE2 with S1 and activation of eNOS was evaluated by FACS analysis. SR-BI and ACE2 expression were evaluated on kidney biopsies from COVID-19 patients. RESULTS At concentrations used, the exposition of S1, S2 and S1 + S2 in the presence of CER-001 and cholesterol did not induce apoptosis of endothelial cells and RPTEC. Endothelial and tubular cells stimulated by S1, in presence of cholesterol, showed an increased intracellular level of SR-BI and ACE-2, with significantly reduced eNOS phosphorylation compared to baseline (P < 0.05). The treatment with CER-001 reversed trans-membrane SR-BI levels and eNOS phosphorylation to baseline values. The detection of S1 spike protein by endothelial cells immunohistochemistry revealed an increased level in S1-exposed cells with cholesterol and reduced S1 intracellular positive staining in CER-001-exposed cells (P < 0.05). Interestingly, S1-exposed cells without cholesterol appeared not to be capable of mediating S1 spike protein internalization. Consistent with in vitro results, analysis of renal biopsies from COVID-19 patients with proteinuria showed increased SR-BI and ACE-2 cytoplasmic signals and reduced expression at the apical domain of injured tubules. CONCLUSION Our data confirmed the key role of lipid profile in SARS-COV2 infection, evaluating the molecular signalling involved in HDL metabolism and inflammatory processes, and could offer new therapeutic strategies for COVID-19 patients.

Safety Profile and Outcomes of Early COVID-19 Treatments in Immunocompromised Patients: A Single-Centre Cohort Study.

BACKGROUND: Early treatment with remdesivir (RMD) or monoclonal antibodies (mAbs) could be a valuable tool in patients at risk of severe COVID-19 with unsatisfactory responses to vaccination. We aim to assess the safety and clinical outcomes of these treatments among immunocompromised subjects. METHODS: We retrospectively reviewed all nonhospitalized patients who received an early treatment with RMD or mAbs for COVID-19, from 25 November 2021 to 25 January 2022, in a large tertiary hospital. Outcomes included frequency of adverse drug reaction (ADR), duration of symptoms and molecular swab positivity, emergency department access, hospital or intensive care unit admission, and mortality in the 14 days following treatment administration. RESULTS: Early treatments were administered to 143 patients, 106/143 (74.1%) immunocompromised, including 41 solid organ and 6 hematopoietic stem cell transplant recipients. Overall, 23/143 (16.1%) subjects reported ADRs. Median time from treatment start to SARS-CoV-2 nasopharyngeal swab negativity and symptom resolution was 10 (IQR 6-16) and 2.5 days (IQR 1.0-6.0), respectively, without differences between immunocompromised and nonimmunocompromised patients. In the 14 days after treatment administration, 5/143 patients (3.5%) were hospitalized and one died as a result of causes related to COVID-19, all of them were immunocompromised. CONCLUSIONS: RMD and mAbs have minimal ADRs and favourable outcomes in immunocompromised patients.

How Vaccinations Changed the Outcome of COVID-19 Infections in Kidney Transplant Patients: Single-Center Experience.

Kidney transplant recipients are a vulnerable population at risk of a life-threatening COVID-19 infection with an incidence of death four-times higher than in the general population. The availability of mRNA COVID-19 vaccines has dramatically changed the fate of this infection also within this fragile population. Transplanted patients have an impaired immunological response also to mRNA vaccines. In March 2021, however, we started a vaccination campaign. These preliminary results show that both the incidence of death and of hospitalization dropped from 13% to 2.4% and from 45% to 12.5% compared to the previous outbreaks reported by our group. In univariate analysis, two variables were associated with an increased risk of hospitalization: older age and dyspnea (p = 0.023, p < 0.0001, respectively). In multivariate analysis, dyspnea (p < 0.0001) and mycophenolate therapy (p = 0.003) were independently associated with the risk of hospitalization. The association was even stronger when the two variables were combined (p < 0.0001). Vaccinations did not reduce the incidence of COVID-19 infections among our transplanted patients, but provided certain protection that was associated with a significantly better outcome for this infection.

Prevalence and Risk Factors for Anti-SARS-CoV-2 Antibody in Chronic Kidney Disease (Dialysis Independent and Not).

BACKGROUND: The evidence in the medical literature regarding the prevalence of antibody towards SARS-CoV-2 in patients with chronic kidney disease is limited, particularly among those at the pre-dialysis stage. AIM: We have prospectively performed a cohort study at a third-level university hospital to evaluate frequency and risk factors for anti-SARS-CoV-2-positive serology among chronic kidney disease patients. METHODS: We have tested a cohort of consecutive outpatients with chronic kidney disease on regular follow-up at a major metropolitan hospital, during the SARS-CoV-2 outbreak in Italy. We adopted an enzyme immunoassay for the assessment of IgM/IgG antibodies to SARS-CoV-2 in human serum or plasma (DIA.PRO COVID-19 Serological Assay); the assay detects antibodies against Spike (1/2) and Nucleocapsid proteins of the SARS-CoV-2 genome. RESULTS: There were 199 (65.8%) out of 302 patients with dialysis-independent CKD; 2 patients were anti-SARS-CoV-2 IgM antibody positive, 23 were anti-SARS-CoV-2 IgM/IgG positive and 37 had detectable anti-SARS-CoV-2 IgG antibody in serum. The prevalence of anti-SARS-CoV-2 IgG was 20.5% (60/302). All patients positive for anti-SARS-CoV-2 antibody tested negative by nasopharyngeal swab. A significant and independent relationship between anti-SARS-CoV-2-positive serologic status and serum albumin (a marker of nutritional status) was observed (p < 0.046). The prevalence of anti-SARS-CoV-2 antibody was greater in CKD than in control populations (health care workers and blood donors) attending the hospital a few months before the current study (7.6% and 5.2%, respectively). CONCLUSIONS: The great prevalence of anti-SARS-CoV-2 antibody in our study group could be, at least partially, explained with the fact that our patients were living in Milan, an area severely hit by SARS-CoV-2 infection. It seems that a poor nutritional status supports the acquisition of SARS-CoV-2 antibody in CKD patients. Clinical studies to understand the mechanisms responsible for the high frequency of SARS-CoV-2 infection are under way.

mTOR inhibitors improve both humoral and cellular response to SARS-CoV-2 messenger RNA BNT16b2 vaccine in kidney transplant recipients.

Kidney transplant recipients (KTRs) have been considered as patients at higher risk of SARS-CoV-2-related disease severity, thus COVID-19 vaccination was highly recommended. However, possible interferences of different immunosuppression with development of both humoral and T cell-mediated immune response to COVID-19 vaccination have not been determined. Here we evaluated the association between mTOR-inhibitors (mTOR-I) and immune response to mRNA BNT162b2 (Pfizer-BioNTech) vaccine in KTR. To this aim 132 consecutive KTR vaccinated against COVID-19 in the early 2021 were enrolled, and humoral and T cell-mediated immune response were assessed after 4-5 weeks. Patients treated with mTOR-I showed significantly higher anti-SARS-CoV-2 IgG titer (p = .003) and higher percentages of anti-SARS-CoV-2 S1/RBD Ig (p = .024), than those without. Moreover, SARS-CoV-2-specific T cell-derived IFNγ release was significantly increased in patients treated with mTOR-I (p < .001), than in those without. Multivariate analysis confirmed that therapy with mTOR-I gained better humoral (p = .005) and T cell-mediated immune response (p = .005) in KTR. The presence of mTOR-I is associated with a better immune response to COVID-19 vaccine in KTR compared to therapy without mTOR-I, not only by increasing vaccine-induced antibodies but also by stimulating anti-SARS-CoV-2 T cell response. These finding are consistent with a potential beneficial role of mTOR-I as modulators of immune response to COVID-19 vaccine in KTR.

Vitamin D Status and SARS-CoV-2 Infection in a Cohort of Kidney Transplanted Patients.

BACKGROUND: Recently the protective role of 25-hydroxyvitamin D (25(OH)D) against viral infections has been hypothesized. We evaluated the association between vitamin D status and SARS-CoV-2 infection susceptibility and severity in a cohort of kidney transplanted patients (KTxp). METHODS: A total of 61 KTxp with SARS-CoV-2 infection (COV+) were matched with 122 healthy KTxp controls (COV-). Main biochemical parameters at 1, 6, and 12 months before SARS-CoV-2 infection were recorded. Vitamin D status was considered as the mean of two 25(OH)D measures obtained 6 ± 2 months apart during the last year. The severity of SARS-CoV-2 infection was based on the need for hospitalization (HOSP+) and death (D+). RESULTS: 25(OH)D levels were lower in COV+ than in controls [19(12-26) vs. 23(17-31) ng/mL, p = 0.01]. No differences among the other biochemical parameters were found. The SARS-CoV-2 infection discriminative power of 25(OH)D was evaluated by ROC-curve (AUC 0.61, 95% CI 0.5-0.7, p = 0.01). 25(OH)D was not significantly different between HOSP+ and HOSP- [17(8-25) vs. 20(15-26) ng/mL, p = 0.19] and between D+ and D- [14(6-23) vs. 20(14-26) ng/mL, p = 0.22] and had no significant correlation with disease length. CONCLUSIONS: During the year preceding the infection, 25(OH)D levels were lower in COV+ KTxp in comparison with controls matched for demographic features and comorbidities. No significant association between vitamin D status and SARS-CoV-2 infection related outcomes was found.

Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications.

High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.

Acute Kidney Injury and Covid-19: A Scoping Review and Meta-Analysis.

Acute kidney injury (AKI) is a fatal complication of the new severe acute respiratory syndrome coronavirus (SARS-CoV-2) which causes COVID-19 disease. Here, we performed a scoping review and meta-analysis including clinical studies on patients with SARS-CoV-2 infection with data on AKI assessment and characteristics, and the overall prevalence of AKI was estimated using a random-effects model. We identified 21 articles which passed the search criteria. All were quantitative observational studies which used a cross-sectional, retrospective, case report, or cohort methodology. This showed that aging, diabetes, cardiovascular disease, previous chronic disease, and other comorbidities were risk factors of AKI. Although the prevalence of proteinuria, hematuria, and increased serum creatinine was reported for up to 60% of the patients with COVID-19, the overall prevalence of AKI was estimated to be 8%. We conclude that although approximately two-thirds of patients with COVID-19 had symptoms of kidney damage, most of these did not meet the diagnostic criteria for AKI. Further studies should be performed to validate biomarkers for improved AKI diagnosis in COVID-19 patients and new treatment options are required to reduce the rate of mortality.

SARS-CoV-2 and Viral Sepsis: Immune Dysfunction and Implications in Kidney Failure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), first emerged in Wuhan, China. The clinical manifestations of patients infected with COVID-19 include fever, cough, and dyspnea, up to acute respiratory distress syndrome (ARDS) and acute cardiac injury. Thus, a lot of severe patients had to be admitted to intensive care units (ICU). The pathogenic mechanisms of SARS-CoV-2 infection are mediated by the binding of SARS-CoV-2 spikes to the human angiotensin-converting enzyme 2 (ACE-2) receptor. The overexpression of human ACE-2 is associated with the disease severity in SARS-CoV-2 infection, demonstrating that viral entry into cells is a pivotal step. Although the lung is the organ that is most commonly affected by SARS-CoV-2 infection, acute kidney injury (AKI), heart dysfunction and abdominal pain are the most commonly reported co-morbidities of COVID-19. The occurrence of AKI in COVID-19 patients might be explained by several mechanisms that include viral cytopathic effects in renal cells and the host hyperinflammatory response. In addition, kidney dysfunction could exacerbate the inflammatory response started in the lungs and might cause further renal impairment and multi-organ failure. Mounting recent evidence supports the involvement of cardiovascular complications and endothelial dysfunction in COVID-19 syndrome, in addition to respiratory disease. To date, there is no vaccine, and no specific antiviral medicine has been shown to be effective in preventing or treating COVID-19. The removal of pro-inflammatory cytokines and the shutdown of the cytokine storm could ameliorate the clinical outcome in severe COVID-19 cases. Therefore, several interventions that inhibit viral replication and the systemic inflammatory response could modulate the severity of the renal dysfunction and increase the probability of a favorable outcome.