AKI in Hospitalized Patients with COVID-19 and Seasonal Influenza: A Comparative Analysis.

Background: Coronavirus disease 2019 (COVID-19) is often compared with seasonal influenza and the two diseases have similarities, including the risk of systemic manifestations such as AKI. The aim of this study was to perform a comparative analysis of the prevalence, risk factors, and outcomes of AKI in patients who were hospitalized with COVID-19 and influenza. Methods: Retrospective cohort study of patients who were hospitalized with COVID-19 (n=325) or seasonal influenza (n=433). AKI was defined by Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Baseline characteristics and hospitalization data were collected, and multivariable analysis was performed to determine the independent predictors for AKI. Results: AKI occurred in 33% of COVID-19 hospitalizations (COV-AKI) and 33% of influenza hospitalizations (FLU-AKI). After adjusting for age, sex, and comorbidity count, the risk of stage 3 AKI was significantly higher in COV-AKI (OR, 3.46; 95% CI, 1.63 to 7.37). Pre-existing CKD was associated with a six- to seven-fold increased likelihood for FLU-AKI and COV-AKI. Mechanical ventilation was associated with a higher likelihood of developing AKI in the COVID-19 cohort (OR, 5.85; 95% CI, 2.30 to 15.63). Black race, after adjustment for comorbidities, was an independent risk for COV-AKI. Conclusions: Pre-existing CKD was a major risk factor for AKI in both cohorts. Black race (independent of comorbidities) and mechanical ventilation were associated with a higher risk of developing COV-AKI, which is characterized by a higher burden of stage 3 AKI and overall poorer prognosis.

Niacinamide May Be Associated with Improved Outcomes in COVID-19-Related Acute Kidney Injury: An Observational Study.

Background: AKI is a significant complication of coronavirus disease 2019 (COVID-19), with no effective therapy. Niacinamide, a vitamin B3 analogue, has some evidence of efficacy in non-COVID-19-related AKI. The objective of this study is to evaluate the association between niacinamide therapy and outcomes in patients with COVID-19-related AKI. Methods: We implemented a quasi-experimental design with nonrandom, prospective allocation of niacinamide in 201 hospitalized adult patients, excluding those with baseline eGFR <15 ml/min per 1.73 m2 on or off dialysis, with COVID-19-related AKI by Kidney Disease Improving Global Outcomes (KDIGO) criteria, in two hospitals with identical COVID-19 care algorithms, one of which additionally implemented treatment with niacinamide for COVID-19-related AKI. Patients on the niacinamide protocol (B3 patients) were compared against patients at the same institution before protocol commencement and contemporaneous patients at the non-niacinamide hospital (collectively, non-B3 patients). The primary outcome was a composite of death or RRT. Results: A total of 38 out of 90 B3 patients and 62 out of 111 non-B3 patients died or received RRT. Using multivariable Cox proportional hazard modeling, niacinamide was associated with a lower risk of RRT or death (HR, 0.64; 95% CI, 0.40 to 1.00; P=0.05), an association driven by patients with KDIGO stage-2/3 AKI (HR, 0.29; 95% CI, 0.13 to 0.65; P=0.03; P interaction with KDIGO stage=0.03). Total mortality also followed this pattern (HR, 0.17; 95% CI, 0.05 to 0.52; in patients with KDIGO stage-2/3 AKI, P=0.002). Serum creatinine after AKI increased by 0.20 (SEM, 0.08) mg/dl per day among non-B3 patients with KDIGO stage-2/3 AKI, but was stable among comparable B3 patients (+0.01 [SEM, 0.06] mg/dl per day; P interaction=0.03). Conclusions: Niacinamide was associated with lower risk of RRT/death and improved creatinine trajectory among patients with severe COVID-19-related AKI. Larger randomized studies are necessary to establish a causal relationship.

AKI in COVID-19-Associated Multisystem Inflammatory Syndrome in Children (MIS-C).

Background: Multisystem inflammatory syndrome in children (MIS-C) is a recently identified entity in association with COVID-19. AKI has been widely reported in patients with primary COVID-19 infection. However, there is a paucity of literature regarding renal injury in MIS-C. We aim to characterize AKI in MIS-C in this cohort identified at a major children's hospital in New York City during the COVID-19 pandemic. Methods: We conducted a retrospective cohort study of children 0-20 years old admitted to Morgan Stanley Children's Hospital (MSCH) between April 18th and September 23rd, 2020. Patients were included if they met criteria for MIS-C on the basis of CDC guidelines. All patients were evaluated for the presence of AKI, and AKI was staged according to KDIGO criteria. Results: Of the 57 children who met inclusion criteria, 46% (26 of 57) were found to have AKI. The majority of patients (58%; 15 of 26) were classified as KDIGO stage 1. AKI was present upon admission in 70% of those identified. All patients had resolution of AKI at discharge, with 61% achieving recovery by day 2. One patient required dialysis. When compared with those without renal injury, the AKI cohort was older (P<0.001) and had higher median peak values of CRP (P<0.001), IL-6 (P=0.02), ferritin (P<0.001), and procalcitonin (P=0.02). More patients with AKI had left ventricular systolic dysfunction (P<0.001) and lymphopenia (P=0.01) when compared with those without AKI. No differences in body mass index or sex were found. Conclusions: Although children with MIS-C may develop AKI, our study suggests that most experience mild disease, swift resolution, and promising outcome. Older age, increased inflammation, and left ventricular systolic dysfunction may be risk factors. Our study highlights the substantial differences in epidemiology and outcomes between AKI associated with pediatric MIS-C versus primary COVID-19 infection.

Evidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 Patients.

Background: SARS-CoV-2 infection has, as of April 2021, affected >133 million people worldwide, causing >2.5 million deaths. Because the large majority of individuals infected with SARS-CoV-2 are asymptomatic, major concerns have been raised about possible long-term consequences of the infection. Methods: Wedeveloped an antigen capture assay to detect SARS-CoV-2 spike protein in urine samples from patients with COVID-19whose diagnosis was confirmed by positive PCR results from nasopharyngeal swabs (NP-PCR+) forSARS-CoV-2. We used a collection of 233 urine samples from 132 participants from Yale New Haven Hospital and the Children's Hospital of Philadelphia that were obtained during the pandemic (106 NP-PCR+ and 26 NP-PCR-), and a collection of 20 urine samples from 20 individuals collected before the pandemic. Results: Our analysis identified 23 out of 91 (25%) NP-PCR+ adult participants with SARS-CoV-2 spike S1 protein in urine (Ur-S+). Interestingly, although all NP-PCR+ children were Ur-S-, one child who was NP-PCR- was found to be positive for spike protein in their urine. Of the 23 adults who were Ur-S+, only one individual showed detectable viral RNA in urine. Our analysis further showed that 24% and 21% of adults who were NP-PCR+ had high levels of albumin and cystatin C, respectively, in their urine. Among individuals with albuminuria (>0.3 mg/mg of creatinine), statistical correlation could be found between albumin and spike protein in urine. Conclusions: Together, our data showed that one of four individuals infected with SARS-CoV-2 develop renal abnormalities, such as albuminuria. Awareness about the long-term effect of these findings is warranted.

Association of AKI-D with Urinary Findings and Baseline eGFR in Hospitalized COVID-19 Patients.

Background: AKI is common in patients hospitalized with coronavirus disease 2019 (COVID-19). Risk factors for AKI requiring dialysis (AKI-D) are not fully understood. We aimed to identify risk factors associated with AKI-D and AKI not requiring dialysis (AKI-ND). Methods: We reviewed electronic health records of 3186 patients aged ≥18 years old who were hospitalized with COVID-19 across six hospitals. Patient characteristics, urinalysis findings, and inflammatory markers were analyzed for association with in-hospital AKI status (AKI-D, AKI-ND, or no AKI), and we subsequently evaluated mortality. Results: After adjustment for multiple covariates, higher baseline eGFR was associated with 30% lower odds of AKI-D and 11% lower odds of AKI-ND (for AKI-D, OR, 0.70; 95% CI, 0.64 to 0.77; for AKI-ND, OR, 0.89; 95% CI, 0.85 to 0.92). Patients with obesity and those who were Latino had increased odds of AKI-D, whereas patients with congestive heart failure or diabetes with complications had increased odds of AKI-ND. Females had lower odds of in-hospital AKI (for AKI-D, OR, 0.28; 95% CI, 0.17 to 0.46; for AKI-ND, OR, 0.83; 95% CI, 0.70 to 0.99). After adjustment for covariates and baseline eGFR, 1-4+ protein on initial urinalysis was associated with a nine-fold increase in odds of AKI-D (OR, 9.00; 95% CI, 2.16 to 37.38) and more than two-fold higher odds of AKI-ND (OR, 2.28; 95% CI, 1.66 to 3.13). Findings of 1-3+ blood and trace glucose on initial urinalysis were also associated with increased odds of both AKI-D and AKI-ND. AKI-D and AKI-ND were associated with in-hospital death (for AKI-D, OR, 2.64; 95% CI, 1.13 to 6.17; for AKI-ND, OR, 2.44; 95% CI, 1.77 to 3.35). Conclusions: Active urine sediments, even after adjustment for baseline kidney function, and reduced baseline eGFR are significantly associated with increased odds of AKI-D and AKI-ND. In-hospital AKI was associated with in-hospital death. These findings may help prognosticate patients hospitalized with COVID-19.

Expression of ACE2 in the Intact and Acutely Injured Kidney.

Background: The actions of angiotensin-converting enzyme 2 (ACE2) oppose those of the renin-angiotensin-aldosterone system. ACE2 may be a cytoprotectant in some tissues. This study examined ACE2 expression in models of AKI. Methods: ACE2 mRNA and protein expression and ACE2 activity were assessed in murine ischemic AKI. Renal ACE2 mRNA expression was evaluated in LPS-induced AKI in wild-type (C57BL/6J) mice, in heme oxygenase-1+/+ and heme oxygenase-1-/- mice, and after unilateral ureteral obstruction (UUO) in wild-type mice. The effect of sex and age on renal ACE2 protein expression was also assessed. Results: In ischemic AKI, ACE2 mRNA and protein expression and ACE2 activity were reduced as compared with such indices in the intact kidney. In ischemic AKI, ACE2, which, in health, is prominently expressed in the tubular epithelium, especially proximal tubules, is decreased in expression in these segments. Decreased ACE2 expression in AKI did not reflect reduced GFR, because ACE2 mRNA expression was unaltered after UUO. LPS induced renal ACE2 mRNA expression in wild-type mice, but this effect did not occur in heme oxygenase-1-deficient mice. In ischemic and LPS-induced AKI, renal expression of the Mas receptor was increased. In the intact kidney, renal ACE2 protein expression decreased in female mice as compared with male mice, but was unaltered with age. Conclusion: We conclude that renal ACE2 expression is decreased in ischemic AKI, characterized by decreased GFR and abundant cell death, but is upregulated in LPS-induced AKI, an effect requiring heme oxygenase-1. Determining the significance of ACE2 expression in experimental AKI merits further study. We suggest that understanding the mechanism underlying ACE2 downregulation in AKI may offer insights relevant to COVID-19: ACE2 expression is downregulated after ACE2 mediates SARS-CoV-2 cellular entry; such downregulation is proinflammatory; and AKI commonly occurs and determines outcomes in COVID-19.

Acute Peritoneal Dialysis During the COVID-19 Pandemic at Bellevue Hospital in New York City.

Background: The COVID-19 pandemic strained hospital resources in New York City, including those for providing dialysis. New York University Medical Center and affiliations, including New York City Health and Hospitals/Bellevue, developed a plan to offset the increased needs for KRT. We established acute peritoneal dialysis (PD) capability, as usual dialysis modalities were overwhelmed by COVID-19 AKI. Methods: Observational study of patients requiring KRT admitted to Bellevue Hospital during the COVID surge. Bellevue Hospital is one of the largest public hospitals in the United States, providing medical care to an underserved population. There were substantial staff, supplies, and equipment shortages. Adult patients admitted with AKI who required KRT were considered for PD. We rapidly established an acute PD program. A surgery team placed catheters at the bedside in the intensive care unit; a nephrology team delivered treatment. We provided an alternative to hemodialysis and continuous venovenous hemofiltration for treating patients in the intensive-care unit, demonstrating efficacy with outcomes comparable to standard care. Results: From April 8, 2020 to May 8, 2020, 39 catheters were placed into ten women and 29 men. By June 10, 39% of the patients started on PD recovered kidney function (average ages 56 years for men and 59.5 years for women); men and women who expired were an average 71.8 and 66.2 years old. No episodes of peritonitis were observed; there were nine incidents of minor leaking. Some patients were treated while ventilated in the prone position. Conclusions: Demand compelled us to utilize acute PD during the COVID-19 pandemic. Our experience is one of the largest recently reported in the United States of which we are aware. Acute PD provided lifesaving care to acutely ill patients when expanding current resources was impossible. Our experience may help other programs to avoid rationing dialysis treatments in health crises.

Characteristics, Outcomes and 60-Day Hospital Mortality of ICU Patients with COVID-19 and Acute Kidney Injury.

Background: AKI has been reported in patients with COVID-19 pneumonia and it is associated with higher mortality. The aim of our study is to describe characteristics, outcomes, and 60-day hospital mortality of patients with COVID-19 pneumonia and AKI in the intensive care unit (ICU). Methods: We conducted a retrospective study in which all adult patients with confirmed COVID-19 who were admitted to ICUs of Montefiore Medical Center and developing AKI were included. The study period ranged from March 10 to April 11, 2020. The 60-day follow-up data through June 11, 2020 were obtained. Results: Of 300 adults admitted to the ICUs with COVID-19 pneumonia, 224 patients (75%) presented with AKI or developed AKI subsequent to admission. A total of 218 (97%) patients required invasive mechanical ventilation for moderate to severe acute respiratory distress syndrome (ARDS). A total of 113 (50%) patients had AKI on day 1 of ICU admission. The peak AKI stages observed were stage 1 in 49 (22%), stage 2 in 35 (16%), and stage 3 in 140 (63%) patients, respectively. Among patients with AKI, 114 patients (51%) required RRT. The mortality rate of patients requiring RRT was 70%. Of the 34 patients who were survivors, 25 (74%) were able to be weaned off RRT completely before hospital discharge. Nonsurvivors were older and had significantly higher admission and peak creatinine levels, admission hemoglobin, and peak phosphate levels compared with survivors. The 60-day hospital mortality was 67%. Conclusions: COVID-19 requiring ICU admission is associated with high incidence of severe AKI, necessitating RRT in approximately half of such patients. The majority of patients with COVID-19 and AKI in ICU developed moderate to severe ARDS, requiring invasive mechanical ventilation. Timing or severity of AKI did not affect outcomes. The 60-day hospital mortality is high (67%). Patients with AKI requiring RRT have high mortality, but survivors have good rates of RRT recovery. Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/K360/2020_12_31_KID0004282020.mp3.

Acute Kidney Injury Associated with Coronavirus Disease 2019 in Urban New Orleans.

Background: AKI is a manifestation of COVID-19 (CoV-AKI). However, there is paucity of data from the United States, particularly from a predominantly black population. We report the phenotype and outcomes of AKI at an academic hospital in New Orleans. Methods: We conducted an observational study in patients hospitalized at Ochsner Medical Center over a 1-month period with COVID-19 and diagnosis of AKI (KDIGO). We examined the rates of RRT and in-hospital mortality as outcome measures. Results: Among 575 admissions (70% black) with COVID-19 [173 (30%) to an intensive care unit (ICU)], we found 161 (28%) cases of AKI (61% ICU and 14% general ward admissions). Patients were predominantly men (62%) and hypertensive (83%). Median body mass index (BMI) was higher among those with AKI (34 versus 31 kg/m2, P<0.0001). AKI over preexisting CKD occurred in 35%. Median follow-up was 25 (1-45) days. The in-hospital mortality rate for the AKI cohort was 50%. Vasopressors and/or mechanical ventilation were required in 105 (65%) of those with AKI. RRT was required in 89 (55%) patients. Those with AKI requiring RRT (AKI-RRT) had higher median BMI (35 versus 33 kg/m2, P=0.05) and younger age (61 versus 68, P=0.0003). Initial values of ferritin, C-reactive protein, procalcitonin, and lactate dehydrogenase were higher among those with AKI; and among them, values were higher for those with AKI-RRT. Ischemic acute tubular injury (ATI) and rhabdomyolysis accounted for 66% and 7% of causes, respectively. In 13%, no obvious cause of AKI was identified aside from COVID-19 diagnosis. Conclusions: CoV-AKI is associated with high rates of RRT and death. Higher BMI and inflammatory marker levels are associated with AKI as well as with AKI-RRT. Hemodynamic instability leading to ischemic ATI is the predominant cause of AKI in this setting.

Single-Cell RNA Sequencing of Urinary Cells Reveals Distinct Cellular Diversity in COVID-19-Associated AKI.

Background: AKI is a common sequela of infection with SARS-CoV-2 and contributes to the severity and mortality from COVID-19. Here, we tested the hypothesis that kidney alterations induced by COVID-19-associated AKI could be detected in cells collected from urine. Methods: We performed single-cell RNA sequencing (scRNAseq) on cells recovered from the urine of eight hospitalized patients with COVID-19 with (n=5) or without AKI (n=3) as well as four patients with non-COVID-19 AKI (n=4) to assess differences in cellular composition and gene expression during AKI. Results: Analysis of 30,076 cells revealed a diverse array of cell types, most of which were kidney, urothelial, and immune cells. Pathway analysis of tubular cells from patients with AKI showed enrichment of transcripts associated with damage-related pathways compared with those without AKI. ACE2 and TMPRSS2 expression was highest in urothelial cells among cell types recovered. Notably, in one patient, we detected SARS-CoV-2 viral RNA in urothelial cells. These same cells were enriched for transcripts associated with antiviral and anti-inflammatory pathways. Conclusions: We successfully performed scRNAseq on urinary sediment from hospitalized patients with COVID-19 to noninvasively study cellular alterations associated with AKI and established a dataset that includes both injured and uninjured kidney cells. Additionally, we provide preliminary evidence of direct infection of urinary bladder cells by SARS-CoV-2. The urinary sediment contains a wealth of information and is a useful resource for studying the pathophysiology and cellular alterations that occur in kidney diseases.