Molecular Pathophysiology of Acid-Base Disorders

Acid-base balance is critical for normal life. Acute and chronic disturbances impact cellular energy metabolism, endocrine signaling, ion channel activity, neuronal activity, and cardiovascular functions such as cardiac contractility and vascular blood flow. Maintenance and adaptation of acid-base homeostasis are mostly controlled by respiration and kidney. The kidney contributes to acid-base balance by reabsorbing filtered bicarbonate, regenerating bicarbonate through ammoniagenesis and generation of protons, and by excreting acid. This review focuses on acid-base disorders caused by renal processes, both inherited and acquired. Distinct rare inherited monogenic diseases affecting acid-base handling in the proximal tubule and collecting duct have been identified. In the proximal tubule, mutations of solute carrier 4A4 (SLC4A4) (electrogenic Na/HCO-cotransporter Na/bicarbonate cotransporter e1 [NBCe1]) and other genes such as CLCN5 (Cl/H-antiporter), SLC2A2 (GLUT2 glucose transporter), or EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) causing more generalized proximal tubule dysfunction can cause proximal renal tubular acidosis resulting from bicarbonate wasting and reduced ammoniagenesis. Mutations in adenosine triphosphate ATP6V1 (B1 H-ATPase subunit), ATPV0A4 (a4 H-ATPase subunit), SLC4A1 (anion exchanger 1), and FOXI1 (forkhead transcription factor) cause distal renal tubular acidosis type I. Carbonic anhydrase II mutations affect several nephron segments and give rise to a mixed proximal and distal phenotype. Finally, mutations in genes affecting aldosterone synthesis, signaling, or downstream targets can lead to hyperkalemic variants of renal tubular acidosis (type IV). More common forms of renal acidosis are found in patients with advanced stages of chronic kidney disease and are owing, at least in part, to a reduced capacity for ammoniagenesis

Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men

Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH)2 vitamin D3 metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH)2 vitamin D3, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH)2 vitamin D3 are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH)2 D3 levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71+ erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH)2 vitamin D3 levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism

Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10-30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD

Potassium channels in control of renal function.

Potassium channels are important to control membrane potential and drive epithelial transport processes. In this issue of Kidney International, Bignon et al. report the role of the Kir4.2 K$^{+}$-channel, localized at the basolateral membrane of proximal tubules, in the reabsorption of bicarbonate and the modulation of renal ammoniagenesis. The findings have implications for our understanding of how the kidney reacts to hypokalemia, an acid load, and the metabolic acidosis of patients with advanced stages of chronic kidney disease

Physiological relevance of proton-activated GPCRs

The detection of H$^{+}$ concentration variations in the extracellular milieu is accomplished by a series of specialized and non-specialized pH-sensing mechanisms. The proton-activated G protein–coupled receptors (GPCRs) GPR4 (Gpr4), TDAG8 (Gpr65), and OGR1 (Gpr68) form a subfamily of proteins capable of triggering intracellular signaling in response to alterations in extracellular pH around physiological values, i.e., in the range between pH 7.5 and 6.5. Expression of these receptors is widespread for GPR4 and OGR1 with particularly high levels in endothelial cells and vascular smooth muscle cells, respectively, while expression of TDAG8 appears to be more restricted to the immune compartment. These receptors have been linked to several well-studied pH-dependent physiological activities including central control of respiration, renal adaption to changes in acid–base status, secretion of insulin and peripheral responsiveness to insulin, mechanosensation, and cellular chemotaxis. Their role in pathological processes such as the genesis and progression of several inflammatory diseases (asthma, inflammatory bowel disease), and tumor cell metabolism and invasiveness, is increasingly receiving more attention and makes these receptors novel and interesting targets for therapy. In this review, we cover the role of these receptors in physiological processes and will briefly discuss some implications for disease processes

Role of proton-activated G protein-coupled receptors in pathophysiology

Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumor growth. Acidic pH is not merely a sequela of disease but contributes to recruitment and regulation of immune cells, modifies metabolism of parenchymal, immune and tumor cells, modulates fibrosis, vascular permeability, oxygen availability, and consumption, invasiveness of tumor cells, and impacts on cell survival. Thus, multiple pH-sensing mechanisms must exist in cells involved in these processes. These pH sensors play important roles in normal physiology and pathophysiology, and hence might be attractive targets for pharmacological interventions. Among the pH-sensing mechanisms, OGR1 ( GPR68), GPR4 ( GPR4), and TDAG8 ( GPR65) have emerged as important molecules. These G protein-coupled receptors are widely expressed, upregulated in inflammation and tumors, sense changes in extracellular pH in the range between pH 8 and 6, and are involved in modulating key processes in inflammation, tumor biology, and fibrosis. This review discusses key features of these receptors and highlights important disease states and pathways affected by their activity

And the fat lady sings about phosphate and calcium.

Adipose tissue has been long recognized as secreting various endocrine factors. Emerging evidence demonstrates that adipokines play a role in modulating systemic mineral homeostasis through endocrine loops involving interleukin-6, leptin, and now also adiponectin, which all interact with FGF23 and vitamin D and thereby change the renal control of calcium and phosphate metabolism. Understanding these regulatory loops may shed light on a complex interorgan crosstalk controlling mineral homeostasis and its dysregulation in diseases associated with obesity

Acidosis and alkali therapy in patients with kidney transplant is associated with transcriptional changes and altered abundance of genes involved in cell metabolism and acid-base balance

BACKGROUND: Metabolic acidosis occurs frequently in patients with kidney transplant and is associated with higher risk for and accelerated loss of graft function. To date, it is not known whether alkali therapy in these patients improves kidney function and whether acidosis and its therapy is associated with altered expression of proteins involved in renal acid-base metabolism. METHODS: We collected retrospectively kidney biopsies from 22 patients. Of these patients, 9 had no acidosis, 9 had metabolic acidosis (plasma HCO3- < 22 mmol/l), and 4 had acidosis and received alkali therapy. We performed transcriptome analysis and immunohistochemistry for proteins involved in renal acid-base handling. RESULTS: We found the expression of 40 transcripts significantly changed between kidneys from non-acidotic and acidotic patients. These genes are mostly involved in proximal tubule amino acid and lipid metabolism and energy homeostasis. Three transcripts were fully recovered by alkali therapy: the Kir4.2 K+-channel, an important regulator of proximal tubule HCO3--metabolism and transport, ACADSB and SHMT1, genes involved in beta-oxidation and methionine metabolism. Immunohistochemistry showed reduced staining for the proximal tubule NBCe1 HCO3- transporter in kidneys from acidotic patients that recovered with alkali therapy. In addition, the HCO3-exchanger pendrin was affected by acidosis and alkali therapy. CONCLUSIONS: Metabolic acidosis in kidney transplant recipients is associated with alterations in the renal transcriptome that are partly restored by alkali therapy. Acid-base transport proteins mostly from proximal tubule were also affected by acidosis and alkali therapy suggesting that the downregulation of critical players contributes to metabolic acidosis in these patients

The H+-Activated Ovarian Cancer G Protein-Coupled Receptor 1 (OGR1) is responsible for Renal Calcium Loss during Acidosis

ABSTRACT Hypercalciuria is a common feature during metabolic acidosis. However, the mechanisms sensing acidosis and inducing increased urinary calcium excretion during acidosis are still unknown. Here we report that mice deficient for the Ovarian cancer G-protein coupled receptor 1 (OGR1 or Gpr68) did not excrete more calcium during chronic metabolic acidosis. Wild type (OGR1+/+) and OGR1-deficient mice (OGR1-/-) were subjected to standard chow (control) or 0.28 M NH4Cl in water for 1 day (acute metabolic acidosis) or 2 % NH4Cl in food for 7 days (chronic metabolic acidosis). OGR1 mRNA is ubiquitously expressed, including kidneys, and found along the entire nephron. No differences in responding to the acid load were observed in OGR1-/- mice, except for higher plasma [HCO3-] after 1 day. Bone mineral density and resorption activity of osteoclasts were similar between OGR1+/+ and OGR1-/- mice. Plasma PTH and Vitamin D3 levels were indistinguishable. However, the expression levels of key proteins for active transepithelial Ca2+ reabsorption in the distal convoluted tubule, TRPV5 and Calbindin-D28k were increased in OGR1-/- mice under metabolic acidosis. TRPV5 abundance was downregulated in wild type mice during metabolic acidosis but maintained at the same level in the absence of OGR1. OGR1-/- also exhibited higher NHE3 abundance when compared to OGR1+/+ under metabolic acidosis. In conclusion, OGR1 is a pH sensor involved in the hypercalciuria developed during metabolic acidosis and may regulate renal calcium excretion through modulation of proximal tubular NHE3 activity and regulation of the distal tubule TRPV5 calcium channel