Renal Manifestations of Covid-19: Physiology and Pathophysiology

Corona virus disease 2019 (COVID-19) imposes a serious public health pandemic affecting the whole world, as it is spreading exponentially. Besides its high infectivity, SARS-CoV-2 causes multiple serious derangements, where the most prominent is severe acute respiratory syndrome as well as multiple organ dysfunction including heart and kidney injury. While the deleterious impact of SARS-CoV-2 on pulmonary and cardiac systems have attracted remarkable attention, the adverse effects of this virus on the renal system is still underestimated. Kidney susceptibility to SARS-CoV-2 infection is determined by the presence of angiotensin-converting enzyme 2 (ACE2) receptor which is used as port of the viral entry into targeted cells, tissue tropism, pathogenicity and subsequent viral replication. The SARS-CoV-2 cellular entry receptor, ACE2, is widely expressed in proximal epithelial cells, vascular endothelial and smooth muscle cells and podocytes, where it supports kidney integrity and function via the enzymatic production of Angiotensin 1-7 (Ang 1-7), which exerts vasodilatory, anti-inflammatory, antifibrotic and diuretic/natriuretic actions via activation of the Mas receptor axis. Loss of this activity constitutes the potential basis for the renal damage that occurs in COVID-19 patients. Indeed, several studies in a small sample of COVID-19 patients revealed relatively high incidence of acute kidney injury (AKI) among them. Although SARS-CoV-1 -induced AKI was attributed to multiorgan failure and cytokine release syndrome, as the virus was not detectable in the renal tissue of infected patients, SARS-CoV-2 antigens were detected in kidney tubules, suggesting that SARS-CoV-2 infects the human kidney directly, and eventually induces AKI characterized with high morbidity and mortality. The mechanisms underlying this phenomenon are largely unknown. However, the fact that ACE2 plays a crucial role against renal injury, the deprivation of the kidney of this advantageous enzyme, along with local viral replication, probably plays a central role. The current review focuses on the critical role of ACE2 in renal physiology, its involvement in the development of kidney injury during SARS-CoV-2 infection, renal manifestations and therapeutic options. The latter includes exogenous administration of Ang (1-7) as an appealing option, given the high incidence of AKI in this ACE2-depleted disorder, and the benefits of ACE2/Ang1-7 including vasodilation, diuresis, natriuresis, attenuation of inflammation, oxidative stress, cell proliferation, apoptosis and coagulation.

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Severe leptospirosis complicated with multiorgan dysfunction successfully managed with plasma exchange: a case report

Journal of Medical Case Reports ◽

10.1186/s13256-021-03135-3 ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Manana Dewage Sankani Vishvara Kularathna ◽

Senanayake Abeysinghe Mudiyanselage Kularatne ◽

Manoji Pathirage ◽

Pala Thanthirige Madhushi Anuradha Nanayakkara

Keyword(s):

Plasma Exchange ◽

Multiorgan Failure ◽

Kidney Injury ◽

Severe Illness ◽

High Morbidity ◽

Dramatic Improvement ◽

Severe Thrombocytopenia ◽

Sri Lankan ◽

Life Saving ◽

Severe Leptospirosis

Abstract Background Leptospirosis is a common zoonotic infection caused by the spirochete Leptospira. The disease is more prevalent in the tropics, causing subclinical to severe illness leading to high morbidity and mortality. Case presentation A 77-year-old healthy Sri Lankan man presented to the Teaching Hospital Peradeniya with severe leptospirosis complicated with acute kidney injury, pulmonary hemorrhages, myocarditis, and severe thrombocytopenia. He was deteriorating despite treatment with intravenous antibiotics and methylprednisolone boluses. He made a dramatic improvement with two cycles of plasma exchange. Conclusion Therapeutic plasma exchange is a life-saving treatment modality in severe leptospirosis with multiorgan failure.

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Hallazgos oftalmológicos en enfermedad de Fabry: relación de su severidad en una familia mexicana

Latin american journal of clinical sciences and medical technology ◽

10.34141/ljcs4143209 ◽

2019 ◽

Vol 1 (1) ◽

pp. 43-49

Author(s):

Araceli Borja Borja ◽

Gabriela Salas Pérez ◽

Pablo Radillo Díaz

Keyword(s):

Premature Mortality ◽

Retinal Vessel ◽

Multiple Organ ◽

High Morbidity ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Non Invasive ◽

High Incidence ◽

Cornea Verticillata ◽

Gla Gene

Introduction. Fabry disease (FD) is a lysosomal storage disorder associated with multiple organ dysfunction which eventually leads to high morbidity and premature mortality. Ophthalmologic findings in FD are very common and have been described extensively. We describe the ophthalmologic findings of a family diagnosed with FD at Hospital de Especialidades de Puebla and establish their relationship with other phenotypic findings. Cases Presentation. A renal, cardiac, audiological, neurological, and ophthalmologic evaluation was carried out. The disease was confirmed by GLA gene sequencing. The ophthalmologic assessment was focused on the changes described in the literature, as well as the search for other anomalies possibly related to the disease. All the patients had the c.260delA (P.Glu87Glyfs*34) mutation in the GLA gene. The main ophthalmologic finding in our patients was cornea verticillata (in 100 % of the female patients). Other ophthalmologic manifestations were dry eye, retinal vessel tortuosity, ametropia, chromatic vision disorders, ocular annexes, eyelids, and conjuntiva disorders. Conclusions. Most of the assessed patients showed ophthalmologic changes, consistent with the results described in the literature. A remarkable finding in the sample was the high incidence of changes in women, in whom one would not expect the disease to be as severe because they are heterozygous. Ophthalmologic abnormalities in FD require deeper evaluation to establish their possible use as markers of disease progression and/or enzyme replacement therapy initiation due to the benefit of the non-invasive nature of ophthalmologic evaluations.

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AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

Scientific Reports ◽

10.1038/s41598-019-55550-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Yongjun Zhu ◽

Hongwang Cui ◽

Jie Lv ◽

Haiqin Liang ◽

Yanping Zheng ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Injury ◽

Critical Role ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Tubular Cell ◽

Tubular Damage ◽

Renal Tubular Cell ◽

Ang Ii ◽

Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

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JOINT ESTIMATION OF THE TRANSMISSIBILITY AND SEVERITY OF EBOLA VIRUS DISEASE IN REAL TIME

Journal of Biological System ◽

10.1142/s0218339017400022 ◽

2017 ◽

Vol 25 (04) ◽

pp. 587-603 ◽

Cited By ~ 2

Author(s):

YUSUKE ASAI ◽

HIROSHI NISHIURA

Keyword(s):

Real Time ◽

Ebola Virus ◽

Virus Disease ◽

Critical Role ◽

Estimation Method ◽

Case Fatality ◽

Ascertainment Bias ◽

Joint Estimation ◽

Ebola Virus Disease ◽

Strong Impact

The effective reproduction number [Formula: see text], the average number of secondary cases that are generated by a single primary case at calendar time [Formula: see text], plays a critical role in interpreting the temporal transmission dynamics of an infectious disease epidemic, while the case fatality risk (CFR) is an indispensable measure of the severity of disease. In many instances, [Formula: see text] is estimated using the reported number of cases (i.e., the incidence data), but such report often does not arrive on time, and moreover, the rate of diagnosis could change as a function of time, especially if we handle diseases that involve substantial number of asymptomatic and mild infections and large outbreaks that go beyond the local capacity of reporting. In addition, CFR is well known to be prone to ascertainment bias, often erroneously overestimated. In this paper, we propose a joint estimation method of [Formula: see text] and CFR of Ebola virus disease (EVD), analyzing the early epidemic data of EVD from March to October 2014 and addressing the ascertainment bias in real time. To assess the reliability of the proposed method, coverage probabilities were computed. When ascertainment effort plays a role in interpreting the epidemiological dynamics, it is useful to analyze not only reported (confirmed or suspected) cases, but also the temporal distribution of deceased individuals to avoid any strong impact of time dependent changes in diagnosis and reporting.

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Combined Renal-Pulmonary Extracorporeal Support with Low Blood Flow Techniques: A Retrospective Observational Study (CICERO Study)

Blood Purification ◽

10.1159/000517280 ◽

2021 ◽

pp. 1-10

Author(s):

Guglielmo Consales ◽

Lucia Zamidei ◽

Franco Turani ◽

Diego Atzeni ◽

Paolo Isoni ◽

...

Keyword(s):

Mechanical Ventilation ◽

Observational Study ◽

Multiorgan Failure ◽

Invasive Mechanical Ventilation ◽

Respiratory Acidosis ◽

Kidney Injury ◽

Protective Ventilation ◽

Retrospective Observational Study ◽

Organ Support ◽

Chronic Obstructive

Background: Critically ill patients with acute respiratory failure frequently present concomitant lung and kidney injury, within a multiorgan failure condition due to local and systemic mediators. To face this issue, extracorporeal carbon dioxide removal (ECCO2R) systems have been integrated into continuous renal replacement therapy (CRRT) platforms to provide a combined organ support, with efficient clearance of CO2 with very low extracorporeal blood flows (<400 mL/min). Objectives: To evaluate efficacy and safety of combined ECCO2R-CRRT support with PrismaLung®-Prismaflex® in patients affected by hypercapnic respiratory acidosis associated with AKI in a second level intensive care unit. Methods: We carried out a retrospective observational study enrolling patients submitted to PrismaLung®-Prismaflex® due to mild to moderate acute respiratory distress syndrome (ARDS) or acute exacerbation of chronic obstructive pulmonary disease (aeCOPD). The primary endpoints were the shift to protective ventilation and extubation of mechanically ventilated patients and the shift to invasive mechanical ventilation of patients receiving noninvasive ventilation (NIV). Clinical-laboratoristic data and operational characteristics of ECCO2R-CRRT were recorded. Results: Overall, 12/17 patients on mechanical ventilation shifted to protective ventilation, CO2 clearance was satisfactorily maintained during the whole observational period, and pH was rapidly corrected. Treatment prevented NIV failure in 4 out of 5 patients. No treatment-related complications were recorded. Conclusion: ECCO2R-CRRT was effective and safe in patients with aeCOPD and ARDS associated with AKI.

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Targeting novel LSD1-dependent ACE2 demethylation domains inhibits SARS-CoV-2 replication

Cell Discovery ◽

10.1038/s41421-021-00279-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Wen Juan Tu ◽

Robert D. McCuaig ◽

Michelle Melino ◽

Daniel J. Rawle ◽

Thuy T. Le ◽

...

Keyword(s):

Viral Replication ◽

Treatment Options ◽

Critical Role ◽

Post Exposure Prophylaxis ◽

Nuclear Entry ◽

Importin Α ◽

Active Transcription ◽

Nuclear Shuttling ◽

Asymptomatic Phase ◽

Exposure Prophylaxis

AbstractTreatment options for COVID-19 remain limited, especially during the early or asymptomatic phase. Here, we report a novel SARS-CoV-2 viral replication mechanism mediated by interactions between ACE2 and the epigenetic eraser enzyme LSD1, and its interplay with the nuclear shuttling importin pathway. Recent studies have shown a critical role for the importin pathway in SARS-CoV-2 infection, and many RNA viruses hijack this axis to re-direct host cell transcription. LSD1 colocalized with ACE2 at the cell surface to maintain demethylated SARS-CoV-2 spike receptor-binding domain lysine 31 to promote virus–ACE2 interactions. Two newly developed peptide inhibitors competitively inhibited virus–ACE2 interactions, and demethylase access to significantly inhibit viral replication. Similar to some other predominantly plasma membrane proteins, ACE2 had a novel nuclear function: its cytoplasmic domain harbors a nuclear shuttling domain, which when demethylated by LSD1 promoted importin-α-dependent nuclear ACE2 entry following infection to regulate active transcription. A novel, cell permeable ACE2 peptide inhibitor prevented ACE2 nuclear entry, significantly inhibiting viral replication in SARS-CoV-2-infected cell lines, outperforming other LSD1 inhibitors. These data raise the prospect of post-exposure prophylaxis for SARS-CoV-2, either through repurposed LSD1 inhibitors or new, nuclear-specific ACE2 inhibitors.

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Long non-coding RNA SNHG14 aggravates LPS-induced acute kidney injury through regulating miR-495-3p/HIPK1

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab034 ◽

2021 ◽

Author(s):

Ni Yang ◽

Hai Wang ◽

Li Zhang ◽

Junhua Lv ◽

Zequn Niu ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Kidney Injury ◽

Inflammatory Cytokine ◽

Cytokine Production ◽

Kidney Injury ◽

Interaction Network ◽

High Morbidity ◽

Abrupt Decrease ◽

Inflammatory Cytokine Production ◽

Non Coding Rna

Abstract Acute kidney injury (AKI) is a complex syndrome with an abrupt decrease of kidney function, which is associated with high morbidity and mortality. Sepsis is the common cause of AKI. Mounting evidence has demonstrated that long non-coding RNAs (lncRNAs) play critical roles in the development and progression of sepsis-induced AKI. In this study, we aimed to illustrate the function and mechanism of lncRNA SNHG14 in lipopolysaccharide (LPS)-induced AKI. We found that SNHG14 was highly expressed in the plasma of sepsis patients with AKI. SNHG14 inhibited cell proliferation and autophagy and promoted cell apoptosis and inflammatory cytokine production in LPS-stimulated HK-2 cells. Functionally, SNHG14 acted as a competing endogenous RNA (ceRNA) to negatively regulate miR-495-3p expression in HK-2 cells. Furthermore, we identified that HIPK1 is a direct target of miR-495-3p in HK-2 cells. We also revealed that the SNHG14/miR-495-3p/HIPK1 interaction network regulated HK-2 cell proliferation, apoptosis, autophagy, and inflammatory cytokine production upon LPS stimulation. In addition, we demonstrated that the SNHG14/miR-495-3p/HIPK1 interaction network regulated the production of inflammatory cytokines (TNF-α, IL-6, and IL-1β) via modulating NF-κB/p65 signaling in LPS-challenged HK-2 cells. In conclusion, our findings suggested a novel therapeutic axis of SNHG14/miR-495-3p/HIPK1 to treat sepsis-induced AKI.

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Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽

10.3390/biomedicines9050457 ◽

2021 ◽

Vol 9 (5) ◽

pp. 457

Author(s):

Kyeong-Seok Kim ◽

Jin-Sol Lee ◽

Jae-Hyeon Park ◽

Eun-Young Lee ◽

Jong-Seok Moon ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Early Stage ◽

Kidney Injury ◽

Diabetic Patients ◽

High Morbidity ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Zucker Diabetic Fatty Rats ◽

Kidney Injury Molecule 1 ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

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Outcome of Acute Peritoneal Dialysis in Northern Tanzania

Peritoneal Dialysis International ◽

10.3747/pdi.2012.00083 ◽

2012 ◽

Vol 32 (3) ◽

pp. 261-266 ◽

Cited By ~ 45

Author(s):

Kajiru Gad Kilonzo ◽

Sudakshina Ghosh ◽

Siya Anaeli Temu ◽

Venance Maro ◽

John Callegari ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Patient Outcomes ◽

Kidney Injury ◽

Cost Effective ◽

High Morbidity ◽

Poor Countries ◽

Resource Limited ◽

Northern Tanzania ◽

Nephrology Care ◽

Technical Simplicity

Data on the burden of acute kidney injury (AKI) in resource-poor countries such as Tanzania are minimal because of a lack of nephrology services and an inability to recognize and diagnose AKI with any certainty. In the few published studies, high morbidity and mortality are reported. Improved nephrology care and dialysis may lower the mortality from AKI in these settings. Hemodialysis is expensive and technically challenging in resource-limited settings. The technical simplicity of peritoneal dialysis and the potential to reduce costs if consumables can be made locally, present an opportunity to establish cost-effective programs for managing AKI. Here, we document patient outcomes in a pilot peritoneal dialysis program established in 2009 at a referral hospital in Northern Tanzania.

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Propofol Attenuated Acute Kidney Injury after Orthotopic Liver Transplantation via Inhibiting Gap Junction Composed of Connexin 32

Anesthesiology ◽

10.1097/aln.0000000000000448 ◽

2015 ◽

Vol 122 (1) ◽

pp. 72-86 ◽

Cited By ~ 38

Author(s):

Chenfang Luo ◽

Dongdong Yuan ◽

Xiaoyun Li ◽

Weifeng Yao ◽

Gangjian Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Transplantation ◽

Acute Kidney Injury ◽

Gap Junction ◽

Orthotopic Liver Transplantation ◽

Critical Role ◽

Kidney Injury ◽

Cellular Injury ◽

Knock Down ◽

Hypoxia Reoxygenation

Abstract Background: Postliver transplantation acute kidney injury (AKI) severely affects patient survival, whereas the mechanism is unclear and effective therapy is lacking. The authors postulated that reperfusion induced enhancement of connexin32 (Cx32) gap junction plays a critical role in mediating postliver transplantation AKI and that pretreatment/precondition with the anesthetic propofol, known to inhibit gap junction, can confer effective protection. Methods: Male Sprague–Dawley rats underwent autologous orthotopic liver transplantation (AOLT) in the absence or presence of treatments with the selective Cx32 inhibitor, 2-aminoethoxydiphenyl borate or propofol (50 mg/kg) (n = 8 per group). Also, kidney tubular epithelial (NRK-52E) cells were subjected to hypoxia–reoxygenation and the function of Cx32 was manipulated by three distinct mechanisms: cell culture in different density; pretreatment with Cx32 inhibitors or enhancer; Cx32 gene knock-down (n = 4 to 5). Results: AOLT resulted in significant increases of renal Cx32 protein expression and gap junction, which were coincident with increases in oxidative stress and impairment in renal function and tissue injury as compared to sham group. Similarly, hypoxia–reoxygenation resulted in significant cellular injury manifested as reduced cell growth and increased lactate dehydrogenase release, which was significantly attenuated by Cx32 gene knock-down but exacerbated by Cx32 enhancement. Propofol inhibited Cx32 function and attenuated post-AOLT AKI. In NRK-52E cells, propofol reduced posthypoxic reactive oxygen species production and attenuated cellular injury, and the cellular protective effects of propofol were reinforced by Cx32 inhibition but cancelled by Cx32 enhancement. Conclusion: Cx32 plays a critical role in AOLT-induced AKI and that inhibition of Cx32 function may represent a new and major mechanism whereby propofol reduces oxidative stress and subsequently attenuates post-AOLT AKI.

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