A CLINICAL CASE OF SARS-CoV-2 INFECTION COMPLICATED BY NEPHROGENIC PULMONARY EDEMA AND COVID-ASSOCIATED PNEUMONITIS, ALVEOLITIS.

COVID-19 is a highly transmissible disease with severe course especially in patients with nephrogenic hypertensive disease and chronic kidney disease due to a higher incidence of all-type infections than in the general population. The aim of the study is to describe a clinical case of SARS-CoV-2 infection complicated by nephrogenic pulmonary edema and COVID-associated pneumonitis, alveolitis. Description of the case. Patient K.S., born in 1975, was hospitalized 24 hours after symptom onset at emergency hospital due to complaints of increased blood pressure up to 180-200/110-120 mm Hg, temperature up to 38.7degreeC, dry cough, feeling of heaviness in the chest, change in urine color. PCR smear for SARS-CoV-2 was positive. Computed tomography revealed a pattern of bilateral COVID-associated pneumonitis, alveolitis, with 75% involvement. The electrocardiogram revealed signs of left ventricular myocardial hypertrophy. Ultrasound examination showed numerous cysts in the kidneys. Urinalysis at admission: leukocytes - 499, erythrocytes - 386. Glomerular filtration rate (CKD-EPI: 29 ml/min/1.73 m2) and corresponds to stage IV of chronic kidney disease. Coagulogram: fibrinogen: 32.3 (1.6-4.0) g/l, D-dimer: 663 (0-250). Despite the treatment, the patient's condition worsened, the phenomena of cardiopulmonary and renal insufficiency increased, which led to a fatal outcome. During a virological study of sectional material: SARS-CoV-2 coronavirus RNA was found in the lung and kidneys. Signs of bilateral COVID-associated pneumonitis, alveolitis with diffuse cellular infiltrates in combination with changes in the alveolar apparatus, signs of pulmonary edema were revealed. Heart-related signs - swelling of the interstitium, fragmented muscle fibers, some of them hypertrophied, a wave-like deformation of cardiomyocytes, blurring of the transverse striation. Arteries with thickened sclerosed walls. In the kidneys - diffuse damage to the proximal tubules of the nephron with areas of cortical and proximal necronephrosis, areas of fibrinoid swelling. Conclusion. The cause of death of a 45-year-old patient was a severe course of bilateral COVID-associated pneumonitis, alveolitis, which contributed to the development of renal medullary hypoxia and type 1 cardiorenal syndrome, which led to early nephrogenic pulmonary edema.Copyright © 2023 Saint Petersburg Pasteur Institute. All rights reserved.

Long COVID: Is there a kidney link?

Metabolic causes such as altered bioenergetics and amino acid metabolism may play a major role in Long COVID. Renal-metabolic regulation is an integral part of these pathways but has not been systematically or routinely investigated in Long COVID. Here we discuss the biochemistry of renal tubular injury as it may contribute to Long COVID symptoms. We propose three potential mechanisms that could be involved in Long COVID namely creatine phosphate metabolism, un-reclaimed glomerular filtrate and COVID specific proximal tubule cells (PTC) injury-a tryptophan paradigm. This approach is intended to allow for improved diagnostics and therapy for the long-haul sufferers.

Quercetin potentially suppresses renal fibrosis in patients with COVID-19 under hypoxic state

Introduction: Renal fibrosis is a main outcome of acute kidney injury in COVID-19 survivors, which is emerging as a global public health concern. Lung damage in the COVID-19 patients leads to acute and chronic hypoxia, which results in inflammation, epithelial-mesenchymal transformation, and fibrosis in kidney. Quercetin is an abundant flavonoid in plant materials. Previous studies indicate that quercetin alleviates the decline of renal function, suppress epithelial to mesenchymal transformation in renal tubules, and reduce fibrosis. The study aimed to explore potential targets of quercetin on treating renal fibrosis in patients with COVID-19-induced hoxpia. Method(s): Gene/protein targets related to COVID-19, renal fibrosis, or quercetin were searched from ten databases, and Cytoscape 3.8.2 was then used to construct the protein-protein interaction network and to identify the core targets. The Metascape platform was used for bioconcentration analysis, while AutoDock Vina was used as the primary molecular docking tool. In vitro, the combination model of hypoxia- and transforming growth factor-beta (TGF-beta)- treated human proximal tubule epithelial cells (HK2 cells) was applied to determine the reno-protective effect of quercetin. Result(s): The network analysis showed that quercetin targeted on TGF-beta pathway in treating COVID-19 induced renal fibrosis. In the intersection PPI network, 115 targets were obtained, and gene enrichment analysis was conducted on 109 key nodes. Molecular docking analysis revealed that quercetin could spontaneously bind to eight targets on the TGF-beta pathway, and the binding energy of TGF-beta1 was 29.82 kJ/mol. The in vitro experiment further showed that quercetin significantly suppressed fibrosis in TGF-beta and hypoxia treated HK2 cells in a dose dependent manner by inhibiting TGF-beta/Smad3 pathway. Conclusion(s): Quercetin could attenuate renal fibrosis in patients with COVID-19 by suppressing TGF-beta/Smad3 pathway. No conflict of interestCopyright © 2023

Mechanisms of kidney injury in COVID-19 and diagnostic methods.

The COVID-19 pandemic is a global healthcare crisis. The frequency of acute kidney injury (AKI) in patients with COVID-19 and the features of its diagnostics indicate the relevance of the topic. Objective of the review. To analyze mechanisms of AKI development in patients with COVID-19 and provide support for methodological approaches to ensure its timely diagnosis. Material and methods. The methodological approaches used in the review are based on a sufficient number of literature sources (more than 150 sources), of which 34 articles are included in the review: 15 original studies, 12 reviews, 2 meta-analyses, 5 re-ports, and letters to the editor. Results. The mechanisms of AKI development and progression, including the direct cytotoxic effect of the SARS-CoV-2 virus, dis-ruption of metabolic pathways of renal blood flow regulation, and the complement system, are considered. We also analyzed AKI risk factors in patients with acute respiratory distress: diabetes mellitus, chronic kidney injury, arterial hypertension with im-paired NOx production, and eNOS expression as significant factors of vasodilation in renal microcirculatory vessels. The analy-sis showed the most perspective directions in the diagnostics of AKI functional stages. These include molecular test methods (pro-teome and metabolome) in blood and urine;they helped define damage markers to proximal tubules and the glomerular system, thus improving the diagnostics accuracy and validity, therapy efficiency, and end points of disease prognosis. Conclusion. The Coronado study aims to assess the phenotypic features of patients with diabetes mellitus and COVID-19. More specific markers of the acute kidney injury functional stage were determined;these markers will improve the diagnostics accuracy and validity, therapy efficiency, and end points of disease prognosis.Copyright © 2023, Media Sphera Publishing Group. All rights reserved.

Proximal Tubular Dysfunction as a Predictor of Aki in Hospitalized Covid-19 Patients

Introduction: Severe acute respiratory syndrome coronavirus 2 associated pneumonia (COVID-19) is a modern pandemic. Recent evidence suggests that kidney is an important target organ in COVID-19. High concentration of Angiotensin converting enzyme receptors in the proximal tubules make them an early target. Proximal tubular dysfunction (PTD) may act as an early predictor of acute kidney injury (AKI), need for renal replacement therapy (RRT), intensive care unit (ICU) transfer, mechanical ventilation, hospital length of stay (LOS) and death. Method(s): This prospective observational study was conducted in the COVID unit, Bangabandhu Sheikh Mujib Medical University. 87 COVID-19 patients without preexisting kidney disease were screened for markers of PTD on admission. Patients having at least 2 of the 4 defining markers of PTD (inappropriate uricosuria, renal phosphate leak, normoglycemic glycosuria and proteinuria) positive on admission were considered to have PTD. 35 patients with PTD and 35 without PTD were followed up throughout their hospital stay and compared. Result(s): 52.9% of the patients had at least 2 of the 4 defining markers of PTD positive on admission. The most prevalent markers were proteinuria (66.7%), followed by hyperuricosuria (42.5%), renal phosphate leak (28.7%) and normoglycemic glycosuria (20.7%). Also, 67% patients had renal sodium leak and 32.2% patients had renal potassium leak. Mean age was 55.7 years. 50% of the patients were diabetic. The PTD group had significantly lower oxygen saturation and higher parenchymal involvement on HRCT chest, CRP and LDH compared to the non PTD group on admission. 32.9% patients developed AKI during their hospital stay. PTD group had higher odds of developing AKI (odds ratio 17.5 for stage 1, 24.8 for stage 2 and 25.5 for stage 3;p<0.0001). The mean duration of hospital stay was 9 days higher in the PTD group (p<0.001). PTD group also had higher odds of transferring to ICU (OR=9.4, p=0.002), need for mechanical ventilation (OR=10.1, p=0.002) and death (OR=10.3, p=0.001). There was complete recovery of PTD in 32.6% and complete renal recovery in 47.8% of patients during their hospital stay. 26.1% of the patients who developed AKI required hemodialysis. 11.4% of all patients died. Conclusion(s): Proximal tubular dysfunction is highly prevalent in COVID-19 patients very early in the disease and may act as a predictor of AKI, ICU transfer, need for mechanical ventilation and death. No conflict of interestCopyright © 2023

Mechanisms of kidney injury in COVID-19 and diagnostic methods

The COVID-19 pandemic is a global healthcare crisis. The frequency of acute kidney injury (AKI) in patients with COVID-19 and the features of its diagnostics indicate the relevance of the topic. Objective of the review. To analyze mechanisms of AKI development in patients with COVID-19 and provide support for methodological approaches to ensure its timely diagnosis. Material and methods. The methodological approaches used in the review are based on a sufficient number of literature sources (more than 150 sources), of which 34 articles are included in the review: 15 original studies, 12 reviews, 2 meta-analyses, 5 re-ports, and letters to the editor. Results. The mechanisms of AKI development and progression, including the direct cytotoxic effect of the SARS-CoV-2 virus, dis-ruption of metabolic pathways of renal blood flow regulation, and the complement system, are considered. We also analyzed AKI risk factors in patients with acute respiratory distress: diabetes mellitus, chronic kidney injury, arterial hypertension with im-paired NOx production, and eNOS expression as significant factors of vasodilation in renal microcirculatory vessels. The analy-sis showed the most perspective directions in the diagnostics of AKI functional stages. These include molecular test methods (pro-teome and metabolome) in blood and urine;they helped define damage markers to proximal tubules and the glomerular system, thus improving the diagnostics accuracy and validity, therapy efficiency, and end points of disease prognosis. Conclusion. The Coronado study aims to assess the phenotypic features of patients with diabetes mellitus and COVID-19. More specific markers of the acute kidney injury functional stage were determined;these markers will improve the diagnostics accuracy and validity, therapy efficiency, and end points of disease prognosis.

Lack of Evidence for Kidney Invasion by SARS-CoV-2 in a Lethal Mouse Model

Background: There is an ongoing controversy as to whether SARS CoV-2 can infect the kidney parenchyma directly. To date, the presence of SARS CoV-2 in the kidney has been described mainly post-mortem in autopsy studies of patients who died of or with COVID-19, but this has not been examined in an experimental model where the timing of SARS-CoV-2 infection can be defined. We used transgenic mice expressing human ACE2 (k18hACE2) susceptible to lethal SARS-CoV-2 infection to study this issue directly on kidney tissue taken at defined time points and using lung tissue as positive control. Method(s): Transgenic k18hACE2 mice were inoculated with 3x104 PFU SARSCoV-2 in a BSL-3 facility. Kidneys and lungs were removed from the animals sacrificed on days 5 to 7 and used for histology (PAS-staining), immunofluorescence (IF) of the S1 spike protein of SARS-CoV-2 and measurement of viral load by plaque assay. Kidney samples were additionally evaluated by IF using kidney injury markers NGAL and KIM-1. Result(s): Kidney tissue stained using an anti-S1-spike antibody showed negative results in all samples (n=15). By plaque assay, viral titers were also not detectable in any of the kidneys. By contrast, lungs from infected mice showed strong staining for the S1 spike protein in 13 of 14 cases and this was associated with positive viral titers in all lung samples. Despite severe lung disease, only mild and variable kidney damage was observed by histopathology. Positive staining for NGAL in the proximal tubules was consistently seen, while KIM-1 staining was rarely positive. Conclusion(s): In a transgenic mouse model with lethal SARS-CoV-2 infection and severe lung but mild kidney disease there is no evidence of S1 spike protein in the kidney, which is consistent with lack of detection of replicating virus by plaque assay.

Subclinical Acute Kidney Injury in COVID-19: Possible Mechanisms and Future Perspectives.

Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis.

SARS-CoV-2 spike protein inhibits megalin-mediated albumin endocytosis in proximal tubule epithelial cells.

Patients with COVID-19 have high prevalence of albuminuria which is used as a marker of progression of renal disease and is associated with severe COVID-19. We hypothesized that SARS-CoV-2 spike protein (S protein) could modulate albumin handling in proximal tubule epithelial cells (PTECs) and, consequently contribute to the albuminuria observed in patients with COVID-19. In this context, the possible effect of S protein on albumin endocytosis in PTECs was investigated. Two PTEC lines were used: HEK-293A and LLC-PK1. Incubation of both cell types with S protein for 16 h inhibited albumin uptake at the same magnitude. This effect was associated with canonical megalin-mediated albumin endocytosis because: (1) DQ-albumin uptake, a marker of the lysosomal degradation pathway, was reduced at a similar level compared with fluorescein isothiocyanate (FITC)-albumin uptake; (2) dextran-FITC uptake, a marker of fluid-phase endocytosis, was not changed; (3) cell viability and proliferation were not changed. The inhibitory effect of S protein on albumin uptake was only observed when it was added at the luminal membrane, and it did not involve the ACE2/Ang II/AT1R axis. Although both cells uptake S protein, it does not seem to be required for modulation of albumin endocytosis. The mechanism underlying the inhibition of albumin uptake by S protein encompasses a decrease in megalin expression without changes in megalin trafficking and stability. These results reveal a possible mechanism to explain the albuminuria observed in patients with COVID-19.

RELATIONSHIP BETWEEN VITAMIN D LEVELS AND SARS-COV-2 INFECTION IN DIALYSIS PATIENTS

BACKGROUND AND AIMS: Hypovitaminosis D is highly prevalent in patients with Chronic Kidney Disease (CKD). This is considered a consequence of a decreased renal mass and a reduction in the number of proximal tubular cells, which absorb the filtered native vitamin D and then be hydroxylated to its active form by 1α-hydroxylase. Hypovitaminosis D is defined as serum levels of 25-hydroxy-vitamin D3 lower than 30 ng/mL. The decrease in vitamin D causes bone and mineral abnormalities and can also play a role in various pathologies, such as cardiovascular disease, insulin resistance, diabetes, autoimmune diseases and infections. Clinical practice guidelines recommend treating hypovitaminosis D. The role of vitamin D in acute respiratory tract infections and other viral infections has been widely studied. It has an immunomodulatory role due to the expression of the enzyme 1α-hydroxylase by the epithelium of the respiratory tract, dendritic cells and lymphocytes, which is essential for the activation of vitamin D in the lungs. In this way, an influence is created on the lung capacity to fight infections and respond to allergic stimuli. Vitamin D has the potential to influence the severity and outcomes of COVID-19. In fact, several studies have established a consistent relationship between hypovitaminosis D and the severity of COVID-19. We have a population of dialysis patients with a tendency to hypovitaminosis D and, on the other hand, an influence of hypovitaminosis D in respiratory infections such as SARS-CoV-2 infection. Thus, we consider it interesting to study whether the incidence of hypovitaminosis D is higher in dialysis patients with SARS-CoV-2 infection than in those who do not. METHOD: An observational, analytical, ambispective, multicentre study was carried out under normal clinical practice conditions. The study subjects are patients on haemodialysis program of the province of Santa Cruz de Tenerife, in the period between January 2021 and January 2022. As variables we selected age, sex, personal history, haemodialysis time, serum levels of 25-hydroxy-vitD3, treatment with native vitamin D, presence of SARS-CoV-2 infection diagnosed by RT-PCR in nasopharyngeal swab, vaccination. The information collected is organized in a database of the SPSS Statistics v22 program. For quantitative variables, the comparison between groups is made by means of an analysis with the Student's t-test for independent samples. Qualitative variables are analyzed using the Chi-squared test or Fisher's exact test. All data were analyzed using the SPSS Statistics v22 program. The level of significance is established for a value of P < 0.05. RESULTS: A total of 60 haemodialysis patients were included, 36 men (60%) and 24 women (40%). The mean age was 64 years. The most common cause of kidney disease was diabetic nephropathy (35%). The median time on dialysis was 24.5 months. 73.3% of the patients presented hypovitaminosis D and 35% received treatment with vitamin D. 23 patients had SARS-CoV-2 infection (38.3%). 2 patients (3.3%) died of COVID-19. There were no significant differences between the two comparison groups (patients with and without SARS-CoV-2 infection) in relation to sex, age, cause of kidney disease, diabetes, time on dialysis, vitamin D intake. We also did not observe significant differences in relation to vitamin D levels or the presence of hypovitaminosis D. There are significant differences in relation to vaccination (p 0.00). 39.1% of the patients with SARS-CoV-2 infection were not vaccinated. 90% of all unvaccinated patients had SARS-CoV-2 infection. 97.3% of the uninfected patients were vaccinated. CONCLUSION: Hypovitaminosis D is very common in CKD patients on dialysis, however, despite its immunomodulatory role, we did not find a higher incidence of hypovitaminosis D in dialysis patients with SARS-CoV-2 infection. In our series, we have not found factors associated with SARS-CoV-2 infection in dialysis patients, with the exception of vaccination. Therefore, vaccination in our dialysis patients is being essential t prevent a higher number of cases of SARS-CoV-2 infection.

PREVALENCE OF COVID-ASSOCIATED RENAL INJURY IN ICU AND PROGNOSIS OF PROXIMAL TUBULAR DYSFUNCTION IN ACUTE RESPIRATORY DISTRESS SYNDROME

BACKGROUND AND AIMS: During COVID-19, the renal impairment is the most frequent after lung impairment and is associated of poor prognosis particularly in the intensive care unit (ICU). In this work, we aim to assess the incidence of acute kidney injury (AKI) in COVID-19-related acute respiratory distress syndrome (ARDS) patients, the existence of an early renal dysfunction and its prognosis, and its specificity compared with patients with non-COVID ARDS. METHOD: This a prospective and multicentric study led in four ICUs. Patients of 18 years and older in ICU with invasive mechanical ventilation for ARDS were enrolled. Precise evaluation of renal dysfunction markers, including urinary protein electrophoresis, was performed within 24 h after the onset of mechanical ventilation. RESULTS: From March 2020 to September 2021, 131 patients in ICU for ARDS were enrolled, 98 COVID-19 ARDS and 33 ARDS from other causes. There was more tubular profile in COVID-19 patients (68% versus 24%;P = .001) and a more mixed, tubular and glomerular profile in non-COVID-19 patients (29% versus 14%;P = .001). COVID-19 patients displayed an important tubular proteinuria, tended to display more AKI (49% versus 31%;P = .07), and had a longer duration of mechanical ventilation (18 versus 10 days;P = .002) and longer ICU length of stay (23 versus 15 days;P = .013). In COVID-19 patients, tubular proteinuria was associated with poor renal prognosis with a significant association with the onset of KDIGO ≥ 2 AKI. CONCLUSION: COVID-19 ARDS patients had a specific renal impairment with tubular dysfunction, which appeared to be of poor prognosis on kidney and disease evolution.

PATHOLOGICAL CHANGES IN THE KIDNEYS IN PATIENTS WITH ACUTE RENAL INJURY DUE TO CORONAVIRUS INFECTION

INTRODUCTION AND OBJECTIVE: Acute kidney injury (AKI) in coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus is much more common than previously thought and is associated with severe disease and high mortality. Despite the fact that the respiratory and immune systems are the main targets of the COVID- 19 virus, AKI is also observed, identified by the occurrence of proteinuria or hematuria, an increase in serum urea and creatinine levels. The aim of the study is to assess the pathomorphological changes in the kidneys in 100 cases of autopsy of patients with COVID-19 using light microscopy and immunohistochemical diagnostic methods in order to clarify the possible mechanism of AKI. METHODS: The study was carried out using samples obtained from 100 patients, the time interval of the onset of the disease corresponded to the 4th wave of the peak of the incidence in Russia (from June 2021). The age of patients varied from 37 to 94 years 72 (s =12.5), men - 34, women - 66. Patients with chronic kidney disease, diabetes mellitus and cancer were not included in the analysis. The cause of death in all cases was acute respiratory failure, histologically defined as diffuse alveolar injury. AKI in accordance with the KDIGO criteria was detected in 34 patients. RESULTS: On light microscopy, diffuse massive damage to the proximal tubules with loss of the brush border, degeneration of vacuoles was detected in 46 patients, massive necrosis of the tubules in 11 patients. In 65 patients, an extremely pronounced congestion of paretic dilated vessels with widespread paravasal hemorrhages was revealed. Paravasal lymphoid infiltration of the vascular endothelium was detected in 27 patients. Severe sludge syndrome in small and medium-sized vessels in 46 patients. In almost all cases, hemosiderin granules and hyaline casts were found. The quantitative and qualitative composition of tissue macrophages corresponded to the population data, without visible correlations with the disease. CONCLUSIONS: According to the study, the factors contributing to AKI include systemic hypoxia, abnormal coagulation, increased catabolism due to fever, drug-related rhabdomyolysis or hyperventilation with increased serum degradation products. Thus, our research provides evidence for AKI during the progression of COVID-10. These results contribute to a better understanding of the course and progression of SARS-CoV-2 virus infection.

Angiotensin II and AT1a Receptors in the Proximal Tubules of the Kidney: New Roles in Blood Pressure Control and Hypertension.

Contrary to public perception, hypertension remains one of the most important public health problems in the United States, affecting 46% of adults with increased risk for heart attack, stroke, and kidney diseases. The mechanisms underlying poorly controlled hypertension remain incompletely understood. Recent development in the Cre/LoxP approach to study gain or loss of function of a particular gene has significantly helped advance our new insights into the role of proximal tubule angiotensin II (Ang II) and its AT1 (AT1a) receptors in basal blood pressure control and the development of Ang II-induced hypertension. This novel approach has provided us and others with an important tool to generate novel mouse models with proximal tubule-specific loss (deletion) or gain of the function (overexpression). The objective of this invited review article is to review and discuss recent findings using novel genetically modifying proximal tubule-specific mouse models. These new studies have consistently demonstrated that deletion of AT1 (AT1a) receptors or its direct downstream target Na+/H+ exchanger 3 (NHE3) selectively in the proximal tubules of the kidney lowers basal blood pressure, increases the pressure-natriuresis response, and induces natriuretic responses, whereas overexpression of an intracellular Ang II fusion protein or AT1 (AT1a) receptors selectively in the proximal tubules increases proximal tubule Na+ reabsorption, impairs the pressure-natriuresis response, and elevates blood pressure. Furthermore, the development of Ang II-induced hypertension by systemic Ang II infusion or by proximal tubule-specific overexpression of an intracellular Ang II fusion protein was attenuated in mutant mice with proximal tubule-specific deletion of AT1 (AT1a) receptors or NHE3. Thus, these recent studies provide evidence for and new insights into the important roles of intratubular Ang II via AT1 (AT1a) receptors and NHE3 in the proximal tubules in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.

Glycosuria induced hypernatremia secondary to COVID-19

Case Report The purpose of this study is to describe a case study of possible glycosuria-induced hypernatremia in a patient hospitalized with COVID-19 acute respiratory distress syndrome. Methods Used Case study and literature review Summary of Results A 55-year-old man with a past medical history of non-insulin-dependent type II diabetes and hypertension developed hypernatremia, glycosuria, and acute kidney injury in the setting of COVID-19 pneumonia after resolution of diabetic ketoacidosis. The patient was initially admitted with a positive SARS-COVID-19 screening, a creatinine of 1.1 mg/dL (0.5-1.2) with glycosuria, and sodium of 137 mmol/L (136-145). Seventeen days into his hospital admission for severe acute respiratory distress syndrome, he developed hypernatremia (147 mmol/L). Over the subsequent twenty-two days, the patient continued to have hypernatremia up to 153 mmol/L refractory to treatment. In addition, the patient had persistent glycosuria and an elevated creatinine of 2.3 mg/dL (greater than thirty percent above his baseline). His total fluid balance was +1444 mL during this phase of hospitalization. The patient's electrolyte derangements concomitant with his worsening renal function suggests possible Fanconi syndrome. We hypothesize this is secondary to COVID-19. Conclusion COVID-19 has been shown to be associated with renal dysfunction, including acute tubular injury, such as membranous nephropathy and Fanconi syndrome. Experimental data have suggested that COVID-19 can infect renal proximal tubular cells via the Angiotensin Converting Enzyme 2 with subsequent development of incomplete Fanconi syndrome preceding acute kidney injury. Studies have also shown that glycosuria, proteinuria, pyuria, and hematuria may occur with COVID-19 regardless of comorbidities. We concluded our patient developed refractory hypernatremia secondary to glycosuria induced incomplete Fanconi syndrome due to COVID- 19.

Single cell profiling in COVID-19 associated acute kidney injury reveals patterns of tubule injury and repair in human

Background: Acute Kidney Injury (AKI) affects up to one in two critically ill patients. The cellular mechanisms of kidney tubule repair after acute kidney injury are poorly characterized in humans. Methods: We recruited 5 patients admitted to the Geneva University Hospital's Intensive Care Unit for severe COVID19 and experiencing AKI. For each of them, a kidney biopsy was performed before the planned withdrawal of resuscitation measures. We further applied single-cell RNA sequencing to analyze the kidney in the first days after acute injury. Results: After data processing and quality control, we obtained 20,165 single-cell transcriptomes. The most prominent finding in the snRNAseq analyses was in the proximal tubule (PT) compartment. We defined two cell populations corresponding to mature and undifferentiated PT cells, connected by two cell state transitions (Figure 1). Undifferentiated PT cells display an injured pattern characterized by metabolic impairment, reduction of the tubule transport function, and expression of injury markers confirmed in immunochemistry. We found that tubule repair follows two converging patterns involving the plasticity of mature tubule cells and the expansion and differentiation of progenitor-like cells. Tubule repair by cell plasticity displayed substantial similarities among mice and men and determined the transient expansion of undifferentiated tubule cells with altered functional and metabolic properties. Progenitorlike cells marked by PROM1 proliferated in response to injury and followed a differentiation process characterized by the sequential activation of the WNT, NOTCH, and HIPPO signaling pathways. Conclusions: Here we generated the first map of PT injury and repair in humans. Taken together, our analyses reveal cell states transitions and fundamental cellular hierarchies underlying kidney injury and repair in patients.

Evidence For and Against Direct Kidney Infection by SARS-CoV-2 in Patients with COVID-19.

Despite evidence of multiorgan tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19), direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV2 can directly infect the kidney is relevant to the understanding of pathogenesis of AKI and collapsing glomerulopathy in patients with COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, RT-PCR, in situ hybridization, and electron microscopy. In our review of studies to date, we found that SARS-CoV-2 in the kidneys of patients with COVID-19 was detected in 18 of 94 (19%) by immunohistochemistry, 71 of 144 (49%) by RT-PCR, and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed because many other studies have been negative for SARS-CoV-2 and it should be noted that when detected, it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19-associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a noninvasive way to evaluate SARS-CoV-2 infection during the evolution of COVID-19-associated kidney disease.

Transcriptomes of Major Proximal Tubule Cell Culture Models.

BACKGROUND: Cultured cell lines are widely used for research in the physiology, pathophysiology, toxicology, and pharmacology of the renal proximal tubule. The lines that are most appropriate for a given use depend upon the genes expressed. New tools for transcriptomic profiling using RNA sequencing (RNA-Seq) make it possible to catalog expressed genes in each cell line. METHODS: Fourteen different proximal tubule cell lines, representing six species, were grown on permeable supports under conditions specific for the respective lines. RNA-Seq followed standard procedures. RESULTS: Transcripts expressed in cell lines variably matched transcripts selectively expressed in native proximal tubule. Opossum kidney (OK) cells displayed the highest percentage match (45% of proximal marker genes [TPM threshold =15]), with pig kidney cells (LLC-PK1) close behind (39%). Lower-percentage matches were seen for various human lines, including HK-2 (26%), and lines from rodent kidneys, such as NRK-52E (23%). Nominally, identical OK cells from different sources differed substantially in expression of proximal tubule markers. Mapping cell line transcriptomes to gene sets for various proximal tubule functions (sodium and water transport, protein transport, metabolic functions, endocrine functions) showed that different lines may be optimal for experimentally modeling each function. An online resource (https://esbl.nhlbi.nih.gov/JBrowse/KCT/) has been created to interrogate cell line transcriptome data. Proteomic analysis of NRK-52E cells confirmed low expression of many proximal tubule marker proteins. CONCLUSIONS: No cell line fully matched the transcriptome of native proximal tubule cells. However, some of the lines tested are suitable for the study of particular metabolic and transport processes seen in the proximal tubule.

Transcriptomes of Major Proximal Tubule Cell Culture Models.

BACKGROUND: Cultured cell lines are widely used for research in the physiology, pathophysiology, toxicology, and pharmacology of the renal proximal tubule. The lines that are most appropriate for a given use depend upon the genes expressed. New tools for transcriptomic profiling using RNA sequencing (RNA-Seq) make it possible to catalog expressed genes in each cell line. METHODS: Fourteen different proximal tubule cell lines, representing six species, were grown on permeable supports under conditions specific for the respective lines. RNA-Seq followed standard procedures. RESULTS: Transcripts expressed in cell lines variably matched transcripts selectively expressed in native proximal tubule. Opossum kidney (OK) cells displayed the highest percentage match (45% of proximal marker genes [TPM threshold =15]), with pig kidney cells (LLC-PK1) close behind (39%). Lower-percentage matches were seen for various human lines, including HK-2 (26%), and lines from rodent kidneys, such as NRK-52E (23%). Nominally, identical OK cells from different sources differed substantially in expression of proximal tubule markers. Mapping cell line transcriptomes to gene sets for various proximal tubule functions (sodium and water transport, protein transport, metabolic functions, endocrine functions) showed that different lines may be optimal for experimentally modeling each function. An online resource (https://esbl.nhlbi.nih.gov/JBrowse/KCT/) has been created to interrogate cell line transcriptome data. Proteomic analysis of NRK-52E cells confirmed low expression of many proximal tubule marker proteins. CONCLUSIONS: No cell line fully matched the transcriptome of native proximal tubule cells. However, some of the lines tested are suitable for the study of particular metabolic and transport processes seen in the proximal tubule.

Transcriptomes of Major Proximal Tubule Cell Culture Models.

BACKGROUND: Cultured cell lines are widely used for research in the physiology, pathophysiology, toxicology, and pharmacology of the renal proximal tubule. The lines that are most appropriate for a given use depend upon the genes expressed. New tools for transcriptomic profiling using RNA sequencing (RNA-Seq) make it possible to catalog expressed genes in each cell line. METHODS: Fourteen different proximal tubule cell lines, representing six species, were grown on permeable supports under conditions specific for the respective lines. RNA-Seq followed standard procedures. RESULTS: Transcripts expressed in cell lines variably matched transcripts selectively expressed in native proximal tubule. Opossum kidney (OK) cells displayed the highest percentage match (45% of proximal marker genes [TPM threshold =15]), with pig kidney cells (LLC-PK1) close behind (39%). Lower-percentage matches were seen for various human lines, including HK-2 (26%), and lines from rodent kidneys, such as NRK-52E (23%). Nominally, identical OK cells from different sources differed substantially in expression of proximal tubule markers. Mapping cell line transcriptomes to gene sets for various proximal tubule functions (sodium and water transport, protein transport, metabolic functions, endocrine functions) showed that different lines may be optimal for experimentally modeling each function. An online resource (https://esbl.nhlbi.nih.gov/JBrowse/KCT/) has been created to interrogate cell line transcriptome data. Proteomic analysis of NRK-52E cells confirmed low expression of many proximal tubule marker proteins. CONCLUSIONS: No cell line fully matched the transcriptome of native proximal tubule cells. However, some of the lines tested are suitable for the study of particular metabolic and transport processes seen in the proximal tubule.

Hypophosphatemia is an independent risk factor for AKI among hospitalized patients with COVID-19 infection.

BACKGROUND: This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. METHODS: In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. RESULTS: In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14-1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. CONCLUSION: The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.