|Year : 2020 | Volume
| Issue : 2 | Page : 21-23
Angiotensin-converting enzyme 2 – A boon or a bane? Gastrointestinal and renal involvement in COVID-19
Editor JRNM, Professor; Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||18-Aug-2020|
|Date of Acceptance||19-Aug-2020|
|Date of Web Publication||01-Sep-2020|
Dr. Anita Saxena
Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Saxena A. Angiotensin-converting enzyme 2 – A boon or a bane? Gastrointestinal and renal involvement in COVID-19. J Renal Nutr Metab 2020;6:21-3
|How to cite this URL:|
Saxena A. Angiotensin-converting enzyme 2 – A boon or a bane? Gastrointestinal and renal involvement in COVID-19. J Renal Nutr Metab [serial online] 2020 [cited 2021 Apr 15];6:21-3. Available from: http://www.jrnm.in/text.asp?2020/6/2/21/294188
Angiotensin-converting enzyme 2 (ACE2) – a boon or a bane? What an irony! The primary physiological role and architecture of ACE2 is in the maturation of angiotensin, a peptide hormone that controls vasoconstriction and blood pressure. Heart (circulatory system) is vital to life, and decreased expression of ACE2 triggers cardiovascular diseases. Hence, Mother Nature has ensured ample presence of ACE2, a type I membrane protein expressed in all the vital organs of the body: the lungs, the heart, the arteries, the kidneys, and the intestines. But, what happens when it is taken over by a virus? The smile of a healthy body changes to sneezing, coughing, hypoxemic, hyperthermic because of failing thermoregulation, anorexic, and a happy gut takes to diarrhea.
Emerging data on novel coronavirus disease 2019 (COVID-19) suggest a significant prevalence of gastrointestinal (GI) involvement. GI involvement may be with digestive symptoms (pure GI form of COVID-19 infection) as the chief complaint alone or antedating respiratory symptoms, which delays the diagnosis of the viral insult. Data suggest that digestive symptoms are correlated with worse clinical outcomes compared with patients without digestive symptoms. The first GI manifestations were reported from the USA, a case which presented with cough, nausea, and vomiting followed by diarrhea 2 days later. The fecal specimen was positive on the 7th day which alarmed the medical fraternity that GI tract could be a potential route of virus spread. In the early stage of the pandemic, only 3%–3.8% cases of diarrhea and 5% cases of nausea and/or vomiting were reported, but later, studies cited as high as 79% of cases having digestive symptoms.,, GI symptomatology ranges from 5% to 50%, and 31.9% of patients experience concurrent GI symptoms before presentation. Elevations in aminotransferase enzyme levels (AST) and decreased serum albumin levels, indicative of liver injury, correlate with the severity of disease., Of the many potential causes for elevated AST levels, hypoxic hepatitis from respiratory compromise or drug-induced hepatocyte injury from COVID-19 treatments is a prominent manifestation.
As SARS-CoV-2 replicates, it causes symptoms in the GI tract such as nausea/vomiting (12.0%), diarrhea, abdominal pain, and loss of appetite (22.3%), symptoms which are very often descriptive of chronic kidney disease? The prevalence of mild-to-severe digestive symptoms, reported in more than one-third of the patients, is higher in those in the intensive care unit, and patients experiencing any digestive symptoms have >4-fold higher odds for hospitalization. Diarrhea (onset 1–8 days after the onset of the COVID-19) is associated with a 7-fold higher likelihood for hospitalization and nausea or vomiting has four times higher odds (adjusted odds ratio: 4.39, 95% confidence interval: 1.61–11.4, P = 0.005)., Even the prevalence of acute renal insult was observed to be higher in patients with digestive symptoms than those without digestive symptoms (9.3% vs. 3.1%).,
The pathogenesis for GI involvement related to SARS-CoV-2 is not clearly elucidated. A crucial cellular receptor in the SARS-CoV-2 lifecycle, ACE 2, is expressed throughout the GI tract, especially in the small and large intestines,, and might play a role in worsening digestive symptoms as COVID-19 progresses and also provide a basis for its possible transmission route through the feces.
The virus enters into the host by binding the viral trimeric spike S protein to the human receptor ACE2, which (glycoprotein S) is then cleaved into two subunits: S1 containing the receptor-binding domain, which directly binds to the peptidase domain of ACE2, and S2 subunits, which are involved in membrane fusion. When S1 binds to the host receptor ACE2, another cleavage site on S2 is exposed and is cleaved by host proteases, a process that is critical for viral infection.,,,,,,, Involvement of pancreatic islets is associated with higher incidence of anorexia and diarrhea and more severe illness on admission, and the probable explanations for its severity include that ACE-2 receptors on pancreatic islets cause acute diabetes, cytokine storm, and/or drug-induced pancreatic injury. How strongly are digestive symptoms suggestive of higher levels of viremia is unknown.,,,,,, Studies recommend that broad-spectrum antibiotics are best avoided in the treatment of COVID-19, as these might cause antibiotic-induced diarrhea. Most of the patients who get severe and stubborn diarrhea are on anti-virals such as oseltamivir and abidol. It is an established fact that intestinal microbiota plays an important role in maintaining human health. If metabolites of intestinal flora can be useful for the treatment of virus, then use of probiotics would be beneficial in maintaining intestinal micro-ecological balance and be a preventive strategy for bacterial secondary infection in COVID-19.
The link between diarrhea and COVID-19 may be underestimated  (digestive symptoms appear to be related to worse outcomes). Data suggest that 60% of patients without digestive symptoms recovered completely but only 34.3% of the patients with digestive symptoms recovered.
GI symptoms are managed according to routine practice. Diarrhea, whether viral, immune, and antibiotic associated or due to dysbiosis, is usually self-limiting. Proper hydration and electrolyte balance should be maintained. Studies support the use of routine antidiarrheal agents such as loperamide to mitigate the symptoms. Probiotics can be prescribed for dysbiosis and antispasmodics can be added for abdominal pain. Evidence supports the fact that SARS-CoV-2 viral particles are viable in environmental conditions that could facilitate fecal–oral transmission. Extended duration of fecal viral shedding for up to 5 weeks after the patients' respiratory specimens tested negative for SARS-CoV-2 RNA has been reported. Targeting gut dysbiosis may help to control the pathogenesis of COVID-19. High viral load in the stool, its stability on regular surfaces, and generation of toilet fumes make the virus a formidable agent for human-to-human spread. The importance of frequent and proper hand hygiene, therefore, should be emphasized with ample precautions for those involved in GI endoscopic procedures.
Along with GI tract involvement, the kidneys (diseased or healthy) also get involved in COVID-19, which complicates management. A meta-analysis has proven beyond doubt that CKD is associated with enhanced risk of severe novel COVID-19, which calls for extra precaution in these patients to minimize the risk of exposure to the virus. Individuals infected with SARS-CoV-2 seem to be affected by acute kidney injury (AKI), a sudden reduction in kidney function, more because of the increased affinity of SARS-CoV-2 for ACE2, explaining its higher renal tropism.,,, ACE2 are expressed by proximal tubules and podocytes, and coronavirus uses ACE2 as a host receptor for cell surface binding; therefore, kidneys are a conceivably targeted victim for SARS-CoV-2. AKI can occur at all stages of COVID-19 infection, which calls for clinical vigilance and consideration of risk factors for AKI. Chronic kidney disease is a chronic inflammatory condition, with higher susceptibility to bacterial and viral infections. The diverse manifestations of the CoV-2 disease are due to the direct effects of the virus or inflammatory mediators, especially interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha. The incidence of AKI, proteinuria, and hematuria is >10%, 40%, and 26%, respectively. NICE practice guidelines recommend “AKI associated with COVID-19 may be caused by volume depletion, multi-organ failure, viral infection leading directly to kidney tubular injury, thrombotic vascular processes, glomerulonephritis, or rhabdomyolysis. Fever and increased respiratory rate increase insensible fluid loss, dehydration (often needing correction with intravenous fluids) which are common on admission to hospital and this may also develop later increase the risk of coagulopathys.”
Hypoperfusion causes microcirculatory dysfunction, which ultimately leads to multiorgan failure. Hypoperfusion causes increased serum lactate levels, which is accompanied by low blood pressure, oliguria, reduced cardiac output, and hepatic dysfunction in patients with sepsis. Moreover, due to known changes in the glycocalyx structure and hyperpermeability of vasculature in sepsis, the administered fluid is rapidly redistributed into an extravascular compartment.,,,
Clinical evidence suggests that increase in intravascular volume after fluid bolus therapy may confer fleeting improvement in hemodynamic parameters such as cardiac output. Evidence now suggests that that cerebral, cardiac, renal, and hepatic dysfunction in sepsis is largely caused by bioenergetic failure rather than microcirculatory dysfunction and impaired organ perfusion. Bioenergetic failure in human sepsis, which is related to endocrine, metabolic, and mitochondrial dysfunction, is a major determinant of defective host immune responses, which increases disease severity and risk of death. A septic heart responds poorly to fluid loading, and aggressive fluid administration may impair the cardiac function.,,,,,,,,,,,
A study conducted by Marik et al. has shown that patients with septic shock demonstrated a minimal increase in end-diastolic volume and stroke volume following a fluid challenge. Due to alterations in ventricular compliance, large volume fluid resuscitation will cause large increases in filling pressures, leading to pulmonary edema (high left atrial pressure) and increased hepatic and renal venous pressures (high right atrial pressure) with consequent organ dysfunction.
Because metabolic syndrome and kidney disease have a lot in common, it is worth mentioning that there are reports suggesting that an excess adiposity (higher body mass index) carries a potential risk for complications arising from COVID-19 infection as obese people do have higher prevalence of pulmonary problems because of restrictive lung ventilatory defect. Obesity is a multifactorial disorder, which is usually accompanied by clinical conditions such as diabetes and hypertension; it predisposes to increased activity of pro-inflammatory cytokines, creating a state of chronic immune deregulation which interferes with immune homeostasis and weakens immune response. Patients with obesity and comorbidities that compromise their heart or lung function are likely at higher risk for developing severe diseases with COVID-19. Maintaining a body weight and composition in line with recommendations for stature and gender is prudent. However, data on the role of obesity on COVID-19 risk and prognosis are still confusing and hard to interpret.
This issue of JRNM brings you an update on the impact of COVID-19 on the health-care system, peritoneal dialysis practice, impact of COVID-19 on care of patients with chronic kidney disease and renal transplant recipients, effect of the lockdown on patient care during the COVID-19 pandemic, and nephrology teaching in the Indian setting. The classroom reading section brings to you solutions from nature for boosting immunity. The Society of Renal Nutrition and Metabolism (India) is happy to announce its 5th annual conference (fully virtual) being hosted by Sir Ganga Ram Hospital, New Delhi, from September 5–6, 2020. All are welcome. There are no registration fees in view of the exceptional circumstances of the COVID pandemic.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest
| References|| |
Hamming I, Cooper ME, Haagmans BL, Hooper NM. Korstanje AD, Osterhaus R, et al
. The emerging role of ACE2 in physiology and disease. J Pathol 2007;212:1-11.
Cholankeril G, Podboy A, Aivaliotis VI, Tarlow B, Pham EA, Spencer S, et al
. High prevalence of concurrent gastrointestinal manifestations in patients with severe acute respiratory syndrome coronavirus 2: Early experience from California. Gastroenterology 2020;159:775-7.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Guan WJ, Ni ZY, Hu Y, Wen-Hua Liang WH, Ou CQ, He JX, et al
. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
Cholankeril G, Podboy A, Irene AV, Edward AP, Sean PS, Kim D, et al.
Association of digestive symptoms and hospitalization in patients with SARS-CoV-2 infection. Am J Gastroenterol 2020;7:1129-32.
Wei-Jie G, Zheng-Yi N, Yu H, Wen-Hua L, Chun-Quan O, Jian-Xing H, et al
. Clinical characteristics of coronavirus disease 2019. China N Engl J Med 2020;382:1708-20.
Sultan S, Altayar O, Siddique SM, Davitkov P, Feuerstein JD, Lim JK, et al
. AGA institute rapid review of the gastrointestinal and liver manifestations of COVID-19, meta-analysis of international data, and recommendations for the consultative anagement of patients with COVID-19. Gastroenterology 2020;159:320-34E+29.
Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al
. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster. Lancet 2020;395:514-23.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al
. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420-2.
Cholankeril G, Podboy A, Aivaliotis VI, Tarlow B, Pham EA, Spencer SP, et al.
High prevalence of concurrent gastrointestinal manifestations in patients with severe acute respiratory syndrome coronavirus 2: early experience from California Gastroenterology. 2020;159:775-7.
Trottein F, Sokol H. Potential causes and consequences of gastrointestinal disorders during a SARS-CoV infection. Cell Rep 2020;32:21.
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-8.
Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J, Li P, Hu B, Wang J, Hu C, et al.
Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: A descriptive, cross-sectional, multicenter study. Am J Gastroenterol 2020;115:766.
Wang F, Wang H, Fan J, Zhang Y, Wang H, Zhao Q. Pancreatic injury patterns in patients with COVID-19 pneumonia. Gastroenterology. 2020;159:367-70.
Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J, et al
. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: A descriptive, cross-sectional, multicenter study. Am J Gastroenterol 2020;115:766-73.
Capuano I, Buonanno P, Eleonora Riccio C, Pisani A. Acute kidney injury in COVID-19. Pandemic Nephron Clin Pract. 2020:1-2.
Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 2005;309:1864-8.
Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U.S.A 2009;106:5871-6.
Selby NM, Forni LG, Laing CM, Horne KL, Evans RD, Lucas BJ, et al
. Covid-19 and acute kidney injury in hospital: Summary of NICE guidelines. BMJ 2020;369:m1963.
Theodore Rokkas Gastrointestinal involvement in COVID-19: A systematic review and meta-analysis. Ann Gastroenterol 2020;33:355-65.
Samanta J, Dhar J, Gao QY, Chen YX, Fang JY.2019 novel coronavirus infection: Gastrointestinal manifestations. J Digestive Endoscopy 2020;11:13-8.
Liang W, Feng Z, Rao S, Xiao C, Xue X, Lin Z, et al
. Diarrhoea may be underestimated: A missing link in 2019 novel coronavirus. Gut 2020;69:1141-3.
Millet JK, Whittaker GR. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res 2015;202:120-34.
Marik PE, Byrne L, van Haren F. Fluid resuscitation in sepsis: The great 30 mL per kg hoax. J Thorac Dis 2020;12:S37-47.
Xu J, Chu M, Zhong F, Tan X, Tang G, Mai J, Lai N, et al
. Digestive symptoms of COVID-19 and expression of ACE2 in digestive tract organs. Cell Death Dis 2020;6:76.
Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U.S.A 2005;102:11876-81.