Approach to Renal Tubular Acidosis – A Review

Abstract

Acid–base homeostasis is maintained by renal and respiratory systems. The inability of the renal tubules to excrete acids or retain bicarbonate in adequate amounts leads to renal tubular acidosis (RTA). These disorders are characterised by the presence of normal anion gap metabolic acidosis with hyperchloremia. Both distal RTA (type 1) and proximal RTA (type 2) can occur due to a primary/inherited defect in the renal tubule or may arise due to some secondary/acquired causes. Urinary acidification defect defines type 1 RTA, while type 2 RTA is characterised by defective bicarbonate handling in the proximal tubule. Type 3 RTA includes features of both type 1 and type 2 RTA, whereas type 4 RTA is characterised by the presence of hyperkalaemia with normal anion gap metabolic acidosis. In this review article, we describe the various types of RTA and its pathophysiology along with a systematic and practical approach to a suspected case of RTA and its management.

INTRODUCTION

Acid–base homeostasis is vital for normal cellular functions in the body. It is primarily maintained by the kidneys, lungs, and also other organs such as the gut, bone, skeletal muscles, and liver.[1] Maintenance of acid–base homeostasis by kidneys is underscored by the fact that patients with end-stage chronic kidney disease frequently develop metabolic acidosis as also patients with rare inherited defects in urinary acidification or bicarbonate absorption.[2] Renal tubular acidosis (RTA) is generally defined by an inability of the renal tubules to excrete acid ions or absorb bicarbonate in a background of normal renal glomerular function, leading to normal anion gap metabolic acidosis with hyperchloremia.[3] RTA is an uncommon disorder, and many cases, particularly those with incomplete forms, remain unrecognised. Inherited variants are far less frequent than acquired ones, with type 4 hyperkalaemic RTA being the most prevalent worldwide, most often resulting from diabetic nephropathy with hyporeninemic hypoaldosteronism or urinary tract obstruction; it is also frequently seen in chronic kidney disease and may occur in more than one-fifth of renal transplant recipients due to rejection or immunosuppressive therapy. Distal (type 1) RTA is encountered more often than proximal disease, presenting in childhood when inherited through mutations in transport genes or later in life as an acquired complication of autoimmune conditions such as Sjögren’s syndrome or systemic lupus erythematosus, or after exposure to drugs like amphotericin B. Proximal (type 2) RTA is comparatively rare and is usually secondary to Fanconi syndrome, itself an uncommon disorder associated with rare metabolic conditions such as cystinosis, Wilson disease, galactosemia, hereditary fructose intolerance, and glycogen storage disease type I, while in adults, it is more often linked to medications including ifosfamide, tenofovir, or carbonic anhydrase inhibitors. Mixed or type 3 RTA is extremely uncommon, largely historical, and primarily described in children of Middle Eastern, North African, or Arabic descent, with features that overlap distal and proximal tubular defects.[4]

METHODS

A comprehensive literature search was conducted to draft this narrative review on the approach to RTA. A PubMed search was performed covering publications from 1960 to July 2025. Key search terms used individually and in combination included: (Renal Tubular Acidosis [Title/Abstract]) OR (Proximal Renal Tubular Acidosis [Title/Abstract]) OR (Distal Renal Tubular Acidosis [Title/Abstract]) OR (Type 3 RTA [Title/Abstract]) OR (Type 4 RTA [Title/Abstract]). Preference was given to original research articles, review papers, clinical guidelines, and seminal articles relevant to acid–base physiology, diagnostic algorithms, and therapeutic approaches. Articles in English were included without geographical restrictions. Of 2592 articles identified through the search strategy, a total of 70 articles were included in the final review based on relevance and contribution to the understanding of RTA in both paediatric and adult populations.

ACID–BASE HOMEOSTASIS: ROLE OF THE KIDNEY

A healthy adult on western diet, with no underlying systemic illness, usually produces 15,000 mEq/day of volatile acids and 1 mEq/kg/day of non-volatile acids from metabolism of food particles.[5] These volatile acids are primarily produced by fat and carbohydrate metabolism and are excreted by lungs, whereas non-volatile acids are produced primarily by protein metabolism and are buffered by body buffers, including HCO₃^-, and are also excreted by kidneys. Kidneys thus maintain acid–base homeostasis by reabsorbing all filtered bicarbonate, regenerating bicarbonate lost through metabolism of food particles via ammoniagenesis (approx. 40 mEq/day) and excretion of acids in form of free ions, ammonium, and titratable acids (approx. 30 mEq/day).[6]

Bicarbonate reabsorption in proximal tubules

Plasma HCO₃^- levels range from 24 mEq/L to 26 mEq/L. Given the glomerular filtration of approximately about 180–200 litres/day, the total amount of filtered HCO₃^- is estimated to be around 4000 to 5000 mEq/day. About 85–90% of this filtered bicarbonate is reabsorbed in the proximal tubule, whereas the rest of the filtered bicarbonate is reabsorbed by the thick ascending limb of the loop of Henle, distal tubules, and collecting ducts.[7]

In the proximal tubule [Figure 1], the luminal transporters like Na⁺/H⁺ exchanger isoform 3 (NHE3) and the H⁺-transporting adenosine triphosphatase (H⁺-ATPase) secrete H⁺ ions into the tubular lumen.[8,9,10] This secreted H⁺ ion then combines with HCO₃^- in the lumen to form carbonic acid, which dissociates to form H₂O and CO₂ by action of luminal carbonic anhydrase type IV.[11] CO₂ then diffuses into intracellular compartment of proximal tubular epithelial cells and reacts with H₂O, catalysed by cytosolic carbonic anhydrase type II to form carbonic acid. Dissociation of carbonic acid releases HCO₃^- and H⁺; the former is then reabsorbed via sodium bicarbonate cotransporter (NBCE1) present in the basolateral membrane, while the H⁺ ion becomes available again to be secreted into the tubular lumen.[12]

Figure 1.

Schematic representation of the tubular defects responsible for different forms of renal tubular acidosis (RTA). In distal or type 1 RTA, the defect arises from either impaired hydrogen ion secretion through H+-ATPase or H+/K+-ATPase, resulting in reduced acid excretion. Proximal or type 2 RTA occurs when bicarbonate reabsorption in the proximal tubule is impaired, due to either defective transport of bicarbonate across the basolateral membrane or inhibition of carbonic anhydrase activity. Hyperkalaemic or type 4 RTA develops from aldosterone deficiency or resistance, leading to reduced sodium uptake via principal cells of the collecting duct, loss of transepithelial voltage, and consequently reduced hydrogen ion secretion by principal cells. Abbreviations: AE1, kidney anion exchanger; ENaC, epithelial sodium channel; MR, mineralocorticoid receptor; NHE3, Na⁺/H⁺ exchanger 3; ROMK, apical membrane K⁺ channel; AQ2, aquaporin 2; AQ3 aquaporin 3; CA II, carbonic anhydrase type II; CA IV, carbonic anhydrase type IV. Created in BioRender. Agarwal, V. (2025) https://BioRender.com/nr90z8u

Urinary acidification in the distal nephron

The late distal convoluted tubules, the connecting tubule, the cortical collecting duct, the outer medullary collecting duct, and the inner medullary collecting duct constitute the collecting system of the nephrons. These segments are involved in acidification of urine. The collecting system expresses three major cell types: the principal cells, type A intercalated cells (acid secreting, also known as α-intercalated cells), and type B intercalated cells (bicarbonate secreting, also known as β-intercalated cells). The principal cells [Figure 1] are mostly involved in Na⁺ and water reabsorption and potassium (K⁺) excretion. They express epithelial Na⁺ channels (ENaC), aquaporin 2 and aquaporin 3 water channels, and ATP-sensitive inward rectifier potassium channel 1 (ROMK1).[13]

Type A acid-secreting intercalated cells [Figure 1], as the name suggest, are involved in acid (H⁺ ions) secretion. The cytosolic carbonic anhydrase type II enzyme converts CO₂ and H₂O to carbonic acid which dissociates further to H⁺ ions and HCO₃^- ions. The H⁺ ions are then secreted into the luminal surface via H⁺-ATPase pump,[14] while the HCO₃^- ion is absorbed in the basolateral surface via basolateral anion exchange protein 1 (AE1), also known as SLC4A1. Anion exchange protein 1 (AE1) is a specific marker for type A acid-secreting intercalated cells.[15] Type B bicarbonate-secreting cells, on the other hand, produce cytosolic H⁺ and HCO₃^- ions in a similar fashion via action of carbonic anhydrase type 2 enzyme on cytosolic CO₂ and H₂O, but it secretes HCO₃^- into the urinary lumen via Cl^-/HCO₃^- exchanger, also known as pendrin (SLC26A4). The H⁺ generated is pumped into the blood via basolateral H⁺-ATPases. Pendrin is a specific marker for type B bicarbonate-secreting intercalated cells.[16,17] The relative number of type A and type B intercalated cells varies depending on the systemic acid–base status. Chronic acidosis favours an increase in number of type A intercalated cells,[18,19] whereas chronic alkalosis leads to an increase in relative number of type B intercalated cells.[20]

TYPES OF RTA

Type 1 RTA or distal RTA (dRTA)

Distal RTA is characterised by defect in hydrogen ion secretion and urinary acidification in the collecting system. It can be primary (inherited) or acquired. Both forms of dRTA can present clinically with renal or extra-renal features.[21] Inherited forms of dRTA present in early childhood, whereas the acquired forms usually present in adulthood. The hallmark of dRTA is the presence of inappropriately alkaline urine (pH > 5.3) in the presence of moderate-to-severe metabolic acidosis.[22] A milder variant of dRTA, described as incomplete distal RTA, is characterised by impaired urinary acidification with normal baseline serum bicarbonate levels. Patients typically maintain near-normal systemic acid–base status but demonstrate an inability to lower urine pH appropriately (<5.3) following an acid load test (e.g. ammonium chloride challenge).[23] Hypercalciuria and hypocitraturia are frequently seen in dRTA. Enhanced bone resorption along with decreased renal calcium absorption induced by systemic acidosis leads to hypercalciuria.[24] Acidosis also enhances proximal tubular citrate absorption via Na⁺/dicarboxylate cotransporter 1 (NaDC1, also known as SLC13A2).[25] The combination of hypercalciuria along with hypocitraturia often leads to nephrocalcinosis and nephrolithiasis, seen in 65% of patients with dRTA on plain X-rays.[26] Even incomplete distal RTA also predisposes to calcium phosphate stone formation and nephrocalcinosis, even in the absence of overt metabolic acidosis, and may remain undiagnosed for years, often revealed during evaluation for recurrent nephrolithiasis.[27] Renal potassium wasting is a frequent feature in dRTA and is mediated by secondary hyperaldosteronism due to volume contraction and increased distal delivery of Na + ions; however, the exact mechanism for hypokalaemia is still not known.[28] It is important to note that low-molecular-weight proteinuria can occur in some patients with dRTA, which may be isolated or a part of generalised proximal tubular defect. The proximal defect disappears on correction of acidosis, differentiating it from primary proximal tubular defect.[29] The aetiological causes of type I RTA are mentioned in Table 1 and depicted in Figure 1. Mutations in ATP6V1B1 and ATP6V0A4 impair H⁺-ATPase pump function in α-intercalated cells, leading to autosomal recessive dRTA, often associated with sensorineural hearing loss. Patients with these mutations usually present during their first year of life.[30,31] SLC4A1 mutations, affecting the basolateral chloride-bicarbonate exchanger (AE1), cause autosomal-dominant and autosomal-recessive forms of dRTA that are not associated with sensorineural hearing loss, with phenotypic variability across families.[32,33] AE1 is also expressed in red cell membranes, and some variants of SLC4A1, mostly identified in South-East Asia, are associated with distal RTA and haemolytic anaemia (ovalocytosis).[34] Mutations of WDR72, which are detected in patients with amelogenesis imperfecta, can also have dRTA.[35,36] FOXI1 (forkhead box protein I1) mutations, a transcription factor involved in development of intercalated cell lineages, have been reported in a few cases of dRTA.[37] Patients presenting in early adulthood or later in life should be evaluated for acquired causes of dRTA [Table 1]. Incomplete distal RTA should be kept as a differential diagnosis in evaluating cases of nephrolithiasis or nephrocalcinosis in the absence of systemic acidosis.

Table 1.

Aetiological causes of type 1 RTA

Inherited
Aetiology	Molecular defect	Clinical and extra-renal features
ATP6V1B1 (Autosomal recessive)	Pathogenic variants in the B1 subunit of H⁺-ATPase	• Early-onset dRTA (often childhood) • Sensorineural hearing loss is common and may be early/severe • Growth failure/rickets in children • Nephrocalcinosis/nephrolithiasis
ATP6V0A4 (Autosomal recessive)	Mutations in the A4 subunit of the V0 domain of H⁺-ATPase	• Childhood or neonatal presentation possible • Sensorineural hearing loss frequently occurs but with variable penetrance (some alleles spare hearing) • Nephrocalcinosis/Nephrolithiasis
SLC4A1/AE1 (Autosomal dominant or recessive, allele dependent)	Mutations in the Cl⁻/HCO3⁻ exchanger (AE1) localised to basolateral membrane of α-intercalated cells	• dRTA phenotype ranges from mild adult onset to severe childhood disease • Hematologic associations: Certain SLC4A1 alleles produce haemolytic anaemia/red-cell membrane abnormalities (hereditary spherocytosis, Southeast-Asian ovalocytosis)
FOXI1 (Autosomal recessive)	Forkhead Transcription factor I1 required for expression of acid–base transport machinery in distal nephron	• Early onset dRTA often with sensorineural hearing loss • May present with growth retardation/nephrocalcinosis
WDR72 (Autosomal recessive)	WDR72 encodes a WD-repeat protein implicated in enamel formation and possible distal nephron function	• Amelogenesis imperfecta/enamel hypoplasia (dental enamel defects) is a key extra-renal clue • dRTA phenotype with nephrocalcinosis; variable hearing involvement
Acquired
Aetiology	Pathophysiology	Clinical features
Autoimmune: Sjögren’s syndrome, Systemic Lupus Erythematosus, Rheumatoid Arthritis and other CTDs)	Immune-mediated interstitial nephritis and/or autoantibody-driven damage to distal tubular cells (loss of α-ICs, disrupted transporter expression)	• Adult women commonly affected (Sjögren’s classic) • Xerostomia, keratoconjunctivitis sicca (Sjögren’s), systemic features of SLE/RA • dRTA may precede or occur without overt interstitial nephritis
Other systemic causes: Sarcoidosis, Wilson disease, vitamin D toxicity, hyperparathyroidism, idiopathic hypercalciuria, medullary sponge kidney, renal transplant	• Sarcoidosis: Granulomatous interstitial nephritis with tubular damage and impaired H⁺ secretion • Wilson Disease: Copper deposition in renal tubules causing tubular toxicity • Vitamin D Toxicity: Chronic hypercalcemia, nephrocalcinosis and tubular injury • Primary Hyperparathyroidism: Hypercalcemia and hypercalciuria leading to interstitial nephrocalcinosis and distal tubular dysfunction • Idiopathic Hypercalciuria and Medullary Sponge Kidney: Calcium deposition damages collecting duct/α-intercalated cells, causing distal acidification defect • Renal Transplant: Chronic allograft dysfunction, calcineurin inhibitor toxicity, and tubulointerstitial scarring impair H⁺ secretion	• Sarcoidosis: Systemic granulomatous disease (pulmonary, ocular, cutaneous signs) • Wilson Disease: Hepatic/neurological features, Kayser–Fleischer rings • Vitamin D Toxicity/Hyperparathyroidism: hypercalcemia, nephrolithiasis • Medullary Sponge Kidney/Idiopathic Hypercalciuria: Recurrent stones, nephrocalcinosis • Post-Renal Transplant: Declining graft function, tubular electrolyte wasting
Drugs and toxins	• Amphotericin B: Direct distal tubular membrane injury producing leaky epithelium and impaired H⁺ secretion • Lithium: Chronic tubular toxicity affecting distal acidification and causing nephrogenic DI, may produce dRTA phenotype • Foscarnet, ifosfamide, tenofovir (rarely dRTA but causes proximal toxicity) • Topiramate/acetazolamide: Carbonic anhydrase inhibition produces mixed effects (can cause metabolic acidosis and stone risk); clinically may mimic distal acidification problems	• Temporal relation to drug exposure (e.g., amphotericin course) is a key clue • Look for concurrent nephrotoxicity signs (AKI, polyuria) • Lithium history: polyuria, polydipsia, chronic use
Obstructive uropathy and chronic tubulointerstitial nephritis	Chronic interstitial scarring and loss of α-intercalated cell mass/function	• History of recurrent UTIs, urolithiasis, urinary obstruction, or prolonged reflux • CKD features may coexist (elevated creatinine, bland urine sediment)
Nephrocalcinosis/severe hypercalciuria (secondary tubular injury)	Interstitial calcium deposition and crystal-induced tubular injury lead to impairment of α-intercalated cell function and distal acidification	• History or imaging evidence of nephrocalcinosis/nephrolithiasis; hypercalciuria on 24-h urine • May present with haematuria, flank pain, recurrent stones

Type 2 or proximal RTA (pRTA)

Impaired proximal tubular bicarbonate absorption with intact distal acidification mechanisms marks the hallmark feature of proximal or type 2 RTA.[38,39] Like distal RTA, the causes of proximal RTA can be classified into primary (or inherited) and secondary causes [Table 2]. Proximal RTA can present as a component of generalised proximal tubular reabsorption dysfunction (Fanconi syndrome), characterised by loss of glucose, low-molecular weight protein, amino acids, phosphate, organic ions, and uric acid.[40,41,42] Its clinical spectrum varies according to the underlying aetiology and age of onset. Inherited forms usually manifest in infancy or early childhood and are often severe, with growth retardation, rickets, polyuria, polydipsia, and recurrent dehydration due to renal salt and water wasting. Mutations in SLC4A4 (encoding the sodium-bicarbonate cotransporter NBCe1) can cause isolated pRTA or syndromic disease with ocular abnormalities (glaucoma, band keratopathy, cataracts), growth impairment, and neurodevelopmental delay.[43] Nephropathic cystinosis, the most common inherited cause of Fanconi syndrome, is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene, leading to defective cystine transport and crystal accumulation in multiple tissues. It typically presents in infancy with polyuria, polydipsia, growth retardation, rickets, and metabolic acidosis. Progressive renal failure, ocular involvement (corneal crystals, photophobia), and multisystemic complications occur without timely treatment such as cysteamine therapy.[44] Other syndromic causes, such as Lowe syndrome (X-linked, OCRL mutations with cataracts, hypotonia, intellectual disability), Dent disease (CLCN5 mutation with proteinuria, nephrocalcinosis, and rickets), and inborn errors of metabolism including hereditary fructose intolerance, tyrosinemia type I, Wilson disease, glycogen storage disorders, and galactosemia, typically present in childhood with generalised proximal tubular dysfunction (Fanconi syndrome) in which pRTA is a prominent feature.[45] In contrast, acquired forms often emerge in adulthood, with a clinical picture shaped by the inciting factor. Drug-induced cases (e.g. ifosfamide, tenofovir, outdated tetracyclines, aminoglycosides, platinum chemotherapy, valproate) usually present with polyuria, hypokalaemia, muscle weakness, and bone pain or osteomalacia secondary to chronic acidosis and phosphate wasting. Paraproteinemia-related proximal tubulopathies, particularly in multiple myeloma and monoclonal gammopathy of renal significance, often manifest in middle-aged or older adults with low-molecular-weight proteinuria, hypophosphatemia, and osteomalacia. Heavy-metal exposure (lead, cadmium) may present subacutely with generalised Fanconi syndrome, while autoimmune conditions such as Sjögren syndrome cause pRTA in adulthood through tubule-interstitial inflammation, typically accompanied by systemic sicca symptoms. Across aetiologies, hypokalaemia, metabolic bone disease (rickets in children, osteomalacia in adults), and growth failure (in pediatric cases) remain common clinical hallmarks. Thus, while childhood presentations usually reflect genetic or metabolic syndromes, adult-onset pRTA is more commonly acquired, related to drugs, toxins, or systemic disease, underscoring the importance of age at presentation in guiding diagnostic evaluation.[46]

Table 2.

Aetiological causes of type 2 RTA

Inherited
Aetiology	Molecular defect	Clinical and extra-renal features
SLC2A2 Fanconi-Bickel syndrome (Autosomal recessive)	Autosomal recessive variants in SLC2A2 (GLUT2), impaired facilitative glucose transport in hepatocytes and proximal tubule cells	• Early infancy/childhood presentation: failure to thrive, hepatomegaly, postprandial hyperglycaemia with fasting hypoglycaemia • Glycosuria, hypophosphatemic rickets, polyuria, polydipsia
SLC34A1 Fanconi renotubular syndrome 2 (Autosomal recessive)	Mutations in SLC34A1, the proximal tubular sodium-phosphate cotransporter (NaPi-IIa)	• Hypophosphatemia leading to rickets/osteomalacia, bone pain, growth failure in children
EHHADH Fanconi renotubular syndrome 3 (Autosomal dominant)	Variants lead to mislocalisation of peroxisomal enzyme proteins to mitochondria leading to mitochondrial dysfunction in proximal tubular cells	• Generalised proximal tubular dysfunction: glycosuria, phosphaturia, aminoaciduria, bicarbonate wasting. • Onset variable (childhood to adult)
HNF1A / HNF4A (Autosomal dominant)	Heterozygous variants in HNF1A or HNF4A (transcription factors best known for maturity-onset diabetes of young) can rarely cause atypical Fanconi/proximal tubulopathy	• May present with overlapping endocrine phenotype (MODY diabetes or history of neonatal hypoglycaemia in HNF4A), plus proximal losses (glycosuria, phosphaturia) • Family history of monogenic diabetes may be a clue
CLCN5 Dent disease (X-linked)	Loss of renal chloride channel function	• Males with low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis; variable hypophosphatemia and pRTA features
OCRL1 Lowe syndrome (X-linked)	Phosphatidyl ionositol bisphosphate phosphatase enzyme defect	• Congenital cataracts, hypotonia, neurodevelopmental delay (Lowe) • Renal proximal tubulopathy (Fanconi features) typically recognized later • Male predominance
CTNS Nephropathic cystinosis (Autosomal Recessive)	Lysosomal cystine accumulation in proximal tubular cells	• Infancy/early childhood: failure to thrive, photophobia (corneal cystine crystals), hypothyroidism, growth failure • Classic Fanconi phenotype (polyuria, polydipsia, rickets)
FAH Tyrosinemia type I (Autosomal recessive)	Fumarylacetoacetate hydrolase deficiency	• Infant/child: Hepatic failure or chronic liver disease, coagulopathy; proximal tubular losses
ATP7B Wilson disease (Autosomal recessive)	Copper accumulation in renal tubules	• Hepatic disease, neuropsychiatric features, Kayser–Fleischer rings; urinary copper excretion
GALT Classic galactosaemia (Autosomal recessive)	Galactose-1-phosphate uridyltransferase deficiency	• Neonatal/infant presentation with feeding intolerance, hypoglycaemia, jaundice
ALDOB Hereditary fructose intolerance (Autosomal recessive)	Fructose-1-phosphate aldolase deficiency	• Fructose-exposed symptoms: vomiting, hypoglycaemia, hepatomegaly
G6PC Glycogen storage disease type 1a (Autosomal recessive)	Glucose-6-phosphatse alpha deficiency	• Hypoglycaemia, lactic acidosis, hyperuricaemia, hepatomegaly, proximal tubulopathy, gout
SLC37A4 Glycogen storage disease type Ib (Autosomal recessive)	Glucose-6-phosphate translocase deficiency	• Hypoglycaemia, lactic acidosis, hyperuricaemia, hepatomegaly • Nephrolithiasis, proteinuria, proximal tubulopathy, gout
Acquired
Aetiology	Pathophysiology	Clinical features
Drugs and toxins:  • Ifosfamide  • Tenofovir (TDF)  • Cisplatin  • Valproate  • Acetazolamide  • Topiramate  • Ranitidine  • Tetracyclines  • Aminoglycosides  • Heavy metals (lead, cadmium)  • Toluene (glue sniffing)	Drugs/toxins cause direct proximal cell injury (mitochondrial toxicity, transporter inhibition, endosomal dysfunction)	• Adult with new-onset Fanconi profile following exposure, or progressive renal tubular dysfunction during/after therapy
Monoclonal gammopathy/multiple myeloma	Light-chain proximal tubulopathy: filtered monoclonal light chains injure proximal tubular cells (endocytic overload/crystalline deposition)	• Older adults with bone pain, anaemia, hypercalcaemia, proteinuria
Other systemic diseases:  • Amyloidosis  • Renal transplant  • After AKI  • Hyperparathyroidism  • Metachromatic leukodystrophy	Tubulointerstitial nephritis and ischaemic/toxic injury, all can damage proximal tubule	• Systemic clues (hepatic, pulmonary, hematologic, exposure history) • Onset variable

Type 3 RTA or mixed RTA

Type 3 RTA is characterised by the presence of features of both proximal RTA and distal RTA. Whether type 3 RTA is an independent entity is not clear yet. It has been commonly described in osteopetrosis due to loss of function mutation in carbonic anhydrase type II enzyme. Clinically, affected individuals, often children, present with growth failure, developmental delay, metabolic acidosis, nephrocalcinosis, and osteopetrosis, with some cases also showing cerebral calcification and intellectual disability. Unlike isolated proximal or distal RTA, type 3 reflects a combined transport defect, and recognition of this entity is important as it points towards specific inherited enzymatic deficiencies rather than acquired disease [Table 3].[47]

Table 3.

Aetiological causes of type 3 RTA

Aetiology	Pathophysiology	Clinical features
Carbonic anhydrase II (CA2) deficiency (Autosomal recessive)	Produces a combined proximal (bicarbonate wasting) and distal (impaired H⁺ secretion) defect, hence mixed RTA phenotype	• Early childhood presentation: osteopetrosis (increased bone density), fractures, growth failure • Neurologic features: developmental delay, cerebral calcifications, seizures • Renal: features of both pRTA and dRTA
Drug-induced/toxin-related mixed (transient type 3 phenotype)	Pharmacologic carbonic anhydrase inhibitors (acetazolamide, topiramate) or severe proximal distal tubular injury from toxins can produce combined biochemical features	• Temporal relation to drug exposure (start or dose escalation) • Symptoms: metabolic acidosis, polyuria, kidney stone risk (topiramate causes hypocitraturia), variable hypokalaemia

Type 4 RTA or hyperkalaemic RTA

As the name suggests, it is characterised by the presence of metabolic acidosis along with hyperkalaemia. Hyperkalaemia is due to failure of aldosterone secretion or resistance [Table 4], while metabolic acidosis is due to the inability of the proximal tubules to generate bicarbonate from ammoniagenesis. The distal tubular urinary acidifying mechanisms remain intact.[48]

Table 4.

Aetiological causes of type 4 RTA

Aetiology	Molecular defect/pathophysiology	Clinical features
Mineralocorticoid receptor (MR) NR3C2 (Pseudohypoaldosteronism type 1) (Autosomal dominant)	Heterozygous loss-of-function in MR, leading to impaired aldosterone signalling	• Neonatal/infant salt-wasting, hyperkalaemia, poor weight gain
ENaC β-subunit SCNN1B (Pseudohypoaldosteronsim type 1) (Autosomal recessive)	Defective distal ENaC	• Severe neonatal salt-wasting, failure to thrive
WNK1, WNK4, KLHL3, CUL3 (Gordon syndrome) (Pseudohypoaldosteronsim type 2) (Autosomal dominant)	Gain-of-function mutations	• Hyperkalaemia with concurrent hypertension. • Onset: childhood to adult • Family history of early hypertension/hyperkalaemia
CYP21A2 (Salt-wasting CAH) (Autosomal recessive)	Impaired 21-hydroxylation	• Neonatal salt-wasting crisis: vomiting, dehydration, hypotension, hyperkalaemia • Virilisation in 46, XX infants
CYP11B2 (Autosomal recessive)	Aldosterone synthase deficiency	• Neonatal/infant salt-wasting, hyperkalaemia; failure to thrive • No cortisol deficiency or virilization (distinguishes from CAH)
Primary adrenal insufficiency	Reduced aldosterone production	• Fatigue, weight loss, hypotension, hyperpigmentation, hyponatraemia, hyperkalaemia
Hyporeninaemic hypoaldosteronism (diabetic nephropathy/CKD)	Impaired distal H⁺/K⁺ secretion, often combined with CKD	• Long-standing diabetes, CKD stage 3–5; mild acidosis, persistent hyperkalaemia
Drug-induced aldosterone deficiency or resistance	ACEi/ARBs, NSAIDs, heparin, trimethoprim, K⁺-sparing diuretics	• Temporal relation to drug initiation/dose change; often in CKD or diabetes
Aldosterone resistance: tubulointerstitial disease/obstructive uropathy/calcineurin inhibitors	Structural tubular damage or receptor signalling defects	• CKD, renal transplant, chronic interstitial nephritis; exposure to calcineurin inhibitors

ENaC, epithelial sodium channel; ACEi, Angiotensin converting enzyme inhibitor; ARBs, angiotensin II receptor blockers; NSAIDS, non-steroidal anti-inflammatory drugs; CKD, chronic kidney disease; CAH, congenital adrenal hyperplasia

WHEN TO SUSPECT RTA?

Any child presenting with failure to thrive, recurrent hypokalaemia, refractory rickets, polyuria or graveluria, polydipsia, and nephrocalcinosis or nephrolithiasis should be evaluated for RTA. Presentation in adults can be subtle with nephrocalcinosis, hypokalaemia, and periodic palsies. When metabolic acidosis persists without adequate correction, a spectrum of skeletal complications develops, collectively described as metabolic bone disease (MBD). In children, rickets is the most characteristic finding, while adults often present with osteomalacia. Other consequences include recurrent fractures, pseudofractures, secondary osteoporosis, and, less commonly, sclerotic bone changes. Several mechanisms underlie these abnormalities: Chronic acidosis stimulates osteoclastic activity and bone resorption; proximal RTA may lead to phosphate wasting and hypophosphataemia, further aggravating mineralisation defects, and reduced activation of vitamin D compounds the problem. In distal RTA, hypercalciuria and secondary hyperparathyroidism play pivotal roles in bone loss. Together, these disturbances compromise bone strength and growth, highlighting the importance of early recognition and sustained alkali therapy to prevent long-term skeletal sequelae.

STEPS IN EALUATION OF RTA

The following steps provide a systemic approach towards diagnosis and management of a case of suspected renal tubular acidosis. The first step involves documentation of the presence of hyperchloremic normal anion gap metabolic acidosis. Anion gap is calculated as follows:

STEP 1: Serum Anion gap (AG) = Serum [Na⁺ - (Cl^-+ HCO₃^-)]

Using this conventional formula, the normal serum anion gap is approximately 8–16 mmol/L when measured with flame photometry and 6–10 mmol/L with modern ion-selective electrode methods.[49,50] Variability arises due to differences in laboratory techniques, albumin concentration, and the presence of unmeasured anions. Since albumin is the major unmeasured anion, the AG should be corrected by about 2.3 mmol/L for every 1 g/dL fall in serum albumin below 4 g/dL [AG = AG + 2.3 (4 – albumin].[49]

Clinical key point: A normal anion gap metabolic acidosis supports the diagnosis of RTA or gastrointestinal bicarbonate loss, whereas an elevated anion gap metabolic acidosis suggests accumulation of organic acids (e.g. lactic acidosis, ketoacidosis, or renal failure).[51] To differentiate between the two, the second step in evaluation of normal anion gap metabolic acidosis is to look for urinary ammonium excretion.[52]

Caveats:

1. Hypoalbuminemia can mask a raised AG acidosis, leading to underestimation if correction is not applied.

2. Hypermagnesemia, hypercalcemia, paraproteinemias, and some toxic ingestions (e.g. bromide, lithium) can alter chloride measurements, leading to spuriously low AG values. Thus, careful interpretation in clinical context is crucial.

STEP 2: Estimation of urinary NH₄⁺ excretion

Direct quantification of urinary ammonium is the most accurate method to assess renal acidification, although historically it was not routinely available in clinical laboratories. With newer assays, 24-hour urinary ammonium measurement is increasingly feasible and should be utilised when possible. In systemic acidosis with intact renal function, ammonium excretion may appropriately increase to 200–300 mmol/day over several days; this adaptive response is markedly attenuated in RTA and in chronic kidney disease (CKD), with urinary ammonium excretion <40 mmol/day.[53,54]

The urine anion gap indirectly measures the amount of urinary ammonia excretion in response to metabolic acidosis as normal kidneys are able to generate ammonium ions (NH₄⁺) which combine with luminal Cl^- ions and are excreted in urine (Urinary anion gap (UAG) = Urine [(Na⁺ + K⁺)-Cl^-]).[52]

Under normal conditions, the UAG is typically positive (+20 to + 90 mmol/L). In the setting of metabolic acidosis, the healthy kidney responds by increasing NH₄⁺ excretion, which is accompanied by chloride, leading to a negative UAG (approximately –30 to –50 mmol/L). Thus, a negative UAG in metabolic acidosis suggests intact renal acidification, whereas a persistently positive UAG despite systemic acidosis strongly supports a diagnosis of distal (type 1) or type 4 RTA, where ammonium excretion is impaired.[55]

Clinical key point: A positive UAG in the presence of hyperchloremic metabolic acidosis indicates defective distal H⁺ secretion or impaired NH₄⁺ production/excretion, favouring distal or type 4 RTA. A negative UAG indicates appropriate renal response to acidosis and suggests extrarenal bicarbonate loss, most often gastrointestinal (e.g. diarrhoea); however, it does not rule out proximal (type 2) RTA, in which urinary anion gap can be negative.

Caveats:

1. Chronic kidney disease may blunt ammonium excretion irrespective of the primary disorder.

2. Estimation of NH₄⁺ excretion is of limited value if urine pH is >6.5 because HCO₃^- is a significant urinary anion in that situation and is not included in the calculation.

3. Not useful in acute hyperchloremic metabolic acidosis.

The urine osmolal gap represents the difference between the measured urine osmolality and the calculated osmolality. It serves as an indirect estimate of urinary ammonium excretion. An elevated gap (>200 mOsm/kg) reflects an appropriate increase in ammonium excretion during metabolic acidosis, whereas a low gap (<150 mOsm/kg) indicates impaired ammonium excretion, consistent with RTA. Interpretation should be cautious as false elevations may occur in the presence of urease-producing organisms or excretion of other unmeasured osmoles such as mannitol, alcohols, or glucose.

STEP 3: Determine the type of RTA

Once the diagnosis of RTA is confirmed, the next step is to differentiate between the different types of RTA. This can be done through following tests:

1. Urine Analysis: Routine urine biochemistry is useful to detect the integrity of renal tubular absorptive function, especially in the proximal tubules. Proteinuria (usually non-nephrotic range, i.e. urine albumin 1+ to 2+) and/or glycosuria indicate proximal tubular defect (type 2 RTA).

2. Urine pH: Urine pH indicates the integrity of distal renal tubular H⁺ excretion. In the presence of normal anion gap metabolic acidosis, a urinary pH of <5.3 favours the diagnosis of proximal RTA, whereas a urinary pH at or above 5.3 reflects primary defect in distal acidification mechanism. However, a urinary pH can be variable in patients with pRTA; it can be >5.3 if the serum bicarbonate level rises above 17 mEq/L, reflecting diminished proximal tubular reabsorptive capacity. This commonly occurs during alkali treatment for pRTA.[56]

   Caveats: Urinary pH can be falsely elevated in two scenarios:

   1. Urinary tract infection by urease-producing organisms, which can convert urea to ammonia and bicarbonate.

   2. Severe hypovolemia, leading to decreased sodium delivery in distal tubule, limits the normal acidification capacity of distal tubule.

3. Bicarbonate Loading Test: In this test, an oral load of sodium bicarbonate (1 gm = 12 mEq) is given at a dose of 2–4 mEq/kg/day for 2–3 consecutive days with the aim to normalise plasma bicarbonate (>22–24 mEq/L). However, oral sodium bicarbonate is often ineffective in normalising plasma HCO₃^- in large proportion of patients owing to marked HCO₃^- wasting. Instead, IV NaHCO₃ infusion (3.75% solution) is used in clinical practice at rates varying from 0.3 to 0.8 mL/min to cause an increment of 2–3 mEq/L/h of plasma HCO₃^-. A steady state is usually achieved in 3–4 hours of start of infusion and urine pH is measured every 30 minutes of start of infusion until three consecutive samples show urine pH >7.5. Urine samples should be collected under mineral oil, and the urine should be voided in upright position. Thereafter, blood samples are collected for serum creatinine and serum HCO₃^- estimation. The fractional excretion of bicarbonate is then calculated as:

   

   A fractional excretion of bicarbonate <5% suggests distal RTA, whereas a fractional excretion >15% suggests bicarbonate wasting and proximal RTA.[52]

   An additional parameter that can be calculated during bicarbonate loading test is urine–blood CO₂ gradient. After a load of sodium bicarbonate, the H⁺ secreted in distal tubules will react with the luminal HCO₃^- to form carbonic acid. In the presence of carbonic anhydrase enzyme, this will get dissociated into water and CO₂, which remains trapped in the lumen, giving rise to a urinary pCO₂ of >70 mmHg, at a urine pH of >7.5 and serum bicarbonate levels of >23–25 mEq/L. The urine–blood pCO₂ gradient in this scenario is >20 mmHg and is seen with normal distal tubule acid secretion. However, in patients with distal RTA, owing to defective distal H⁺ ion secretion, the urine–blood pCO₂ gradient is usually ≤20 mmHg, with urine pCO₂ <50 mmHg.[57,58]

4. Ammonium Chloride Loading Test: If systemic acidosis is mild or absent and renal tubular defect is clinically suspected, the role of ammonium chloride loading test comes into play. Ammonium chloride when given orally at a dose of 0.1 gm/kg over a period of 1 hour (to prevent gastric irritation) induces systemic acidosis via metabolism in liver to NH₄⁺ and urea. During the test, following administration of oral ammonium chloride, urine pH and plasma HCO₃^- need to be measured every hourly for the next 6 hours. The plasma HCO₃^- should fall by 3–5 mEq/L, and urine pH should be <5.3. The presence of urinary pH >5.3 despite fall in plasma HCO₃^- by 3–5 mEq/L suggests distal renal tubular acid secretion defect or distal RTA. The test is contraindicated in patients with documented liver disease, urinary tract infection, hypokalaemia, or hypercalcemia.[59]

5. Furosemide Fludrocortisone Test: This test serves as an alternative to ammonium chloride loading test as the latter is not well tolerated and frequently leads to gastrointestinal upset. Delivery of sodium ions to the distal tubules is enhanced by furosemide, which enhances H⁺ secretion from distal tubules. Addition of fludrocortisone further enhances H⁺ secretion. After an overnight fast, oral furosemide is administered at a dose of 1 mg/kg (maximum 40 mg) and fludrocortisone at a dose of 0.025 mg/kg (maximum 1 mg). Urine pH needs to be measured hourly for 6 hours thereafter. A urine pH < 5.3 indicates that the distal acidification mechanism is intact. Failure to reduce urinary pH to < 5.3 indicates distal renal tubular H + secretory defect or distal RTA.[59] This test has good sensitivity and high negative predictive value; however, it lacks specificity, and hence, an abnormal test needs to be confirmed by ammonium chloride test.[60]

6. Additional Test for Proximal RTA:

   1. Fractional Excretion of Phosphate: Fractional excretion of phosphate >15% (normal 10–15%) suggests renal phosphate wasting. Renal phosphaturia must be confirmed by calculating tubular maximum phosphate resorption per unit glomerular filtration rate (TmP/GFR). It is calculated by using Walton and Bijvoet’s normogram. Normal TmP/GFR varies in different age group and ranges 2.8–4.4 mg/dL in adults.[61]

   2. Urinary Amino Acid Estimation: Proximal tubular wasting is characterised by generalised aminoaciduria of >5%.[38]

   3. Urinary ℜ₂ Microglobulin Estimation: An elevated level is suggestive of Fanconi syndrome.[62]

7. Additional Test for Distal RTA:

   1. Ultrasonography KUB/Non-Contrast CT KUB: To look for nephrocalcinosis

   2. Urinary Calcium Creatinine Ratio: Hypercalciuria (defined as 24 hours urinary calcium excretion >4 mg/kg/day or >250 mg/day in females and >300 mg/day in males) is a prominent feature of distal RTA and some forms of proximal RTA like Dent’s disease. A spot urinary calcium to creatinine ratio of >0.2 in children >2 years of age indicates hypercalciuria.[63]

STEP 4: Determine the aetiology of RTA

An additional test that would help determine the aetiology of RTA, as guided by clinical scenario, includes the following:

1. Genetic Test for RTA: Whole exome sequencing.

2. Suspected Sjogren’s Syndrome: Schirmer test, minor salivary gland biopsy.

3. Suspected Wilson’s Disease or Cystinosis: Opthalmological workup for band keratopathy, corneal deposits, and cataract.

4. Auditory Assessment: For evaluation of sensorineural hearing loss, associated with some genetic forms of RTA (ATP6V1B1, FOXI1, and ATP6VOA4).

5. Dental Assessment: For suspected WDR72 mutations associated with amelogenesis imperfecta.

6. Peripheral Blood Smear: AE1 mutations associated with red cell membrane defects.

MANAGEMENT OF RTA

Type 1 RTA

Alkali supplementation is the mainstay of treatment in distal RTA. All symptoms, except deafness and nephrocalcinosis, resolves with appropriate alkali supplementation. Alkali supplementation is usually initiated at the dose of 2–4 mEq/kg/day in the form of potassium citrate formulations. Potassium citrate is preferred over sodium bicarbonate because administration of sodium bicarbonate raises extracellular fluid volume and increases hypercalciuria owing to increased sodium load. However, supplementation of potassium citrate improves hypokalaemia and hypocitraturia. Correction of metabolic acidosis spontaneously improves hypokalaemia and hypercalciuria.[64]

Type 2 RTA

The management of proximal RTA depends on management of the underlying aetiology. High doses of alkali (10–15 mEq/kg/day) are used as the proximal tubular defect in bicarbonate reabsorption.[65] Other metabolic parameters arising out of proximal tubular defect need to be addressed; for example, hypokalaemia needs to be managed with oral potassium supplementation (1–5 mEq/kg/day), hypophosphatemia is managed with oral phosphate supplementation (20–40 mg/kg/day),[66] and sodium supplementation (3–5 mEq/kg/day) and magnesium supplementation (25–50 mg/kg/day) may be needed in some children.[67,68] Thiazide diuretics cause volume depletion which can enhance bicarbonate reabsorption in type 2 RTA. Due to proximal tubular defect, some patients may have reduced activation of vitamin D, indicating calcitriol therapy in selected patients.

Type 3 RTA

Type 3 RTA is uncommon and typically reflects combined proximal and distal tubular dysfunction, most classically seen in carbonic anhydrase II deficiency. Because of its mixed pathophysiology, management is tailored to address both impaired bicarbonate reabsorption and defective distal acid secretion. Patients usually require higher doses of alkali therapy than those with isolated distal RTA, often in the range used for proximal RTA, to compensate for bicarbonate losses. Potassium supplementation is frequently necessary since large alkali doses can exacerbate urinary potassium wasting. When proximal tubular phosphate wasting is present, phosphate and active vitamin D analogues should be added to prevent or treat rickets and osteomalacia.

Hyperkalaemic RTA

Stabilisation of the serum potassium concentration is the primary aim in management of type IV RTA. It can be done by stopping all medications that can lead to hyperkalaemia, dietary modification with avoiding K⁺ rich foods, and addition of potassium-binding resins (calcium polystyrene sulfonate 1 g/kg/day in 2–3 divided doses). Bicarbonate supplementation can be added to correct acidosis. In patients with hyperkalaemic type 4 RTA, newer potassium-binding agents such as patiromer and sodium zirconium cyclosilicate (SZC) have transformed management. Patiromer is a non-absorbed resin that binds potassium in the colon in exchange for calcium, leading to a gradual and sustained fall in serum potassium. SZC, on the other hand, is an inorganic crystalline compound that traps potassium and, to some extent, ammonium in exchange for hydrogen and sodium ions throughout the gut. What makes these agents particularly valuable is that they allow clinicians to continue renin–angiotensin–aldosterone system (RAAS) inhibitors, which are essential for many patients with chronic kidney disease, diabetes, or heart failure, but are often stopped because of recurrent hyperkalaemia.[69,70]

CONCLUSION

Renal tubular acidosis comprises a group of uncommon yet treatable disorders. A thorough and stepwise evaluation is the cornerstone in reaching the appropriate diagnosis of RTA followed by evaluation of possible aetiologies. Clinical presentation can give the clue towards diagnosis of a primary or secondary causes of RTA and the biochemical investigations need to be tailored as per the clinical scenario.

Author contributions

SD, VA and TVP conceptualized the manuscript. SD, VA, TVP, and KEP wrote the manuscript. All authors have contributed equally in drafting the final version of the manuscript.

Conflicts of interest

There are no conflicts of interest

Use of artificial intelligence

Artificial intelligence was not used in any form for analysis or writing of this research article.

Funding Statement

Nil.