Inherited Proximal and Distal Renal Tubular Acidosis

Anion Gap ◽

Intercalated Cells ◽

Acid Excretion ◽

Acid Base ◽

Urine Ph ◽

Renal Tubular ◽

Net Acid Excretion

Acid-base homeostasis by the kidney is maintained through proximal tubular reclamation of filtered bicarbonate and the excretion of the daily acid load by collecting duct type A intercalated cells. The impairment of either process results in renal tubular acidosis (RTA), a group of disorders characterized by a reduced net acid excretion and a persistent hyperchloremic, non–anion gap metabolic acidosis. The primary or hereditary forms of proximal (pRTA) and distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in either reduced bicarbonate reabsorption or reduced H+ secretion and impaired acid excretion. dRTA is characterized by reduced net acid excretion and an inability to lower urine pH despite severe acidemia (but minimal HCO3– wastage). pRTA (type 2), by contrast, is characterized by marked HCO3– wastage but preserved ability to lower urine pH when plasma HCO3– (and therefore filtered HCO3–) is below a certain threshold. In children with dRTA, growth retardation caused by chronic metabolic acidosis is the key manifestation but is fully reversible with appropriate alkali therapy if initiated early in life. A striking manifestation of many patients with dRTA is the development of severe hypokalemia that may cause muscle paralysis. In this review, we discuss these types of hereditary RTA and the mechanisms involved in the genesis of these inherited tubular disorders. This review contains 5 figures, 1 table, and 103 references. Key words: Proximal renal tubular acidosis (pRTA), Distal renal tubular acidosis (dRTA), Hyperchloremic, non–anion gap metabolic acidosis, Hypokalemia, Fractional HCO3– excretion, Urinary gap, Fanconi Syndrome.ATP6V1B1 and ATP6V0A4 gene mutations . Intercalated cells ,

Glue-sniffing and distal renal tubular acidosis: sticking to the facts.

Journal of the American Society of Nephrology ◽

10.1681/asn.v181019 ◽

1991 ◽

Vol 1 (8) ◽

pp. 1019-1027 ◽

Cited By ~ 1

Author(s):

E J Carlisle ◽

S M Donnelly ◽

S Vasuvattakul ◽

K S Kamel ◽

S Tobe ◽

...

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Extracellular Fluid ◽

Anion Gap ◽

Acid Base ◽

Major Question ◽

The Subject ◽

Renal Tubular ◽

Sodium And Potassium

An index case is presented to introduce the subject of the acid-base and electrolyte abnormalities resulting from toluene abuse. These include metabolic acidosis associated with a normal anion gap and excessive loss of sodium and potassium in the urine. The major question addressed is, what is the basis for the metabolic acidosis? Overproduction of hippuric acid resulting from the metabolism of toluene plays a more important role in the genesis of the metabolic acidosis than was previously believed. This conclusion is supported by the observation that the rate of excretion of ammonium was not low during metabolic acidosis in six of eight patients, suggesting that distal renal tubular acidosis was not an important acid-base abnormality in most cases where ammonium was measured. The excretion of hippurate in the urine unmatched by ammonium also mandates an enhanced rate of excretion of the cations, sodium and potassium. The loss of sodium causes extracellular fluid volume contraction and a fall in the glomerular filtration rate, which may transform the normal anion gap type of metabolic acidosis into one with a high anion gap (accumulation of hippurate and other anions). Continuing loss of potassium in the urine leads to hypokalemia. An understanding of the metabolism of toluene provides the basis for the unusual biochemical abnormalities seen with abuse of this solvent.

Gut It Out: Laxative Abuse Mimicking Distal Renal Tubular Acidosis

Kidney & Blood Pressure Research ◽

10.1159/000501855 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1294-1299 ◽

Cited By ~ 2

Author(s):

Marius Sidler ◽

Nilufar Mohebbi ◽

Ewout J. Hoorn ◽

Carsten A. Wagner

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Kidney Stones ◽

Relative Number ◽

Potassium Citrate ◽

Anion Gap ◽

Intercalated Cells ◽

Laxative Abuse ◽

Background: Distal renal tubular acidosis (dRTA) can be inherited or acquired. Case Presentation: Here, we describe the case of a 45-year-old female patient with non-anion gap metabolic acidosis, hypokalemia, and alkaline urine. She had a history of rheumatoid arthritis and kidney stones and failed to acidify urine upon the fludrocortisone and furosemide test. Therefore, the diagnosis of dRTA secondary to an autoimmune disease was made. A kidney biopsy was examined for markers of acid-secretory intercalated cells. Surprisingly, no obvious difference in the relative number of acid-secretory intercalated cells or in the distribution of major proteins involved in acid secretion was found. Furthermore, increasing doses of potassium citrate failed to correct the hypokalemia and acidosis. Since these findings were rather atypical for autoimmune dRTA, alternative causes of her hypokalemia and metabolic acidosis were sought. The patient was found to chronically consume laxatives, which can also cause kidney stones and may result in a false-positive urinary acidification test. Conclusion: Chronic laxative abuse may mimic dRTA and should therefore be considered in unexplained hypokalemia with non-anion gap metabolic acidosis.

Metabolic acidosis in toluene sniffing

CJEM ◽

10.2310/8000.2013.130974 ◽

2013 ◽

Vol 15 (04) ◽

pp. 249-252 ◽

Cited By ~ 3

Author(s):

Jon Tuchscherer ◽

Habib Rehman

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Excretion Rate ◽

Ammonia Excretion ◽

Anion Gap ◽

Renal Tubular ◽

Conjugate Bases ◽

Osmolal Gap ◽

Ammonia Excretion Rate

ABSTRACT Toluene sniffing, frequently described under the generic category of “glue sniffing,” is a potential cause of normal anion gap metabolic acidosis due to distal renal tubular acidosis. Urine anion gap is used to diagnose metabolic acidosis of a normal anion gap variety; however, pitfalls exist when using urine anion gap in the setting of toluene sniffing. We present the case of a young woman who had a normal anion gap metabolic acidosis due to toluene sniffing and an unexpectedly low urine anion gap. In such a scenario, the urine anion gap will underestimate the rate of ammonia excretion when the conjugate bases of acids other than HCl are excreted in large quantities. Estimation of the urine osmolal gap will provide a more accurate ammonia excretion rate in these circumstances. The challenges in interpretation of the urine anion gap and ammonia excretion in the setting of distal renal tubular acidosis due to toluene toxicity are discussed.

SUN-185 Severe Hyponatremia and Type 4 Renal Tubular Acidosis (Functional Hypoaldosteronism) Secondary to Trimethoprim

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1235 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Yun Qing Koh ◽

Kian Ming Jeremy Hoe ◽

Timothy Peng Lim Quek

Keyword(s):

Metabolic Acidosis ◽

Sodium Chloride ◽

Sodium Bicarbonate ◽

Renal Tubular Acidosis ◽

Anion Gap ◽

Aortic Graft ◽

Acid Base ◽

Severe Hyponatremia ◽

Renal Tubular ◽

Oral Sodium

Abstract Introduction: Trimethoprim-sulfamethoxazole (TMP-SMX) is a commonly used antibiotic. We present a case of severe hyponatremia and Type 4 renal tubular acidosis (functional hypoaldosteronism) in a patient treated with TMP-SMX. Clinical Case: A 62 year old gentleman with hypertension, dyslipidemia and a surgically repaired abdominal aortic aneurysm developed an aortic graft infection. He was admitted to hospital for acute right lower limb ischemia with embolic phenomena, and underwent surgical graft explantation. He required multiple courses of antibiotics post operatively. He was initially referred to Endocrinology for severe hyponatremia, deemed likely to be from a salt losing nephropathy secondary to polymyxin. Thyroid function and morning cortisol levels were normal. He was managed with intravenous hypertonic saline and oral salt tablets. The hyponatraemia resolved a week after polymyxin was stopped. Intravenous TMP-SMX was commenced the next day at 240 mg BD. A week later, the hyponatremia recurred, with concomitant hyperkalemia and a normal anion gap metabolic acidosis. The serum sodium was 126 mmol/L (reference interval (RI) 135-145) and the serum osmolality 275 mmol/kg (RI 275- 305). Urine studies showed a high urinary sodium (154 mmol/L) and osmolality (481 mmol/kg), consistent with renal salt wasting. The serum potassium rose to a peak of 6.1 mmol/L (RI 3.5 - 5.0), with a normal anion gap metabolic acidosis (bicarbonate 17 mmol/L (RI 21 – 31)). A paired urine pH of 8 pointed to an inability to acidify the urine. Given the clinical course and laboratory investigations, the diagnosis of TMP-associated hyponatremia and Type 4 RTA was made. Oral resonium was started to correct hyperkalemia, with a combination of oral sodium chloride and sodium bicarbonate used to treat the hyponatremia and metabolic acidosis. Fludrocortisone was not used given the concerns of causing hypertension in a patient with a diseased aortic graft. The dose of TMP-SMX was gradually reduced with improvement of the acid-base and electrolyte abnormalities, lending weight to our diagnosis. After the dose of the TMP-SMX was reduced to 80 mg BD, the hyperkalemia and metabolic acidosis resolved. The oral sodium chloride and sodium bicarbonate were gradually tailed off and stopped after cessation of the TMP-SMX. Clinical Lesson: Trimethoprim blocks the epithelial sodium channel (ENaC) of the principal cells in the terminal portion of the nephron, similar to potassium sparing diuretics like amiloride and triampterene. The resulting hyponatremia, hyperkalemia and metabolic acidosis can be life threatening. Therefore, monitoring of electrolytes and acid base status is important, particularly in susceptible patients or in those where a high dose of trimethoprim is required.

Results of a Gene Panel Approach in a Cohort of Patients with Incomplete Distal Renal Tubular Acidosis and Nephrolithiasis

Kidney & Blood Pressure Research ◽

10.1159/000516389 ◽

2021 ◽

pp. 1-6

Author(s):

Viola D’Ambrosio ◽

Alessia Azzarà ◽

Eugenio Sangiorgi ◽

Fiorella Gurrieri ◽

Bernhard Hess ◽

...

Keyword(s):

Metabolic Acidosis ◽

Genetic Testing ◽

Renal Tubular Acidosis ◽

Tubular Dysfunction ◽

Urine Ph ◽

Cross Sectional ◽

Urinary Acidification ◽

Stone Formers ◽

Background: Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH4Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. Methods: In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72. Results: Two unrelated individuals were found to have two different variants in SLC4A1 that had never been described before. Conclusions: Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients.

Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis.

Journal of the American Society of Nephrology ◽

10.1681/asn.v871109 ◽

1997 ◽

Vol 8 (7) ◽

pp. 1109-1117

Author(s):

B Bastani ◽

D Underhill ◽

N Chu ◽

R D Nelson ◽

L Haragsim ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Tubular Acidosis ◽

Frozen Section ◽

Collecting Duct ◽

Rat Kidney ◽

Intercalated Cells ◽

Urine Ph ◽

Control Serum ◽

In patients with Sjögren's syndrome and a secretory-defect distal renal tubular acidosis (dRTA), absence of vacuolar H(+)-ATPase from collecting duct intercalated cells has been reported. The H(+)-ATPase was examined in two patients with lupus nephritis and hyperkalemic (presumed voltage defect) dRTA. Both patients had a positive urine anion gap, alkaline urine despite acidemia, no rise in urine PCO2 with alkaluria, a urine pH > 5.5, and urine potassium excretion rate not significantly increased after 80 mg of intravenous furosemide. In both patients, immunocytochemistry of renal biopsy frozen sections with an anti-H(+)-ATPase monoclonal antibody showed bright staining of the proximal tubule brush border and collecting duct intercalated cells. In one patient, routine immunofluorescence analysis of a frozen section of her kidney biopsy with antihuman IgG showed staining of the collecting duct, indicative of autoantibodies to this segment. Moreover, rat kidney sections incubated with her serum showed labeling of the intercalated cells. On immunoblots of human kidney microsomal membranes performed with serum from both patients, an immunoreactive polypeptide was observed at M(r) approximately 56 kD that was not seen with control serum. Neither patient's sera reacted with affinity-purified bovine H(+)-ATPase or with lysates from 293 cell fibroblasts in which either of both isoforms of the human H(+)-ATPase B subunit (56 kD) were expressed. These findings demonstrate that the spectrum of dRTA includes the preservation of H(+)-ATPase in intercalated cells, in patients with presumed voltage defect dRTA. Moreover, some patients may have autoantibodies to the intercalated cells that are not directed to subunits of the H(+)-ATPase.

Renal and systemic acid-base effects of chronic spironolactone administration

AJP Renal Physiology ◽

10.1152/ajprenal.1981.240.5.f381 ◽

1981 ◽

Vol 240 (5) ◽

pp. F381-F387

Author(s):

H. N. Hulter ◽

E. L. Bonner ◽

R. D. Glynn ◽

A. Sebastian

Keyword(s):

Metabolic Acidosis ◽

Chronic Administration ◽

Nitrogen Excretion ◽

Acid Excretion ◽

Renal Secretion ◽

Acid Base ◽

Sulfuric Acid Production ◽

Renal Tubular ◽

Mineralocorticoid Activity ◽

Net Acid Excretion

Studies in dogs were carried out to investigate the effects of chronic administration of the mineralcorticoid antagonist spironolactone (15 mg/kg orally) on renal and systemic acid-base metabolism. In adrenalectomized dogs administered fixed mineralocorticoid and glucocorticoid replacement, spironolactone resulted in a definite renal antimineralocorticoid effect, as evidenced by natriuresis and chloruresis, and sustained metabolic acidosis and hyperkalemia due in part to impaired renal secretion of hydrogen and potassium. In adrenalectomized dogs receiving physiological glucocorticoid without mineralocorticoid, metabolic acidosis also occurred, but a marked stimulatory effect of spironolactone on net acid excretion occurred in association with increased urinary SO4-2 and total nitrogen excretion. Accordingly, spironolactone results in sustained renal tubular acidosis when administered in the presence of constant physiological levels of mineralocorticoid and glucocorticoid steroids. When administered under conditions of complete lack of mineralocorticoid activity, spironolactone exerts systemic and renal acid-base effects similar to those of a glucocorticoid steroid, namely, increased protein catabolism and sulfuric acid production with resultant extrarenal metabolic acidosis associated with increased net acid excretion.

Acid-Base Disorders

10.2310/tywc.4088 ◽

2018 ◽

Author(s):

Aaron Skolnik ◽

Jessica Monas

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Metabolic Alkalosis ◽

Respiratory Acidosis ◽

The Body ◽

Anion Gap ◽

Hydrogen Ions ◽

Acid Base Balance ◽

Acid Base ◽

Under physiologic conditions, the acid-base balance of the body is maintained via changes in ventilation that eliminate carbon dioxide, buffering of acid loads, and renal excretion of hydrogen ions. Failure to maintain the pH of the blood between 7.35 and 7.45 can result in life-threatening conditions. This review details the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of acid-base disorders. Figures show the relationship between hydrogen ions and blood pH, proximal tubular bicarbonate reabsorption, the secretion of hydrogen ions, renal ammonia production, ammonium diffusion, metabolic alkalosis, electrocardiographic changes in hypokalemia and hyperkalemia, pseudoinfarction caused by hyperkalemia, and an algorithmic approach to suspected acid-base disorders. Tables list causes of high–anion gap metabolic acidosis, metabolic acidosis with a normal anion gap, type 1 renal tubular acidosis, type 4 renal tubular acidosis and aldosterone resistance, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis; treatment of hyperkalemia; and a stepwise approach for the evaluation of suspected acid-base disorders. This review contains 9 highly rendered figures, 9 tables, 64 references, and a list of pertinent Web sites.

Acid-Base Disorders

10.2310/em.4088 ◽

2015 ◽

Author(s):

Aaron Skolnik ◽

Jessica Monas

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Metabolic Alkalosis ◽

Respiratory Acidosis ◽

The Body ◽

Anion Gap ◽

Hydrogen Ions ◽

Acid Base Balance ◽

Acid Base ◽

Role of organic anions in renal response to dietary acid and base loads

AJP Renal Physiology ◽

10.1152/ajprenal.1989.257.2.f170 ◽

1989 ◽

Vol 257 (2) ◽

pp. F170-F176 ◽

Cited By ~ 11

Author(s):

J. C. Brown ◽

R. K. Packer ◽

M. A. Knepper

Keyword(s):

Organic Anion ◽

Organic Anions ◽

Acid Excretion ◽

Acid Base Balance ◽

Acid Base ◽

Urine Ph ◽

Renal Response ◽

Base Balance ◽

Net Acid Excretion

Bicarbonate is formed when organic anions are oxidized systemically. Therefore, changes in organic anion excretion can affect systemic acid-base balance. To assess the role of organic anions in urinary acid-base excretion, we measured urinary excretion in control rats, NaHCO3-loaded rats, and NH4Cl-loaded rats. Total organic anions were measured by the titration method of Van Slyke. As expected, NaHCO3 loading increased urine pH and decreased net acid excretion (NH4+ + titratable acid - HCO3-), whereas NH4Cl loading had the opposite effect. Organic anion excretion was increased in response to NaHCO3 loading and decreased in response to NH4Cl loading. We quantified the overall effect of organic ion plus inorganic buffer ion excretion on acid-base balance. The amounts of organic anions excreted by all animals in this study were greater than the amounts of NH4+, HCO3-, or titratable acidity excreted. In addition, in response to acid and alkali loading, changes in urinary organic anion excretion were 40-50% as large as changes in net acid excretion. We conclude that, in rats, regulation of organic anion excretion can contribute importantly to the overall renal response to acid-base disturbances.