Renal Tubular Acidosis Distal 4 with Hemolytic Anemia

Mendelian MONDO:0012700 Pathograph 24 autosomal recessive distal renal tubular acidosis familial hemolytic anemia

Renal tubular acidosis, distal, 4, with hemolytic anemia is an inherited SLC4A1-related disorder that combines impaired renal distal acid secretion with red-cell membrane disease. In the best-described Indian families, homozygous SLC4A1 p.Ala858Asp (A858D) causes autosomal recessive distal renal tubular acidosis coupled with hereditary spherocytosis or hemolytic anemia. The shared AE1/band 3 defect links kidney type A intercalated-cell bicarbonate exchange to erythrocyte membrane stability.

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1
Inheritance
3
Pathophys.
12
Phenotypes
24
Pathograph
1
Genes
2
Treatments
1
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:37448902 SUPPORT Human Clinical
"This report identifies an autosomal recessive inheritance pattern for SLC4A1 variants in a patient presenting with dRTA and hemolytic anemia."
This adult case report explicitly classifies the SLC4A1-associated dRTA with hemolytic anemia presentation as autosomal recessive.
⚙

Pathophysiology

3
SLC4A1 Anion Exchanger Dysfunction
Biallelic pathogenic SLC4A1 variants impair anion exchanger 1 function in kidney collecting-duct alpha-intercalated cells and in erythrocytes.
renal intercalated cell link erythrocyte link
bicarbonate transport link ↓ DECREASED monoatomic anion transport link ↓ DECREASED
Downstream
Distal Urinary Acidification Failure Impaired renal anion exchanger function disrupts distal acid secretion.
Red Cell Membrane Instability Altered erythrocyte anion exchanger function destabilizes red-cell membranes.
Show evidence (2 references)
PMID:20799361 SUPPORT Human Clinical
"Familial distal renal tubular acidosis (dRTA) can be caused by mutations in the Cl2/HCO32 exchanger of the renal Type A intercalated cell, kidney AE1/SLC4A1."
This mechanistic passage identifies SLC4A1/AE1 as a collecting-duct intercalated-cell exchanger required for distal urinary acidification.
PMID:20799361 SUPPORT Human Clinical
"AE1 is expressed not only in Type A intercalated cells, but also in late erythroid precursors, reticulocytes, and circulating red cells."
This supports the same gene product acting in both kidney acidification cells and erythroid lineages.
Distal Urinary Acidification Failure
Distal nephron acidification failure prevents appropriate urinary acidification, causing metabolic acidosis and electrolyte complications.
renal intercalated cell link
bicarbonate transport link ↓ DECREASED acid secretion link ↓ DECREASED
Downstream
Distal renal tubular acidosis Acidification failure produces the clinical distal renal tubular acidosis phenotype.
Metabolic acidosis Failed distal urinary acidification causes systemic metabolic acidosis.
Hypokalemia Distal RTA can produce hypokalemia as part of the electrolyte phenotype.
Hyperchloremia Distal RTA produces a hyperchloremic metabolic acidosis pattern.
Nephrocalcinosis Distal RTA predisposes to nephrocalcinosis in SLC4A1-related disease.
Growth delay Pediatric distal RTA can impair growth.
Rickets Pediatric distal RTA can cause rickets through chronic acid-base disturbance.
Serum bicarbonate Decreased serum bicarbonate reports systemic metabolic acidosis.
Urine pH Inappropriately alkaline urine is a direct readout of failed distal urinary acidification.
Serum potassium Low serum potassium reports the electrolyte branch of distal RTA.
Serum chloride Hyperchloremia accompanies the metabolic acidosis pattern of distal RTA.
Show evidence (2 references)
PMID:20799361 SUPPORT Human Clinical
"Additional findings of “metabolic acidosis with alkaline urine pH” (detailed medical records are unavailable) led to the clinical diagnosis of distal renal tubular acidosis."
This patient-level observation links metabolic acidosis with inappropriately alkaline urine to the dRTA diagnosis.
PMID:37448902 SUPPORT Human Clinical
"Distal renal tubular acidosis (dRTA) can be caused by mutations in SLC4A1, which encodes the Cl-/HCO3- exchanger of the renal type A intercalated cell, kidney AE1."
This case-report abstract directly links SLC4A1 mutations to dRTA through the renal type A intercalated-cell exchanger.
Red Cell Membrane Instability
Abnormal erythrocyte membrane anion exchange causes red-cell fragility and chronic hemolysis.
erythrocyte link
erythrocyte homeostasis link ↓ DECREASED
Downstream
Hemolytic anemia Red-cell membrane instability causes hemolytic anemia.
Spherocytosis Red-cell membrane instability produces spherocytic red-cell morphology.
Elliptocytosis Red-cell membrane instability can produce elliptocytic red-cell morphology.
Jaundice Chronic hemolysis increases bilirubin and can produce jaundice.
Hepatosplenomegaly Chronic hemolysis can produce hepatosplenomegaly in severe cases.
Hemoglobin Lower hemoglobin is the measured blood readout of hemolytic anemia severity.
Bilirubin Increased bilirubin reports heme breakdown during hemolysis.
Show evidence (2 references)
PMID:20799361 SUPPORT Human Clinical
"The presence of band 3-deficient ovalocytic hemolytic anemia together with evidence of distal renal tubular acidosis suggested possible mutation of the SLC4A1 gene encoding erythroid and kidney isoforms of Band 3/AE1/SLC4A1."
This links band 3-deficient hemolytic red-cell disease to the same SLC4A1 lesion causing the renal phenotype.
PMID:18266205 SUPPORT Human Clinical
"Mutations of the human SLC4A1 gene encoding erythroid and kidney isoforms of anion exchanger 1 (AE1, band 3) result in erythrocyte abnormalities or distal renal tubular acidosis (dRTA) and such mutations are observed in Southeast Asia, where hemoglobinopathies are prevalent."
This cohort-based abstract supports SLC4A1 as a shared erythroid and kidney mechanism for red-cell abnormalities and dRTA.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Renal Tubular Acidosis Distal 4 with Hemolytic Anemia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Blood 2
Hemolytic anemia Hemolytic anemia (HP:0001878)
Show evidence (1 reference)
PMID:37448902 SUPPORT Human Clinical
"In some rare instances, SLC4A1 dRTA can present with hemolytic anemia resulting in marked anemia that is not responsive to standard interventions."
This adult case report supports hemolytic anemia as a rare but explicit SLC4A1-dRTA presentation.
Spherocytosis Spherocytosis (HP:0004444)
Show evidence (1 reference)
PMID:37448902 SUPPORT Human Clinical
"In this case study, we report an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia."
This case report documents spherocytosis in an adult with homozygous SLC4A1-associated dRTA and hemolytic anemia.
Cardiovascular 1
Hepatosplenomegaly Hepatosplenomegaly (HP:0001433)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Physical examination revealed hepatosplenomegaly."
This directly supports hepatosplenomegaly as a documented clinical finding in a reported patient.
Digestive 1
Jaundice Jaundice (HP:0000952)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Patient 1, a 15 year old from Maharasthtra of Kunbi caste born of a non-consanguinous marriage, presented at age 6 years with growth retardation, jaundice and a history of fracture on falling."
This supports jaundice as part of the hemolytic presentation in a homozygous A858D case.
Metabolism 2
Metabolic acidosis Metabolic acidosis (HP:0001942)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Metabolic acidosis was noted concomitant with spot urine pH of 8 and absence of glucosuria."
This supports metabolic acidosis with alkaline urine as a clinical presentation feature.
Hypokalemia Hypokalemia (HP:0002900)
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The children present with metabolic acidosis with high urinary pH, accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth retardation and hematological abnormalities should be suspected as dRTA and suggested a genetic testing."
This systematic review conclusion lists hypokalemia among the clinical features that should prompt suspicion for SLC4A1-related dRTA.
Musculoskeletal 1
Rickets Rickets (HP:0002748)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Physical exam revealed a weight of 13 kg (<5th %ile for age) and rickets."
This directly documents rickets in a pediatric patient with homozygous SLC4A1 A858D-associated dRTA and hemolytic anemia.
Growth 1
Growth delay Growth delay (HP:0001510)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Patient 1, a 15 year old from Maharasthtra of Kunbi caste born of a non-consanguinous marriage, presented at age 6 years with growth retardation, jaundice and a history of fracture on falling."
This supports growth delay in a pediatric homozygous A858D case.
Other 4
Distal renal tubular acidosis Distal renal tubular acidosis (HP:0008341)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"We report here two unrelated Indian patients with combined hemolytic anemia and dRTA who share homozygous A858D mutations of the AE1/SLC4A1 gene."
This establishes dRTA as part of the combined homozygous SLC4A1 A858D presentation.
Elliptocytosis Elliptocytosis (HP:0004445)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Peripheral blood smear was remarkable for spherostomatocytosis, anisopoikilocytosis, acanthocytosis, and elliptocytes."
The smear description explicitly documents elliptocytes, supporting elliptocytosis as a red-cell morphology feature.
Hyperchloremia Hyperchloremia (HP:0011423)
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The children present with metabolic acidosis with high urinary pH, accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth retardation and hematological abnormalities should be suspected as dRTA and suggested a genetic testing."
This systematic review conclusion lists hyperchloremia among features that should prompt suspicion for SLC4A1-related dRTA.
Nephrocalcinosis Nephrocalcinosis (HP:0000121)
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Sonography detected hepatosplenomegaly and nephrocalcinosis."
This supports nephrocalcinosis as part of the reported patient phenotype.
🧬

Genetic Associations

1
SLC4A1 (Causative biallelic pathogenic variants)
Autosomal recessive
Show evidence (2 references)
PMID:33068675 SUPPORT Human Clinical
"We here described the clinical, hematological and genetic data of 16 individuals from 12 families having AR dRTA coupled with HS. All patients carried homozygous SLC4A1 (A858D) mutation, whereas their family members had heterozygous A858D obtained by HRM analysis and confirmed by RFLP and Sanger..."
This Indian-family series supports homozygous SLC4A1 A858D as a recurrent causal genotype for autosomal recessive dRTA coupled with hereditary spherocytosis.
PMID:20799361 SUPPORT Human Clinical
"As shown in Fig. 2C, nominally nonconsanguinous patient 1 was homozygous for the SLC4A1/AE1/Band 3 missense mutation A858D, encoded by a C-to-A transversion changing codon GCC to GAC in exon 19."
This original report identifies the homozygous SLC4A1 A858D variant in a patient with combined hemolytic anemia and dRTA.
💊

Treatments

2
Oral alkali supplementation
Action: Pharmacotherapy NCIT:C15986
Agent: sodium bicarbonate ↗ potassium citrate ↗
Oral sodium bicarbonate and potassium citrate correct systemic acidosis in reported patients, although nephrocalcinosis may persist and hematologic severity can vary.
Mechanism Target:
BYPASSES Distal Urinary Acidification Failure — Oral alkali bypasses failed distal acid secretion by replacing systemic base and correcting metabolic acidosis, but it does not repair the SLC4A1 exchanger defect.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Both patients responded to oral base supplementation with resolution of acidosis, but without reversal of nephrocalcinosis."
The response of acidosis to oral base supplementation supports a bypass link to the distal acidification-failure branch.
Show evidence (2 references)
PMID:20799361 SUPPORT Human Clinical
"He was transfused and treated with oral sodium bicarbonate and potassium citrate."
This supports the specific alkali regimen used in a reported patient.
PMID:20799361 SUPPORT Human Clinical
"Both patients responded to oral base supplementation with resolution of acidosis, but without reversal of nephrocalcinosis."
This supports alkali responsiveness for acidosis while preserving the limitation that nephrocalcinosis may not reverse.
Blood transfusion
Action: blood transfusion MAXO:0000756
Red blood cell transfusion may be required for marked or transfusion-dependent hemolytic anemia in severe reported cases.
Mechanism Target:
BYPASSES Red Cell Membrane Instability — Transfusion bypasses the defective erythrocyte membrane branch by supplying donor red cells for severe anemia rather than correcting the inherited SLC4A1 membrane defect.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"However, patient 2 is severely anemic with dependence on frequent transfusion, and is at risk for progressive nephrotoxicity from renal hemosiderosis (8) and chronic scarring (9) in the setting of nephrocalcinosis."
This supports transfusion as downstream support for severe anemia in the red-cell membrane instability branch.
Show evidence (2 references)
PMID:20799361 SUPPORT Human Clinical
"He was transfused and treated with oral sodium bicarbonate and potassium citrate."
This documents transfusion as part of clinical management for the severe pediatric presentation.
PMID:20799361 SUPPORT Human Clinical
"However, patient 2 is severely anemic with dependence on frequent transfusion, and is at risk for progressive nephrotoxicity from renal hemosiderosis (8) and chronic scarring (9) in the setting of nephrocalcinosis."
This supports transfusion dependence as an important management context in the severe hemolytic anemia phenotype.
🔬

Biochemical Markers

6
Serum bicarbonate (DECREASED)
Pathograph Readouts
Readout Of Distal Urinary Acidification Failure Negative Diagnostic
Low serum bicarbonate reports the metabolic acidosis caused by failed distal acid excretion.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Additional findings of “metabolic acidosis with alkaline urine pH” (detailed medical records are unavailable) led to the clinical diagnosis of distal renal tubular acidosis."
Metabolic acidosis supports decreased bicarbonate as a diagnostic acid-base readout of distal urinary acidification failure.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Metabolic acidosis was noted concomitant with spot urine pH of 8 and absence of glucosuria."
This supports serum bicarbonate decrease as the core biochemical abnormality underlying metabolic acidosis.
Urine pH (INCREASED)
Pathograph Readouts
Readout Of Distal Urinary Acidification Failure Positive Diagnostic
High urine pH during metabolic acidosis reports failure of distal urinary acidification.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Metabolic acidosis was noted concomitant with spot urine pH of 8 and absence of glucosuria."
The spot urine pH of 8 directly supports high urine pH as a diagnostic readout of distal acidification failure.
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The age of onset was younger (P < 0.01), urine pH was higher (P < 0.01), and serum potassium was lower (P < 0.001) in recessive patients than patients with dominant SLC4A1 mutations."
The published-case synthesis supports higher urine pH in recessive SLC4A1-related dRTA.
Serum potassium (DECREASED)
Pathograph Readouts
Readout Of Distal Urinary Acidification Failure Negative Diagnostic
Low serum potassium reports the electrolyte disturbance downstream of distal RTA.
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The age of onset was younger (P < 0.01), urine pH was higher (P < 0.01), and serum potassium was lower (P < 0.001) in recessive patients than patients with dominant SLC4A1 mutations."
The systematic review directly supports lower serum potassium as a biochemical readout in recessive SLC4A1-related dRTA.
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The children present with metabolic acidosis with high urinary pH, accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth retardation and hematological abnormalities should be suspected as dRTA and suggested a genetic testing."
The review conclusion lists hypokalemia in the SLC4A1-related dRTA presentation.
Serum chloride (INCREASED)
Pathograph Readouts
Readout Of Distal Urinary Acidification Failure Positive Diagnostic
High chloride reports the hyperchloremic metabolic acidosis branch of distal RTA.
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The children present with metabolic acidosis with high urinary pH, accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth retardation and hematological abnormalities should be suspected as dRTA and suggested a genetic testing."
The review conclusion supports hyperchloremia as part of the diagnostic biochemical pattern.
Show evidence (1 reference)
PMID:36776909 SUPPORT Human Clinical
"The children present with metabolic acidosis with high urinary pH, accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth retardation and hematological abnormalities should be suspected as dRTA and suggested a genetic testing."
The systematic review identifies hyperchloremia in the dRTA presentation.
Hemoglobin (DECREASED)
Pathograph Readouts
Readout Of Red Cell Membrane Instability Negative Monitoring
Lower hemoglobin tracks anemia severity from erythrocyte membrane instability.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Hematological indices revealed Hgb 4.9 g/dL, Hct 15.9%, MCV 80.7 fL, MCHC 30.8 g/dL, reticulocyte count 5%."
The severe case documents markedly low hemoglobin as a monitoring readout of the hemolytic anemia branch.
Show evidence (1 reference)
PMID:37448902 SUPPORT Human Clinical
"In this case study, we report an adult patient presenting with generalized weakness, marked anemia, spherocytosis, and no features of thalassemia."
Marked anemia supports decreased hemoglobin as a clinically relevant blood readout.
Bilirubin (INCREASED)
Pathograph Readouts
Readout Of Red Cell Membrane Instability Positive Monitoring
Increased bilirubin reports hemolysis-driven heme breakdown.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Total bilirubin was 4.9 mg/dL with indirect bilirubin 4.7 mg/dL, and serum alkaline phosphatase was elevated at 530 IU/L."
The case documents elevated total and indirect bilirubin in the hemolytic presentation.
Show evidence (1 reference)
PMID:20799361 SUPPORT Human Clinical
"Total bilirubin was 4.9 mg/dL with indirect bilirubin 4.7 mg/dL, and serum alkaline phosphatase was elevated at 530 IU/L."
This supports increased bilirubin as a biochemical correlate of hemolysis and jaundice.
{ }

Source YAML

click to show 
name: Renal Tubular Acidosis Distal 4 with Hemolytic Anemia
creation_date: "2026-05-11T00:00:00Z"
updated_date: "2026-05-20T19:18:17Z"
description: >-
  Renal tubular acidosis, distal, 4, with hemolytic anemia is an inherited
  SLC4A1-related disorder that combines impaired renal distal acid secretion
  with red-cell membrane disease. In the best-described Indian families,
  homozygous SLC4A1 p.Ala858Asp (A858D) causes autosomal recessive distal renal
  tubular acidosis coupled with hereditary spherocytosis or hemolytic anemia.
  The shared AE1/band 3 defect links kidney type A intercalated-cell
  bicarbonate exchange to erythrocyte membrane stability.
category: Mendelian
parents:
- autosomal recessive distal renal tubular acidosis
- familial hemolytic anemia
disease_term:
  preferred_term: renal tubular acidosis, distal, 4, with hemolytic anemia
  term:
    id: MONDO:0012700
    label: renal tubular acidosis, distal, 4, with hemolytic anemia
synonyms:
- Distal renal tubular acidosis 4 with hemolytic anemia
- Distal renal tubular acidosis with anemia
- dRTA with anemia
- Autosomal recessive distal renal tubular acidosis coupled with hereditary spherocytosis
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37448902
    reference_title: Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report identifies an autosomal recessive inheritance pattern for
      SLC4A1 variants in a patient presenting with dRTA and hemolytic anemia.
    explanation: >-
      This adult case report explicitly classifies the SLC4A1-associated dRTA
      with hemolytic anemia presentation as autosomal recessive.
pathophysiology:
- name: SLC4A1 Anion Exchanger Dysfunction
  description: >-
    Biallelic pathogenic SLC4A1 variants impair anion exchanger 1 function in
    kidney collecting-duct alpha-intercalated cells and in erythrocytes.
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial distal renal tubular acidosis (dRTA) can be caused by mutations
      in the Cl2/HCO32 exchanger of the renal Type A intercalated cell, kidney
      AE1/SLC4A1.
    explanation: >-
      This mechanistic passage identifies SLC4A1/AE1 as a collecting-duct
      intercalated-cell exchanger required for distal urinary acidification.
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AE1 is expressed not only in Type A intercalated cells, but also in late
      erythroid precursors, reticulocytes, and circulating red cells.
    explanation: >-
      This supports the same gene product acting in both kidney acidification
      cells and erythroid lineages.
  cell_types:
  - preferred_term: renal intercalated cell
    term:
      id: CL:0005010
      label: renal intercalated cell
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  gene:
    preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  biological_processes:
  - preferred_term: bicarbonate transport
    modifier: DECREASED
    term:
      id: GO:0015701
      label: bicarbonate transport
  - preferred_term: monoatomic anion transport
    modifier: DECREASED
    term:
      id: GO:0006820
      label: monoatomic anion transport
  downstream:
  - target: Distal Urinary Acidification Failure
    causal_link_type: DIRECT
    description: Impaired renal anion exchanger function disrupts distal acid secretion.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Distal urinary acidification requires coordinated function of several
        proteins in the Type A intercalated cell of the renal collecting duct:
        the multi-subunit, vacuolar (v)H+-ATPase of the apical membrane,
        cytoplasmic carbonic anhydrase II, and the SLC4A1/AE1 Cl−/HCO3−
        exchanger (kidney Band 3, kAE1).
      explanation: >-
        This mechanistic passage directly places SLC4A1/AE1 in the distal
        urinary acidification machinery.
  - target: Red Cell Membrane Instability
    causal_link_type: DIRECT
    description: Altered erythrocyte anion exchanger function destabilizes red-cell membranes.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        AE1 is expressed not only in Type A intercalated cells, but also in late
        erythroid precursors, reticulocytes, and circulating red cells.
      explanation: >-
        This supports the erythrocyte branch of the shared SLC4A1/AE1 defect.
- name: Distal Urinary Acidification Failure
  description: >-
    Distal nephron acidification failure prevents appropriate urinary
    acidification, causing metabolic acidosis and electrolyte complications.
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional findings of “metabolic acidosis with alkaline urine pH”
      (detailed medical records are unavailable) led to the clinical diagnosis
      of distal renal tubular acidosis.
    explanation: >-
      This patient-level observation links metabolic acidosis with inappropriately
      alkaline urine to the dRTA diagnosis.
  - reference: PMID:37448902
    reference_title: Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distal renal tubular acidosis (dRTA) can be caused by mutations in
      SLC4A1, which encodes the Cl-/HCO3- exchanger of the renal type A
      intercalated cell, kidney AE1.
    explanation: >-
      This case-report abstract directly links SLC4A1 mutations to dRTA through
      the renal type A intercalated-cell exchanger.
  cell_types:
  - preferred_term: renal intercalated cell
    term:
      id: CL:0005010
      label: renal intercalated cell
  biological_processes:
  - preferred_term: bicarbonate transport
    modifier: DECREASED
    term:
      id: GO:0015701
      label: bicarbonate transport
  - preferred_term: acid secretion
    modifier: DECREASED
    term:
      id: GO:0046717
      label: acid secretion
  downstream:
  - target: Distal renal tubular acidosis
    causal_link_type: DIRECT
    description: Acidification failure produces the clinical distal renal tubular acidosis phenotype.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additional findings of “metabolic acidosis with alkaline urine pH”
        (detailed medical records are unavailable) led to the clinical diagnosis
        of distal renal tubular acidosis.
      explanation: >-
        This links the acidification-failure biochemical pattern to clinical
        distal renal tubular acidosis.
  - target: Metabolic acidosis
    causal_link_type: DIRECT
    description: Failed distal urinary acidification causes systemic metabolic acidosis.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Metabolic acidosis was noted concomitant with spot urine pH of 8 and
        absence of glucosuria.
      explanation: >-
        This directly supports metabolic acidosis as the systemic consequence of
        the distal acidification defect.
  - target: Hypokalemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - renal potassium wasting in distal renal tubular acidosis
    description: Distal RTA can produce hypokalemia as part of the electrolyte phenotype.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The children present with metabolic acidosis with high urinary pH,
        accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
        retardation and hematological abnormalities should be suspected as dRTA
        and suggested a genetic testing.
      explanation: >-
        The systematic review lists hypokalemia with the acidification-failure
        presentation of SLC4A1-related dRTA.
  - target: Hyperchloremia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hyperchloremic normal-anion-gap metabolic acidosis
    description: Distal RTA produces a hyperchloremic metabolic acidosis pattern.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The children present with metabolic acidosis with high urinary pH,
        accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
        retardation and hematological abnormalities should be suspected as dRTA
        and suggested a genetic testing.
      explanation: >-
        The systematic review lists hyperchloremia in the acid-base phenotype of
        SLC4A1-related dRTA.
  - target: Nephrocalcinosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - persistently alkaline urine and calcium salt precipitation
    description: Distal RTA predisposes to nephrocalcinosis in SLC4A1-related disease.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Nephrocalcinosis or kidney stones were found in 72.27%, impairment in
        renal function in 14.29%, developmental disorders in 61.16%,
        hematological abnormalities in 33.88%, and muscle weakness in 13.45% of
        patients.
      explanation: >-
        The published-case synthesis supports nephrocalcinosis/kidney stones as
        a frequent renal complication in SLC4A1-related dRTA.
  - target: Growth delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic metabolic acidosis and mineral bone disease
    description: Pediatric distal RTA can impair growth.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient 1, a 15 year old from Maharasthtra of Kunbi caste born of a
        non-consanguinous marriage, presented at age 6 years with growth
        retardation, jaundice and a history of fracture on falling.
      explanation: >-
        The homozygous A858D case report documents growth retardation in the
        pediatric acidification-failure phenotype.
  - target: Rickets
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic metabolic acidosis and skeletal mineralization impairment
    description: Pediatric distal RTA can cause rickets through chronic acid-base disturbance.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Physical exam revealed a weight of 13 kg (<5th %ile for age) and
        rickets.
      explanation: >-
        The pediatric case directly documents rickets in homozygous
        SLC4A1-associated dRTA with hemolytic anemia.
  - target: Serum bicarbonate
    causal_link_type: DIRECT
    description: Decreased serum bicarbonate reports systemic metabolic acidosis.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additional findings of “metabolic acidosis with alkaline urine pH”
        (detailed medical records are unavailable) led to the clinical diagnosis
        of distal renal tubular acidosis.
      explanation: >-
        Metabolic acidosis supports decreased bicarbonate as an acid-base
        readout of distal acidification failure.
  - target: Urine pH
    causal_link_type: DIRECT
    description: Inappropriately alkaline urine is a direct readout of failed distal urinary acidification.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Metabolic acidosis was noted concomitant with spot urine pH of 8 and
        absence of glucosuria.
      explanation: >-
        The spot urine pH of 8 directly supports alkaline urine as a diagnostic
        readout of the distal acidification defect.
  - target: Serum potassium
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - renal potassium wasting in distal renal tubular acidosis
    description: Low serum potassium reports the electrolyte branch of distal RTA.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The age of onset was younger (P < 0.01), urine pH was higher (P < 0.01),
        and serum potassium was lower (P < 0.001) in recessive patients than
        patients with dominant SLC4A1 mutations.
      explanation: >-
        The case synthesis supports lower serum potassium as an SLC4A1-dRTA
        biochemical readout, especially in recessive disease.
  - target: Serum chloride
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hyperchloremic normal-anion-gap metabolic acidosis
    description: Hyperchloremia accompanies the metabolic acidosis pattern of distal RTA.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The children present with metabolic acidosis with high urinary pH,
        accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
        retardation and hematological abnormalities should be suspected as dRTA
        and suggested a genetic testing.
      explanation: >-
        The systematic review lists hyperchloremia as part of the SLC4A1-dRTA
        biochemical presentation.
- name: Red Cell Membrane Instability
  description: >-
    Abnormal erythrocyte membrane anion exchange causes red-cell fragility and
    chronic hemolysis.
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of band 3-deficient ovalocytic hemolytic anemia together
      with evidence of distal renal tubular acidosis suggested possible mutation
      of the SLC4A1 gene encoding erythroid and kidney isoforms of Band
      3/AE1/SLC4A1.
    explanation: >-
      This links band 3-deficient hemolytic red-cell disease to the same SLC4A1
      lesion causing the renal phenotype.
  - reference: PMID:18266205
    reference_title: Hematological abnormalities in patients with distal renal tubular acidosis and hemoglobinopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations of the human SLC4A1 gene encoding erythroid and kidney isoforms
      of anion exchanger 1 (AE1, band 3) result in erythrocyte abnormalities or
      distal renal tubular acidosis (dRTA) and such mutations are observed in
      Southeast Asia, where hemoglobinopathies are prevalent.
    explanation: >-
      This cohort-based abstract supports SLC4A1 as a shared erythroid and
      kidney mechanism for red-cell abnormalities and dRTA.
  cell_types:
  - preferred_term: erythrocyte
    term:
      id: CL:0000232
      label: erythrocyte
  biological_processes:
  - preferred_term: erythrocyte homeostasis
    modifier: DECREASED
    term:
      id: GO:0034101
      label: erythrocyte homeostasis
  downstream:
  - target: Hemolytic anemia
    causal_link_type: DIRECT
    description: Red-cell membrane instability causes hemolytic anemia.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The presence of band 3-deficient ovalocytic hemolytic anemia together
        with evidence of distal renal tubular acidosis suggested possible
        mutation of the SLC4A1 gene encoding erythroid and kidney isoforms of
        Band 3/AE1/SLC4A1.
      explanation: >-
        This directly links SLC4A1/band 3 red-cell abnormality to hemolytic
        anemia in the combined phenotype.
  - target: Spherocytosis
    causal_link_type: DIRECT
    description: Red-cell membrane instability produces spherocytic red-cell morphology.
    evidence:
    - reference: PMID:37448902
      reference_title: Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In this case study, we report an adult patient presenting with
        generalized weakness, marked anemia, spherocytosis, and no features of
        thalassemia.
      explanation: >-
        The adult homozygous SLC4A1 case documents spherocytosis with marked
        hemolytic anemia.
  - target: Elliptocytosis
    causal_link_type: DIRECT
    description: Red-cell membrane instability can produce elliptocytic red-cell morphology.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Peripheral blood smear was remarkable for spherostomatocytosis,
        anisopoikilocytosis, acanthocytosis, and elliptocytes.
      explanation: >-
        The patient smear explicitly documents elliptocytes, supporting an
        elliptocytosis phenotype in the red-cell branch.
  - target: Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - heme catabolism with indirect hyperbilirubinemia
    description: Chronic hemolysis increases bilirubin and can produce jaundice.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patient 1, a 15 year old from Maharasthtra of Kunbi caste born of a
        non-consanguinous marriage, presented at age 6 years with growth
        retardation, jaundice and a history of fracture on falling.
      explanation: >-
        The case report documents jaundice in the hemolytic branch of homozygous
        A858D disease.
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic hemolysis and reticuloendothelial red-cell clearance
    description: Chronic hemolysis can produce hepatosplenomegaly in severe cases.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sonography detected hepatosplenomegaly and nephrocalcinosis.
      explanation: >-
        The severe pediatric case documents hepatosplenomegaly alongside
        nephrocalcinosis in the combined phenotype.
  - target: Hemoglobin
    causal_link_type: DIRECT
    description: Lower hemoglobin is the measured blood readout of hemolytic anemia severity.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematological indices revealed Hgb 4.9 g/dL, Hct 15.9%, MCV 80.7 fL,
        MCHC 30.8 g/dL, reticulocyte count 5%.
      explanation: >-
        The severe case documents markedly low hemoglobin as a readout of the
        hemolytic anemia branch.
  - target: Bilirubin
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - erythrocyte breakdown and heme catabolism
    description: Increased bilirubin reports heme breakdown during hemolysis.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Total bilirubin was 4.9 mg/dL with indirect bilirubin 4.7 mg/dL, and
        serum alkaline phosphatase was elevated at 530 IU/L.
      explanation: >-
        Increased total and indirect bilirubin supports bilirubin as a
        biochemical readout of the hemolytic branch.
phenotypes:
- name: Distal renal tubular acidosis
  description: Impaired distal urinary acidification with systemic metabolic acidosis.
  phenotype_term:
    preferred_term: Distal renal tubular acidosis
    term:
      id: HP:0008341
      label: Distal renal tubular acidosis
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here two unrelated Indian patients with combined hemolytic
      anemia and dRTA who share homozygous A858D mutations of the AE1/SLC4A1
      gene.
    explanation: >-
      This establishes dRTA as part of the combined homozygous SLC4A1 A858D
      presentation.
- name: Hemolytic anemia
  description: Chronic hemolysis due to red-cell membrane dysfunction.
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:37448902
    reference_title: Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some rare instances, SLC4A1 dRTA can present with hemolytic anemia
      resulting in marked anemia that is not responsive to standard
      interventions.
    explanation: >-
      This adult case report supports hemolytic anemia as a rare but explicit
      SLC4A1-dRTA presentation.
- name: Spherocytosis
  description: Spherical red-cell morphology can accompany the hemolytic anemia phenotype.
  phenotype_term:
    preferred_term: Spherocytosis
    term:
      id: HP:0004444
      label: Spherocytosis
  evidence:
  - reference: PMID:37448902
    reference_title: Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this case study, we report an adult patient presenting with generalized
      weakness, marked anemia, spherocytosis, and no features of thalassemia.
    explanation: >-
      This case report documents spherocytosis in an adult with homozygous
      SLC4A1-associated dRTA and hemolytic anemia.
- name: Elliptocytosis
  description: Elliptocytic red-cell morphology is reported in homozygous A858D cases.
  phenotype_term:
    preferred_term: Elliptocytosis
    term:
      id: HP:0004445
      label: Elliptocytosis
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Peripheral blood smear was remarkable for spherostomatocytosis,
      anisopoikilocytosis, acanthocytosis, and elliptocytes.
    explanation: >-
      The smear description explicitly documents elliptocytes, supporting
      elliptocytosis as a red-cell morphology feature.
- name: Metabolic acidosis
  description: Hyperchloremic metabolic acidosis is the biochemical consequence of dRTA.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic acidosis was noted concomitant with spot urine pH of 8 and
      absence of glucosuria.
    explanation: >-
      This supports metabolic acidosis with alkaline urine as a clinical
      presentation feature.
- name: Hypokalemia
  description: Low serum potassium can accompany the distal renal tubular acidosis phenotype.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The children present with metabolic acidosis with high urinary pH,
      accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
      retardation and hematological abnormalities should be suspected as dRTA
      and suggested a genetic testing.
    explanation: >-
      This systematic review conclusion lists hypokalemia among the clinical
      features that should prompt suspicion for SLC4A1-related dRTA.
- name: Hyperchloremia
  description: Hyperchloremia accompanies the metabolic acidosis pattern of distal RTA.
  phenotype_term:
    preferred_term: Hyperchloremia
    term:
      id: HP:0011423
      label: Hyperchloremia
  evidence:
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The children present with metabolic acidosis with high urinary pH,
      accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
      retardation and hematological abnormalities should be suspected as dRTA
      and suggested a genetic testing.
    explanation: >-
      This systematic review conclusion lists hyperchloremia among features that
      should prompt suspicion for SLC4A1-related dRTA.
- name: Nephrocalcinosis
  description: Renal medullary calcification/nephrocalcinosis is a reported renal complication.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sonography detected hepatosplenomegaly and nephrocalcinosis.
    explanation: >-
      This supports nephrocalcinosis as part of the reported patient phenotype.
- name: Growth delay
  description: Pediatric cases can present with impaired growth.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1, a 15 year old from Maharasthtra of Kunbi caste born of a
      non-consanguinous marriage, presented at age 6 years with growth
      retardation, jaundice and a history of fracture on falling.
    explanation: >-
      This supports growth delay in a pediatric homozygous A858D case.
- name: Rickets
  description: Skeletal mineralization defects can accompany pediatric distal renal tubular acidosis.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical exam revealed a weight of 13 kg (<5th %ile for age) and rickets.
    explanation: >-
      This directly documents rickets in a pediatric patient with homozygous
      SLC4A1 A858D-associated dRTA and hemolytic anemia.
- name: Hepatosplenomegaly
  description: Combined liver and spleen enlargement was documented in the severe pediatric case.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical examination revealed hepatosplenomegaly.
    explanation: >-
      This directly supports hepatosplenomegaly as a documented clinical
      finding in a reported patient.
- name: Jaundice
  description: Hyperbilirubinemia from hemolysis can present clinically as jaundice.
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1, a 15 year old from Maharasthtra of Kunbi caste born of a
      non-consanguinous marriage, presented at age 6 years with growth
      retardation, jaundice and a history of fracture on falling.
    explanation: >-
      This supports jaundice as part of the hemolytic presentation in a
      homozygous A858D case.
biochemical:
- name: Serum bicarbonate
  presence: DECREASED
  notes: >-
    Decreased bicarbonate is the blood chemistry correlate of systemic
    metabolic acidosis in distal renal tubular acidosis.
  biomarker_term:
    preferred_term: bicarbonate
    term:
      id: CHEBI:17544
      label: hydrogencarbonate
  readouts:
  - target: Distal Urinary Acidification Failure
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low serum bicarbonate reports the metabolic acidosis caused by failed distal acid excretion.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additional findings of “metabolic acidosis with alkaline urine pH”
        (detailed medical records are unavailable) led to the clinical diagnosis
        of distal renal tubular acidosis.
      explanation: >-
        Metabolic acidosis supports decreased bicarbonate as a diagnostic
        acid-base readout of distal urinary acidification failure.
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic acidosis was noted concomitant with spot urine pH of 8 and
      absence of glucosuria.
    explanation: >-
      This supports serum bicarbonate decrease as the core biochemical
      abnormality underlying metabolic acidosis.
- name: Urine pH
  presence: INCREASED
  notes: >-
    Inappropriately high urine pH during systemic metabolic acidosis is a
    diagnostic acidification readout in distal RTA.
  readouts:
  - target: Distal Urinary Acidification Failure
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: High urine pH during metabolic acidosis reports failure of distal urinary acidification.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Metabolic acidosis was noted concomitant with spot urine pH of 8 and
        absence of glucosuria.
      explanation: >-
        The spot urine pH of 8 directly supports high urine pH as a diagnostic
        readout of distal acidification failure.
  evidence:
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The age of onset was younger (P < 0.01), urine pH was higher (P < 0.01),
      and serum potassium was lower (P < 0.001) in recessive patients than
      patients with dominant SLC4A1 mutations.
    explanation: >-
      The published-case synthesis supports higher urine pH in recessive
      SLC4A1-related dRTA.
- name: Serum potassium
  presence: DECREASED
  notes: Hypokalemia is part of the electrolyte signature of SLC4A1-related distal RTA.
  biomarker_term:
    preferred_term: potassium
    term:
      id: CHEBI:29103
      label: potassium(1+)
  readouts:
  - target: Distal Urinary Acidification Failure
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low serum potassium reports the electrolyte disturbance downstream of distal RTA.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The age of onset was younger (P < 0.01), urine pH was higher (P < 0.01),
        and serum potassium was lower (P < 0.001) in recessive patients than
        patients with dominant SLC4A1 mutations.
      explanation: >-
        The systematic review directly supports lower serum potassium as a
        biochemical readout in recessive SLC4A1-related dRTA.
  evidence:
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The children present with metabolic acidosis with high urinary pH,
      accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
      retardation and hematological abnormalities should be suspected as dRTA
      and suggested a genetic testing.
    explanation: >-
      The review conclusion lists hypokalemia in the SLC4A1-related dRTA
      presentation.
- name: Serum chloride
  presence: INCREASED
  notes: Hyperchloremia accompanies the normal-anion-gap metabolic acidosis pattern of dRTA.
  biomarker_term:
    preferred_term: chloride
    term:
      id: CHEBI:17996
      label: chloride
  readouts:
  - target: Distal Urinary Acidification Failure
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: High chloride reports the hyperchloremic metabolic acidosis branch of distal RTA.
    evidence:
    - reference: PMID:36776909
      reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The children present with metabolic acidosis with high urinary pH,
        accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
        retardation and hematological abnormalities should be suspected as dRTA
        and suggested a genetic testing.
      explanation: >-
        The review conclusion supports hyperchloremia as part of the diagnostic
        biochemical pattern.
  evidence:
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The children present with metabolic acidosis with high urinary pH,
      accompanying hypokalemia, hyperchloremia, nephrocalcinosis, growth
      retardation and hematological abnormalities should be suspected as dRTA
      and suggested a genetic testing.
    explanation: The systematic review identifies hyperchloremia in the dRTA presentation.
- name: Hemoglobin
  presence: DECREASED
  notes: Low hemoglobin reports the severity of the SLC4A1-associated hemolytic anemia branch.
  biomarker_term:
    preferred_term: hemoglobin measurement
    term:
      id: NCIT:C64848
      label: Hemoglobin Measurement
  readouts:
  - target: Red Cell Membrane Instability
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: MONITORING
    interpretation: Lower hemoglobin tracks anemia severity from erythrocyte membrane instability.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematological indices revealed Hgb 4.9 g/dL, Hct 15.9%, MCV 80.7 fL,
        MCHC 30.8 g/dL, reticulocyte count 5%.
      explanation: >-
        The severe case documents markedly low hemoglobin as a monitoring
        readout of the hemolytic anemia branch.
  evidence:
  - reference: PMID:37448902
    reference_title: Rare Case of Hemolytic Anemia and Distal Renal Tubular Acidosis in an adult due to Homozygous SLC4A1 Mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this case study, we report an adult patient presenting with generalized
      weakness, marked anemia, spherocytosis, and no features of thalassemia.
    explanation: >-
      Marked anemia supports decreased hemoglobin as a clinically relevant
      blood readout.
- name: Bilirubin
  presence: INCREASED
  notes: Indirect bilirubin elevation reflects heme catabolism during hemolysis.
  biomarker_term:
    preferred_term: bilirubin
    term:
      id: CHEBI:16990
      label: bilirubin IXalpha
  readouts:
  - target: Red Cell Membrane Instability
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Increased bilirubin reports hemolysis-driven heme breakdown.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Total bilirubin was 4.9 mg/dL with indirect bilirubin 4.7 mg/dL, and
        serum alkaline phosphatase was elevated at 530 IU/L.
      explanation: >-
        The case documents elevated total and indirect bilirubin in the
        hemolytic presentation.
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Total bilirubin was 4.9 mg/dL with indirect bilirubin 4.7 mg/dL, and serum
      alkaline phosphatase was elevated at 530 IU/L.
    explanation: >-
      This supports increased bilirubin as a biochemical correlate of hemolysis
      and jaundice.
genetic:
- name: SLC4A1
  gene_term:
    preferred_term: SLC4A1
    term:
      id: hgnc:11027
      label: SLC4A1
  association: Causative biallelic pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
  features: >-
    Recurrent homozygous SLC4A1 c.2573C>A (p.Ala858Asp; A858D) has been
    reported in Indian families with autosomal recessive distal renal tubular
    acidosis coupled with hereditary spherocytosis or hemolytic anemia.
  evidence:
  - reference: PMID:33068675
    reference_title: Genotypic analysis of SLC4A1 A858D mutation in Indian population associated with distal renal tubular Acidosis (dRTA) coupled with hemolytic anemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We here described the clinical, hematological and genetic data of 16
      individuals from 12 families having AR dRTA coupled with HS. All patients
      carried homozygous SLC4A1 (A858D) mutation, whereas their family members
      had heterozygous A858D obtained by HRM analysis and confirmed by RFLP and
      Sanger sequencing.
    explanation: >-
      This Indian-family series supports homozygous SLC4A1 A858D as a recurrent
      causal genotype for autosomal recessive dRTA coupled with hereditary
      spherocytosis.
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As shown in Fig. 2C, nominally nonconsanguinous patient 1 was homozygous
      for the SLC4A1/AE1/Band 3 missense mutation A858D, encoded by a C-to-A
      transversion changing codon GCC to GAC in exon 19.
    explanation: >-
      This original report identifies the homozygous SLC4A1 A858D variant in a
      patient with combined hemolytic anemia and dRTA.
epidemiology:
- name: Published SLC4A1-dRTA case spectrum
  description: >-
    A systematic review of published SLC4A1-related dRTA cases found both
    autosomal dominant and autosomal recessive inheritance, with recessive cases
    more often reported in Asian patients and more severe biochemical
    presentation.
  evidence:
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-three eligible articles involving 169 patients were included and 41
      mutations were identified totally.
    explanation: >-
      This provides the published-case denominator for SLC4A1-related dRTA
      literature synthesis.
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nephrocalcinosis or kidney stones were found in 72.27%, impairment in
      renal function in 14.29%, developmental disorders in 61.16%,
      hematological abnormalities in 33.88%, and muscle weakness in 13.45% of
      patients.
    explanation: >-
      This summarizes the frequency of major renal, developmental, hematologic,
      and neuromuscular features among published SLC4A1-dRTA patients.
  - reference: PMID:36776909
    reference_title: "Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations: Analysis based on published patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive inheritance was more often found in Asian patients,
      and more attentions should be paid to the Asian patients.
    explanation: >-
      This supports the report's population observation for recessive
      SLC4A1-related dRTA.
treatments:
- name: Oral alkali supplementation
  description: >-
    Oral sodium bicarbonate and potassium citrate correct systemic acidosis in
    reported patients, although nephrocalcinosis may persist and hematologic
    severity can vary.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium bicarbonate
      term:
        id: CHEBI:32139
        label: sodium hydrogencarbonate
    - preferred_term: potassium citrate
      term:
        id: CHEBI:64733
        label: potassium citrate (anhydrous)
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was transfused and treated with oral sodium bicarbonate and potassium
      citrate.
    explanation: >-
      This supports the specific alkali regimen used in a reported patient.
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients responded to oral base supplementation with resolution of
      acidosis, but without reversal of nephrocalcinosis.
    explanation: >-
      This supports alkali responsiveness for acidosis while preserving the
      limitation that nephrocalcinosis may not reverse.
  target_mechanisms:
  - target: Distal Urinary Acidification Failure
    treatment_effect: BYPASSES
    description: >-
      Oral alkali bypasses failed distal acid secretion by replacing systemic
      base and correcting metabolic acidosis, but it does not repair the SLC4A1
      exchanger defect.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both patients responded to oral base supplementation with resolution of
        acidosis, but without reversal of nephrocalcinosis.
      explanation: >-
        The response of acidosis to oral base supplementation supports a bypass
        link to the distal acidification-failure branch.
- name: Blood transfusion
  description: >-
    Red blood cell transfusion may be required for marked or transfusion-dependent
    hemolytic anemia in severe reported cases.
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: MAXO:0000756
      label: blood transfusion
  evidence:
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He was transfused and treated with oral sodium bicarbonate and potassium
      citrate.
    explanation: >-
      This documents transfusion as part of clinical management for the severe
      pediatric presentation.
  - reference: PMID:20799361
    reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, patient 2 is severely anemic with dependence on frequent
      transfusion, and is at risk for progressive nephrotoxicity from renal
      hemosiderosis (8) and chronic scarring (9) in the setting of
      nephrocalcinosis.
    explanation: >-
      This supports transfusion dependence as an important management context in
      the severe hemolytic anemia phenotype.
  target_mechanisms:
  - target: Red Cell Membrane Instability
    treatment_effect: BYPASSES
    description: >-
      Transfusion bypasses the defective erythrocyte membrane branch by
      supplying donor red cells for severe anemia rather than correcting the
      inherited SLC4A1 membrane defect.
    evidence:
    - reference: PMID:20799361
      reference_title: Hemolytic anemia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, patient 2 is severely anemic with dependence on frequent
        transfusion, and is at risk for progressive nephrotoxicity from renal
        hemosiderosis (8) and chronic scarring (9) in the setting of
        nephrocalcinosis.
      explanation: >-
        This supports transfusion as downstream support for severe anemia in the
        red-cell membrane instability branch.
references:
- reference: PMID:31600044
  title: "Hereditary Distal Renal Tubular Acidosis."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:31600044
Hereditary Distal Renal Tubular Acidosis.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
1. Disease Information
Edison Scientific Literature 41 citations 2026-05-11T13:08:32.511740

1. Disease Information

Disease overview

Renal tubular acidosis (RTA) comprises disorders of renal acid handling that cause chronic, normal-anion-gap (hyperchloremic) metabolic acidosis. Distal RTA (dRTA; type 1) is defined by the failure to acidify urine below pH ~5.5 despite systemic acidosis and is primarily a disorder of type A (α-) intercalated cells in the collecting duct. In the subset “dRTA with hemolytic anemia,” the renal phenotype co-occurs with hereditary hemolytic anemia and red-cell morphological abnormalities, most often due to biallelic SLC4A1 (AE1/band 3) variants, linking kidney and erythrocyte pathology. (batlle2012geneticcausesand pages 1-2, a2023thepathophysiologyof pages 1-5, alexander2025hereditarydistalrenal pages 5-7)

Key identifiers

  • OMIM phenotype: 611590 (reported in the literature as distal RTA; also used in genetic discussions of AR dRTA with hematologic involvement) (deejai2022impairedtraffickingand pages 1-2)
  • OMIM gene: SLC4A1 / AE1 / band 3: +109270 (deejai2022impairedtraffickingand pages 1-2)

Other requested identifiers (Orphanet, MONDO, MeSH, ICD-10/ICD-11): not retrievable from the available full-text evidence in this run; would require direct database lookup.

Synonyms / alternative names (used in literature)

  • Distal renal tubular acidosis (dRTA), type 1 RTA (watanabe2018improvingoutcomesfor pages 1-2, batlle2012geneticcausesand pages 1-2)
  • SLC4A1-related distal renal tubular acidosis (watanabe2018improvingoutcomesfor pages 1-2, yang2023mutationsandclinical pages 1-2)
  • dRTA with hereditary spherocytosis (dRTA/HS) or with Southeast Asian ovalocytosis (dRTA/SAO) used to denote the combined renal+hematologic phenotype in case compilations (yang2023mutationsandclinical pages 3-4)

Evidence source type

Evidence for this entity is largely derived from aggregated disease-level resources and reviews (e.g., Nature Reviews Nephrology 2023; systematic review Frontiers in Pediatrics 2023) plus primary case reports/series and functional studies (Thailand pediatric cohort; HEK293T trafficking work; mouse models). (a2023thepathophysiologyof pages 1-5, yang2023mutationsandclinical pages 1-2, khositseth2007distalrenaltubular pages 1-2, deejai2022impairedtraffickingand pages 6-9, stehberger2007distalrenaltubular pages 1-3)

2. Etiology

Primary causal factors (genetic)

The core causal factor for “distal RTA with hemolytic anemia” is pathogenic variation in SLC4A1, encoding the anion exchanger 1 (AE1) (band 3), with the combined renal+hematologic phenotype most often arising from autosomal recessive (biallelic) loss-of-function / inactivating or compound alleles. (alexander2025hereditarydistalrenal pages 5-7, deejai2022impairedtraffickingand pages 1-2)

Broader hereditary dRTA can also be caused by ATP6V1B1 and ATP6V0A4 (V-ATPase subunits), among other genes, but these are typically associated with renal phenotype (and often hearing loss) rather than hemolytic anemia. (batlle2012geneticcausesand pages 1-2, watanabe2018improvingoutcomesfor pages 1-2)

Risk factors

  • Genetic: carrying biallelic SLC4A1 pathogenic variants, including compound heterozygosity with the SAO deletion allele and another pathogenic allele, is a key risk factor for developing dRTA with hemolysis. (deejai2022impairedtraffickingand pages 1-2, yang2023mutationsandclinical pages 3-4)
  • Physiologic/clinical modifier: metabolic acidosis itself can exacerbate hemolysis in SLC4A1-related disease, consistent with clinical observations that RBCs can be more “vulnerable to hemolysis under conditions of metabolic acidosis.” (alexander2025hereditarydistalrenal pages 5-7, khositseth2007distalrenaltubular pages 1-2)

Protective factors / gene–environment interaction

No specific protective variants or clear gene–environment interaction data for this specific Mendelian entity were found in the available evidence. Clinically, adequate alkali therapy is repeatedly associated with improved systemic acid-base status and can reduce hemolytic manifestations, effectively acting as a protective clinical modifier. (alexander2025hereditarydistalrenald pages 5-7, khositseth2007distalrenaltubular pages 1-2)

3. Phenotypes

Core phenotype set (renal + hematologic)

Distal RTA phenotype (renal acidification failure) - Hyperchloremic metabolic acidosis with normal anion gap; inappropriately alkaline urine (urine pH >5.5) in the presence of systemic acidosis (watanabe2018improvingoutcomesfor pages 1-2, batlle2012geneticcausesand pages 1-2, khositseth2007distalrenaltubular pages 1-2) - Hypokalemia is common (watanabe2018improvingoutcomesfor pages 1-2, yang2023mutationsandclinical pages 3-4) - Nephrocalcinosis and/or nephrolithiasis, often with hypercalciuria and hypocitraturia (watanabe2018improvingoutcomesfor pages 1-2, stehberger2007distalrenaltubular pages 1-3) - Growth delay/failure to thrive; rickets/osteomalacia (watanabe2018improvingoutcomesfor pages 1-2, yang2023mutationsandclinical pages 1-2)

Hematologic phenotype - Hemolytic anemia with RBC morphological abnormalities (e.g., hereditary spherocytosis, SAO/ovalocytosis; acanthocytosis in some reports) (watanabe2018improvingoutcomesfor pages 1-2, alexander2025hereditarydistalrenal pages 5-7, yang2023mutationsandclinical pages 3-4)

Quantitative phenotype frequencies (recent systematic review)

A 2023 systematic review of published SLC4A1-dRTA cases (169 patients; 53 articles) reported: - Nephrocalcinosis or kidney stones: 72.27% - Developmental disorders: 61.16% - Hematological abnormalities: 33.88% - Impaired renal function: 14.29% - Muscle weakness: 13.45% (yang2023mutationsandclinical pages 1-2)

More granular counts from extracted datasets in the same work include: - Nephrocalcinosis: 65/121 (53.72%); kidney stones 23/121 (19.01%) - Renal impairment: 17/121 (14.29%) - Hematologic abnormalities: 41/121 (33.88%) - Alkaline urine pH >6.5: 64/79 (81.01%) - Hypokalemia: 72/109 (66.06%) - Hyperchloremia: 50/53 (94.34%) (yang2023mutationsandclinical pages 3-4)

AR enrichment of hematologic findings: hematologic abnormalities were particularly common among AR patients (30/61; 49.18%) in this synthesis. (yang2023mutationsandclinical pages 3-4)

Onset/severity/progression

AR SLC4A1-dRTA cases tend to have earlier onset and more severe biochemical phenotype than AD SLC4A1-dRTA, with earlier age at onset, higher urine pH, and lower serum potassium in AR cases. (yang2023mutationsandclinical pages 1-2)

Suggested HPO terms (non-exhaustive)

  • Distal renal tubular acidosis: HP:0001947 (dRTA) (term suggestion; not directly evidenced in text)
  • Metabolic acidosis: HP:0001942 (watanabe2018improvingoutcomesfor pages 1-2)
  • Hypokalemia: HP:0002900 (yang2023mutationsandclinical pages 3-4)
  • Nephrocalcinosis: HP:0000121 (watanabe2018improvingoutcomesfor pages 1-2)
  • Nephrolithiasis: HP:0000787 (watanabe2018improvingoutcomesfor pages 1-2)
  • Hyperchloremia: HP:0011421 (yang2023mutationsandclinical pages 3-4)
  • Hemolytic anemia: HP:0001878 (alexander2025hereditarydistalrenal pages 5-7)
  • Hereditary spherocytosis: HP:0004444 (watanabe2018improvingoutcomesfor pages 1-2)
  • Ovalocytosis: HP:0004426 (yang2023mutationsandclinical pages 3-4)
  • Growth delay / short stature: HP:0004322 / HP:0001510 (yang2023mutationsandclinical pages 1-2)
  • Rickets / osteomalacia: HP:0002748 / HP:0000938 (watanabe2018improvingoutcomesfor pages 1-2)

(Notes: HPO IDs are suggested for ontology mapping; the evidence supports the phenotypes, not the specific IDs.)

4. Genetic / Molecular Information

Causal gene(s)

  • SLC4A1 (AE1; band 3) is the key gene linking renal and erythrocyte phenotypes; it encodes the basolateral Cl−/HCO3− exchanger in kidney α-intercalated cells and the dominant RBC membrane anion exchanger/structural protein in erythrocytes. (guo2023geneticdiagnosisand pages 1-3, batlle2012geneticcausesand pages 3-4)

Inheritance patterns

  • The combined phenotype “dRTA with hemolytic anemia” is typically autosomal recessive with biallelic SLC4A1 pathogenic variants. (alexander2025hereditarydistalrenal pages 5-7, alexander2025hereditarydistalrenal pages 1-3)
  • SLC4A1 can also cause autosomal dominant dRTA via dominant-negative mechanisms, usually without prominent hemolysis. (batlle2012geneticcausesand pages 3-4, alexander2025hereditarydistalrenal pages 1-3)

Pathogenic variants (examples; not exhaustive)

A 2023 synthesis of published cases identified 41 distinct SLC4A1 mutations with both AD and AR forms. (yang2023mutationsandclinical pages 1-2)

Variant examples explicitly appearing in compiled evidence include: - p.Ala858Asp (A858D) (recurrent; associated with dRTA and hemolytic anemia in some biallelic contexts) (alexander2025hereditarydistalrenalc pages 5-7, yang2023mutationsandclinical pages 3-4) - p.Gly701Asp (G701D) (frequent in AR Southeast Asian cases; reported with hemolytic anemia in some genotypes) (deejai2022impairedtraffickingand pages 1-2, yang2023mutationsandclinical pages 3-4) - SAO deletion p.Ala400_Ala408del (c.1199_1225del) (deejai2022impairedtraffickingand pages 1-2) - p.Thr444Asn (T444N) in compound genotype with SAO deletion (deejai2022impairedtraffickingand pages 1-2) - p.Ser477* (truncating) listed in case compilations (yang2023mutationsandclinical pages 3-4) - p.Ser725Arg described as abolishing transport and producing anemia + RTA (as cited within broader AE1/dRTA mechanistic discussions) (batlle2012geneticcausesand pages 3-4)

Compound heterozygous patterns repeatedly associated with dRTA plus hematologic abnormalities include SAO/G701D, SAO/Q759H, SAO/A858D, G701D/A858D, and others. (deejai2022impairedtraffickingand pages 1-2)

Functional consequence classes

Mechanisms described across reviews and functional studies include: - Trafficking defects / intracellular retention (ER/Golgi), reduced stability/shorter half-life of mutant kAE1 (deejai2022impairedtraffickingand pages 6-9, fry2007inheritedrenalacidoses. pages 3-4) - Mistargeting (e.g., apical mislocalization in polarized epithelia) (batlle2012geneticcausesand pages 3-4) - Transport loss-of-function for some variants (batlle2012geneticcausesand pages 3-4)

Population frequency

No gnomAD or population allele-frequency values were available in the retrieved evidence.

Modifier genes / epigenetics

No validated modifier genes or epigenetic mechanisms specific to this disease were identified in the retrieved evidence.

5. Environmental Information

This is primarily a genetic disease. Environmental contributions are mainly relevant as clinical modifiers (e.g., acid–base status affecting hemolysis risk), rather than primary causes. (alexander2025hereditarydistalrenal pages 5-7)

6. Mechanism / Pathophysiology

Current understanding (renal)

In kidney type A (α-) intercalated cells, apical H+-ATPase secretes protons into the tubular lumen; this process is functionally coupled to basolateral bicarbonate extrusion via AE1 (SLC4A1), a Cl−/HCO3− exchanger. Cytosolic carbonic anhydrase provides intracellular H+ and HCO3− substrates. Therefore, AE1 dysfunction disrupts the basolateral bicarbonate exit step needed for sustained proton secretion, producing distal acidification failure. (batlle2012geneticcausesand pages 1-2, batlle2012geneticcausesand pages 2-3, batlle2012geneticcausesand pages 3-4)

Current understanding (hematologic)

In erythrocytes, AE1/band 3 contributes both to anion exchange and to membrane skeleton anchoring; mutations can cause red-cell morphological disorders (HS, SAO/ovalocytosis) and hemolysis. In the combined phenotype, RBCs can be especially susceptible to hemolysis during systemic acidosis. (parker2018mousemodelsof pages 2-3, alexander2025hereditarydistalrenal pages 5-7)

Trafficking/processing mechanism (key expert consensus)

Several authoritative discussions emphasize that many AE1 mutations have near-normal anion exchange in heterologous systems, and that trafficking and targeting defects are a major disease mechanism (intracellular retention in nonpolarized cells; apical mistargeting/retention in polarized renal epithelia). (fry2007inheritedrenalacidoses. pages 3-4, batlle2012geneticcausesand pages 3-4)

A 2022 mechanistic study of AR dRTA with mild hemolytic anemia identified compound heterozygous SAO deletion + T444N and demonstrated: - WT and T444N kAE1 localized at the cell surface, whereas SAO and SAO/T444N were intracellularly retained - Mutant kAE1 proteins had shorter half-lives than WT, supporting impaired trafficking and instability as pathogenic mechanisms. (deejai2022impairedtraffickingand pages 1-2, deejai2022impairedtraffickingand pages 6-9)

Visual evidence supporting this mechanism: immunofluorescence localization of WT vs mutant kAE1 (cell-surface vs intracellular retention) and structural modeling were retrieved from Deejai et al. (deejai2022impairedtraffickingand media 9d60dc11, deejai2022impairedtraffickingand media 94347afb)

Model organism evidence

Slc4a1-null mice recapitulate core dRTA features: spontaneous hyperchloremic metabolic acidosis with inappropriate urine alkalinity, nephrocalcinosis and related urinary abnormalities, supporting AE1’s causal role in distal acidification. (stehberger2007distalrenaltubular pages 1-3)

Pathway/ontology mappings (suggested)

Key cell types (CL): - α-intercalated cell (collecting duct): CL:0000653 (suggested) - Erythrocyte: CL:0000232 (suggested)

Key anatomical structures (UBERON): - Kidney collecting duct: UBERON:0001230 (suggested) - Renal cortical collecting duct / distal nephron segments (suggested; evidence supports collecting duct localization) (batlle2012geneticcausesand pages 3-4)

Key GO Biological Process terms (suggested): - Renal acid secretion / urinary acidification (supported conceptually by coupling described) (batlle2012geneticcausesand pages 1-2) - Bicarbonate transport; chloride transport; anion exchange (batlle2012geneticcausesand pages 3-4) - Protein targeting to membrane; intracellular protein transport; ER retention/quality control (fry2007inheritedrenalacidoses. pages 3-4, deejai2022impairedtraffickingand pages 6-9)

(Notes: ontology IDs are suggested; supporting mechanistic statements are cited.)

7. Anatomical Structures Affected

Primary organs

  • Kidney (collecting duct α-intercalated cells) (batlle2012geneticcausesand pages 3-4)
  • Blood / red blood cells (erythroid AE1/band 3) (batlle2012geneticcausesand pages 3-4)

Secondary involvement/complications

  • Bone (rickets/osteomalacia) secondary to chronic acidosis and mineral handling issues (watanabe2018improvingoutcomesfor pages 1-2)

8. Temporal Development

  • Typical onset: often infancy/childhood in AR disease; AD disease can present later and may be milder (yang2023mutationsandclinical pages 1-2, batlle2012geneticcausesand pages 3-4)
  • Course: chronic lifelong disease; long-term risk includes nephrocalcinosis and potential progression to CKD in dRTA cohorts (watanabe2018improvingoutcomesfor pages 1-2, a2023thepathophysiologyof pages 1-5)

9. Inheritance and Population

Inheritance

  • Most characteristic “dRTA with hemolytic anemia” presentations: autosomal recessive, biallelic SLC4A1 variants. (alexander2025hereditarydistalrenal pages 5-7, alexander2025hereditarydistalrenal pages 1-3)

Epidemiology and prevalence

Disease-specific prevalence for the hemolytic anemia subset was not found in the retrieved evidence.

For dRTA overall, a 2023 Nature Reviews Nephrology synthesis reported prevalence estimates from administrative datasets: - UK database: ~0.46 recorded and 1.60 suspected/recorded per 10,000 - US insurance data: ~0.38 primary and 3.88 acquired dRTA per 100,000 (a2023thepathophysiologyof pages 1-5)

Geographic distribution

AR SLC4A1-dRTA is disproportionately reported in Asian populations in systematic synthesis, and many dRTA/hemolysis cases are reported from Southeast Asia and India. (yang2023mutationsandclinical pages 1-2, alexander2025hereditarydistalrenal pages 5-7)

10. Diagnostics

Clinical/laboratory diagnosis

Key diagnostic pattern for dRTA includes: - Normal anion gap (hyperchloremic) metabolic acidosis - Inappropriately high urine pH (>5.5) during systemic acidosis - Frequent hypokalemia - Evidence of hypercalciuria/hypocitraturia and imaging evidence of nephrocalcinosis/nephrolithiasis (watanabe2018improvingoutcomesfor pages 1-2, khositseth2007distalrenaltubular pages 1-2)

Genetic testing

For suspected hereditary dRTA with or without hemolysis, reviews recommend genetic testing of known genes including SLC4A1 (and ATP6V1B1, ATP6V0A4, FOXI1, WDR72 in broader dRTA). (yang2023mutationsandclinical pages 1-2, alexander2025hereditarydistalrenal pages 1-3)

Differential diagnosis

Differential diagnosis includes other genetic and acquired causes of dRTA (autoimmune disease, drug-induced) as well as other causes of hemolytic anemia; the specific co-occurrence suggests SLC4A1 involvement. (a2023thepathophysiologyof pages 1-5, watanabe2018improvingoutcomesfor pages 1-2)

11. Outcome / Prognosis

With appropriate alkali therapy, prognosis is often described as generally good, but long-term follow-up studies indicate risk of chronic kidney disease (CKD) in dRTA cohorts, and nephrocalcinosis can persist despite therapy. (watanabe2018improvingoutcomesfor pages 1-2, a2023thepathophysiologyof pages 1-5, bertholetthomas20256yeartreatmentfollowup pages 7-10)

12. Treatment

Standard of care

Oral alkali therapy (bicarbonate and/or citrate) is central; early and sufficient dosing is emphasized to support growth, bone health, and reduce kidney complications. (watanabe2018improvingoutcomesfor pages 1-2)

Clinical principles summarized in expert guidance include: - Maintain bicarbonate and potassium to reduce acute symptoms and long-term complications - Avoid sodium salts when possible because sodium can worsen hypercalciuria - Citrate provides bicarbonate equivalents in vivo and can reduce required dosing. (alexander2025hereditarydistalrenald pages 10-12, alexander2025hereditarydistalrenalc pages 10-12)

For hemolytic anemia: supportive transfusion and iron therapy as needed; correction of systemic acidosis may improve anemia/reticulocytosis in SLC4A1-related hemolysis. (alexander2025hereditarydistalrenald pages 5-7)

Recent therapeutic development / real-world implementation: ADV7103 (Sibnayal®)

ADV7103 is a prolonged-release, twice-daily combination of potassium bicarbonate and potassium citrate.

Real-world pediatric implementation (2024): At a UK center after Oct 2022 availability, 20 children with RTA were prescribed Sibnayal; 14/20 (70%) preferred and tolerated it; 6/20 (30%) reverted due to refusal or texture issues, especially in younger/developmentally affected children. Efficacy was comparable to standard therapy with maintenance of normal plasma bicarbonate; dosing was similar between standard vs Sibnayal. (tan2024treatmentofpaediatric pages 1-5)

Long-term outcomes (peer-reviewed 2025): In a 6-year open-label follow-up (B22CS; n=30; mean age 10.6 years), plasma bicarbonate control was sustained (22.0→22.6 mmol/L), growth improved (height Z −0.6→−0.3), eGFR remained stable (105→104 mL/min/1.73m²) with no progression to CKD stage 3–5, and lumbar spine BMD Z-score improved (−1.1→−0.8). Nephrocalcinosis remained common (86% at baseline; 92% at end), illustrating prevention/stabilization rather than reversal. (bertholetthomas20256yeartreatmentfollowup pages 7-10, bertholetthomas20256yeartreatmentfollowup pages 1-2)

Preprint (Dec 2024): A preprint describing the same long-term B22CS dataset reports similar outcomes and describes the formulation as prolonged-release, tasteless granules providing ~12-hour effect with twice-daily dosing. (bertholetthomas2024longtermclinicaloutcomes pages 1-5)

Clinical trials

  • NCT03644706 (ClinicalTrials.gov): phase 3 randomized withdrawal study of ADV7103 in primary dRTA; record notes TERMINATED, enrollment 3, completion 2023-12-20; primary endpoint focused on preventing metabolic acidosis during withdrawal. (NCT03644706 chunk 1)

Suggested MAXO terms (examples; suggested)

  • Alkali therapy / bicarbonate supplementation
  • Potassium citrate supplementation
  • Blood transfusion
  • Iron supplementation

(Notes: MAXO IDs not retrieved in evidence; terms suggested for mapping.)

13. Prevention

Primary prevention is not applicable for most Mendelian cases beyond genetic counseling and reproductive options. Clinically, tertiary prevention focuses on preventing nephrocalcinosis progression and growth/bone complications through sustained alkali therapy and adherence. (watanabe2018improvingoutcomesfor pages 1-2, alexander2025hereditarydistalrenalc pages 10-12)

14. Other Species / Natural Disease

No natural disease in other species specific to SLC4A1-related dRTA with hemolytic anemia was retrieved in the available evidence.

15. Model Organisms

  • Mouse (Slc4a1-null): exhibits a robust dRTA phenotype with hyperchloremic metabolic acidosis and nephrocalcinosis, supporting causal biology and enabling mechanistic investigation. (stehberger2007distalrenaltubular pages 1-3)
  • Additional Slc4 model discussion contextualizes AE1 isoforms and how mutations can cause both kidney and RBC phenotypes. (parker2018mousemodelsof pages 2-3)

Expert synthesis / key takeaways

  1. The disorder is best conceptualized as a shared-molecule syndrome: a single gene (SLC4A1/AE1) expressed in kidney α-intercalated cells and erythrocytes produces combined defects in urinary acidification and RBC integrity. (batlle2012geneticcausesand pages 3-4, guo2023geneticdiagnosisand pages 1-3)
  2. The most typical “dRTA + hemolytic anemia” cases are autosomal recessive, often involving compound alleles including SAO or other inactivating variants; systematic synthesis shows hematologic abnormalities are common in AR SLC4A1-dRTA. (yang2023mutationsandclinical pages 1-2, deejai2022impairedtraffickingand pages 1-2)
  3. A major mechanistic theme is protein mistrafficking/instability (not just loss of exchanger activity), supported by cellular studies and kidney epithelial targeting biology. (deejai2022impairedtraffickingand pages 6-9, fry2007inheritedrenalacidoses. pages 3-4)
  4. 2023–2024 literature emphasizes improved characterization (systematic review statistics) and improved real-world treatment options (prolonged-release alkali therapy) supporting adherence and long-term outcomes. (yang2023mutationsandclinical pages 1-2, tan2024treatmentofpaediatric pages 1-5)

Evidence table (summary)

Topic Key evidence Citation
Causal gene The combined phenotype is chiefly linked to SLC4A1 (encoding AE1/band 3), expressed in both erythrocytes and type A intercalated cells of the distal nephron, providing the molecular basis for coexisting renal acidification failure and red-cell disease. (guo2023geneticdiagnosisand pages 1-3, a2023thepathophysiologyof pages 1-5)
Disease mechanism In kidney, mutant kAE1 impairs basolateral Cl-/HCO3- exchange, disrupting distal acid secretion and causing distal renal tubular acidosis; in red cells, AE1 defects alter membrane/cytoskeletal anchoring and can increase erythrocyte fragility, especially during acidosis, producing hemolytic anemia or RBC morphologic abnormalities. (alexander2025hereditarydistalrenala pages 5-7, a2023thepathophysiologyof pages 1-5)
Inheritance and hemolytic-anemia association Autosomal recessive (AR) SLC4A1 disease is the form most strongly associated with hemolytic anemia / hereditary spherocytosis / ovalocytosis; autosomal dominant (AD) SLC4A1 dRTA more often causes isolated renal disease, though rare AD families with hematologic involvement exist. (batlle2012geneticcausesand pages 3-4, watanabe2018improvingoutcomesfor pages 1-2)
AR vs AD distribution in published cases 2023 systematic review of 169 patients identified 41 SLC4A1 mutations: 15 mutations / 100 patients AD and 21 mutations / 61 patients AR; AR patients had younger onset, higher urine pH, and lower serum K+ than AD patients. (yang2023mutationsandclinical pages 1-2)
Key reported variants linked to dRTA ± hemolysis Reported pathogenic/likely pathogenic SLC4A1 variants associated with this spectrum include p.Ala858Asp (A858D), p.Gly701Asp (G701D), SAO deletion p.Ala400_Ala408del, p.Thr444Asn, p.Ser477*, p.Ser725Arg, plus combinations such as SAO/G701D, SAO/R602H, SAO/Q759H, SAO/A858D, and G701D/A858D. (yang2023mutationsandclinical pages 3-4, deejai2022impairedtraffickingand pages 1-2)
A858D-specific evidence Biallelic p.Ala858Asp (A858D) is a recurrent variant in Indian families with the combined phenotype; reported with hemolytic anemia/acanthocytosis plus dRTA, and heterozygous parents may show only mild erythrocyte changes. (alexander2025hereditarydistalrenalc pages 5-7, alexander2025hereditarydistalrenalb pages 5-7)
SAO/T444N evidence A 2022 case identified compound heterozygous SAO deletion (p.Ala400_Ala408del) + p.Thr444Asn, causing AR dRTA with mild hemolytic anemia; functional work showed intracellular retention of SAO-containing kAE1 and reduced protein stability. (deejai2022impairedtraffickingand pages 1-2)
Truncating / severe variants The 2023 review includes p.Ser477* among reported SLC4A1 dRTA alleles, and severe truncating disease has been described with marked hemolysis and complete dRTA; these support loss-of-function/trafficking-defect mechanisms. (yang2023mutationsandclinical pages 3-4)
Transport-null missense variant p.Ser725Arg was reported to abolish AE1 transport function and cause anemia plus renal tubular acidosis, illustrating that some variants directly impair exchanger activity in addition to trafficking defects. (batlle2012geneticcausesand pages 3-4)
Core clinical/laboratory phenotype Typical findings are hyperchloremic normal-anion-gap metabolic acidosis, inability to acidify urine (urine pH >5.5 despite acidosis), hypokalemia, nephrocalcinosis/nephrolithiasis, growth failure, rickets/osteomalacia, and hemolysis / RBC morphology abnormalities. (watanabe2018improvingoutcomesfor pages 1-2, batlle2012geneticcausesand pages 1-2)
Quantitative phenotype statistics (2023 systematic review) Across published SLC4A1-dRTA patients, nephrocalcinosis or kidney stones 72.27%, developmental disorders 61.16%, hematological abnormalities 33.88%, renal impairment 14.29%, muscle weakness 13.45%. (yang2023mutationsandclinical pages 1-2)
More detailed phenotype frequencies In the subset with data: nephrocalcinosis 65/121 (53.72%), kidney stones 23/121 (19.01%), renal impairment 17/121 (14.29%), hematologic abnormalities 41/121 (33.88%); alkaline urine pH >6.5 in 64/79 (81.01%), hypokalemia 72/109 (66.06%), hyperchloremia 50/53 (94.34%). (yang2023mutationsandclinical pages 3-4)
AR hematologic burden Hematologic abnormalities were particularly enriched in AR disease: 30/61 (49.18%) in AR cases in the 2023 review; AR inheritance was also more common in Asian patients. (yang2023mutationsandclinical pages 3-4, yang2023mutationsandclinical pages 1-2)
Prevalence estimates (recent authoritative review) 2023 Nature Reviews Nephrology reported dRTA prevalence estimates of about 0.46 recorded and 1.60 suspected/recorded per 10,000 in a UK database, and about 0.38 primary and 3.88 acquired dRTA per 100,000 in US insurance data; these are for dRTA overall, not specifically the hemolytic-anemia subset. (a2023thepathophysiologyof pages 1-5)
Diagnostic clues Suspect SLC4A1-related disease in a child with metabolic acidosis + high urine pH + hypokalemia + hyperchloremia + nephrocalcinosis/growth delay, especially if there is hemolytic anemia or abnormal RBC morphology; genetic testing is recommended. (yang2023mutationsandclinical pages 1-2, khositseth2007distalrenaltubular pages 1-2)
Treatment and outcomes Alkali therapy is the core treatment; studies/reviews report that adequate alkalinization improves acidosis, growth, bone disease, and may reduce or correct reticulocytosis/anemia in SLC4A1-related hemolytic cases. (alexander2025hereditarydistalrenald pages 5-7, khositseth2007distalrenaltubular pages 1-2)

Table: This table condenses the main genetic, mechanistic, phenotypic, and epidemiologic evidence for renal tubular acidosis distal 4 with hemolytic anemia. It emphasizes how SLC4A1/AE1 variants connect distal acidification failure with erythrocyte pathology and highlights recent quantitative data.

Key references (URLs and publication dates where available)

  • Wagner CA et al. Nature Reviews Nephrology (Apr 2023). “The pathophysiology of distal renal tubular acidosis.” https://doi.org/10.1038/s41581-023-00699-9 (a2023thepathophysiologyof pages 1-5)
  • Yang M et al. Frontiers in Pediatrics (Jan 2023). “Mutations and clinical characteristics of dRTA caused by SLC4A1 mutations…” https://doi.org/10.3389/fped.2023.1077120 (yang2023mutationsandclinical pages 1-2)
  • Deejai N et al. BMC Medical Genomics (Oct 2022). “Impaired trafficking and instability of mutant kidney anion exchanger 1…” https://doi.org/10.1186/s12920-022-01381-y (deejai2022impairedtraffickingand pages 1-2)
  • Tan HL et al. Pediatric Nephrology (May 2024). “Treatment of paediatric renal tubular acidosis with a prolonged-release alkali supplementation.” https://doi.org/10.1007/s00467-024-06411-8 (tan2024treatmentofpaediatric pages 1-5)
  • Bertholet-Thomas A et al. Orphanet Journal of Rare Diseases (Aug 2025). “6-year treatment follow-up…” https://doi.org/10.1186/s13023-025-03953-4 (bertholetthomas20256yeartreatmentfollowup pages 1-2)
  • ClinicalTrials.gov NCT03644706 (record includes dates/status). (NCT03644706 chunk 1)

Limitations of this run

  • Direct Orphanet/MONDO/MeSH/ICD identifiers were not found in the retrieved full-text evidence; OMIM identifiers (611590; SLC4A1 +109270) were supported by primary literature excerpts. (deejai2022impairedtraffickingand pages 1-2)
  • Not all variant-level details and PMIDs for every cited paper could be extracted from the current tool outputs; however, the cited sources provide DOIs and journal metadata, and include a 2023 systematic review covering 53 primary reports. (yang2023mutationsandclinical pages 1-2)

References

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