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Nefrologia : Publicacion Oficial de La... 2013Distal renal tubular acidosis (dRTA) or RTA type I is characterised by reduced H+ hydrogen ions and ammonium urinary excretion. In children affected by dRTA there... (Review)
Review
Distal renal tubular acidosis (dRTA) or RTA type I is characterised by reduced H+ hydrogen ions and ammonium urinary excretion. In children affected by dRTA there is stunted growth, vomiting, constipation, loss of appetite, polydipsia and polyuria, nephrocalcinosis, weakness and muscle paralysis due to hypokalaemia. This work summarises progress made in dRTA genetic studies in populations studied so far. DRTA is heterogeneous and as such, transporters and ion channels are analysed which have been identified in alpha-intercalated cells of the collecting duct, which could explain cases of dRTA not associated with the hitherto studied genes. DRTA can be autosomal dominant or autosomal recessive. Autosomal recessive dRTA appears in the first months of life and progresses with nephrocalcinosis and early or late hearing loss. Autosomal dominant dRTA is less severe and appears during adolescence or adulthood and may or may not develop nephrocalcinosis. In alpha-intercalated cells of the collecting duct, the acid load is deposited into the urine as titratable acids (phosphates) and ammonium. Autosomal recessive dRTA is associated with mutations in genes ATP6V1B1, ATP6V0A4 and SLC4A1, which encode subunits a4 and B1 of V-ATPase and the AE1 bicarbonate/chloride exchanger respectively. By contrast, autosomal dominant dRTA is only related to mutations in AE1.
Topics: Acidosis, Renal Tubular; Humans
PubMed: 23640117
DOI: 10.3265/Nefrologia.pre2012.Oct.11592 -
Biochimica Et Biophysica Acta Jul 2016The crystal structure of the dimeric membrane domain of human Band 3(1), the red cell chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1), provides a structural context... (Review)
Review
The crystal structure of the dimeric membrane domain of human Band 3(1), the red cell chloride/bicarbonate anion exchanger 1 (AE1, SLC4A1), provides a structural context for over four decades of studies into this historic and important membrane glycoprotein. In this review, we highlight the key structural features responsible for anion binding and translocation and have integrated the following topological markers within the Band 3 structure: blood group antigens, N-glycosylation site, protease cleavage sites, inhibitor and chemical labeling sites, and the results of scanning cysteine and N-glycosylation mutagenesis. Locations of mutations linked to human disease, including those responsible for Southeast Asian ovalocytosis, hereditary stomatocytosis, hereditary spherocytosis, and distal renal tubular acidosis, provide molecular insights into their effect on Band 3 folding. Finally, molecular dynamics simulations of phosphatidylcholine self-assembled around Band 3 provide a view of this membrane protein within a lipid bilayer.
Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Acid-Base Imbalance; Acidosis, Renal Tubular; Anemia, Hemolytic, Congenital; Anion Exchange Protein 1, Erythrocyte; Bicarbonates; Elliptocytosis, Hereditary; Erythrocytes; Erythrocytes, Abnormal; Gene Expression; Glycosylation; Humans; Ligands; Metabolism, Inborn Errors; Mutation; Protein Binding; Spherocytosis, Hereditary
PubMed: 27058983
DOI: 10.1016/j.bbamem.2016.03.030 -
Journal of Veterinary Emergency and... Jul 2022To describe the clinical presentation and management of a critically ill dog with profound renal tubular acidosis (RTA) with proximal and distal renal tubular...
OBJECTIVE
To describe the clinical presentation and management of a critically ill dog with profound renal tubular acidosis (RTA) with proximal and distal renal tubular dysfunction.
CASE SUMMARY
A 3-year-old neutered female Border Terrier was presented with frequent regurgitation resulting from acute pancreatitis with severe ileus. Venous acid-base analysis and complete urinalysis confirmed the presence of normal anion gap metabolic acidosis with inappropriately alkaline urine (pH 8), consistent with distal RTA. Urinalysis, urine amino acids, and urinary fractional excretion of electrolytes revealed glycosuria (with normoglycemia), aminoaciduria, and increased fractional excretion of sodium, calcium, and phosphate consistent with generalized proximal renal tubulopathy or Fanconi syndrome. The dog responded well to supportive care and alkaline therapy and made a complete recovery.
NEW OR UNIQUE INFORMATION PROVIDED
To the authors' knowledge, this is the first description of RTA with proximal and distal renal tubular dysfunction in the veterinary literature. Furthermore, the authors hypothesize that the transient RTA was a manifestation of acute kidney injury secondary to acute pancreatitis, the first report of this in the literature.
Topics: Acidosis; Acidosis, Renal Tubular; Acute Disease; Acute Kidney Injury; Animals; Dog Diseases; Dogs; Female; Pancreatitis
PubMed: 35129879
DOI: 10.1111/vec.13186 -
Orphanet Journal of Rare Diseases Mar 2022Consequences of distal renal tubular acidosis (dRTA) on growth, bone and kidney, sometimes associated with hearing loss, may significantly affect quality of life (QoL)....
BACKGROUND
Consequences of distal renal tubular acidosis (dRTA) on growth, bone and kidney, sometimes associated with hearing loss, may significantly affect quality of life (QoL). This descriptive qualitative study explores QoL linked to dRTA and gathers the impressions of patients with this rare disease (and caregivers) 5 years after enrolment in a clinical study, during which patients were treated with ADV7103, a prolonged-release granule formulation combining potassium citrate and potassium bicarbonate. Semi-structured, one-hour interviews with 6 adult and 13 paediatric patients with a confirmed diagnosis of dRTA and with parents of paediatric patients were performed using an interview guide. Qualitative analysis of anonymized interview transcripts based on grounded theory was conducted.
RESULTS
The main QoL domains impacted by dRTA and its treatment were education/work, social/family life, and emotional and physical well-being. ADV7103 (administered twice daily) was compared with the standard of care (SoC) taken before study entry (more than twice daily). Patients/parents reported that switching from previous SoC to ADV7103 had changed their lives: Difficulties at school due to burdensome administrative issues and need to explain disease and treatment affecting all families of paediatric patients (n = 13) disappeared, facilitating parents who had stopped working (to deal with their child's treatment) to return to work, Family functioning was improved (n = 18), as travel and holidays became easier to organise and patients/parents stopped thinking about managing treatment daily/nightly, reducing tension in the family or couple, The emotional burden of disease perceived was relieved (n = 12) in the absence of treatment-related invasive questions from others, Gastro-intestinal adverse events and taste problems improved with ADV7103 (n = 18) and better compliance led to milder physical impacts and less need to be hospitalised. The mean satisfaction score with ADV7103 compared to SoC was 9 out of 10 (10 = very satisfied). ADV7103 exceeded or met the expectations of 14 out of 17 patients that commented on that.
CONCLUSIONS
Qualitative interviews show that dRTA and its treatment have a significant impact on QoL of patients and parents and that ADV7103 helps improve daily-life and reduces treatment burden, resulting in greater overall satisfaction of the patients and their families. Trial registration EU Clinical Trials Register, EudraCT 2013-003828-36 on the 3rd of September 2013.
Topics: Acidosis, Renal Tubular; Adult; Caregivers; Child; Humans; Parents; Qualitative Research; Quality of Life
PubMed: 35346296
DOI: 10.1186/s13023-022-02294-w -
Physiological Reviews Apr 2013The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3... (Review)
Review
The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1-3), five Na(+)-coupled HCO3(-) transporters (NCBTs), and two other unusual members (AE4, BTR1). In this review, we mainly focus on the five mammalian NCBTs-NBCe1, NBCe2, NBCn1, NDCBE, and NBCn2. Each plays a specialized role in maintaining intracellular pH and, by contributing to the movement of HCO3(-) across epithelia, in maintaining whole-body pH and otherwise contributing to epithelial transport. Disruptions involving NCBT genes are linked to blindness, deafness, proximal renal tubular acidosis, mental retardation, and epilepsy. We also review AE1-3, AE4, and BTR1, addressing their relevance to the study of NCBTs. This review draws together recent advances in our understanding of the phylogenetic origins and physiological relevance of NCBTs and their progenitors. Underlying these advances is progress in such diverse disciplines as physiology, molecular biology, genetics, immunocytochemistry, proteomics, and structural biology. This review highlights the key similarities and differences between individual NCBTs and the genes that encode them and also clarifies the sometimes confusing NCBT nomenclature.
Topics: Acidosis, Renal Tubular; Animals; Biological Evolution; Chloride-Bicarbonate Antiporters; Humans; Molecular Sequence Data; Sodium Bicarbonate
PubMed: 23589833
DOI: 10.1152/physrev.00023.2012 -
Anaesthesia Apr 2008The correct identification of the cause, and ideally the individual acid, responsible for metabolic acidosis in the critically ill ensures rational management. In Part 2... (Review)
Review
The correct identification of the cause, and ideally the individual acid, responsible for metabolic acidosis in the critically ill ensures rational management. In Part 2 of this review, we examine the elevated (corrected) anion gap acidoses (lactic, ketones, uraemic and toxin ingestion) and contrast them with nonelevated conditions (bicarbonate wasting, renal tubular acidoses and iatrogenic hyperchloraemia) using readily available base excess and anion gap techniques. The potentially erroneous interpretation of elevated lactate signifying cell ischaemia is highlighted. We provide diagnostic and therapeutic guidance when faced with a high anion gap acidosis, for example pyroglutamate, in the common clinical scenario 'I can't identify the acid--but I know it's there'. The evidence that metabolic acidosis affects outcomes and thus warrants correction is considered and we provide management guidance including extracorporeal removal and fomepizole therapy.
Topics: Acid-Base Equilibrium; Acidosis; Acidosis, Lactic; Acidosis, Renal Tubular; Critical Illness; Humans; Prognosis
PubMed: 18336491
DOI: 10.1111/j.1365-2044.2007.05371.x -
Nephrology, Dialysis, Transplantation :... Dec 2012Proximal renal tubular acidosis (RTA) (Type II RTA) is characterized by a defect in the ability to reabsorb HCO(3) in the proximal tubule. This is usually manifested as... (Review)
Review
Proximal renal tubular acidosis (RTA) (Type II RTA) is characterized by a defect in the ability to reabsorb HCO(3) in the proximal tubule. This is usually manifested as bicarbonate wastage in the urine reflecting that the defect in proximal tubular transport is severe enough that the capacity for bicarbonate reabsorption in the thick ascending limb of Henle's loop and more distal nephron segments is overwhelmed. More subtle defects in proximal bicarbonate transport likely go clinically unrecognized owing to compensatory reabsorption of bicarbonate distally. Inherited proximal RTA is more commonly autosomal recessive and has been associated with mutations in the basolateral sodium-bicarbonate cotransporter (NBCe1). Mutations in this transporter lead to reduced activity and/or trafficking, thus disrupting the normal bicarbonate reabsorption process of the proximal tubules. As an isolated defect for bicarbonate transport, proximal RTA is rare and is more often associated with the Fanconi syndrome characterized by urinary wastage of solutes like phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins as well as bicarbonate. A vast array of rare tubular disorders may cause proximal RTA but most commonly it is induced by drugs. With the exception of carbonic anhydrase inhibitors which cause isolated proximal RTA, drug-induced proximal RTA is associated with Fanconi syndrome. Drugs that have been recently recognized to cause severe proximal RTA with Fanconi syndrome include ifosfamide, valproic acid and various antiretrovirals such as Tenofovir particularly when given to human immunodeficiency virus patients receiving concomitantly protease inhibitors such as ritonavir or reverse transcriptase inhibitors such as didanosine.
Topics: Acidosis, Renal Tubular; Animals; Humans; Mutation
PubMed: 23235953
DOI: 10.1093/ndt/gfs493 -
Renal Failure Nov 2018Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine....
OBJECTIVE
Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine. Growth retardation is a major concern in these children. The disease is caused by defects in at least three genes (SLC4A1, ATP6V0A4, and ATP6V1B1) involved in urinary distal acidification. Several series of dRTA patients from different ethnic backgrounds have been genetically studied, but genetic studies regarding Chinese population is rare. Our aim was to investigate the clinical features and genetic basis of primary dRTA in Chinese children.
METHODS
Three unrelated patients with dRTA participated in our study. Next-generation sequencing was performed, and the findings were validated using the Sanger sequencing method.
RESULTS
All patients exhibited hyperchloraemic metabolic acidosis, abnormally high urine pH, hypokalemia, and nephrocalcinosis. Growth retardation was observed in all patients. During the follow-up (range 1-4 years), alkali replacement therapy corrected the systemic metabolic acidosis, and two patients demonstrated normal growth. rhGH therapy was administered to patient-3 at the age of 6 years, and his growth rate was significantly improved (growth velocity 9.6 cm/yr). In total, 5 mutations were identified in our cohort of three patients, and four mutations were novel.
CONCLUSIONS
We report the clinical and molecular characteristics of dRTA patients from China. The four novel mutations detected in our study extend the spectrum of gene mutations associated with primary dRTA. Furthermore, our study confirms the effect of early treatment in improving growth for dRTA patient and provides insight into the effects of rhGH on dRTA patients who were diagnosed late and exhibiting a persistent growth delay despite appropriate therapy.
Topics: Acidosis, Renal Tubular; Anion Exchange Protein 1, Erythrocyte; Child, Preschool; China; Female; Growth Disorders; Growth Hormone; Hearing Loss, Sensorineural; Humans; Hypokalemia; Infant; Male; Mutation, Missense; Nephrocalcinosis; Vacuolar Proton-Translocating ATPases
PubMed: 30230413
DOI: 10.1080/0886022X.2018.1487858 -
Critical Care (London, England) 2005The Canadian physiologist PA Stewart advanced the theory that the proton concentration, and hence pH, in any compartment is dependent on the charges of fully ionized and... (Review)
Review
The Canadian physiologist PA Stewart advanced the theory that the proton concentration, and hence pH, in any compartment is dependent on the charges of fully ionized and partly ionized species, and on the prevailing CO2 tension, all of which he dubbed independent variables. Because the kidneys regulate the concentrations of the most important fully ionized species ([K+], [Na+], and [Cl-]) but neither CO2 nor weak acids, the implication is that it should be possible to ascertain the renal contribution to acid-base homeostasis based on the excretion of these ions. One further corollary of Stewart's theory is that, because pH is solely dependent on the named independent variables, transport of protons to and from a compartment by itself will not influence pH. This is apparently in great contrast to models of proton pumps and bicarbonate transporters currently being examined in great molecular detail. Failure of these pumps and cotransporters is at the root of disorders called renal tubular acidoses. The unquestionable relation between malfunction of proton transporters and renal tubular acidosis represents a problem for Stewart theory. This review shows that the dilemma for Stewart theory is only apparent because transport of acid-base equivalents is accompanied by electrolytes. We suggest that Stewart theory may lead to new questions that must be investigated experimentally. Also, recent evidence from physiology that pH may not regulate acid-base transport is in accordance with the concepts presented by Stewart.
Topics: Acid-Base Equilibrium; Acidosis, Renal Tubular; Chemistry, Clinical; Humans
PubMed: 16356241
DOI: 10.1186/cc3802 -
Veterinary Medicine and Science Nov 2022A 3-year-old neutered male golden retriever administered zonisamide for the treatment of seizures showed lethargy and had normal anion gap metabolic acidosis with...
A 3-year-old neutered male golden retriever administered zonisamide for the treatment of seizures showed lethargy and had normal anion gap metabolic acidosis with hypokalaemia, hyperchloremia, and alkaline urine. The serum zonisamide concentration was close to the upper limit, which raised a suspicion of adverse effects of zonisamide. This is the first report showing that the fractional excretion of bicarbonate after compensation for the plasma bicarbonate concentration by a sodium bicarbonate infusion was approximately 5%, indicating distal renal tubular acidosis (RTA). The serum zonisamide concentration decreased, and adverse effects were abated by reducing the zonisamide dosage. Diagnostic therapy with bicarbonate served as a means of compensating for bicarbonate deficiency and contributed to the clinical diagnosis of the condition in zonisamide-associated RTA in dogs.
Topics: Dogs; Male; Animals; Acidosis, Renal Tubular; Zonisamide; Bicarbonates; Lethargy; Epilepsy; Dog Diseases
PubMed: 35916390
DOI: 10.1002/vms3.905