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A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19.
Malek Mahdavi, A
Reviews in medical virology. 2020;(5):e2119
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Abstract
The novel coronavirus disease 2019 (COVID-19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2), a part of the renin-angiotensin system (RAS), serves as the major entry point into cells for SARS-CoV-2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat-soluble-vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang-(1-7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang-(1-7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down-regulation with vitamin D in SARS-CoV-2 infection is a potential therapeutic approach to combat COVID-19 and induced ARDS.
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Hyperkalemia Associated with Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blockers in Chronic Kidney Disease.
Oktaviono, YH, Kusumawardhani, N
Acta medica Indonesiana. 2020;(1):74-79
Abstract
Inhibition of the renin-angiotensin-aldosterone system (RAAS) is a key strategy in treating hypertension in cardiovascular and renal diseases. However, RAAS inhibitors (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, and direct renin inhibitors) increase the risk of hyperkalemia (serum potassium >5.5 mmol/L). This poses a therapeutic challenge because these patient groups comprise in whom the drugs are therapeutically indicated. Important considerations when initiating ACEI or ARB therapy include obtaining an estimate of glomerular filtration rate and a baseline serum potassium concentration, as well as assessing whether the patient has excessive potassium intake from diet, supplements, or drugs that can also increase serum potassium. Serum potassium monitoring shortly after initiation of therapy can assist in preventing hyperkalemia. If hyperkalemia does develop, prompt recognition of cardiac dysrhythmias and effective treatment to antagonize the cardiac effects of potassium, redistribute potassium into cells, and remove excess potassium from the body is important. Understanding the mechanism of action and monitoring of ACEI and ARB coupled with judicious drug use and clinical vigilance can minimize the risk to the patient of developing hyperkalemia.
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Diabetes and COVID-19: evidence, current status and unanswered research questions.
Gupta, R, Hussain, A, Misra, A
European journal of clinical nutrition. 2020;(6):864-870
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Abstract
Patients with diabetes who get coronavirus disease 2019 (COVID-19) are at risk of a severe disease course and mortality. Several factors especially the impaired immune response, heightened inflammatory response and hypercoagulable state contribute to the increased disease severity. However, there are many contentious issues about which the evidence is rather limited. There are some theoretical concerns about the effects of different anti-hyperglycaemic drugs. Similarly, despite the recognition of angiotensin converting enzyme 2 (ACE2) as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), and the role of ACE2 in lung injury; there are conflicting results with the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in these patients. Management of patients with diabetes in times of restrictions on mobility poses some challenges and novel approaches like telemedicine can be useful. There is a need to further study the natural course of COVID-19 in patients with diabetes and to understand the individual, regional and ethnic variations in disease prevalence and course.
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ACE inhibitor-mediated angioedema.
Montinaro, V, Cicardi, M
International immunopharmacology. 2020;:106081
Abstract
Angioedema (AE) occurring during ACE inhibitor therapy (ACEi-AE) is a rare complication involving between 0.1 and 0.7% of treated patients. AE can also complicate other therapeutic regimens that block the renin-angiotensin aldosterone system. Other drugs, such as immune suppressors, some type of antidiabetics or calcium antagonists, can increase the likelihood of ACEi-AE when associated to ACEi. There is a clear ethnic predisposition, since African-Americans or Hispanics show a higher prevalence of this condition compared to Caucasians. At least in African-Americans the genetic predisposition accounts for a general higher prevalence of AE, independently from the cause. People that experience ACEi-AE may have some recurrence when they are switched to an angiotensin-receptor blocker (ARB); however, epidemiological studies on large cohorts have shown that angiotensin receptor blockers (ARB) do not increase the likelihood of AE compared to other antihypertensives. Clinical manifestations consist of edema of face, lips, tongue, uvula and upper airways, requiring intubation or tracheotomy in severe cases. Attacks last for 48-72 h and require hospital admission in most cases. Intestinal involvement with sub-occlusive symptoms has also been reported. The pathogenesis of ACEi-AE depends mainly on a reduced catabolism and accumulation of bradykinin, which is normally metabolized by ACE. Genetic studies have shown that some single nucleotide polymorphisms at genes encoding relevant molecules for bradykinin metabolism and action may be involved in ACEi-AE, giving a basis for the ethnic predisposition. Treatment of ACEi-AE is still a matter of debate. Corticosteroids and antihistamines do not show efficacy. Some therapeutic attempts have shown some efficacy for fresh frozen plasma or C1 inhibitor concentrate infusion. Interventional studies with the specific bradykinin receptor antagonist icatibant have shown conflicting results; there might be a different ethnic predisposition to icatibant efficacy which has been proven in caucasian but not in black patients.
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Managing Hypertension Using Combination Therapy.
Smith, DK, Lennon, RP, Carlsgaard, PB
American family physician. 2020;(6):341-349
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Abstract
More than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents, either initially as combination therapy or as add-on therapy if monotherapy and lifestyle modifications do not achieve adequate blood pressure control. Four main classes of medications are used in combination therapy for the treatment of hypertension: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). ACEIs and ARBs should not be used simultaneously. In black patients, at least one agent should be a thiazide diuretic or a calcium channel blocker. Patients with heart failure with reduced ejection fraction should be treated initially with a beta blocker and an ACEI or ARB (or an angiotensin receptor-neprilysin inhibitor), followed by add-on therapy with a mineralocorticoid receptor antagonist and a diuretic based on volume status. Treatment for patients with chronic kidney disease and proteinuria should include an ACEI or ARB plus a thiazide diuretic or a calcium channel blocker. Patients with diabetes mellitus should be treated similarly to those without diabetes unless proteinuria is present, in which case combination therapy should include an ACEI or ARB.
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Coronavirus Disease 2019 and Hypertension: The Role of Angiotensin-Converting Enzyme 2 and the Renin-Angiotensin System.
Edmonston, DL, South, AM, Sparks, MA, Cohen, JB
Advances in chronic kidney disease. 2020;(5):404-411
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Abstract
Hypertension emerged from early reports as a potential risk factor for worse outcomes for persons with coronavirus disease 2019 (COVID-19). Among the putative links between hypertension and COVID-19 is a key counter-regulatory component of the renin-angiotensin system (RAS): angiotensin-converting enzyme 2 (ACE2). ACE2 facilitates entry of severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, into host cells. Because RAS inhibitors have been suggested to increase ACE2 expression, health-care providers and patients have grappled with the decision of whether to discontinue these medications during the COVID-19 pandemic. However, experimental models of analogous viral pneumonias suggest RAS inhibitors may exert protective effects against acute lung injury. We review how RAS and ACE2 biology may affect outcomes in COVID-19 through pulmonary and other systemic effects. In addition, we briefly detail the data for and against continuation of RAS inhibitors in persons with COVID-19 and summarize the current consensus recommendations from select specialty organizations.
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Medical Management of Heart Failure With Reduced Ejection Fraction in Patients With Advanced Renal Disease.
Hein, AM, Scialla, JJ, Edmonston, D, Cooper, LB, DeVore, AD, Mentz, RJ
JACC. Heart failure. 2019;(5):371-382
Abstract
Large randomized clinical trials (RCT) supporting guidelines for the management of heart failure with reduced ejection fraction (HFrEF) have typically excluded patients with advanced chronic kidney disease (CKD). Patients with concomitant advanced CKD and HFrEF experience poor cardiovascular outcomes and mortality relative to either disease in isolation and have been shown to consistently receive lower rates of HFrEF guideline-directed medical therapy (GDMT). This review evaluated recent evidence for the use of GDMT in patients with HFrEF and advanced CKD approaching dialysis from RCTs and observational cohorts. The authors also discuss the limitations and challenges inherent in the evidence for GDMT in this population, and offer guidance to clinicians for proper clinical use and future research directions.
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Sickle Cell Nephropathy in the Pediatric Population.
Olaniran, KO, Eneanya, ND, Nigwekar, SU, Vela-Parada, XF, Achebe, MM, Sharma, A, Thadhani, RI
Blood purification. 2019;(1-3):205-213
Abstract
BACKGROUND Compared to the past, patients with sickle cell disease (SCD) currently live longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD. In particular, sickle cell nephropathy (SCN) is associated with significant morbidity and mortality across all age groups. Furthermore, SCN is an understudied condition with relatively few symptoms and therefore requires close surveillance. In this review, we sought to explore the epidemiology, natural history, and treatment options for SCN with an emphasis on the pediatric population. SUMMARY SCN invariably begins in childhood with evidence of structural changes detected as early as infancy. These indolent changes can progress undetected to advanced chronic kidney disease by late adolescence or early adulthood. The risk factors for progression are not well defined, but significant albuminuria (which is also the most common presentation in childhood) is a key factor in progression. One of the main challenges in understanding SCN in children is the poor correlation between estimated and measured glomerular filtration rates. Another challenge is the lack of large-scale longitudinal studies that track the clinical outcomes of pediatric patients over time. Several studies aim to identify early biomarkers of SCN in children, as albuminuria presents only following significant chronic damage. The utility of angiotensin converting enzyme inhibitors and hydroxyurea in treating albuminuria is addressed here as well as novel treatments that may be of benefit.
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The Preventive Role of Angiotensin Converting Enzyme Inhibitors/Angiotensin-II Receptor Blockers and β-Adrenergic Blockers in Anthracycline- and Trastuzumab-Induced Cardiotoxicity.
Blanter, JB, Frishman, WH
Cardiology in review. 2019;(5):256-259
Abstract
Anthracycline (doxorubicin) and trastuzumab treatments for cancer patients have been known to cause cardiotoxicity. The current recommendations for prevention of cardiac events from cancer chemotherapies are largely based on opinion. The American Society of Clinical Oncology recommends active screening and prevention of modifiable cardiovascular risk factors. The risk factors are defined as tobacco use, high blood pressure, high cholesterol, alcohol use, obesity, and physical inactivity. Beta-adrenergic blockers and angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) have been the mainstay of treatment for heart failure patients with reduced left ventricular ejection fraction for many years. This review analyzed the use of beta-adrenergic blockers and ACE inhibitors/ARBs as protection against cardiomyopathy caused by anthracyclines and trastuzumab. Although many more studies are warranted, it was concluded that the addition of a beta-blocker early in the treatment of cancer patients who are undergoing anthracycline or trastuzumab treatment can have beneficial effects in preserving left ventricular ejection fraction and preventing chemotherapy-induced cardiotoxicity. The effects are more apparent in the short term. More studies of the long-term effects are warranted, as are the additive effects of using a beta-blocker and ACE inhibitor/ARB together to prevent chemotherapy-induced cardiotoxicity.
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ACE inhibitors and ARBs: Managing potassium and renal function.
Momoniat, T, Ilyas, D, Bhandari, S
Cleveland Clinic journal of medicine. 2019;(9):601-607
Abstract
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are used primarily to treat hypertension and are also useful for conditions such as heart failure and chronic kidney disease, independent of their effect on blood pressure. This article reviews the indications for ACE inhibitors and ARBs and offers advice for managing their adverse effects, particularly declining renal function and hyperkalemia.