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

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.

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P0058THE ROLE OF GENETICS IN INCOMPLETE DISTAL RENAL TUBULAR ACIDOSIS IN NEPHROLITHIASIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0058 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Viola D'Ambrosio ◽

Eugenio Sangiorgi ◽

Bernhard Hess ◽

Giovanni Gambaro ◽

Pietro Manuel Ferraro

Keyword(s):

Metabolic Acidosis ◽

Genetic Testing ◽

Family History ◽

Renal Tubular Acidosis ◽

Kidney Stones ◽

Distal Renal Tubular Acidosis ◽

Urinary Acidification ◽

Stone Formers ◽

History Of ◽

Renal Tubular

Abstract Background and Aims Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in a hyperchloremic non-anion gap metabolic acidosis, hypokalemia and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis and recurrent nephrolithiasis, impaired renal function and bone demineralization due to reabsorption of bicarbonate and phosphate complexed with calcium from the bone as a buffer for metabolic acidosis. Distal RTA is therefore a well-defined entity that can be diagnosed by genetic testing of five genes known to be disease-causative (ATPV1B1 and ATPV0A4, FOXi1, SLC4A1 and WDR72). Incomplete distal renal tubular acidosis (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 other acid load tests. It is observed in 10-20% of calcium stone formers. It is still uncertain whether idRTA represents a distinct entity or it is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. Heterozygous ATP6V1B1 pathogenic variants have been linked to idRTA, as well as mutations in SLC4A1. Method In this cross-sectional study we investigated a group of 23 stone formers whose clinical features were suspicious of idRTA: a history of nephrolithiasis or nephrocalcinosis with morning urinary pH > 5.8 in the absence of overt metabolic acidosis. They therefore underwent a simplified NH4Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 4 genes: SLC4A1, ATP6V1B1, ATP6V0A4 and FOXi1. Results Two unrelated individuals were found to have mutations in SLC4A1: 2 different variants in heterozygosis that had never been described before. The first patient was a 47-year old man, recurrent stone former (mainly apatite, but also some calcium oxalate), with hypercalciuria but normal bone mineral density (BMD). His family history revealed 1 uncle with kidney stones. The second patient was a 56-year old woman with a diagnosis of osteogenesis imperfecta, a history of reduced BMD and severe restrictive ventilation disorder and passed 1 stone (35% apatite, 65% CaOx). She was found to have bilateral nephrocalcinosis and hypocitraturia. Her family history revealed a sister with kidney stones. Conversely, 21 patients did not show any mutations for the genes sequenced, leading to a prevalence of genetic mutations of 8.7%. This is a much lower figure compared with overt dRTA, in which only 30% of patients with a clinical diagnosis of hereditary dRTA have no identified causative mutations in the currently known genes. Conclusion This suggests the involvement of other genes (WDR72 or others) or non-genetic tubular dysfunction in the pathogenesis of idRTA in stone formers.

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Clinical and Molecular Findings in a Moroccan Family with Primary Distal Renal Tubular Acidosis and Deafness by Mutation of ATP60A4 Gene: Case Report

Asian Journal of Pediatric Research ◽

10.9734/ajpr/2021/v6i430200 ◽

2021 ◽

pp. 9-14

Author(s):

Nadia Mebrouk ◽

Rachid Abilkassem ◽

Aomar Agadr

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Collecting Duct ◽

Gene Mutations ◽

Recessive Gene ◽

Failure To Thrive ◽

Distal Renal Tubular Acidosis ◽

Tubular Dysfunction ◽

Dominant Form ◽

Renal Tubular

Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine. It is associated with impaired acid excretion by the intercalated cells in the renal collecting duct. dRTA is developed during the first months of life and the main clinical and biologic features are failure to thrive, vomiting, dehydration, anorexia, hyperchloremic non-anion gap metabolic acidosis, hypocitraturia, hypercalciuria and nephrocalcinosis. The disease is caused by defects in genes involved in urinary distal acidification: ATP6V0A4 and ATP6V1B1 for the recessive form, and SLC4A1 for the dominant form. Some dRTA cases due to recessive gene mutations are associated with hearing impairment. We report the case of two siblings with dRTA, and early-onset SNHL, due to ATP6V0A4 mutations, and whose parents are heterozygous carriers of ATP6V0A4 mutations.

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Prospective long-term evaluation of incomplete distal renal tubular acidosis in idiopathic calcium nephrolithiasis diagnosed (treated) by low-dose NH4CL loading – gender prevalences and impact of alkali treatment

Journal of Nephrology ◽

10.1007/s40620-021-01207-7 ◽

2022 ◽

Author(s):

Juri Sromicki ◽

Georg Kacl ◽

Malin Föhl ◽

Bernhard Hess

Keyword(s):

Calcium Phosphate ◽

Renal Tubular Acidosis ◽

Alkali Treatment ◽

Distal Renal Tubular Acidosis ◽

Urine Ph ◽

Calcium Stone ◽

Stone Formers ◽

Alkali Therapy ◽

Renal Tubular

Abstract Purpose Prospective evaluation of the prevalence of incomplete distal renal tubular acidosis (idRTA) in idiopathic calcium stone formers (ICSF) diagnosed by half-dose ammonium chloride loading (NH4Cl, 0.05 g/kg body weight/day) and impact of alkali treatment of idRTA. Methods Evaluation of 386 consecutive idiopathic calcium stone formers (ICSF) (280 males, 106 females) for idRTA. If screening fasting urine pH was > 5.80, 1-day NH4Cl loading was performed without severe adverse effects. Normally, urine pH falls below 5.45. Results Sixty-four idiopathic calcium stone formers exhibited idRTA, one complete dRTA. Prevalence was higher in women (25.4%) than in men (13.6%). Thus, for more equilibrated comparisons, we formed pairs of 62 idiopathic calcium stone formers (ICSF) with and 62 without idRTA, matched for gender, age, BMI and serum creatinine. Idiopathic calcium stone formers with idRTA more often had hypercalciuria (p < 0.025) and urine citrate < 2 mmol/d (p < 0.05), formed calcium phosphate stones more frequently, exhibited higher numbers of stones/year (1.4 ± 1.5 vs. 0.9 ± 0.8, p = 0.034) and 2.5 times more intrarenal calcifications (4.6 ± 5.9 vs. 1.8 ± 3.6, p = 0.002). All idiopathic calcium stone formers with idRTA were recommended chronic alkali therapy. After 4–15 years of follow-up, stone events /years follow-up (stone passage or urologic intervention) were higher in patients non-adherent to alkali therapy (0.61 ± 0.92) than in patients adherent to treatment (0.11 ± 0.21, p = 0.006). Conclusion Incomplete distal renal tubular acidosis is 1.8-fold more prevalent among female idiopathic calcium stone formers, predicts more stone recurrences, predisposes to calcium phosphate stones and is associated with 2.5 times more intrarenal calcifications vs. non-idRTA patients. Chronic alkali treatment reduces clinical stone recurrences by 5.5 times. Graphical abstract

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Inherited Proximal and Distal Renal Tubular Acidosis

10.2310/nephro.12046 ◽

2017 ◽

Author(s):

Patricia Valles ◽

Jesus Moran-Farias ◽

Daniel Batlle

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

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 ,

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Acute Respiratory Failure Due to Hypokalaemic Muscular Paralysis from Renal Tubular Acidosis

Anaesthesia and Intensive Care ◽

10.1177/0310057x0503300517 ◽

2005 ◽

Vol 33 (5) ◽

pp. 656-658 ◽

Cited By ~ 1

Author(s):

S. Gombar ◽

P. J. Mathew ◽

K. K. Gombar ◽

S. D'Cruz ◽

G. Goyal

Keyword(s):

Mechanical Ventilation ◽

Metabolic Acidosis ◽

Respiratory Failure ◽

Acute Respiratory Failure ◽

Renal Tubular Acidosis ◽

Cardiac Arrhythmias ◽

Distal Renal Tubular Acidosis ◽

Life Threatening ◽

Renal Tubular ◽

Potassium Replacement

We report a case of hypokalaemic quadriplegia with acute respiratory failure and life-threatening cardiac arrhythmias in a 26-year-old woman who was diagnosed to have distal renal tubular acidosis. She had persistent metabolic acidosis with severe hypokalaemia and required mechanical ventilation and potassium replacement. The anaesthetic implications of renal tubular acidosis are also discussed.

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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 ◽

Distal Renal Tubular Acidosis ◽

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.

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Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit

AJP Renal Physiology ◽

10.1152/ajprenal.00408.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. F1063-F1071 ◽

Cited By ~ 33

Author(s):

Jianning Zhang ◽

Daniel G. Fuster ◽

Mary Ann Cameron ◽

Henry Quiñones ◽

Carolyn Griffith ◽

...

Keyword(s):

Plasma Membrane ◽

Renal Tubular Acidosis ◽

Distal Renal Tubular Acidosis ◽

Heterozygous Mutation ◽

Wild Type ◽

Urine Ph ◽

293 Cells ◽

Heterozygous Carriers ◽

Renal Tubular ◽

Negative Dominance

Congenital distal renal tubular acidosis (RTA) from mutations of the B1 subunit of V-ATPase is considered an autosomal recessive disease. We analyzed a distal RTA kindred with a truncation mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO3−concentrations and thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria were present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also had inappropriate urinary acidification with acute ammonium chloride loading and an impaired urine-blood Pco2gradient during bicarbonaturia, indicating the presence of a H+gradient and flux defects. In normal human renal papillae, wild-type B1 is located primarily on the plasma membrane, but papilla from one of the heterozygote who had kidney stones but not nephrocalcinosis showed B1 in both the plasma membrane as well as diffuse intracellular staining. Titration of increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+pump activity of wild-type B1 in mammalian human embryonic kidney-293 cells and in V-ATPase-deficient Saccharomyces cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of a mutant B1 subunit that cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.

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ASIDOSIS TUBULAR RENAL DISTAL

Human Care Journal ◽

10.32883/hcj.v5i1.609 ◽

2020 ◽

Vol 5 (1) ◽

pp. 265

Author(s):

Ayu Pathya ◽

Harnavi Harun

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Bone Growth ◽

Hydrogen Ion ◽

Genetic Mutations ◽

Growth Disorders ◽

Urine Ph ◽

Renal Tubular ◽

Hands And Feet

Asidosis tubular renal (ATR) merupakan tubulopati ginjal yang jarang terjadi, dimana terdapat ketidakmampuan ginjal untuk menjaga perbedaan pH normal antara darah dan lumen tubulus ginjal. Pada kondisi ini terjadi gangguan pengasaman urin disebabkan gangguan reabsorbsi bikarbonat, gangguan ekskresi ion hidrogen, atau keduanya sehingga mengakibatkan asidosis metabolik. ATR ditandai dengan adanya asidosis metabolik dengan senjang anion plasma yang normal, hiperkloremik dan laju filtrasi glomerulus normal. ATR terbagi menjadi 3 tipe utama, yaitu ATR tipe 1 (ATR distal), tipe-2 (ATR proksimal), dan tipe 4 (ATR hiperkalemia). ATR distal merupakan ATR yang disebabkan oleh defek pada tubulus distal ginjal, dimana defek ini menyebabkan gangguan pada sekresi ion hidrogen. Beberapa penelitian menunjukkan bahwa ATR tipe 1 dikaitkan dengan mutasi genetik. Mutasi genetik herediter dapat autosomal dominan atau autosomal resesif. Gambaran klinis dapat mencakup kelainan pertumbuhan tulang, kelemahan atau kelumpuhan otot, deposit kalsium di ginjal, anoreksia, muntah, konstipasi, diare, dehidrasi, dan poliuria. Telah dilaporkan kasus pasien wanita usia 19 tahun dengan keluhan utama kelemahan di kedua tangan dan kaki. Dari penelusuran klinis dan laboratorium didapatkan hipokalemia dan berdasarkan pendekatan hipokalemia dengan HCO3- rendah dan pH urine >5,5, diagnosis pada pasien ini ditegakkan sebagai asidosis tubulus renal distal (ATRd).Kata kunci: ATR, ATRd, asidosis metabolik, hiperkloremik, hipokalemia AbstractRenal tubular acidosis (RTA) is a condition caused by the inability of the kidneys to maintain normal pH differences between the blood and tubules lumen of the kidney. Renal tubular acidosis is a rare kidney tubulopathy. In this condition, urine acidification is caused by bicarbonate reabsorption, disruption of hydrogen ion excretion, or both, resulting in metabolic acidosis. RTA is characterized by metabolic acidosis with normal plasma anion, hyperchloremic gaps and normal glomerular filtration rates. RTA is divided into 3 main types, namely type 1 RTA (distal RTA), type-2 (proximal RTA), and type 4 (hyperkalemia RTA). Distal RTA caused by defects in the distal tubules of the kidney, where these defects cause interference with the hydrogen ion secretion. Several studies have shown that type 1 RTA is associated with genetic mutations. Hereditary genetic mutations can be autosomal dominant or autosomal recessive. Clinical features can include bone growth disorders, muscle weakness or paralysis, calcium deposits in the kidneys, anorexia, vomiting, constipation, diarrhea, dehydration, and polyuria. There has been a reported case of a 19-year-old female patient with a chief complaint weakness in both hands and feet. From clinical and laboratory investigations, it was found that hypopotassium and based on the hypokalemia approach with low HCO3- and urine pH >5,5, the diagnosis in this patient was established as a distal renal tubular acidosis (RTAd) Keywords: RTA, RTAd ,metabolic acidosis, hypopotassium, hiperchloremic

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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 ◽

Distal Renal Tubular Acidosis ◽

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.

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Rickets with hypophosphatemia, hypokalemia and normal anion gap metabolic acidosis: not always an easy diagnosis

BMJ Case Reports ◽

10.1136/bcr-2019-233350 ◽

2020 ◽

Vol 13 (1) ◽

pp. e233350

Author(s):

Saurav Shishir Agrawal ◽

Chandan Kumar Mishra ◽

Chhavi Agrawal ◽

Partha Pratim Chakraborty

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Potassium Citrate ◽

Anion Gap ◽

Tubular Dysfunction ◽

Diagnostic Challenge ◽

Primary Defect ◽

Proximal Tubular Dysfunction ◽

Proximal Tubular ◽

Renal Tubular

Rickets other than those associated with advanced kidney disease, isolated distal renal tubular acidosis (dRTA) and hypophosphatasia (defective tissue non-specific alkaline phosphatase) are associated with hypophosphatemia due to abnormal proximal tubular reabsorption of phosphate. dRTA, however, at times is associated with completely reversible proximal tubular dysfunction. On the other hand, severe hypophosphatemia of different aetiologies may also interfere with both distal tubular acid excretion and proximal tubular functions giving rise to transient secondary renal tubular acidosis (distal and/or proximal). Hypophosphatemia and non-anion gap metabolic acidosis thus pose a diagnostic challenge occasionally. A definitive diagnosis and an appropriate management of the primary defect results in complete reversal of the secondary abnormality. A child with vitamin D resistant rickets was thoroughly evaluated and found to have primary dRTA with secondary proximal tubular dysfunction in the form of phosphaturia and low molecular weight proteinuria. The child was treated only with oral potassium citrate. A complete clinical, biochemical and radiological improvement was noticed in follow-up.

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