-
Annual Review of Physiology Feb 2024Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron.... (Review)
Review
Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption.
Topics: Humans; Kidney Tubules; Bartter Syndrome; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria
PubMed: 38012047
DOI: 10.1146/annurev-physiol-042222-025000 -
Frontiers in Physiology 2022Metabolic acidosis, a common complication in patients with chronic kidney disease (CKD), results in a multitude of deleterious effects. Though the restoration of kidney... (Review)
Review
Metabolic acidosis, a common complication in patients with chronic kidney disease (CKD), results in a multitude of deleterious effects. Though the restoration of kidney function following transplantation is generally accompanied by a correction of metabolic acidosis, a subset of transplant recipients remains afflicted by this ailment and its subsequent morbidities. The vulnerability of kidney allografts to metabolic acidosis can be attributed to reasons similar to pathogenesis of acidosis in non-transplant CKD, and to transplant specific causes, including donor related, recipient related, immune mediated factors, and immunosuppressive medications. Correction of metabolic acidosis in kidney transplantation either with alkali therapy or through dietary manipulations may have potential benefits and the results of such clinical trials are eagerly awaited. This review summarizes the published evidence on the pathogenesis and clinical consequences of chronic metabolic acidosis in kidney transplant recipients.
PubMed: 36082221
DOI: 10.3389/fphys.2022.989816 -
Cureus Feb 2023Renal tubular acidosis (RTA) refers to a group of disorders in which the elimination of hydrogen ions from the kidney or the reabsorption of filtered bicarbonate is...
Renal tubular acidosis (RTA) refers to a group of disorders in which the elimination of hydrogen ions from the kidney or the reabsorption of filtered bicarbonate is impaired, resulting in metabolic acidosis. Hypokalemia is also prominent in different types of RTA. We are presenting an interesting case about a chronic alcoholic patient who presented to the emergency department and was found to be severely hypokalemic. During her hospital stay, she had multiple cardiac arrests likely secondary to her hypokalemia despite adequate treatment with potassium supplementation. We came to the conclusion of distal RTA in our patient based on hyperchloremic metabolic acidosis, sodium bicarbonate of 10 mmol/L, low potassium, blood urea nitrogen, and creatinine within normal limits, alkaline urine, and a positive urinary anion gap. It is likely that the cause of our patient's underlying type 1 RTA was secondary to her chronic alcohol abuse. Her potassium eventually returned to baseline, and she was discharged.
PubMed: 36942187
DOI: 10.7759/cureus.35034 -
Advances in Chronic Kidney Disease Jul 2022The various mechanisms responsible for the development of metabolic acidosis are briefly reviewed, and the metabolic acidoses are categorized both by mechanism and by... (Review)
Review
The various mechanisms responsible for the development of metabolic acidosis are briefly reviewed, and the metabolic acidoses are categorized both by mechanism and by the presence or absence of an increased anion gap. When a diagnosis of metabolic acidosis is established, it becomes imperative to identify the primary causative etiology as quickly as possible. This is often readily apparent from the history and physical exam (ie, diabetic ketoacidosis when the glucose is very high in a patient with diabetes mellitus; lactic acidosis in a patient with sepsis and hypotension, etc.). However, when the etiology is not obvious, it is very helpful to determine if the metabolic acidosis is of the hyperchloremic or high-anion-gap type (or a combination of both). Once this categorization has been established, a stepwise consideration of each of the potential causative etiologies will usually direct the clinician to order the appropriate diagnostic studies.
Topics: Acid-Base Imbalance; Acidosis; Anions; Glucose; Humans; Physical Examination
PubMed: 36175073
DOI: 10.1053/j.ackd.2022.07.004 -
Cancer Gene Therapy Nov 2022Transmembrane ATPases are membrane-bound enzyme complexes and ion transporters that can be divided into F-, V-, and A-ATPases according to their structure. The... (Review)
Review
Transmembrane ATPases are membrane-bound enzyme complexes and ion transporters that can be divided into F-, V-, and A-ATPases according to their structure. The V-ATPases, also known as H-ATPases, are large multi-subunit protein complexes composed of a peripheral domain (V1) responsible for the hydrolysis of ATP and a membrane-integrated domain (V0) that transports protons across plasma membrane or organelle membrane. V-ATPases play a fundamental role in maintaining pH homeostasis through lysosomal acidification and are involved in modulating various physiological and pathological processes, such as macropinocytosis, autophagy, cell invasion, and cell death (e.g., apoptosis, anoikis, alkaliptosis, ferroptosis, and lysosome-dependent cell death). In addition to participating in embryonic development, V-ATPase pathways, when dysfunctional, are implicated in human diseases, such as neurodegenerative diseases, osteopetrosis, distal renal tubular acidosis, and cancer. In this review, we summarize the structure and regulation of isoforms of V-ATPase subunits and discuss their context-dependent roles in cancer biology and cell death. Updated knowledge about V-ATPases may enable us to design new anticancer drugs or strategies.
Topics: Humans; Vacuolar Proton-Translocating ATPases; Cell Membrane; Neoplasms; Cell Death
PubMed: 35504950
DOI: 10.1038/s41417-022-00477-y -
Annual Review of Physiology Feb 2022Nephrolithiasis is a worldwide problem with increasing prevalence, enormous costs, and significant morbidity. Calcium-containing kidney stones are by far the most common... (Review)
Review
Nephrolithiasis is a worldwide problem with increasing prevalence, enormous costs, and significant morbidity. Calcium-containing kidney stones are by far the most common kidney stones encountered in clinical practice, and thus, hypercalciuria is the greatest risk factor for kidney stone formation. Hypercalciuria can result from enhanced intestinal absorption, increased bone resorption, or altered renal tubular transport. Kidney stone formation is complex and driven by high concentrations of calcium-oxalate or calcium-phosphate in the urine. After discussing the mechanism mediating renal calcium salt precipitation, we review recent discoveries in renal tubular calcium transport from the proximal tubule, thick ascending limb, and distal convolution. Furthermore, we address how calcium is absorbed from the intestine and mobilized from bone. The effect of acidosis on bone calcium resorption and urinary calcium excretion is also considered. Although recent discoveries provide insight into these processes, much remains to be understood in order to provide improved therapies for hypercalciuria and prevent kidney stone formation.
Topics: Calcium; Calcium Oxalate; Calcium, Dietary; Humans; Hypercalciuria; Kidney Calculi
PubMed: 34699268
DOI: 10.1146/annurev-physiol-052521-121822 -
Kidney International Jun 2022The homeostatic regulation of a stable systemic pH is of critical importance for mammalian survival. During metabolic acidosis (a reduction in systemic pH caused by a... (Review)
Review
The homeostatic regulation of a stable systemic pH is of critical importance for mammalian survival. During metabolic acidosis (a reduction in systemic pH caused by a primary decrease in serum bicarbonate concentration), as seen in clinical disorders such as the later stages of chronic kidney disease, renal tubular acidosis, or chronic diarrhea, bone buffers the accumulated acid; however, this homeostatic function of the skeleton occurs at the expense of the bone mineral content and leads to decreased bone quality. During short-term studies to model acute metabolic acidosis, there is initial physiochemical bone mineral dissolution, releasing carbonate and phosphate proton buffers into the extracellular fluid. In addition, there is net proton influx into the mineral with release of bone sodium and potassium. During long-term studies to model chronic metabolic acidosis, there is also inhibition of osteoblast activity, resulting in reduced bone formation, and an increase in osteoclast activity, resulting in increased bone resorption and release of calcium and anionic proton buffers. These physicochemical and cell-mediated bone responses to metabolic acidosis, in addition to an acidosis-induced increased urine calcium excretion, without a corresponding increase in intestinal calcium absorption, induce a net loss of body calcium that is almost certainly derived from the mineral stores of bone.
Topics: Acidosis; Animals; Bone and Bones; Calcium; Hydrogen-Ion Concentration; Mammals; Phosphates; Protons
PubMed: 35351460
DOI: 10.1016/j.kint.2022.02.032 -
Bone Apr 2023Carbonic anhydrase II deficiency (OMIM # 259730), initially called "osteopetrosis with renal tubular acidosis and cerebral calcification syndrome", reveals an important...
Carbonic anhydrase II deficiency (OMIM # 259730), initially called "osteopetrosis with renal tubular acidosis and cerebral calcification syndrome", reveals an important role for the enzyme carbonic anhydrase II (CA II) in osteoclast and renal tubule function. Discovered in 1972 and subsequently given various names, CA II deficiency now describes >100 affected individuals encountered predominantly from the Middle East and Mediterranean region. In 1983, CA II deficiency emerged as the first osteopetrosis (OPT) understood metabolically, and in 1991 the first understood molecularly. CA II deficiency is the paradigm OPT featuring failure of osteoclasts to resorb bone due to inability to acidify their pericellular milieu. The disorder presents late in infancy or early in childhood with fracturing, developmental delay, weakness, short stature, and/or cranial nerve compression and palsy. Mental retardation is common. The skeletal findings may improve by adult life, and CA II deficiency can be associated with a normal life-span. Therefore, it has been considered an "intermediate" type of OPT. In CA II deficiency, OPT is uniquely accompanied by renal tubular acidosis (RTA) of proximal, distal, or combined type featuring hyperchloremic metabolic acidosis, rarely with hypokalemia and paralysis. Cerebral calcification uniquely appears in early childhood. The etiology is bi-allelic loss-of-function mutations of CA2 that encodes CA II. Prenatal diagnosis requires mutational analysis of CA2. Although this enzymopathy reveals how CA II is important for the skeleton and kidney tubule, the pathogenesis of the mental subnormality and cerebral calcification is less well understood. Several mouse models of CA II deficiency have shown growth hormone deficiency, yet currently there is no standard pharmacologic therapy for patients. Treatment of the systemic acidosis is often begun when growth is complete. Although CA II deficiency is an "osteoclast-rich" OPT, and therefore transplantation of healthy osteoclasts can improve the skeletal disease, the RTA and central nervous system difficulties persist.
Topics: Animals; Child, Preschool; Female; Humans; Mice; Pregnancy; Acidosis, Renal Tubular; Calcinosis; Carbonic Anhydrases; Intellectual Disability; Osteopetrosis; Urea Cycle Disorders, Inborn; Carbonic Anhydrase II
PubMed: 36709914
DOI: 10.1016/j.bone.2023.116684