Electrolyte Disturbances and Acid-Base Imbalance

Electrolyte disorders are among the most common clinical problems encountered in critically ill patients. Disorders such as severe burns, trauma, sepsis, acute brain injury, and heart failure lead to disturbances in fluid and electrolyte homeostasis through complex mechanisms involving deregulation or activation of hormonal systems and ischemic or nephrotoxic kidney injury. Inappropriate fluid management should also be considered in the differential diagnosis of electrolyte disturbances in patients in intensive care units. Electrolyte imbalances produce both central and peripheral neurologic dysfunction because electrochemical membrane potentials in brain, nerve, and muscle tissues are particularly sensitive to chemical, ionic, and osmolar shifts.

Sex Specific Adaptations to High Salt Diet Preserve Electrolyte Homeostasis with Distinct Sodium Transporter Profiles

Kidneys continuously filter an enormous amount of sodium and adapt kidney Na+ reabsorption to match Na+ intake to maintain circulatory volume and electrolyte homeostasis. Males (M) respond to high salt (HS) diet by translocating proximal tubule Na+/H+ exchanger 3 (NHE3) to the base of the microvilli, reducing activated forms of the distal NaCl cotransporter (NCC) and epithelial Na+ channel (ENaC). Males and females (M, F) on normal salt (NS) diets present sex-specific profiles of "transporters" (co-transporters, channels, pumps and claudins) along the nephron, e.g., F exhibit 40% lower NHE3 and 200% higher NCC abundance vs. M. We tested the hypothesis that adaptations to HS diet along the nephron will, likewise, exhibit sexual dimorphisms. C57BL/6J mice were fed 15 d with 4% NaCl diet (HS) vs. 0.26% NaCl diet (NS). On HS, M and F exhibited normal plasma [Na+] and [K+], and similar urine volume, Na+, K+, and osmolal excretion rates normalized to body weight. In F, like M, HS lowered abundance of distal NCC, phosphorylated NCC, and cleaved (activated) forms of ENaC. The adaptations associated with achieving electrolyte homeostasis exhibit sex-dependent and independent mechanisms: Sex differences in baseline "transporters" abundance persist during HS diet, yet the fold changes during HS diet (normalized to NS) are similar along the distal nephron and collecting duct. Sex dependent differences observed along the proximal tubule during HS show that female kidneys adapt differently from patterns reported in males yet achieve and maintain fluid and electrolyte homeostasis.

The kidney in systemic disease

The kidneys are frequently involved in several systemic conditions, including autoimmune disorders, vasculitides, haematological conditions, malignancy, and disorders of other organ systems. Moreover, drugs used to treat these conditions could have an effect on the kidneys, presenting as acute kidney injury (AKI), electrolyte disorders due to disruption of the absorptive function of the kidneys, or as a form of glomerulonephritis. Due to the high vasculature and volume of blood flow in the kidneys, autoimmune disorders and vasculitides have been reported to cause immune-complex mediated disorders and inflammatory lesions of both glomeruli and tubulointerstitium. Likewise, monoclonal gammopathies have a propensity for the kidneys, with several reported phenotypes causing characteristic renal lesions. Due to the high capacity for glomerular filtration and excretory function, the kidneys are often the insult of disorders of cellular breakdown such as pigment disorders or tumour lysis syndrome, where AKI is common, resulting in a reduced ability for electrolyte homeostasis. Finally, both cardiorenal and hepatorenal syndromes have been well described, highlighting the interdependency of various organ systems and the pathological response of the kidneys to disorders of heart and liver.

The role of the mineralocorticoid receptor and mineralocorticoid-receptor-directed therapies in heart failure

Mineralocorticoid receptor (MR) antagonists (MRA), also referred to as aldosterone blockers, are now well recognised for their clinical benefit in patients with heart failure with reduced ejection fraction (HFrEF). Recent studies have also shown MRA can improve outcomes in patients with ‘HFpEF’, where the ejection fraction is preserved but left ventriclar filling is reduced. While the MR is a steroid hormone receptor best known for anti-natriuretic actions on electrolyte homeostasis in the distal nephron, it is now estalished that the MR has many physiological and pathophysiological roles in the heart, vasculature and other non-epithelial tissue types. It is the impact of MR activation on these tissues that underpins the use of MRA in cardiovascular disease, in particular heart failure. This minireview will discuss the origins and the development of MRA and highlight how their use has evolved from the ‘potassium-sparing diuretics’ spironolactone and canrenone over 60 years ago, to the more receptor-selective eplerenone and most recently the emergence of new non-steroidal receptor antagonists esaxerenone and finerenone.

A primitive type of renin-expressing lymphocyte protects the organism against infections

The hormone renin plays a crucial role in the regulation of blood pressure and fluid-electrolyte homeostasis. Normally, renin is synthesized by juxtaglomerular (JG) cells, a specialized group of myoepithelial cells located near the entrance to the kidney glomeruli. In response to low blood pressure and/or a decrease in extracellular fluid volume (as it occurs during dehydration, hypotension, or septic shock) JG cells respond by releasing renin to the circulation to reestablish homeostasis. Interestingly, renin-expressing cells also exist outside of the kidney, where their function has remained a mystery. We discovered a unique type of renin-expressing B-1 lymphocyte that may have unrecognized roles in defending the organism against infections. These cells synthesize renin, entrap and phagocyte bacteria and control bacterial growth. The ability of renin-bearing lymphocytes to control infections—which is enhanced by the presence of renin—adds a novel, previously unsuspected dimension to the defense role of renin-expressing cells, linking the endocrine control of circulatory homeostasis with the immune control of infections to ensure survival.

Fluid, pH and electrolyte imbalance associated with COVID-19 mortality

The threat of COVID-19 has harried the world since early 2020. Risk of death from the infection is associated with age and pre-existing comorbidities such as diabetes, dementia, cancer, and impairment of immunological, hepatic or renal function. It still remains incompletely understood why some patients survive the disease, while others perish. Our univariate and multivariate analyses of real world data from U.S. electronic health records indicate that a priori diagnoses of fluid, pH and electrolyte imbalance are highly and independently associated with COVID-19 mortality. We propose that pre-existing homeostatic aberrations are magnified upon the loss of ACE2, which is a core component of the electrolyte management system as well as the entry point of internalizing SARS-CoV-2 viruses. Moreover, we also suggest such fragility of electrolyte homeostasis may increase the risk of plasma volume disturbances during the infection. Future interventional studies should investigate whether the risk of death can be alleviated by personalized management of the fluid and electrolyte balance of at-risk individuals before and during COVID-19.

The protease corin regulates electrolyte homeostasis in eccrine sweat glands

Sweating is a basic skin function in body temperature control. In sweat glands, salt excretion and reabsorption are regulated to avoid electrolyte imbalance. To date, the mechanism underlying such regulation is not fully understood. Corin is a transmembrane protease that activates atrial natriuretic peptide (ANP), a cardiac hormone essential for normal blood volume and pressure. Here, we report an unexpected role of corin in sweat glands to promote sweat and salt excretion in regulating electrolyte homeostasis. In human and mouse eccrine sweat glands, corin and ANP are expressed in the luminal epithelial cells. In corin-deficient mice on normal- and high-salt diets, sweat and salt excretion is reduced. This phenotype is associated with enhanced epithelial sodium channel (ENaC) activity that mediates Na+ and water reabsorption. Treatment of amiloride, an ENaC inhibitor, normalizes sweat and salt excretion in corin-deficient mice. Moreover, treatment of aldosterone decreases sweat and salt excretion in wild-type (WT), but not corin-deficient, mice. These results reveal an important regulatory function of corin in eccrine sweat glands to promote sweat and salt excretion.

ACE2 Receptor in the skin and Cutaneous Manifestations of SARS-Cov-2: A Review of the Literature

A B S T R A C TSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a newlydiscovered coronavirus that causes Coronavirus Disease 2019 (COVID-19). Theinteraction of SARS-CoV-2 transmembrane spike (S) glycoprotein with the humanangiotensin-converting enzyme-2 (hACE2) is the primary method of virus entry tothe cell. ACE2 is a transmembrane enzyme involved in the renin-angiotensin-aldosterone system. This enzyme plays pivotal roles in blood pressure regulationsand also electrolyte homeostasis. The expression of ACE2 in various skin cells hasbeen demonstrated in previous studies. Keratinocytes in the epidermis show anexceptionally high expression of ACE2. In addition to human skin, ACE2 is alsofound in animals’ tissues and were exceptionally high in cats and dogs’ skin andeyes. This finding suggests their obscure role in COVID-19 transmission. Cutaneoussymptoms of COVID-19 in humans exist as the consequence of ACE2 presence inthe skin. The possible mechanisms of COVID-19 clinical manifestations in the skinare upregulated innate immune human response, hypercoagulable state, and non-structural proteins in SARS-CoV-2. These processes are presented as differentdermatologic manifestations, which are maculopapular rash, papulovesicular rash,and livedo reticularis. This review aims to link the theoretical framework andpublished findings to establish the connection between ACE2 expression in skin andcutaneous manifestations of COVID-19.