RARE DISEASE
Distal renal tubular acidosis
Distal renal tubular acidosis
Distal renal tubular acidosis
Synonyms: Classic RTA, Familial distal primary acidosis, Renal tubular acidosis type 1, dRTA
Synonyms: Classic RTA, Familial distal primary acidosis, Renal tubular acidosis type 1, dRTA
Synonyms: Classic RTA, Familial distal primary acidosis, Renal tubular acidosis type 1, dRTA
Drug discovery
2
drugs
With orphan designations
Overview
Distal Renal Tubular Acidosis (dRTA) is a disorder of impaired urinary acidification in the distal nephron, causing hyperchloremic metabolic acidosis. It arises from genetic mutations (e.g., ATP6V1B1, SLC4A1) or secondary causes (autoimmune diseases, medications). Key features include hypokalemia, nephrolithiasis, nephrocalcinosis, and bone demineralization. Diagnosis involves urinary pH >5.3 despite systemic acidosis and confirmed via acid-loading tests [1][2][6][9].
Population
Rare; hereditary forms (autosomal dominant/recessive) are more prevalent in consanguineous populations (e.g., North Africa, Southeast Asia). Acquired dRTA is associated with autoimmune diseases (e.g., Sjögren’s syndrome, SLE) or medications (e.g., amphotericin B) [2][4][14].
Onset varies: autosomal recessive forms present in infancy/childhood; autosomal dominant and acquired forms often manifest in adolescence/adulthood [2][6][11].
Burden
Complications: Nephrolithiasis (56%), CKD progression, osteomalacia/rickets, growth failure in children, and sensorineural hearing loss (genetic forms) [2][9][11].
Long-term impact: Chronic treatment adherence is critical; untreated cases risk renal failure [3][6][12].
Economic/psychosocial: Frequent monitoring, lifelong therapy, and reduced quality of life due to recurrent hospitalization and comorbidities [4][6].
Therapies
Alkali therapy: Sodium bicarbonate (1–8 mEq/kg/day) or potassium citrate to correct acidosis, hypokalemia, and reduce stone risk [1][3][12].
Targeted management: Potassium supplementation for hypokalemia; address underlying causes (e.g., immunosuppression for autoimmune-associated dRTA) [3][9][13].
Monitoring: Regular serum electrolytes, urinary calcium/citrate, and renal function to prevent CKD progression [2][6][12].
Categories: rare genetic diseases, rare renal diseases, rare transplant-related disorders
Research Papers
400 drug discovery papers about Distal renal tubular acidosis, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
400 drug discovery papers about Distal renal tubular acidosis, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Whole exome sequencing identifies three novel variants and establishes the molecular diagnosis of ATP6V0A4-related distal renal tubular acidosis in a lebanese infant.
Distal renal tubular acidosis (dRTA) is a rare inherited disorder characterized by impaired urinary acidification, leading to metabolic acidosis, hypokalemia, nephrocalcinosis, and growth impairment. Pathogenic variants in ATP6V0A4 are among the most common genetic causes of autosomal recessive dRTA. We report a Lebanese infant presenting with failure to thrive, recurrent vomiting, severe hyperchloremic metabolic acidosis, hypokalemia, and bilateral nephrocalcinosis, in whom whole-exome sequencing (WES) was performed to establish the molecular diagnosis and perform a comprehensive genomic evaluation. WES identified three novel variants, including a novel homozygous likely pathogenic ATP6V0A4 variant, consistent with the patient's phenotype. Two additional novel variants in TTN and CEP290 were also detected. Family segregation analysis confirmed the inheritance pattern of all three variants and refined the interpretation of the additional genomic findings. The patient showed sustained clinical and biochemical improvement to alkali therapy, with normalization of biochemical abnormalities and improvement in growth during follow-up. This report expands the molecular spectrum of ATP6V0A4-related dRTA and illustrates the clinical utility of comprehensive WES combined with segregation analysis for accurate molecular diagnosis, variant interpretation, genetic counseling, and the evaluation of additional genomic findings in rare inherited disorders.
2026-08-03 | Renal cysts in WDR72-associated distal renal tubular acidosis: expanding the phenotypic spectrum.
Pathogenic variants in the WDR72 gene are known to cause hypoplastic amelogenesis imperfecta (AI) and have recently been linked to distal renal tubular acidosis (dRTA). This case report highlights an unusual presentation of WDR72-associated dRTA with renal cysts. A 12-year-old boy presented with difficulty walking, lower limb deformities, and significant growth retardation. On examination, hypoplastic AI, rickets, and short stature were present. Biochemical investigations showed hypokalemia, hypophosphatemia, elevated alkaline phosphatase, and hypercalciuria. Imaging revealed medullary nephrocalcinosis and renal cysts. Clinical exome sequencing identified a homozygous pathogenic nonsense variant in WDR72 (NM_182758.4): c.2934G > A (p.Trp978Ter), consistent with autosomal recessive inheritance. He was diagnosed with dRTA and managed with potassium citrate and phosphate supplementation. Over two years, the patient showed improved growth velocity and reduced hypercalciuria, though nephrocalcinosis and renal cysts persisted. This case of WDR72-associated dRTA complicated by renal cyst formation is an underrecognized phenotype of this rare disorder. It further highlights that delayed diagnosis and prolonged, uncorrected tubulopathy may result in structural renal injury that is not fully reversible with treatment. Systematic renal evaluation, including biochemical assessment and renal ultrasonography, is strongly warranted in all children presenting with AI, particularly in the presence of concurrent growth failure, electrolyte disturbances, or rachitic changes, to facilitate early diagnosis and mitigate the risk of long-term renal sequelae.
2026-08-03 | Nephrogenic Diabetes Insipidus Presenting with Hypokalemic Paralysis in an Adolescent with Primary Sjögren's Syndrome: A Case Report.
Diabetes insipidus (DI) is a rare disorder characterized by polyuria, polydipsia, and dilute urine. Nephrogenic diabetes insipidus (NDI) secondary to distal renal tubular acidosis (dRTA) in primary Sjögren's syndrome (pSS) is exceedingly rare in children. A 16-year-old girl presented with hypokalemic paralysis (potassium 1.89 mmol/L), polyuria (>5 L/day),and growth retardation (height 141 cm, <3rd percentile). Laboratory studies revealed dRTA with secondary NDI. Autoimmune workup confirmed pSS. A systematic literature review identified only five similar pediatric cases. Initial management with hydrochlorothiazide exacerbated hypokalemia and precipitated hypochloremic metabolic alkalosis. Switching to amiloride combined with glucocorticoids and potassium supplementation normalized electrolytes, reduced urine output to 1.5 L/day, and resulted in catch-up growth at the 6-month follow-up. This case highlights the pathophysiologic cascade of pSS-related dRTA causing secondary NDI and underscores the importance of early recognition and tailored diuretic selection in adolescents.
2026-06-29 | Tislelizumab-induced distal renal tubular acidosis presenting with life-threatening hypokalemia: a case report.
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) affecting multiple organs. Distal renal tubular acidosis (dRTA) as a renal irAE is exceedingly rare, often delaying diagnosis due to nonspecific symptoms. A 63-year-old man with stage IIIA lung squamous cell carcinoma developed recurrent nausea and vomiting after three cycles of nab-paclitaxel/carboplatin combined with tislelizumab. Laboratory evaluation revealed profound metabolic acidosis (CO2-CP nadir 11.6 mmol/L) and life-threatening hypokalemia (serum potassium nadir 1.1 mmol/L), requiring ICU admission and mechanical ventilation. Despite aggressive intravenous potassium supplementation (up to 20 mEq/h), hypokalemia paradoxically worsened. Urine pH was 7.0 during systemic acidosis, indicating impaired renal acidification. After excluding other causes, a diagnosis of tislelizumab-induced dRTA was established. Tislelizumab was discontinued, and treatment with oral potassium citrate and prednisone (60 mg/day, tapered over 5.5 months) led to complete resolution of metabolic abnormalities. Over one year of follow-up, the patient has maintained normal renal function without recurrence and achieved a major partial response of his lung cancer. This first reported case of tislelizumab-induced dRTA highlights the need for vigilance when encountering unexplained, potassium-refractory electrolyte disturbances during ICI therapy, emphasizing early diagnosis, drug discontinuation, and pathophysiology-guided therapy.
2026-06-11 | Table 1_Tislelizumab-induced distal renal tubular acidosis presenting with life-threatening hypokalemia: a case report.docx
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) affecting multiple organs. Distal renal tubular acidosis (dRTA) as a renal irAE is exceedingly rare, often delaying diagnosis due to nonspecific symptoms. A 63-year-old man with stage IIIA lung squamous cell carcinoma developed recurrent nausea and vomiting after three cycles of nab-paclitaxel/carboplatin combined with tislelizumab. Laboratory evaluation revealed profound metabolic acidosis (CO2-CP nadir 11.6 mmol/L) and life-threatening hypokalemia (serum potassium nadir 1.1 mmol/L), requiring ICU admission and mechanical ventilation. Despite aggressive intravenous potassium supplementation (up to 20 mEq/h), hypokalemia paradoxically worsened. Urine pH was 7.0 during systemic acidosis, indicating impaired renal acidification. After excluding other causes, a diagnosis of tislelizumab-induced dRTA was established. Tislelizumab was discontinued, and treatment with oral potassium citrate and prednisone (60 mg/day, tapered over 5.5 months) led to complete resolution of metabolic abnormalities. Over one year of follow-up, the patient has maintained normal renal function without recurrence and achieved a major partial response of his lung cancer. This first reported case of tislelizumab-induced dRTA highlights the need for vigilance when encountering unexplained, potassium-refractory electrolyte disturbances during ICI therapy, emphasizing early diagnosis, drug discontinuation, and pathophysiology-guided therapy.
gene therapies
2025-01-21 | Accelerating nephrogenetics: from gene discovery to clinical application
This thesis aimed to advance nephrogenetics research from fundamental discoveries to clinical applications. First, it provides an overview of the current knowledge on genetic testing in monogenic kidney disease with a specific focus on copy number variants (CNVs). This thesis further highlights the importance of CNV analysis, which contributed to 10.5% of the diagnostic yield from genetic testing in patients with suspected monogenic kidney disease at the University Medical Centre Utrecht over an eight-year period. To improve the Dutch infrastructure for research on genetic kidney disease, the data- and biobank GeNepher was established, in which patients give broad consent for future research. Furthermore, to accelerate research into kidney gene discovery, a kidney-specific co-expression network was developed. This is an innovative tool that can predict and prioritize genes involved in kidney disease. With these resources in place, three (potential) new genetic causes of kidney disease were identified. The gene-disease association of heterozygous NEK8 variants with cystic kidney disease was discovered and TMEM72 and ALG6 were identified as novel ciliopathy candidate genes. Finally, this thesis demonstrates the benefits of adopting a genetics-first approach, exemplified by patients with medullary sponge kidneys who were diagnosed with primary distal renal tubular acidosis (dRTA), resulting in a genetic diagnosis that modified their treatment, and highlighting this underrecognized gene-disease association.
2022-07-05 | Sjogren- Larsson Syndrome with Type-1 Distal Renal Tubular Acidosis in Siblings
Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive lipid metabolic disorder caused because of the defect in fatty alcohol oxidation resulting from fatty aldehyde dehydrogenase (FALDH3A2) deficiency. Sjogren-Larsson syndrome is constituted by the trio of generalised spastic paralysis, intellectual impairment, & ichthyosis. The inability of hydrogen ions secretion from the distal tubule characterises dRTA (distal (Type 1) renal tubular acidosis). The dRTA aetiology is diverse, but it can be acquired or inherited. We report siblings who presented with congenital ichthyotic hyperkeratosis, spastic diplegia and severe learning disabilities, which were suggestive of SLS. Distal renal tubular acidosis diagnosis was done on the basis of severe serum hypokalaemia, urine electrolytes showing high potassium levels, metabolic acidosis with a positive anion gap, high pH of urine, Urinary & Blood PCO2 difference (UB PCO2) on the lower side, (FeHCO3%) showing mild bicarbonaturia (<5%), medullary nephrocalcinosis, Hypercalciuria as well as the omission of other differential diagnosis. Management in SLS was supportive. The child demonstrated symptomatic improvement after starting standard therapy for SLS & distal renal tubular acidosis. To conclude, distal renal tubular acidosis ailment in children can be controlled with a good long-term prognosis, but precise diagnosis as well as management are critical. Early detection can assist the physician in implementing appropriate supportive care as well as possible curative gene therapy. Keywords: Ichthyosis, spastic diplegia, Intellectual disability, Distal Renal Tubular Acidosis, Hypokalaemia
2014-08-28 | Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit
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 V 1 domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO 3 − 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 Pco 2 gradient 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.
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
2026-03-30 | Case report: Thymoma-associated GAD65 autoimmunity: a unifying mechanism for multi-organ injury involving nervous, endocrine, and renal systems.
Thymomas are well-established disruptors of central immune tolerance, yet their capacity to drive systemic autoimmunity via a single autoantigen remains incompletely characterized. We report a 59-year-old male who, following resection of a Masaoka stage IIb type B2 thymoma, developed sequential neurological, endocrine, and renal manifestations over 18 months. Clinical evaluation confirmed stiff-person syndrome (SPS) with axial muscle hypermetabolism on PET-CT, latent autoimmune diabetes (HbA1c 11%), subclinical hypothyroidism (TSH 15.28 μIU/mL), and distal renal tubular acidosis (dRTA) evidenced by severe hypokalemia (K+ 2.4 mmol/L) and inappropriately alkaline urine (pH 7.5). All three syndromes were associated with persistently high-titer glutamic acid decarboxylase 65 (GAD65) autoantibodies (>500 nmol/L in serum). Epitope mapping identified molecular mimicry between the GAD65 peptide ²60PEVKEK²65 and homologous sequences in renal H+-ATPase and thyroid peroxidase, providing a mechanistic basis for multi-organ cross-reactivity. Treatment with intravenous immunoglobulin (IVIG) led to a 53.6% reduction in serum and an 80% decline in cerebrospinal fluid GAD65 antibody levels, paralleling clinical improvement. This case illustrates how thymoma-induced loss of tolerance to GAD65 can trigger widespread autoimmune injury through conformational epitope spreading, positioning GAD65 as a paraneoplastic pan-autoantigen. High-titer GAD65 antibodies may serve as a biomarker for systemic involvement, supporting early multidisciplinary surveillance in thymoma patients.
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.
2017-08-03 | Hypokalemic Paralysis: A Hidden Card of Several Autoimmune Diseases
Acute hypokalemic paralysis is a rare and potentially fatal condition, with few related causes, one of which highlights distal renal tubular acidosis (dRTA). Distal renal tubular acidosis is a rare complication of several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and Hashimoto thyroiditis. We report a case of a lupic patient who presented rapidly progressive quadriparesis in the context of active renal disease. Research revealed severe refractory hypokalemia, metabolic acidosis, and alkaline urine suggestive of dRTA. We diagnosed Sjögren's syndrome based on sicca symptoms, an abnormal salivary glands' nuclear scan and the presence of anti-Ro/SSA and anti-La/SSB. In addition, the finding of thyroid peroxidase, thyroglobulin antibodies, and hypothyroidism led us to the diagnosis of Hashimoto thyroiditis. Due to the active renal involvement on the context of systemic lupus erythematosus and Sjögren's syndrome, the patient received immunosuppression with rituximab, resulting in a progressive and complete improvement.
2014-09-18 | Delayed and Long-term Remission of Refractory Hemolytic Anemia in a Child with Systemic Lupus Erythematosus Treated with Rituximab
Autoimmune hemolytic anemia (AIHA) is a relatively common cause of anemia in children and adults with systemic lupus erythematosus (SLE). Although AIHA responds to steroids, in case of refractory or steroid-dependent AIHA, immunosuppressants and intravenous immunoglobulin have been used as second line agents. Rituximab, an anti-CD20 monoclonal antibody, is emerging in the treatment of SLE refractory to conventional therapy. Herein, we report a case of delayed and sustained remission of refractory hemolytic anemia in a child with SLE, post rituximab treatment. A 12-year-old female child with dizziness was referred to our department and was diagnosed with SLE combined with hemolytic anemia and renal tubular acidosis. Since frequent relapse of hemolytic anemia had occurred during the steroid tapering course, even though she had been treated with additional immunosuppressants (azathioprine, mycophenolate mofetil), the patient received 2 doses of rituximab 500 mg at 2 weeks interval at 18 months post diagnosis. After 15 months of rituximab administration, her anemia and renal tubular acidosis were fully recovered, enough to stop all medications. She remained well without recurrence for up to 3 years and 4 months after rituximab treatment.
small molecules
2026-08-13 | Whole exome sequencing identifies three novel variants and establishes the molecular diagnosis of ATP6V0A4-related distal renal tubular acidosis in a lebanese infant.
Distal renal tubular acidosis (dRTA) is a rare inherited disorder characterized by impaired urinary acidification, leading to metabolic acidosis, hypokalemia, nephrocalcinosis, and growth impairment. Pathogenic variants in ATP6V0A4 are among the most common genetic causes of autosomal recessive dRTA. We report a Lebanese infant presenting with failure to thrive, recurrent vomiting, severe hyperchloremic metabolic acidosis, hypokalemia, and bilateral nephrocalcinosis, in whom whole-exome sequencing (WES) was performed to establish the molecular diagnosis and perform a comprehensive genomic evaluation. WES identified three novel variants, including a novel homozygous likely pathogenic ATP6V0A4 variant, consistent with the patient's phenotype. Two additional novel variants in TTN and CEP290 were also detected. Family segregation analysis confirmed the inheritance pattern of all three variants and refined the interpretation of the additional genomic findings. The patient showed sustained clinical and biochemical improvement to alkali therapy, with normalization of biochemical abnormalities and improvement in growth during follow-up. This report expands the molecular spectrum of ATP6V0A4-related dRTA and illustrates the clinical utility of comprehensive WES combined with segregation analysis for accurate molecular diagnosis, variant interpretation, genetic counseling, and the evaluation of additional genomic findings in rare inherited disorders.
2026-08-03 | Renal cysts in WDR72-associated distal renal tubular acidosis: expanding the phenotypic spectrum.
Pathogenic variants in the WDR72 gene are known to cause hypoplastic amelogenesis imperfecta (AI) and have recently been linked to distal renal tubular acidosis (dRTA). This case report highlights an unusual presentation of WDR72-associated dRTA with renal cysts. A 12-year-old boy presented with difficulty walking, lower limb deformities, and significant growth retardation. On examination, hypoplastic AI, rickets, and short stature were present. Biochemical investigations showed hypokalemia, hypophosphatemia, elevated alkaline phosphatase, and hypercalciuria. Imaging revealed medullary nephrocalcinosis and renal cysts. Clinical exome sequencing identified a homozygous pathogenic nonsense variant in WDR72 (NM_182758.4): c.2934G > A (p.Trp978Ter), consistent with autosomal recessive inheritance. He was diagnosed with dRTA and managed with potassium citrate and phosphate supplementation. Over two years, the patient showed improved growth velocity and reduced hypercalciuria, though nephrocalcinosis and renal cysts persisted. This case of WDR72-associated dRTA complicated by renal cyst formation is an underrecognized phenotype of this rare disorder. It further highlights that delayed diagnosis and prolonged, uncorrected tubulopathy may result in structural renal injury that is not fully reversible with treatment. Systematic renal evaluation, including biochemical assessment and renal ultrasonography, is strongly warranted in all children presenting with AI, particularly in the presence of concurrent growth failure, electrolyte disturbances, or rachitic changes, to facilitate early diagnosis and mitigate the risk of long-term renal sequelae.
2026-08-03 | Nephrogenic Diabetes Insipidus Presenting with Hypokalemic Paralysis in an Adolescent with Primary Sjögren's Syndrome: A Case Report.
Diabetes insipidus (DI) is a rare disorder characterized by polyuria, polydipsia, and dilute urine. Nephrogenic diabetes insipidus (NDI) secondary to distal renal tubular acidosis (dRTA) in primary Sjögren's syndrome (pSS) is exceedingly rare in children. A 16-year-old girl presented with hypokalemic paralysis (potassium 1.89 mmol/L), polyuria (>5 L/day),and growth retardation (height 141 cm, <3rd percentile). Laboratory studies revealed dRTA with secondary NDI. Autoimmune workup confirmed pSS. A systematic literature review identified only five similar pediatric cases. Initial management with hydrochlorothiazide exacerbated hypokalemia and precipitated hypochloremic metabolic alkalosis. Switching to amiloride combined with glucocorticoids and potassium supplementation normalized electrolytes, reduced urine output to 1.5 L/day, and resulted in catch-up growth at the 6-month follow-up. This case highlights the pathophysiologic cascade of pSS-related dRTA causing secondary NDI and underscores the importance of early recognition and tailored diuretic selection in adolescents.
2026-06-29 | Tislelizumab-induced distal renal tubular acidosis presenting with life-threatening hypokalemia: a case report.
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) affecting multiple organs. Distal renal tubular acidosis (dRTA) as a renal irAE is exceedingly rare, often delaying diagnosis due to nonspecific symptoms. A 63-year-old man with stage IIIA lung squamous cell carcinoma developed recurrent nausea and vomiting after three cycles of nab-paclitaxel/carboplatin combined with tislelizumab. Laboratory evaluation revealed profound metabolic acidosis (CO2-CP nadir 11.6 mmol/L) and life-threatening hypokalemia (serum potassium nadir 1.1 mmol/L), requiring ICU admission and mechanical ventilation. Despite aggressive intravenous potassium supplementation (up to 20 mEq/h), hypokalemia paradoxically worsened. Urine pH was 7.0 during systemic acidosis, indicating impaired renal acidification. After excluding other causes, a diagnosis of tislelizumab-induced dRTA was established. Tislelizumab was discontinued, and treatment with oral potassium citrate and prednisone (60 mg/day, tapered over 5.5 months) led to complete resolution of metabolic abnormalities. Over one year of follow-up, the patient has maintained normal renal function without recurrence and achieved a major partial response of his lung cancer. This first reported case of tislelizumab-induced dRTA highlights the need for vigilance when encountering unexplained, potassium-refractory electrolyte disturbances during ICI therapy, emphasizing early diagnosis, drug discontinuation, and pathophysiology-guided therapy.
2026-06-11 | Table 1_Tislelizumab-induced distal renal tubular acidosis presenting with life-threatening hypokalemia: a case report.docx
Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs) affecting multiple organs. Distal renal tubular acidosis (dRTA) as a renal irAE is exceedingly rare, often delaying diagnosis due to nonspecific symptoms. A 63-year-old man with stage IIIA lung squamous cell carcinoma developed recurrent nausea and vomiting after three cycles of nab-paclitaxel/carboplatin combined with tislelizumab. Laboratory evaluation revealed profound metabolic acidosis (CO2-CP nadir 11.6 mmol/L) and life-threatening hypokalemia (serum potassium nadir 1.1 mmol/L), requiring ICU admission and mechanical ventilation. Despite aggressive intravenous potassium supplementation (up to 20 mEq/h), hypokalemia paradoxically worsened. Urine pH was 7.0 during systemic acidosis, indicating impaired renal acidification. After excluding other causes, a diagnosis of tislelizumab-induced dRTA was established. Tislelizumab was discontinued, and treatment with oral potassium citrate and prednisone (60 mg/day, tapered over 5.5 months) led to complete resolution of metabolic abnormalities. Over one year of follow-up, the patient has maintained normal renal function without recurrence and achieved a major partial response of his lung cancer. This first reported case of tislelizumab-induced dRTA highlights the need for vigilance when encountering unexplained, potassium-refractory electrolyte disturbances during ICI therapy, emphasizing early diagnosis, drug discontinuation, and pathophysiology-guided therapy.
gene therapies
2025-01-21 | Accelerating nephrogenetics: from gene discovery to clinical application
This thesis aimed to advance nephrogenetics research from fundamental discoveries to clinical applications. First, it provides an overview of the current knowledge on genetic testing in monogenic kidney disease with a specific focus on copy number variants (CNVs). This thesis further highlights the importance of CNV analysis, which contributed to 10.5% of the diagnostic yield from genetic testing in patients with suspected monogenic kidney disease at the University Medical Centre Utrecht over an eight-year period. To improve the Dutch infrastructure for research on genetic kidney disease, the data- and biobank GeNepher was established, in which patients give broad consent for future research. Furthermore, to accelerate research into kidney gene discovery, a kidney-specific co-expression network was developed. This is an innovative tool that can predict and prioritize genes involved in kidney disease. With these resources in place, three (potential) new genetic causes of kidney disease were identified. The gene-disease association of heterozygous NEK8 variants with cystic kidney disease was discovered and TMEM72 and ALG6 were identified as novel ciliopathy candidate genes. Finally, this thesis demonstrates the benefits of adopting a genetics-first approach, exemplified by patients with medullary sponge kidneys who were diagnosed with primary distal renal tubular acidosis (dRTA), resulting in a genetic diagnosis that modified their treatment, and highlighting this underrecognized gene-disease association.
2022-07-05 | Sjogren- Larsson Syndrome with Type-1 Distal Renal Tubular Acidosis in Siblings
Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive lipid metabolic disorder caused because of the defect in fatty alcohol oxidation resulting from fatty aldehyde dehydrogenase (FALDH3A2) deficiency. Sjogren-Larsson syndrome is constituted by the trio of generalised spastic paralysis, intellectual impairment, & ichthyosis. The inability of hydrogen ions secretion from the distal tubule characterises dRTA (distal (Type 1) renal tubular acidosis). The dRTA aetiology is diverse, but it can be acquired or inherited. We report siblings who presented with congenital ichthyotic hyperkeratosis, spastic diplegia and severe learning disabilities, which were suggestive of SLS. Distal renal tubular acidosis diagnosis was done on the basis of severe serum hypokalaemia, urine electrolytes showing high potassium levels, metabolic acidosis with a positive anion gap, high pH of urine, Urinary & Blood PCO2 difference (UB PCO2) on the lower side, (FeHCO3%) showing mild bicarbonaturia (<5%), medullary nephrocalcinosis, Hypercalciuria as well as the omission of other differential diagnosis. Management in SLS was supportive. The child demonstrated symptomatic improvement after starting standard therapy for SLS & distal renal tubular acidosis. To conclude, distal renal tubular acidosis ailment in children can be controlled with a good long-term prognosis, but precise diagnosis as well as management are critical. Early detection can assist the physician in implementing appropriate supportive care as well as possible curative gene therapy. Keywords: Ichthyosis, spastic diplegia, Intellectual disability, Distal Renal Tubular Acidosis, Hypokalaemia
2014-08-28 | Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit
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 V 1 domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO 3 − 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 Pco 2 gradient 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.
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
2026-03-30 | Case report: Thymoma-associated GAD65 autoimmunity: a unifying mechanism for multi-organ injury involving nervous, endocrine, and renal systems.
Thymomas are well-established disruptors of central immune tolerance, yet their capacity to drive systemic autoimmunity via a single autoantigen remains incompletely characterized. We report a 59-year-old male who, following resection of a Masaoka stage IIb type B2 thymoma, developed sequential neurological, endocrine, and renal manifestations over 18 months. Clinical evaluation confirmed stiff-person syndrome (SPS) with axial muscle hypermetabolism on PET-CT, latent autoimmune diabetes (HbA1c 11%), subclinical hypothyroidism (TSH 15.28 μIU/mL), and distal renal tubular acidosis (dRTA) evidenced by severe hypokalemia (K+ 2.4 mmol/L) and inappropriately alkaline urine (pH 7.5). All three syndromes were associated with persistently high-titer glutamic acid decarboxylase 65 (GAD65) autoantibodies (>500 nmol/L in serum). Epitope mapping identified molecular mimicry between the GAD65 peptide ²60PEVKEK²65 and homologous sequences in renal H+-ATPase and thyroid peroxidase, providing a mechanistic basis for multi-organ cross-reactivity. Treatment with intravenous immunoglobulin (IVIG) led to a 53.6% reduction in serum and an 80% decline in cerebrospinal fluid GAD65 antibody levels, paralleling clinical improvement. This case illustrates how thymoma-induced loss of tolerance to GAD65 can trigger widespread autoimmune injury through conformational epitope spreading, positioning GAD65 as a paraneoplastic pan-autoantigen. High-titer GAD65 antibodies may serve as a biomarker for systemic involvement, supporting early multidisciplinary surveillance in thymoma patients.
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.
2017-08-03 | Hypokalemic Paralysis: A Hidden Card of Several Autoimmune Diseases
Acute hypokalemic paralysis is a rare and potentially fatal condition, with few related causes, one of which highlights distal renal tubular acidosis (dRTA). Distal renal tubular acidosis is a rare complication of several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and Hashimoto thyroiditis. We report a case of a lupic patient who presented rapidly progressive quadriparesis in the context of active renal disease. Research revealed severe refractory hypokalemia, metabolic acidosis, and alkaline urine suggestive of dRTA. We diagnosed Sjögren's syndrome based on sicca symptoms, an abnormal salivary glands' nuclear scan and the presence of anti-Ro/SSA and anti-La/SSB. In addition, the finding of thyroid peroxidase, thyroglobulin antibodies, and hypothyroidism led us to the diagnosis of Hashimoto thyroiditis. Due to the active renal involvement on the context of systemic lupus erythematosus and Sjögren's syndrome, the patient received immunosuppression with rituximab, resulting in a progressive and complete improvement.
2014-09-18 | Delayed and Long-term Remission of Refractory Hemolytic Anemia in a Child with Systemic Lupus Erythematosus Treated with Rituximab
Autoimmune hemolytic anemia (AIHA) is a relatively common cause of anemia in children and adults with systemic lupus erythematosus (SLE). Although AIHA responds to steroids, in case of refractory or steroid-dependent AIHA, immunosuppressants and intravenous immunoglobulin have been used as second line agents. Rituximab, an anti-CD20 monoclonal antibody, is emerging in the treatment of SLE refractory to conventional therapy. Herein, we report a case of delayed and sustained remission of refractory hemolytic anemia in a child with SLE, post rituximab treatment. A 12-year-old female child with dizziness was referred to our department and was diagnosed with SLE combined with hemolytic anemia and renal tubular acidosis. Since frequent relapse of hemolytic anemia had occurred during the steroid tapering course, even though she had been treated with additional immunosuppressants (azathioprine, mycophenolate mofetil), the patient received 2 doses of rituximab 500 mg at 2 weeks interval at 18 months post diagnosis. After 15 months of rituximab administration, her anemia and renal tubular acidosis were fully recovered, enough to stop all medications. She remained well without recurrence for up to 3 years and 4 months after rituximab treatment.
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Drug Discovery Landscape
2 orphan drug designations for Distal renal tubular acidosis.
2 orphan drug designations for Distal renal tubular acidosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
fixed-dose combination of potassium citrate and potassium bicarbonate | small molecules | FDA | 2022-12-09 | — | Advicenne |
Potassium citrate monohydrate, Potassium hydrogen carbonate [Sibnayal] | small molecules | EMA | 2017-06-20 | — | [INACTIVE] Advicenne |
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