RARE DISEASE
Proximal renal tubular acidosis
Proximal renal tubular acidosis
Proximal renal tubular acidosis
Synonyms: Renal tubular acidosis type 2, pRTA
Synonyms: Renal tubular acidosis type 2, pRTA
Synonyms: Renal tubular acidosis type 2, pRTA
Drug discovery
0
drugs
With orphan designations
Overview
Proximal Renal Tubular Acidosis (pRTA)
A disorder of impaired bicarbonate reabsorption in the proximal tubule, causing hyperchloremic metabolic acidosis. Often linked to Fanconi syndrome (generalized proximal tubular dysfunction) or isolated genetic defects (e.g., SLC4A4 mutations). Characterized by hypokalemia, growth retardation in children, osteomalacia, and urinary bicarbonate wasting. Diagnosis relies on fractional bicarbonate excretion (>15%) and bicarbonate titration tests [1][2][7]. Treatment centers on high-dose alkali replacement and electrolyte management [3][8][11].
Population
Hereditary forms: Present in childhood (autosomal recessive SLC4A4 mutations often feature ocular abnormalities; autosomal dominant forms are milder) [7][10].
Acquired causes: Include medications (ifosfamide, tenofovir), systemic diseases (multiple myeloma, cystinosis), and Fanconi syndrome [1][2][11].
Burden
Chronic acidosis risks growth failure, rickets/osteomalacia, nephrolithiasis, and CKD progression [1][9][16].
Lifelong therapy adherence is required, with frequent electrolyte monitoring [8][10][11].
Hypokalemia increases arrhythmia risk, while bone complications elevate fracture susceptibility [2][7][11].
Therapies
Alkali therapy: Sodium bicarbonate or citrate (10–15 mEq/kg/day in children) to counteract acidosis [3][8][16].
Adjunctive measures: Thiazide diuretics to reduce bicarbonate loss; potassium supplementation for hypokalemia [1][9][11].
Comorbidity management: Vitamin D/calcium for bone demineralization; discontinuation of nephrotoxic drugs [2][8][15].
Categories: rare genetic diseases, rare renal diseases
Research Papers
210 drug discovery papers about Proximal renal tubular acidosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
210 drug discovery papers about Proximal renal tubular acidosis, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-27 | Perioperative fluid management in a patient with Fanconi syndrome and renal tubular acidosis undergoing major orthopaedic surgery: A case report
Fanconi syndrome (FS) due to tenofovir disoproxil fumarate (TDF) can lead to proximal renal tubular acidosis (type 2 RTA), bone fragility and pathological fractures. Perioperative fluid and acid-base management in this setting is complex and not well described. To outline the perioperative fluid approach, acid-base management and early outcome in a young woman with TDF-related FS and type 2 RTA undergoing major orthopaedic surgery. Case report of a 29-year-old human immunodeficiency virus-positive woman with kyphoscoliosis and bilateral subtrochanteric fractures who underwent bilateral femur osteotomies and cephalomedullary nail fixation. Perioperative care included multidisciplinary optimisation, adjustment of antiretroviral therapy, avoidance of nephrotoxins, correction of electrolytes, preference for balanced crystalloids, titrated bicarbonate therapy and close monitoring with serial blood gases and fluid balance in the intensive care unit (ICU). The patient was admitted to the ICU with severe non-anion gap metabolic acidosis (pH 7.22; base excess –11.3). With balanced crystalloids and bicarbonate therapy, acid-base status normalised within 72 h (Day 3: pH 7.39; HCO3 26.4 mmol/L), lactate resolved, haemodynamics stabilised and electrolytes corrected. Renal function remained stable, and she was discharged from the ICU with normal acid-base status for further orthopaedic rehabilitation. Contribution: In patients with TDF-associated FS and proximal RTA, a tailored physiology-based perioperative strategy emphasising balanced crystalloids, electrolyte correction and guided bicarbonate therapy can restore acid-base balance and allow safe recovery after major surgery. This case highlights practical considerations for fluid management in a high-risk group.
2026-05-01 | C43-20 When the Lungs Look Normal but Breathing Is Not: A Case of Hidden Metabolic Dyspnea
Abstract Introduction Unexplained dyspnea with normal imaging and pulmonary function testing poses a diagnostic challenge, particularly in patients with connective tissue disease (CTD). Systemic, metabolic, and mitochondrial disorders can mimic primary pulmonary pathology, leading to diagnostic uncertainty. We describe a case of a woman with undifferentiated CTD and persistent exertional dyspnea despite a normal cardiopulmonary evaluation, ultimately found to have a metabolic disturbance secondary to medication effect. Case Presentation A 36-year-old woman with undifferentiated CTD and a history of minocycline-induced lupus presented with progressive exertional dyspnea and fatigue beginning in early 2024. Her history was notable for chronic migraines and hemicrania continua treated with topiramate. She denied smoking or environmental exposures. High-resolution computed tomography (HRCT) of the chest and transthoracic echocardiography revealed no interstitial lung disease (ILD), pulmonary hypertension, or diaphragmatic dysfunction. Spirometry, total lung capacity and DLCO measurements were normal but reduced maximal inspiratory (MIP) and expiratory pressures (MEP) were observed, suggestive of respiratory muscle weakness. . Resting arterial blood gas analysis revealed chronic metabolic acidosis (serum bicarbonate 17 mmol/L) with respiratory compensation. Neurological evaluation noted normal limb strength but raised suspicion for subtle neuromuscular or mitochondrial dysfunction as this could cause chronic metabolic acidosis. Creatinine phosphokinase (CPK) levels, sniff test, and nerve conduction studies were normal, and the concern for neuromuscular disease was then ruled out by neurology. Nephrology attributed the acidosis to a proximal renal tubular acidosis, likely secondary to topiramate’s carbonic anhydrase inhibition. Sodium bicarbonate supplementation normalized serum bicarb level and improved symptoms. Following multidisciplinary discussion, topiramate was tapered and alternative migraine therapies pursued. Discussion This case underscores the complexity of evaluating dyspnea in CTD when conventional investigations—HRCT, PFTs, and echocardiography—are unrevealing. Metabolic acidosis caused by carbonic anhydrase inhibitors can provoke compensatory hyperventilation and contribute to dyspnea. In this patient, normalization of bicarbonate levels led to symptom improvement, emphasizing the importance of systemic assessment. A multidisciplinary approach is essential to identify overlapping systemic, neuromuscular, and metabolic contributors to dyspnea in patients with confounding CTD. This case highlights how medication effects, particularly those with multisystem impact, should be reviewed across specialties. In patients with CTD and unexplained dyspnea, diagnostic evaluation should extend beyond ILD to include metabolic, mitochondrial, and neuromuscular causes. Recognition of these subtler etiologies can guide targeted management and improve patient outcomes. This abstract is funded by: None
2026-03-26 | Renal tubular acidosis complication of non-steroidal anti-inflammatory drugs induced interstitial nephritis and its complete resolution with steroids: A case report.
Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively utilized for their analgesic and anti-inflammatory properties; however, their potential to induce renal adverse events remains a significant clinical concern. NSAID-induced interstitial nephritis (IN) and renal tubular acidosis (RTA) are rare but important complications of prolonged NSAID consumption. NSAID-induced RTA has been documented in limited case reports and usually resolves after stopping NSAIDs. However, our case shows a persistent, severe hypokalemia and hypophosphatemia linked to RTA from NSAID-induced IN, which resolved with steroid therapy. A 70-year-old woman with a history of chronic NSAID use presented with weakness and palpitations. She had atrial fibrillation, severe hypokalemia (K 1.5 mmol/L), non-anion gap metabolic acidosis (HCO3 11 mmol/L, anion gap 11), hypophosphatemia (1.2 mg/dL), acute kidney injury (creatinine 2 mg/dL from 0.6), and rhabdomyolysis (creatine kinase 15620 U/L). Urinalysis showed pH 6.5, proteinuria, sterile pyuria, and a positive urine anion gap, indicating RTA. Electrolytes improved with supplementation and spironolactone, but didn't normalize. At 4 weeks post-hospitalization, she still required supplementation; creatinine remained high. Renal biopsy revealed interstitial inflammation with active tubulitis, moderate interstitial fibrosis, and tubular atrophy. She was treated with 4 weeks of prednisone, leading to normalized electrolytes and improved creatinine (1 mg/dL), and the improvements were sustained 6 months post-treatment. Our patient exhibited persistent metabolic disturbances even after the cessation of NSAID therapy. Despite moderate chronicity, active interstitial inflammation responded favorably to corticosteroid treatment, resulting in improved renal function and restoration of tubular function, with normalization of acid-base and electrolyte parameters.
2026-03-17 | A Depolarizing Leak in Sodium Bicarbonate Cotransporter NBCe1 Causes Brain Edema.
SLC4A4 encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in SLC4A4 cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in SLC4A4 in patients with brain edema and investigate how it affects NBCe1 function. Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed to determine the localization of the transporter in the brain and the functional consequence of the patient variant. The same heterozygous variant in SLC4A4 was found in all three patients and one parent. The children displayed infantile-onset progressive macrocephaly, motor and cognitive impairment, autism, epilepsy, and recurrent episodes of increased intracranial pressure. Bicarbonate treatment of two patients led to clinical and MRI improvement. Immunohistochemistry revealed that brain NBCe1 is mainly present in astrocytes, more in cortex than white matter. Functional experiments revealed impaired transporter activity of mutant NBCe1 due to reduced membrane expression and a prominent depolarizing ion leak. The most likely pathomechanism of this novel SLC4A4-related disease is that a depolarizing leak in NBCe1 disrupts astrocyte pH regulation, promoting swelling and impairing volume control. These findings uncover a previously unrecognized mechanism of genetic brain edema and establish NBCe1 as a critical modulator of astrocyte homeostasis.
2026-02-11 | Metabolic acidosis causes a Fanconi-like syndrome with intracellular trafficking defects and proximal tubule dysfunction.
Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low-molecular weight proteins, a condition also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on ATPase H+ transporting V0 subunit a4 (Atp6v0a4) knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that ras analog in brain 7 (Rab7), a key regulator of endolysosomal trafficking and lysosomal biogenesis, was diminished, and the number of abnormal lysosomal-associated membrane protein 1 (Lamp1)-positive vesicles labeled for increased sodium tolerance 1 (Ist1) was increased in proximal tubules of Atp6v0a4 KO mice. This was accompanied by the accumulation of autophagosomes, autolysosomes, and autophagic substrates. Correction of metabolic acidosis with bicarbonate therapy resolved proximal tubule dysfunction and trafficking defects in Atp6v0a4 KO mice. After 28 days of acid challenge, wild-type mice showed comparable trafficking defects to Rab7 down-regulation and an increase in Ist1-labeled Lamp1-positive vesicles and proximal tubule damage. Acidosis-induced decreases in RAB7-labeled particles and increased numbers of IST1-labeled LAMP1-positive particles also occurred in proximal tubule correlates of human kidney organoids derived from the widely used induced pluripotent stem cell line KOLF2.1J. Together, our data provide insight into why patients suffering from severe dRTA can develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.
gene therapies
2022-08-17 | Case report: Altered pre-mRNA splicing caused by intronic variant c.1499 + 1G > A in the SLC4A4 gene
Proximal renal tubular acidosis (pRTA) with ocular abnormalities is an autosomal recessive disease caused by variants in the Solute Carrier Family 4 Member 4 ( SLC4A4 ) gene. Patients present with metabolic acidosis and low plasma bicarbonate concentration (3∼17 mmol/L). In addition, they are often accompanied by ocular abnormalities, intellectual disability, and growth retardation. The patient underwent whole exome sequencing (WES) and bioinformatics analysis of variant pathogenicity in this study. Then, a minigene assay was conducted to analyze the splicing site variant further. Compound heterozygous variants in the SLC4A4 gene (NM_003759.3), c.145C > T (p.Arg49*) and c.1499 + 1G > A, were detected by WES. The minigene assay showed an mRNA splicing aberration caused by the c.1499 + 1G > A variant. Compared with the wild type, the mutant type caused 4-base insertion between exons 10 and 11 of SLC4A4 after expression in HEK293 cells. In conclusion, the c.1499 + 1G > A variant in the SLC4A4 gene may be one of the genetic causes in the patient. Moreover, our study provides the foundation for future gene therapy of such pathogenic variants.
2020-02-01 | Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion
The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood.Here we evaluated the role of the inwardly rectifying potassium channel subunit Kir4.2 (Kcnj15 gene product) in this process.In mice, Kir4.2 was present exclusively at the basolateral membrane of proximal tubular cells and disruption of Kcnj15 caused a hyperchloremic metabolic acidosis associated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubule dysfunction.Urinary ammonium excretion rates in Kcnj15-deleted mice were inappropriate to acidosis under basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transporters in the collecting duct.In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximal cells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase enzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15deleted mice.Additionally, Kcnj15 deletion depolarized the proximal cell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization.Thus, the Kir4.2 potassium channel subunit is a newly recognized regulator of proximal ammonia metabolism.The kidney consequences of its loss of function in mice support the proposal for KCNJ15 as a molecular basis for human isolated proximal renal tubular acidosis.
2004-01-05 | Deficient HCO3- transport in an AE1 mutant with normal Cl- transport can be rescued by carbonic anhydrase II presented on an adjacent AE1 protomer.
Cl-/HCO3- exchange activity mediated by the AE1 anion exchanger is reduced by carbonic anhydrase II (CA2) inhibition or by prevention of CA2 binding to the AE1 C-terminal cytoplasmic tail. This type of AE1 inhibition is thought to represent reduced metabolic channeling of HCO3- to the intracellular HCO3- binding site of AE1. To test the hypothesis that CA2 binding might itself allosterically activate AE1 in Xenopus oocytes, we compared Cl-/Cl- and Cl-/HCO3- exchange activities of AE1 polypeptides with truncation and missense mutations in the C-terminal tail. The distal renal tubular acidosis-associated AE1 901X mutant exhibited both Cl-/Cl- and Cl-/HCO3- exchange activities. In contrast, AE1 896X, 891X, and AE1 missense mutants in the CA2 binding site were inactive as Cl-/HCO3- exchangers despite exhibiting normal Cl-/Cl- exchange activities. Co-expression of CA2 enhanced wild-type AE1-mediated Cl-/HCO3- exchange, but not Cl-/Cl- exchange. CA2 co-expression could not rescue Cl-/HCO3- exchange activity in AE1 mutants selectively impaired in Cl-/HCO3- exchange. However, co-expression of transport-incompetent AE1 mutants with intact CA2 binding sites completely rescued Cl-/HCO3- exchange by an AE1 missense mutant devoid of CA2 binding, with activity further enhanced by CA2 co-expression. The same transport-incompetent AE1 mutants failed to rescue Cl-/HCO3- exchange by the AE1 truncation mutant 896X, despite preservation of the latter's core CA2 binding site. These data increase the minimal extent of a functionally defined CA2 binding site in AE1. The inter-protomeric rescue of HCO3- transport within the AE1 dimer shows functional proximity of the C-terminal cytoplasmic tail of one protomer to the anion translocation pathway in the adjacent protomer within the AE1 heterodimer. The data strongly support the hypothesis that an intact transbilayer anion translocation pathway is completely contained within an AE1 monomer.
1998-07-31 | Promoter activity of carbonic anhydrase II regulatory regions in cultured renal proximal tubular cells.
Carbonic anhydrase II (CAII) plays an important role in the acid-base homeostasis of the body and its deficiency results in renal tubular acidosis. In order to identify the regulatory regions in the CAII gene for the future development of kidney-targeted gene therapy, we investigated the 5' region of the gene for its promoter activity. Deletion constructs with various lengths of the 5' flanking region of the human CAII promoter were ligated to the CAT reporter gene and lipofected in primary cultures of mouse proximal renal tubular cells and in cells of the established porcine proximal tubular cell line, LLC-PK1. The CAT activity was measured 48 hours after gene transfection. The -12000/CAT and -1300/CAT constructs expressed the highest CAT activity in both types of renal tubular cells (143- and 180-fold increase, respectively, in mouse proximal tubular cells; 50- and 70-fold increase, respectively, in LLC-PK1 cells) but not the -420/CAT, -270/CAT, or -180/CAT constructs (9, 12, and 9% of that of -1300/CAT construct, respectively, in mouse proximal tubular cells and, 23, 9, and 8%, respectively, in LLC-PK1 cells, all p <0.01 vs. -1300/CAT construct). No cytotoxicity was detected in the transfected cells. A computer search identified multiple putative transcription factor binding elements including Ap1 and Ap2 binding elements, which are present in the -1300/CAT construct but not in the shorter constructs. In conclusion, we demonstrate that the human CAII 5' sequence of proximal 1.3 kb contains strong promoter sequence(s) for renal tubular cells.
1998-04-23 | Correction of renal tubular acidosis in carbonic anhydrase II-deficient mice with gene therapy.
Carbonic anhydrase II (CAII) deficiency in humans is associated with a syndrome of renal tubular acidosis, osteopetrosis, and cerebral calcification. A strain of mice of CAII deficiency due to a point mutation also manifests renal tubular acidosis. We report here that retrograde injection of cationic liposome complexed with a CAII chimeric gene, using a cytomegalovirus (CMV) promoter/enhancer as an expression cassette to drive human CAII cDNA, into the renal pelvis of CAII-deficient mice results in expression of CAII in the kidney. The levels of both the CAII gene and its corresponding mRNA were highest by day 3 after treatment, diminishing thereafter, but remaining detectable by 1 mo. After gene therapy, CAII-deficient mice restored the ability to acidify urine after oral administration of ammonium chloride. The ability to acidify urine was maintained at 3 wk after gene therapy, and was eventually lost by 6 wk. Immunohistochemistry studies using anti-CAII antibodies showed that CAII was expressed in tubular cells of the outer medulla and corticomedullary junction. The gene therapy was not associated with nephrotoxicity as assessed by blood urea nitrogen levels and renal histology. To our knowledge, this is the first successful gene therapy of a genetic renal disease. Our results demonstrate the potential of gene therapy as a novel treatment for hereditary renal tubular defects.
antibodies
2025-04-02 | Case Report: A refractory unusual tetrad of overlap syndrome involving rheumatoid arthritis, Sjögren's syndrome, autoimmune hepatitis, and type 1 renal tubular acidosis, successfully treated with a BLyS/APRIL dual inhibitor.
Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) are systemic autoimmune conditions. SS frequently occurs associated with RA. In patients with RA, those with SS exhibit a higher disease burden, increased disease activity, and more complex comorbidities compared with those without SS. We report a 54-year-old female patient who was previously diagnosed with early-stage RA less than 1 year ago. She was subsequently confirmed to have SS associated with RA. Additionally, she developed multiple autoimmune comorbidities, including autoimmune hepatitis and type 1 renal tubular acidosis. The patient resisted various treatments, including immunosuppressive drugs, disease-modifying antirheumatic drugs, and anti-inflammatory small-molecule drugs. This was evidenced by poor DA28 responses, persistent laboratory abnormalities, and ongoing symptoms and signs. Finally, she responded well to Telitacicept, a BLyS/APRIL dual inhibitor. Even in the early stage, multiple autoimmune comorbidities can exhibit high levels of disease activity and may not respond to conventional therapies. Telitacicept, the first dual inhibitor of BLyS/APRIL, has the potential to provide significant efficacy and safety for RA patients who also have overlapping SS and other autoimmune diseases that do not respond to standard treatments. The limitations included the absence of a liver biopsy and the short follow-up period.
2015-05-19 | Secondary Sjogren's syndrome presenting with hypokalemic periodic paralysis.
Renal tubular acidosis (RTA) may develop in a large population of patients with Sjogren's syndrome (SS), but most of the subjects are asymptomatic. Here, we report a patient with known rheumatoid arthritis and symptoms of xerostomia, xerophthalmia and periodic paralysis. SS should be considered as a cause of RTA. The treatment of the underlying disorder may ameliorate the symptoms.
small molecules
2026-05-27 | Perioperative fluid management in a patient with Fanconi syndrome and renal tubular acidosis undergoing major orthopaedic surgery: A case report
Fanconi syndrome (FS) due to tenofovir disoproxil fumarate (TDF) can lead to proximal renal tubular acidosis (type 2 RTA), bone fragility and pathological fractures. Perioperative fluid and acid-base management in this setting is complex and not well described. To outline the perioperative fluid approach, acid-base management and early outcome in a young woman with TDF-related FS and type 2 RTA undergoing major orthopaedic surgery. Case report of a 29-year-old human immunodeficiency virus-positive woman with kyphoscoliosis and bilateral subtrochanteric fractures who underwent bilateral femur osteotomies and cephalomedullary nail fixation. Perioperative care included multidisciplinary optimisation, adjustment of antiretroviral therapy, avoidance of nephrotoxins, correction of electrolytes, preference for balanced crystalloids, titrated bicarbonate therapy and close monitoring with serial blood gases and fluid balance in the intensive care unit (ICU). The patient was admitted to the ICU with severe non-anion gap metabolic acidosis (pH 7.22; base excess –11.3). With balanced crystalloids and bicarbonate therapy, acid-base status normalised within 72 h (Day 3: pH 7.39; HCO3 26.4 mmol/L), lactate resolved, haemodynamics stabilised and electrolytes corrected. Renal function remained stable, and she was discharged from the ICU with normal acid-base status for further orthopaedic rehabilitation. Contribution: In patients with TDF-associated FS and proximal RTA, a tailored physiology-based perioperative strategy emphasising balanced crystalloids, electrolyte correction and guided bicarbonate therapy can restore acid-base balance and allow safe recovery after major surgery. This case highlights practical considerations for fluid management in a high-risk group.
2026-05-01 | C43-20 When the Lungs Look Normal but Breathing Is Not: A Case of Hidden Metabolic Dyspnea
Abstract Introduction Unexplained dyspnea with normal imaging and pulmonary function testing poses a diagnostic challenge, particularly in patients with connective tissue disease (CTD). Systemic, metabolic, and mitochondrial disorders can mimic primary pulmonary pathology, leading to diagnostic uncertainty. We describe a case of a woman with undifferentiated CTD and persistent exertional dyspnea despite a normal cardiopulmonary evaluation, ultimately found to have a metabolic disturbance secondary to medication effect. Case Presentation A 36-year-old woman with undifferentiated CTD and a history of minocycline-induced lupus presented with progressive exertional dyspnea and fatigue beginning in early 2024. Her history was notable for chronic migraines and hemicrania continua treated with topiramate. She denied smoking or environmental exposures. High-resolution computed tomography (HRCT) of the chest and transthoracic echocardiography revealed no interstitial lung disease (ILD), pulmonary hypertension, or diaphragmatic dysfunction. Spirometry, total lung capacity and DLCO measurements were normal but reduced maximal inspiratory (MIP) and expiratory pressures (MEP) were observed, suggestive of respiratory muscle weakness. . Resting arterial blood gas analysis revealed chronic metabolic acidosis (serum bicarbonate 17 mmol/L) with respiratory compensation. Neurological evaluation noted normal limb strength but raised suspicion for subtle neuromuscular or mitochondrial dysfunction as this could cause chronic metabolic acidosis. Creatinine phosphokinase (CPK) levels, sniff test, and nerve conduction studies were normal, and the concern for neuromuscular disease was then ruled out by neurology. Nephrology attributed the acidosis to a proximal renal tubular acidosis, likely secondary to topiramate’s carbonic anhydrase inhibition. Sodium bicarbonate supplementation normalized serum bicarb level and improved symptoms. Following multidisciplinary discussion, topiramate was tapered and alternative migraine therapies pursued. Discussion This case underscores the complexity of evaluating dyspnea in CTD when conventional investigations—HRCT, PFTs, and echocardiography—are unrevealing. Metabolic acidosis caused by carbonic anhydrase inhibitors can provoke compensatory hyperventilation and contribute to dyspnea. In this patient, normalization of bicarbonate levels led to symptom improvement, emphasizing the importance of systemic assessment. A multidisciplinary approach is essential to identify overlapping systemic, neuromuscular, and metabolic contributors to dyspnea in patients with confounding CTD. This case highlights how medication effects, particularly those with multisystem impact, should be reviewed across specialties. In patients with CTD and unexplained dyspnea, diagnostic evaluation should extend beyond ILD to include metabolic, mitochondrial, and neuromuscular causes. Recognition of these subtler etiologies can guide targeted management and improve patient outcomes. This abstract is funded by: None
2026-03-26 | Renal tubular acidosis complication of non-steroidal anti-inflammatory drugs induced interstitial nephritis and its complete resolution with steroids: A case report.
Non-steroidal anti-inflammatory drugs (NSAIDs) are extensively utilized for their analgesic and anti-inflammatory properties; however, their potential to induce renal adverse events remains a significant clinical concern. NSAID-induced interstitial nephritis (IN) and renal tubular acidosis (RTA) are rare but important complications of prolonged NSAID consumption. NSAID-induced RTA has been documented in limited case reports and usually resolves after stopping NSAIDs. However, our case shows a persistent, severe hypokalemia and hypophosphatemia linked to RTA from NSAID-induced IN, which resolved with steroid therapy. A 70-year-old woman with a history of chronic NSAID use presented with weakness and palpitations. She had atrial fibrillation, severe hypokalemia (K 1.5 mmol/L), non-anion gap metabolic acidosis (HCO3 11 mmol/L, anion gap 11), hypophosphatemia (1.2 mg/dL), acute kidney injury (creatinine 2 mg/dL from 0.6), and rhabdomyolysis (creatine kinase 15620 U/L). Urinalysis showed pH 6.5, proteinuria, sterile pyuria, and a positive urine anion gap, indicating RTA. Electrolytes improved with supplementation and spironolactone, but didn't normalize. At 4 weeks post-hospitalization, she still required supplementation; creatinine remained high. Renal biopsy revealed interstitial inflammation with active tubulitis, moderate interstitial fibrosis, and tubular atrophy. She was treated with 4 weeks of prednisone, leading to normalized electrolytes and improved creatinine (1 mg/dL), and the improvements were sustained 6 months post-treatment. Our patient exhibited persistent metabolic disturbances even after the cessation of NSAID therapy. Despite moderate chronicity, active interstitial inflammation responded favorably to corticosteroid treatment, resulting in improved renal function and restoration of tubular function, with normalization of acid-base and electrolyte parameters.
2026-03-17 | A Depolarizing Leak in Sodium Bicarbonate Cotransporter NBCe1 Causes Brain Edema.
SLC4A4 encodes electrogenic sodium bicarbonate cotransporter NBCe1, prominently expressed in kidney and brain. Recessive loss-of-function variants in SLC4A4 cause proximal renal tubular acidosis, no brain edema. In the brain, NBCe1 is expressed by astrocytes, where it regulates pH and mediates astrocyte volume changes. Here we describe a novel dominant variant in SLC4A4 in patients with brain edema and investigate how it affects NBCe1 function. Genetic studies identified a novel gene variant in three unrelated pediatric patients with the same MRI pattern of cerebral subcortical white matter signal abnormality and swelling, and medulla lesions. Immunohistochemical and electrophysiological experiments were performed to determine the localization of the transporter in the brain and the functional consequence of the patient variant. The same heterozygous variant in SLC4A4 was found in all three patients and one parent. The children displayed infantile-onset progressive macrocephaly, motor and cognitive impairment, autism, epilepsy, and recurrent episodes of increased intracranial pressure. Bicarbonate treatment of two patients led to clinical and MRI improvement. Immunohistochemistry revealed that brain NBCe1 is mainly present in astrocytes, more in cortex than white matter. Functional experiments revealed impaired transporter activity of mutant NBCe1 due to reduced membrane expression and a prominent depolarizing ion leak. The most likely pathomechanism of this novel SLC4A4-related disease is that a depolarizing leak in NBCe1 disrupts astrocyte pH regulation, promoting swelling and impairing volume control. These findings uncover a previously unrecognized mechanism of genetic brain edema and establish NBCe1 as a critical modulator of astrocyte homeostasis.
2026-02-11 | Metabolic acidosis causes a Fanconi-like syndrome with intracellular trafficking defects and proximal tubule dysfunction.
Patients suffering from distal renal tubular acidosis (dRTA) are sometimes diagnosed with proximal tubule dysfunction with leaks of phosphate, uric acid, amino acids, and low-molecular weight proteins, a condition also known as Fanconi-like syndrome. The underlying molecular basis is largely elusive. We previously reported on ATPase H+ transporting V0 subunit a4 (Atp6v0a4) knockout (KO) mice, which exhibit severe metabolic acidosis in combination with proximal tubule dysfunction as evidenced by phosphaturia and proteinuria. Here, we show that ras analog in brain 7 (Rab7), a key regulator of endolysosomal trafficking and lysosomal biogenesis, was diminished, and the number of abnormal lysosomal-associated membrane protein 1 (Lamp1)-positive vesicles labeled for increased sodium tolerance 1 (Ist1) was increased in proximal tubules of Atp6v0a4 KO mice. This was accompanied by the accumulation of autophagosomes, autolysosomes, and autophagic substrates. Correction of metabolic acidosis with bicarbonate therapy resolved proximal tubule dysfunction and trafficking defects in Atp6v0a4 KO mice. After 28 days of acid challenge, wild-type mice showed comparable trafficking defects to Rab7 down-regulation and an increase in Ist1-labeled Lamp1-positive vesicles and proximal tubule damage. Acidosis-induced decreases in RAB7-labeled particles and increased numbers of IST1-labeled LAMP1-positive particles also occurred in proximal tubule correlates of human kidney organoids derived from the widely used induced pluripotent stem cell line KOLF2.1J. Together, our data provide insight into why patients suffering from severe dRTA can develop a Fanconi-like syndrome, which may contribute to the progression of chronic kidney failure.
gene therapies
2022-08-17 | Case report: Altered pre-mRNA splicing caused by intronic variant c.1499 + 1G > A in the SLC4A4 gene
Proximal renal tubular acidosis (pRTA) with ocular abnormalities is an autosomal recessive disease caused by variants in the Solute Carrier Family 4 Member 4 ( SLC4A4 ) gene. Patients present with metabolic acidosis and low plasma bicarbonate concentration (3∼17 mmol/L). In addition, they are often accompanied by ocular abnormalities, intellectual disability, and growth retardation. The patient underwent whole exome sequencing (WES) and bioinformatics analysis of variant pathogenicity in this study. Then, a minigene assay was conducted to analyze the splicing site variant further. Compound heterozygous variants in the SLC4A4 gene (NM_003759.3), c.145C > T (p.Arg49*) and c.1499 + 1G > A, were detected by WES. The minigene assay showed an mRNA splicing aberration caused by the c.1499 + 1G > A variant. Compared with the wild type, the mutant type caused 4-base insertion between exons 10 and 11 of SLC4A4 after expression in HEK293 cells. In conclusion, the c.1499 + 1G > A variant in the SLC4A4 gene may be one of the genetic causes in the patient. Moreover, our study provides the foundation for future gene therapy of such pathogenic variants.
2020-02-01 | Defective bicarbonate reabsorption in Kir4.2 potassium channel deficient mice impairs acid-base balance and ammonia excretion
The kidneys excrete the daily acid load mainly by generating and excreting ammonia but the underlying molecular mechanisms are not fully understood.Here we evaluated the role of the inwardly rectifying potassium channel subunit Kir4.2 (Kcnj15 gene product) in this process.In mice, Kir4.2 was present exclusively at the basolateral membrane of proximal tubular cells and disruption of Kcnj15 caused a hyperchloremic metabolic acidosis associated with a reduced threshold for bicarbonate in the absence of a generalized proximal tubule dysfunction.Urinary ammonium excretion rates in Kcnj15-deleted mice were inappropriate to acidosis under basal and acid-loading conditions, and not related to a failure to acidify urine or a reduced expression of ammonia transporters in the collecting duct.In contrast, the expression of key proteins involved in ammonia metabolism and secretion by proximal cells, namely the glutamine transporter SNAT3, the phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase enzymes, and the sodium-proton exchanger NHE-3 was inappropriate in Kcnj15deleted mice.Additionally, Kcnj15 deletion depolarized the proximal cell membrane by decreasing the barium-sensitive component of the potassium conductance and caused an intracellular alkalinization.Thus, the Kir4.2 potassium channel subunit is a newly recognized regulator of proximal ammonia metabolism.The kidney consequences of its loss of function in mice support the proposal for KCNJ15 as a molecular basis for human isolated proximal renal tubular acidosis.
2004-01-05 | Deficient HCO3- transport in an AE1 mutant with normal Cl- transport can be rescued by carbonic anhydrase II presented on an adjacent AE1 protomer.
Cl-/HCO3- exchange activity mediated by the AE1 anion exchanger is reduced by carbonic anhydrase II (CA2) inhibition or by prevention of CA2 binding to the AE1 C-terminal cytoplasmic tail. This type of AE1 inhibition is thought to represent reduced metabolic channeling of HCO3- to the intracellular HCO3- binding site of AE1. To test the hypothesis that CA2 binding might itself allosterically activate AE1 in Xenopus oocytes, we compared Cl-/Cl- and Cl-/HCO3- exchange activities of AE1 polypeptides with truncation and missense mutations in the C-terminal tail. The distal renal tubular acidosis-associated AE1 901X mutant exhibited both Cl-/Cl- and Cl-/HCO3- exchange activities. In contrast, AE1 896X, 891X, and AE1 missense mutants in the CA2 binding site were inactive as Cl-/HCO3- exchangers despite exhibiting normal Cl-/Cl- exchange activities. Co-expression of CA2 enhanced wild-type AE1-mediated Cl-/HCO3- exchange, but not Cl-/Cl- exchange. CA2 co-expression could not rescue Cl-/HCO3- exchange activity in AE1 mutants selectively impaired in Cl-/HCO3- exchange. However, co-expression of transport-incompetent AE1 mutants with intact CA2 binding sites completely rescued Cl-/HCO3- exchange by an AE1 missense mutant devoid of CA2 binding, with activity further enhanced by CA2 co-expression. The same transport-incompetent AE1 mutants failed to rescue Cl-/HCO3- exchange by the AE1 truncation mutant 896X, despite preservation of the latter's core CA2 binding site. These data increase the minimal extent of a functionally defined CA2 binding site in AE1. The inter-protomeric rescue of HCO3- transport within the AE1 dimer shows functional proximity of the C-terminal cytoplasmic tail of one protomer to the anion translocation pathway in the adjacent protomer within the AE1 heterodimer. The data strongly support the hypothesis that an intact transbilayer anion translocation pathway is completely contained within an AE1 monomer.
1998-07-31 | Promoter activity of carbonic anhydrase II regulatory regions in cultured renal proximal tubular cells.
Carbonic anhydrase II (CAII) plays an important role in the acid-base homeostasis of the body and its deficiency results in renal tubular acidosis. In order to identify the regulatory regions in the CAII gene for the future development of kidney-targeted gene therapy, we investigated the 5' region of the gene for its promoter activity. Deletion constructs with various lengths of the 5' flanking region of the human CAII promoter were ligated to the CAT reporter gene and lipofected in primary cultures of mouse proximal renal tubular cells and in cells of the established porcine proximal tubular cell line, LLC-PK1. The CAT activity was measured 48 hours after gene transfection. The -12000/CAT and -1300/CAT constructs expressed the highest CAT activity in both types of renal tubular cells (143- and 180-fold increase, respectively, in mouse proximal tubular cells; 50- and 70-fold increase, respectively, in LLC-PK1 cells) but not the -420/CAT, -270/CAT, or -180/CAT constructs (9, 12, and 9% of that of -1300/CAT construct, respectively, in mouse proximal tubular cells and, 23, 9, and 8%, respectively, in LLC-PK1 cells, all p <0.01 vs. -1300/CAT construct). No cytotoxicity was detected in the transfected cells. A computer search identified multiple putative transcription factor binding elements including Ap1 and Ap2 binding elements, which are present in the -1300/CAT construct but not in the shorter constructs. In conclusion, we demonstrate that the human CAII 5' sequence of proximal 1.3 kb contains strong promoter sequence(s) for renal tubular cells.
1998-04-23 | Correction of renal tubular acidosis in carbonic anhydrase II-deficient mice with gene therapy.
Carbonic anhydrase II (CAII) deficiency in humans is associated with a syndrome of renal tubular acidosis, osteopetrosis, and cerebral calcification. A strain of mice of CAII deficiency due to a point mutation also manifests renal tubular acidosis. We report here that retrograde injection of cationic liposome complexed with a CAII chimeric gene, using a cytomegalovirus (CMV) promoter/enhancer as an expression cassette to drive human CAII cDNA, into the renal pelvis of CAII-deficient mice results in expression of CAII in the kidney. The levels of both the CAII gene and its corresponding mRNA were highest by day 3 after treatment, diminishing thereafter, but remaining detectable by 1 mo. After gene therapy, CAII-deficient mice restored the ability to acidify urine after oral administration of ammonium chloride. The ability to acidify urine was maintained at 3 wk after gene therapy, and was eventually lost by 6 wk. Immunohistochemistry studies using anti-CAII antibodies showed that CAII was expressed in tubular cells of the outer medulla and corticomedullary junction. The gene therapy was not associated with nephrotoxicity as assessed by blood urea nitrogen levels and renal histology. To our knowledge, this is the first successful gene therapy of a genetic renal disease. Our results demonstrate the potential of gene therapy as a novel treatment for hereditary renal tubular defects.
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2025-04-02 | Case Report: A refractory unusual tetrad of overlap syndrome involving rheumatoid arthritis, Sjögren's syndrome, autoimmune hepatitis, and type 1 renal tubular acidosis, successfully treated with a BLyS/APRIL dual inhibitor.
Rheumatoid arthritis (RA) and Sjögren's syndrome (SS) are systemic autoimmune conditions. SS frequently occurs associated with RA. In patients with RA, those with SS exhibit a higher disease burden, increased disease activity, and more complex comorbidities compared with those without SS. We report a 54-year-old female patient who was previously diagnosed with early-stage RA less than 1 year ago. She was subsequently confirmed to have SS associated with RA. Additionally, she developed multiple autoimmune comorbidities, including autoimmune hepatitis and type 1 renal tubular acidosis. The patient resisted various treatments, including immunosuppressive drugs, disease-modifying antirheumatic drugs, and anti-inflammatory small-molecule drugs. This was evidenced by poor DA28 responses, persistent laboratory abnormalities, and ongoing symptoms and signs. Finally, she responded well to Telitacicept, a BLyS/APRIL dual inhibitor. Even in the early stage, multiple autoimmune comorbidities can exhibit high levels of disease activity and may not respond to conventional therapies. Telitacicept, the first dual inhibitor of BLyS/APRIL, has the potential to provide significant efficacy and safety for RA patients who also have overlapping SS and other autoimmune diseases that do not respond to standard treatments. The limitations included the absence of a liver biopsy and the short follow-up period.
2015-05-19 | Secondary Sjogren's syndrome presenting with hypokalemic periodic paralysis.
Renal tubular acidosis (RTA) may develop in a large population of patients with Sjogren's syndrome (SS), but most of the subjects are asymptomatic. Here, we report a patient with known rheumatoid arthritis and symptoms of xerostomia, xerophthalmia and periodic paralysis. SS should be considered as a cause of RTA. The treatment of the underlying disorder may ameliorate the symptoms.
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