Explore the complexities of renal tubular acidosis, from its diverse types and causes to the latest in diagnosis and management.

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Types of RTA

There are four subtypes of RTA, each corresponding to different mechanisms involved in renal acid-base handling:

• Type 1: Distal RTA, where there's an impaired acid secretion in the distal tubules.
• Type 2: Proximal RTA, characterised by impaired reabsorption of bicarbonate in the proximal tubules.
• Type 3: Mixed RTA, which involves a combination of both distal and proximal tubular dysfunction.
• Type 4: Hyporeninemic hypoaldosteronism RTA, associated with reduced levels of renin and aldosterone, resulting in impaired potassium and hydrogen ion secretion.

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Aetiology

Type 1 Distal Renal Tubular Acidosis (RTA)

Causes:

1. Autoimmune diseases: Systemic lupus erythematosus (SLE), Sjogren syndrome, rheumatoid arthritis, etc.
2. Inherited factors: Mutations in genes encoding chloride-bicarbonate exchanger (AE1) or H-ATPase pump subunits.
3. Genetic associations: Marfan syndrome, Ehler-Danlos syndrome, sickle cell disease, congenital urinary tract obstruction.
4. Nephrocalcinosis: Chronic hypercalcemia, medullary sponge kidney.
5. Tubulointerstitial diseases: Chronic pyelonephritis, interstitial nephritis, obstructive uropathy, renal transplant rejection.
6. Hypergammaglobulinemic states: Monoclonal gammopathy, multiple myeloma, amyloidosis, chronic liver disease.
7. Drugs: Lithium, amphotericin B, NSAIDs, lead, antivirals.
8. Miscellaneous: Idiopathic, familial hypercalciuria, glue sniffing (toluene inhalation).

Type 2 Proximal RTA

Causes:

1. Hypergammaglobulinemic states: Monoclonal gammopathy (light chain), multiple myeloma, amyloidosis.
2. Inherited factors: Mutations in Na-H antiporter or Na-HCO3 cotransporter genes.
3. Drugs: Lead or other heavy metals, carbonic anhydrase inhibitors, out-of-date tetracyclines, aminoglycosides, valproate, mercury, tenofovir, ifosfamide.
4. Autoimmune: Sjogren syndrome, SLE.
5. Miscellaneous: Interstitial nephritis, Fanconi syndrome, vitamin D deficiency, secondary hyperparathyroidism, chronic hepatitis.

Type 3 Mixed RTA

Cause: Mutations in carbonic anhydrase II gene.

Type 4 Hyperkalemic RTA

Causes:

1. Hyporeninemic hypoaldosteronism: Commonly due to diabetic nephropathy.
2. Drugs: Potassium-sparing diuretics, beta-blockers, NSAIDs, calcineurin inhibitors, ACE inhibitors, ARBs, renin inhibitors, heparin, TMP/SMX.
3. Autoimmune: SLE.
4. Genetic: Sickle cell disease, pseudohypoaldosteronism.
5. Miscellaneous: Interstitial nephritis, chronic urinary tract obstruction, adrenal insensitivity to angiotensin II, renal insufficiency.

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History and physical examination

Type 1 Distal

This type presents with:

1. Rickets, growth failure, osteomalacia due to metabolic acidosis.
2. Hypercalciuria, hypocitraturia (citrate is reabsorbed as a buffer for hydrogen ions), alkaline urine lead to nephrocalcinosis (calcium phosphate stones) and recurrent UTI.
3. Hypokalemia can lead to muscle weakness and arrhythmia.

Type 2 Proximal

1. Chronic metabolic acidosis leeches calcium out of bones and causes osteomalacia.
2. Hypokalemia as potassium binds to HCO3 in urine and loss of phosphate in urine leads to hypophosphatemic rickets.
3. There is also the loss of glucose, urate, and amino acids in the urine.

Type 3 Mixed

1. This clinical condition, also called Guibaud-Vainsel syndrome or marble brain disease, is characterised by a syndrome featuring osteopetrosis, mixed-type renal tubular acidosis, cerebral calcification, and intellectual disability.
2. Additional manifestations include increased bone fragility leading to fractures and growth impairment.
3. Moreover, excessive growth of facial bones results in facial distortion, while nerve compression causes conductive hearing loss and vision impairment.

Type 4 Hyperkalemic

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Evaluation

Diagnosing RTA:

1. Clinicians should suspect RTA in patients with unexplained normal anion gap (hyperchloremic) metabolic acidosis. Confirmation involves measuring blood pH to confirm metabolic acidosis. Different types of RTA present with specific plasma bicarbonate levels:

• Type 1: Less than 10 to 20 mEq/L
• Type 2: 12 to 18 mEq/L
• Type 4: Greater than 17 mEq/L

2. Plasma potassium levels are low in Type 1 and Type 2, and high in Type 4 due to various mechanisms.
3. BUN/Cr levels are usually normal or near-normal, ruling out renal failure.
4. Urinalysis reveals an inappropriately alkaline urine pH (>5.5) despite metabolic acidosis in Type 1, and it may be acidic (<5.5) in Type 2 and Type 4.
5. A positive urine anion gap suggests RTA, as it signifies low NH4Cl excretion causing decreased chloride in urine along with hyperchloremic metabolic acidosis.

Specific tests include:

1. Acid load test: Involves infusing acid into the blood and monitoring urine pH and plasma HCO3 levels. Patients with distal RTA cannot excrete acid, resulting in persistently basic urine pH despite increasingly acidic serum.
2. Bicarbonate infusion test: Measures fractional bicarbonate excretion after bicarbonate infusion. Patients with proximal RTA have a threshold for bicarbonate reabsorption below the infused level, leading to a rise in urine pH.
3. Urine Na: In type 4 renal tubular acidosis, there is a persistent elevation of urine sodium levels despite limited sodium intake, often attributed to aldosterone insufficiency or insensitivity.

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Treatment and management of RTA

1. Correction of chronic acidemia is crucial to prevent its adverse effects on bones and muscles.

1. This involves oral bicarbonate replacement, typically at a dose of 1-2 mEq/kg per day using sodium bicarbonate or potassium citrate.
2. Potassium citrate may be necessary for patients with hypokalemia, nephrolithiasis, or nephrocalcinosis.
3. Underlying conditions contributing to RTA should be identified and treated.

2. Type 1 Distal RTA: Distal RTA is relatively easy to correct with bicarbonate replacement as most of the bicarbonate is absorbed in the proximal tubule. High doses of bicarbonate may be required (>10 mmol/kg per day).

3. Type 2 Proximal RTA: Higher doses of bicarbonate (>10 mmol/kg per day) are needed due to marked bicarbonate diuresis.

1. Potassium salts should be administered to minimise hypokalemia associated with alkali therapy.
2. Phosphate and vitamin D supplementation may also be necessary to normalise serum phosphate levels and reverse metabolic bone disease.

4. Type 4 Hyperkalemic RTA:

1. Management includes limiting dietary potassium intake and, if necessary, using diuretics like loop or thiazide diuretics.
2. Fludrocortisone may be effective in managing hyperkalemia associated with aldosterone deficiency, but it's not commonly used due to potential adverse effects.

Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Bhavin Mandowara is a practising nephrologist at Zydus Hospital, Ahmedabad.