Metabolic acidosis

Summary

Metabolic acidosis (MONDO:0000440) is a disease with 2 cohort genes and 50 clinical trials. Top therapeutic interventions include sodium bicarbonate, potassium citrate anhydrous, and meglumine.

At a glance

• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 50

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metabolic acidosis
Mondo ID	MONDO:0000440
DOID	DOID:0050758
SNOMED CT	59455009
UMLS	C0220981
MedGen	65117
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › disorder of acid-base balance › acidosis disorder › metabolic acidosis

Related subtypes (2): renal tubular acidosis, alcoholic ketoacidosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
694733	NM_001128831.4(CA1):c.368_369del (p.His123fs)	CA1	Uncertain significance	criteria provided, single submitter
830363	NM_000183.3(HADHB):c.110-2324G>C	HADHB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HADHB	Orphanet:746	Mitochondrial trifunctional protein deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CA1	HGNC:1368	ENSG00000133742	P00915	Carbonic anhydrase 1	clinvar
HADHB	HGNC:4803	ENSG00000138029	P55084	Trifunctional enzyme subunit beta, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CA1	Carbonic anhydrase 1	Catalyzes the reversible hydration of carbon dioxide.
HADHB	Trifunctional enzyme subunit beta, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CA1	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
HADHB	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
mucosa of transverse colon	1
trabecular bone tissue	1
deltoid	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CA1	177	tissue_specific	marker	mucosa of transverse colon, trabecular bone tissue, colonic mucosa
HADHB	295	ubiquitous	marker	heart right ventricle, left ventricle myocardium, deltoid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADHB	4,047
CA1	1,800

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CA1	P00915	56
HADHB	P55084	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Beta oxidation of myristoyl-CoA to lauroyl-CoA	1	1903.3×	0.003	HADHB
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	1	1903.3×	0.003	HADHB
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	1142.0×	0.003	HADHB
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	1142.0×	0.003	HADHB
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	1142.0×	0.003	HADHB
Acyl chain remodeling of CL	1	951.7×	0.003	HADHB
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	951.7×	0.003	HADHB
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	951.7×	0.003	HADHB
Erythrocytes take up oxygen and release carbon dioxide	1	634.4×	0.003	CA1
O2/CO2 exchange in erythrocytes	1	634.4×	0.003	CA1
Reversible hydration of carbon dioxide	1	475.8×	0.004	CA1
Erythrocytes take up carbon dioxide and release oxygen	1	439.2×	0.004	CA1
Interleukin-12 family signaling	1	237.9×	0.006	CA1
Interleukin-12 signaling	1	203.9×	0.007	CA1
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	150.3×	0.009	CA1
Signaling by Interleukins	1	32.1×	0.039	CA1
Cytokine Signaling in Immune system	1	20.4×	0.057	CA1
Transport of small molecules	1	12.6×	0.087	CA1
Immune System	1	6.5×	0.156	CA1
Metabolism	1	5.8×	0.165	CA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to fructose	1	1203.7×	0.003	CA1
fatty acid beta-oxidation	1	187.2×	0.011	HADHB
cellular response to lipopolysaccharide	1	49.0×	0.025	HADHB
gene expression	1	39.9×	0.025	HADHB

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CA1	METHAZOLAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CA1	70	4
HADHB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
METHAZOLAMIDE	4	CA1
ACETAZOLAMIDE	4	CA1
ZONISAMIDE	4	CA1
TRICHLORMETHIAZIDE	4	CA1
CHLORTHALIDONE	4	CA1
ACETAMINOPHEN	4	CA1
NITROUS ACID	4	CA1
CELECOXIB	4	CA1
SULFUR	4	CA1
LEVETIRACETAM	4	CA1
SODIUM ACETATE	4	CA1
PHENOL	4	CA1
DICHLORPHENAMIDE	4	CA1
ETHOXZOLAMIDE	4	CA1
SULFANILAMIDE	4	CA1
VERALIPRIDE	4	CA1
DORZOLAMIDE	4	CA1
BRINZOLAMIDE	4	CA1
TOPIRAMATE	4	CA1
NILOTINIB	4	CA1
SULPIRIDE	4	CA1
BORTEZOMIB	4	CA1
SULTHIAME	4	CA1
FUROSEMIDE	4	CA1
INDAPAMIDE	4	CA1
MAFENIDE	4	CA1
SULFASALAZINE	4	CA1
SALICYLIC ACID	4	CA1
HYDROCHLOROTHIAZIDE	4	CA1
TAVABOROLE	4	CA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CA1	886	Binding:852, ADMET:32, Functional:2
HADHB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CA1	4.2.1.1	carbonic anhydrase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CA1	886

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
METHAZOLAMIDE	4	CA1
ACETAZOLAMIDE	4	CA1
ZONISAMIDE	4	CA1
TRICHLORMETHIAZIDE	4	CA1
CHLORTHALIDONE	4	CA1
ACETAMINOPHEN	4	CA1
NITROUS ACID	4	CA1
CELECOXIB	4	CA1
SULFUR	4	CA1
LEVETIRACETAM	4	CA1
SODIUM ACETATE	4	CA1
PHENOL	4	CA1
DICHLORPHENAMIDE	4	CA1
ETHOXZOLAMIDE	4	CA1
SULFANILAMIDE	4	CA1
VERALIPRIDE	4	CA1
DORZOLAMIDE	4	CA1
BRINZOLAMIDE	4	CA1
TOPIRAMATE	4	CA1
NILOTINIB	4	CA1
SULPIRIDE	4	CA1
BORTEZOMIB	4	CA1
SULTHIAME	4	CA1
FUROSEMIDE	4	CA1
INDAPAMIDE	4	CA1
MAFENIDE	4	CA1
SULFASALAZINE	4	CA1
SALICYLIC ACID	4	CA1
HYDROCHLOROTHIAZIDE	4	CA1
TAVABOROLE	4	CA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HADHB

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HADHB	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 50.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	27
PHASE3	9
PHASE4	5
PHASE2	4
PHASE1	2
PHASE2/PHASE3	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05005793	PHASE4	RECRUITING	Effect of Alkali Therapy on Vascular and Graft Function in Kidney Transplant Recipients
NCT07424625	PHASE4	NOT_YET_RECRUITING	A Study of Tris-Hydroxymethyl Aminomethane (THAM) Versus Sodium Bicarbonate in Cardiac Surgical Patients
NCT07464431	PHASE4	NOT_YET_RECRUITING	Sodium Bicarbonate for Critically Ill Patients With Metabolic Acidosis and Acute Kidney Injury
NCT03035812	PHASE4	COMPLETED	Alkalinization by Urologists & Nephrologists
NCT03846258	PHASE4	WITHDRAWN	High Versus Low Bicarbonate Bath in Critically-ill Patients Receiving Continuous Renal Replacement Therapy
NCT05697770	PHASE3	ACTIVE_NOT_RECRUITING	SODium BICarbonate for Metabolic Acidosis in the ICU
NCT06545565	PHASE3	RECRUITING	Prevention of Metabolic Acidosis in Preterm Neonates by Replacing Sodium Chloride With Sodium Acetate in Parenteral Nutrition
NCT07355062	PHASE3	RECRUITING	A Study to Evaluate the Efficacy and Safety of Veverimer for the Treatment of Metabolic Acidosis
NCT01452412	PHASE2/PHASE3	COMPLETED	Alkali Therapy in Chronic Kidney Disease
NCT01640119	PHASE3	UNKNOWN	Correction of Metabolic Acidosis in End Stage Renal Disease (ESRD)
NCT02476253	PHASE3	COMPLETED	Sodium Bicarbonate to Treat Severe Acidosis in the Critically Ill
NCT03317444	PHASE3	COMPLETED	Evaluation of TRC101 in Subjects With Metabolic Acidosis Associated With Chronic Kidney Disease
NCT03390842	PHASE3	COMPLETED	Long-term Safety Extension to Study TRCA-301
NCT03710291	PHASE3	TERMINATED	Evaluation of Effect of TRC101 on Progression of Chronic Kidney Disease in Subjects With Metabolic Acidosis
NCT04727528	PHASE3	TERMINATED	Study of the Effect of SZC on Serum Potassium and Serum Bicarbonate in Patients With Hyperkalemia and Metabolic Acidosis Associated With Chronic Kidney Disease
NCT04984226	PHASE2	RECRUITING	Sodium Bicarbonate and Mitochondrial Energetics in Persons With CKD
NCT06366230	PHASE1/PHASE2	RECRUITING	Adding Urea to the Final Dialysis Fluid
NCT00913796	PHASE2	COMPLETED	Metabolic Acidosis in Renal Transplant Patients
NCT02303548	PHASE2	COMPLETED	Bicarbonate in Patients With Out-of-hospital Cardiac Arrest
NCT05147051	PHASE2	COMPLETED	Meglimine Sodium Succinate for Correction of Metabolic Acidosis in Critically Ill Patients
NCT01777178	PHASE1	COMPLETED	Comparison of Standard Versus Low Bicarbonate Hemodialysis
NCT01894594	PHASE1	TERMINATED	Efficacy, Safety Study and Benefit of Alkali Therapy in Sickle Cell Disease
NCT04600323	EARLY_PHASE1	COMPLETED	Bicarbonate Administration and Cognitive Function in Midlife and Older Adults With CKD
NCT05113641	Not specified	ACTIVE_NOT_RECRUITING	Reducing Dietary Acid With Food Versus Oral Alkali in People With Chronic Kidney Disease (ReDACKD)
NCT06237712	Not specified	ACTIVE_NOT_RECRUITING	Explorative Study to Investigate the Acid-base Response to Sodium and Potassium Salts in Patients With Chronic Kidney Disease.
NCT06881641	Not specified	RECRUITING	A Study on Bedside Formate Assay as a Diagnostic Tool in Methanol Poisoning
NCT06932042	Not specified	RECRUITING	PLADO for Conservative Management of CKD
NCT01075750	Not specified	COMPLETED	Perioperative Fluid Management in Patients Receiving Cadaveric Renal Transplants
NCT01293266	Not specified	COMPLETED	Effect of Propofol and Sevoflurane on Lactate During Anesthesia for Pediatric Heart Catheterisation
NCT01295190	Not specified	COMPLETED	Substitution of Propofol by Sevoflurane During Pediatric Cardiopulmonary Bypass
NCT01506258	Not specified	UNKNOWN	Autologous Stem Cells in Newborns With Oxygen Deprivation
NCT01860001	Not specified	UNKNOWN	Incidence of Postoperative Ketosis and Metabolic Acidosis
NCT02031770	Not specified	COMPLETED	Metabolic Acidosis and Vascular Function in Patients With Chronic Kidney Disease
NCT02098356	Not specified	COMPLETED	Comparison of High Versus Low Bicarbonate Hemodialysis
NCT02800343	Not specified	COMPLETED	Intraoperative Cell Salvage and Postoperative Acidosis
NCT02915601	Not specified	COMPLETED	Bicarbonate Administration in CKD
NCT03354507	Not specified	UNKNOWN	Use of Sodium Bicarbonate in Patients Treated With Topiramate
NCT03428464	Not specified	COMPLETED	Bicarbonate Administration in Kidney Transplant Recipients
NCT03897101	Not specified	UNKNOWN	Inflammation and Metabolic Acidosis at Birth (AGAIN: AutophaGy AcIdosis Newborn)
NCT04010630	Not specified	COMPLETED	Sodium Bicarbonate for the Treatment of Severe Metabolic Acidosis With Moderate or Severe Acute Kidney Injury in ICU

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM BICARBONATE	4	15
POTASSIUM CITRATE ANHYDROUS	4	2
MEGLUMINE	4	1
POTASSIUM CHLORIDE	4	1
SODIUM ZIRCONIUM CYCLOSILICATE	4	1
VEVERIMER	3	4
BICARBONATE	3	1