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Renal tubular acidosis
Classification & external resources

Nephrocalcinosis on xray as seen in dRTA
ICD-10	N25.8
OMIM	179800
DiseasesDB	11687 11673 11705
MeSH	D000141

Renal tubular acidosis, or RTA, is a medical condition in which the kidneys fail to dispose of a normal amount of acid into the urine, which may lead to acidosis ,where the blood becomes too acidic.

This is due to the renal tubules failing to acidify the urine, rather than acid accumulating in the body due to kidney failure. As such it is a cause of a normal anion gap acidosis.

In RTA, the renal tubules either fail to appropriately reclaim bicarbonate (in the proximal tubule) or excrete hydrogen ions (in the distal tubule).

Contents 1 Types 1.1 Distal RTA (Type I) 1.1.1 Causes 1.1.2 Treatment 1.2 Proximal RTA 1.2.1 Causes 1.2.2 Treatment 1.3 Type 3 RTA 1.4 Type 4 RTA (Hypoaldosteronism) 1.4.1 Treatment 2 Trivia 3 See also 4 References

There are several different types of RTA (which are different syndromes with different causes).

The different subtypes:

• Distal or type 1 RTA
• Proximal or type 2 RTA
• Type 3 RTA (very rare)
• Hypoaldosteronism or type 4 RTA

Distal RTA (dRTA) is the most common and also the classical form of RTA, being the first described. It has a number of causes which cause a common underlying problem, which is a failure of acid secretion by the alpha intercalated cells of the cortical collecting duct of the distal nephron. This leads to a failure acidify the urine to a pH of less than 5.3 even if the blood is too acidic (ie there is systemic acidemia), and consequently there is a tendency towards acidemia. This leads to the clinical features of dRTA;^[1]

• Variable metabolic acidosis/acidemia
• Hypokalemia (which may be severe)
• Urinary stone formation
• Nephrocalcinosis (deposition of calcium in the substance of the kidney)
• Bone demineralisation (causing rickets in children and osteomalacia in adults)

The acidosis is variable, and one may have dRTA with alpha intercalated cell failure without necessarily being acidemic, this is termed incomplete dRTA. The diagnosis of dRTA can be made by the observation of a urinary pH of greater than 5.3 in the face of a systemic acidemia (usually taken to be a serum bicarbonate of 20 mmol/l or less). In the case of an incomplete dRTA, failure to acidify the urine following an oral acid loading challenge is often used as a test. The test usually performed is the short ammonium chloride test,^[2] in which ammonium chloride capsules are used as the acid load.

The symptoms and sequelae of dRTA are variable and ranging from being completely asymptomatic, through loin pain and hematuria from kidney stones to failure to thrive and severe rickets in childhood forms as well as possible renal failure and even death.

• Hereditary causes include mutations of Band 3^[3] the basolateral bicarbonate transporter of the intercalated cell, which may transmit autosomal dominantly in western European cases, or recessively in South East Asian cases, which are associated with more severe hypokaemia.^[4]They also include mutations of subunits of the apical proton pump vH⁺ATPase,^[5] which transmit in an autosomal recessive fashion, and may be associated with sensorineural deafness.^[6]
• Autoimmune disease, classically Sjögren's syndrome but may be associated with any autoimmune disease, including systemic lupus erythematosus, Rheumatoid Arthritis and even hypergammaglobulinemia. Hypokalaemia is often more severe in these cases.^[7]
• Nephrocalcinosis, which may cause dRTA as well as be caused by it-due to calcium disruption of the cortical collecting duct.
• Toxins, including Ifosfamide,^[8] Toluene,^[9]Lithium Carbonate^[10] and Amphotericin B.^[11]
• Urinary tract obstruction
• Renal transplantation
• Sickle cell anemia
• Liver Cirrhosis

This is relatively straightforward. It involves correction of the acidemia with oral sodium bicarbonate or sodium citrate. This will correct the acidemia and reverse bone demineralisation. Hypokalema and urinary stone formation and nephrocalcinosis can be treated with potassium citrate tablets which not only replace potassium but won't increase calcium excretion and thus exacerbate stone disease as sodium bicarbonate or citrate may do.^[12]

Proximal RTA (pRTA) is caused by a failure of the proximal tubular cells to resorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the urine can acidify to a pH of less than 5.3. pRTA also has several causes, and may occasionally be present as a solitary defect, but is usually associated with a more generalised dysfunction of the proximal tubular cells called Fanconi's syndrome where there is also phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria. The principle feature of Fanconi's syndrome is bone demineralisation due to phosphate wasting. Correction with oral bicarbonate may exacerbate urinary potassium losses and precipitate hypokalemia.

Familial disorders

• Cystinosis
• Wilson's disease
• Galactosemia
• Tyrosinemia
• Hereditary fructose intolerance
• Lowe's syndrome
• Glycogen storage disease (type I)

Acquired disorders

• Multiple myeloma
• Amyloidosis
• Toxins, such as HAART, ifosfamide,^[13]Lead and Cadmium
• Paroxysmal Nocturnal Hemoglobinuria

Again this depends on oral bicarbonate supplementation. However, this will increase urinary bicarbonate wasting and may well promote a bicarbonate diuresis. The amount of bicarbonate given may have to be very large, to stay ahead of the urinary losses. As with dRTA, reversal of the chronic acidosis should reverse bone demineralisation.^[14]

This was previously used to designate a rare and transient mixed dRTA and pRTA of uncertain aetiology. Now it is used to describe a genetic defect in type 2 carbonic anhydrase (CA2), which is found in both the proximal and distal tubular cells, as well in bone. As a result it causes;

• proximal renal tubular acidosis
• distal renal tubular acidosis
• osteopetrosis
• cerebral calcification and subsequent mental impairment;

It is very rare and cases from all over the world have been reported, of which about 70% are from the Magreb region of North Africa, possibly due to the high prevalence of consanguinity there.^[15] The kidney problems are treated as described above, there is no treatment for the osteopetrosis or cerebral calcification, unfortunately.

Type 4 RTA is not actually a tubular disorder at all, and nor does it have a clinical syndrome similar to the other types of RTA described above. It was included in the classification of renal tubular acidoses as it is associated with a mild (normal anion gap) metabolic acidosis due to a physiological reduction in distal tubular ammonium excretion, which is secondary to hypoaldosteronism. It's cardinal feature is hyperkalemia, and measured urinary acidification is normal.

Causes;

• Aldosterone deficiency-Primary (rare)

1. Primary adrenal insufficiency
2. Congenital adrenal hyperplasia
3. Aldosterone synthase deficiency
4. Potassium sparing diuretics

• Hyporeninemic hypoaldosteronism (due to decreased angiotensin 2 production as well as intra-adrenal dysfunction^[16])

1. Renal dysfunction-most commonly diabetic nephropathy
2. HIV infection
3. ACE inhibitors
4. NSAIDs
5. Ciclosporin

• Aldosterone resistance

1. Drugs (Amiloride, Spironolactone,Trimethoprim, Pentamidine)
2. Pseudohypoaldosteronism

• Aldosterone deficiency should be treated with a mineralocorticoid (such as fludrocortisone), as well as possibly a glucocorticoid for cortisol deficiency, if present.
• Hyporeninemic hypoaldosteronism is ammenable to fludrocortisone treatment,^[17] but the accompanying hypertension and oedema can prove a problem in these patients, so often a diuretic (such as the thiazide diuretic, bendrofluazide,or a loop diuretic, such as furosemide) is used to control the hyperkalemia.^[18]

dRTA has been proposed as a possible diagnosis for the unknown malady plaguing Tiny Tim in Charles Dickens' A Christmas Carol.^[19][20]

• Hyperchloremic acidosis
• Hypokalemia
• Kidney stone

1. ^ Laing, C M (Jun 2005). "Renal tubular acidosis: developments in our understanding of the molecular basis.". Int J Biochem Cell Biol 37 (6): 1151-61. 
2. ^ Wrong, O; Davies HEF (1959). "The Excretion of Acid in Renal Disease". QJM 28: 259-313. 
3. ^ Bruce, L J (1997). "Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene". J Clin Invest 100: 1693-1707. 
4. ^ Bruce, L J (2000). "Band 3 mutations, renal tubular acidosis and South-East Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band 3 transport in red cells". Biochem J 350: 41-51. 
5. ^ Karet, F E (May 1998). "Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis". PNAS 95 (11): 6337-6342. 
6. ^ Karet, F E (1999). "Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness". Nature Genetics 21: 81-90. 
7. ^ Wrong, OM (1993). "Immune-related potassium-losing interstitial nephritis: a comparison with distal renal tubular acidosis". QJM 86 (8): 513-542. 
8. ^ Skinner, R (Aug 1996). "Risk factors for ifosfamide nephrotoxicity in children". Lancet 348(9027): 578-80. 
9. ^ Battle, DC (1988). "On the mechanism of toluene-induced renal tubular acidosis". Nephron 49 (3): 210-8. 
10. ^ Boton, R (Nov 1987). "Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy". Am J Kidney Dis 10 (5): 329-45. 
11. ^ McCurdy, DK (Jan 1968). "Renal tubular acidosis due to amphotericin B". NEJM 278 (3): 124-30. 
12. ^ Morris, R C (2002). "Alkali Therapy In Renal Tubular Acidosis: Who Needs It?". J Am Soc Nephrol 13: 2186–2188. 
13. ^ Skinner, R (July 2003). "Chronic ifosfamide nephrotoxicity in children". Medical and Pediatric Oncology 41 (3): 190-197. 
14. ^ McSherry, E (1981). "Renal tubular acidosis in childhood". Kidney International 20: 799. 
15. ^ Fathallah, D. M. (1997). "Carbonic anhydrase II (CA II) deficiency in Maghrebian patients: evidence for founder effect and genomic recombination at the CA II locus". Human Genetics (99): 634-637. 10.1007/s004390050419. 
16. ^ DeFronzo, RA (1980). "Hyperkalemia in hyporeninemic hypoaldosteronism". Kidney International (17): 118.. 
17. ^ DeFronzo, RA (1980). "Hyperkalemia in hyporeninemic hypoaldosteronism". Kidney International (17): 118.. 
18. ^ Sebastian, A (1984). "Amelioration of hyperchloremic acidosis with furosemide therapy in patients with chronic renal insufficiency and type 4 renal tubular acidosis". Am J Nephrol 4 (5): 287-300. 
19. ^ Lewis D (1992). "What was wrong with Tiny Tim?". Am J Dis Child 146 (12): 1403-7. PMID 1340779. 
20. ^ http://www.time.com/time/magazine/article/0,9171,977391,00.html