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There are various disorders of tubular function, both generalised and specific. These disorders may be isolated defects, generalised tubular defects, as in Fanconi's syndrome, or associated with more generalised disease processes.
Clinical features suggestive of renal tubular disorders include:
- Growth restriction, failure to thrive.
- Polyuria, polydipsia.
- Refractory rickets.
- Renal calculi, nephrocalcinosis.
- Unexplained hypertension.
Laboratory features include:
- Hyperchloraemic metabolic acidosis.
- Metabolic alkalosis with or without hypokalaemia.
- Hyponatraemia with hyperkalaemia.
- Hypercalciuria with normal serum calcium.
See separate Renal Fanconi Syndrome article.
Renal tubular acidosis
Type 1 (classic distal) renal tubular acidosis
- Inability to form an acid urine in the distal tubule.
- May be inherited as a primary disorder or associated with autoimmune disorders (eg, Sjögren's syndrome, systemic lupus erythematosus (SLE)), hyperparathyroidism, analgesic nephropathy, renal transplant rejection, obstructive uropathy and chronic urinary tract infections (UTIs).
- Without treatment, it leads to growth restriction and progressive renal failure.
- Hyperventilation, muscle weakness, cardiac arrhythmias (hypokalaemia) and bone pain (due to rickets or osteomalacia).
- Renal calculi, recurrent UTI, chronic kidney disease.
- Hypokalaemia, hyperchloraemic metabolic acidosis.
- Urinary pH is above 6, hypercalciuria.
- Acute: correct hypokalaemia before acidosis.
- Chronic: oral bicarbonate; long-term potassium supplements are usually not required, as alkali therapy prevents excessive urinary potassium loss.
Type 2 (proximal) renal tubular acidosis
- May occur in isolation but is more often associated with other tubular defects as part of Fanconi's syndrome.
- Defective bicarbonate reabsorption in the proximal tubule leads to an excess of bicarbonate in the urine.
- Polyuria, polydipsia, proximal myopathy.
- Osteomalacia or rickets.
- Hypokalaemia, hyperchloraemic metabolic acidosis.
- High doses of bicarbonate are required but the prognosis is good. Correcting acidosis and low potassium levels allows normal growth and prevents bone disease; however, vitamin D supplements may also be required.
- Hydrochlorothiazide can be added to create mild volume depletion and increase proximal tubular resorption if bicarbonate level fails to rise; however, if this is done, potassium supplementation needs to be increased.
It is not clear whether this is a specific entity in itself or a combination of type 1 and type 2.
- There is impaired proximal bicarbonate resorption and impaired distal acidification. It is a rare entity. An inherited form due to recessive mutation has also been reported. Iatrogenic causes include acetazolamide and topiramate.
- Osteopetrosis marble bone disease) and cerebral calcification can occur, in association with renal tubular acidosis. This is called Guibaud-Vainsel syndrome, or marble brain disease. Conductive hearing loss and sight impairment can occur due to excessive bone growth and nerve pressure.
- Needs to be individualised to the patient's biochemical status, depending on whether proximal or distal renal tubular acidosis predominates.
Type 4 (hyperkalaemic) renal tubular acidosis
- Occurs in diseases associated with reduced aldosterone activity; causes include:
- Addison's disease, inborn errors of steroid metabolism, diabetes mellitus, SLE, amyloidosis, chronic tubulointerstitial disease.
- Drugs: angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, potassium-sparing diuretics, non-steroidal anti-inflammatory drugs (NSAIDs).
- Mineralocorticoid deficiency: reduced hydrogen secretion in the distal nephron causes reduced ammonium excretion.
- Urinary pH below 5.4.
- Hyperkalaemia, hyperchloraemic metabolic acidosis.
- Fludrocortisone is required if there is acidosis or hyperkalaemia.
See separate Glycosuria article.
Nephrogenic diabetes insipidus
See also separate Diabetes Insipidus article.
- Caused by renal insensitivity to antidiuretic hormone.
- It may be primary (familial, X-linked) or secondary to a number of causes:
- Drugs - eg, lithium, diuretics.
- Metabolic: hypokalaemia, hypercalcaemia.
- Tubulointerstitial disease: partial obstruction, pyelonephritis, cystic diseases, granulomatous diseases, sickle cell disease.
- Presents with polyuria, hypernatraemia and uraemia.
- The kidney is largely responsible for controlling extracellular phosphate levels, under the control of parathyroid hormone.
- There are several types of phosphate transport defect causing hypophosphataemia and inappropriate phosphaturia. The most common forms include:
- Hereditary hypophosphataemic rickets (vitamin D-resistant rickets).
- Hypophosphataemia with rickets or osteomalacia.
- Presents with growth restriction and early bone deformity.
- Does not respond to vitamin D but resistance to 1,25-dihydroxyvitamin D only occurs with functional defects of the vitamin D receptor.
- Treatment is with 1,25-dihydroxyvitamin D plus amiloride and thiazide to reduce calcium reabsorption.
- X-linked hypophosphataemic rickets:
- Is the most common cause of an isolated defect in tubular phosphate reabsorption.
- Presentation is with poor growth and rickets in early childhood.
- There is a defect in proximal tubular phosphate transport that results in persistent hypophosphataemia and inappropriate phosphaturia.
- Large doses of oral phosphate supplements are required, together with 1,25-dihydroxyvitamin D.
- Hypoparathyroidism and pseudohypoparathyroidism (renal resistance to parathyroid hormone) causing reduced renal phosphate excretion.
Relatively common disorders causing hypercalciuria and, less commonly, hypocalciuria:
- Idiopathic hypercalciuria:
- High risk of calcium stone formation with hypercalciuria but normal blood calcium.
- Usually results from calcium hyperabsorption in the intestine with hypercalciuria being of overspill type.
- Hypercalciuria is treated with dietary restriction of calcium intake (plus careful monitoring of bone formation in children). Thiazide diuretic is used where this fails.
- Hereditary hypercalciuric nephrolithiasis:
- A rare disorder associated with proteinuria, nephrocalcinosis, renal stones and frequently chronic kidney disease.
- Familial hypocalciuric hypercalcaemia:
- An autosomal-dominant disorder following a generally benign course, associated with a defective extracellular sensing receptor.
- Hypocalciuria and hypercalcaemia are accompanied by hypermagnesaemia with parathyroid hormone levels in the normal range.
- In general, treatment is not required.
See separate Aminoacidurias article.
Hereditary hypokalaemic tubulopathies
See also separate Hypokalaemic Alkalosis article. Examples include:
- Bartter's syndrome: caused by a gene mutation affecting potassium transport at the ascending limb of the tubule.
- Gitelman's syndrome:
- A rare inherited autosomal-recessive disorder caused by a defect in the renal tubule.
- It causes the kidneys to pass excess sodium, magnesium, chloride and potassium into the urine.
- Gitelman's syndrome is linked to a loss of function of the encoded thiazide-sensitive sodium chloride co-transporter.
- People with Gitelman's syndrome present with hypochloraemic metabolic alkalosis, hypokalaemia and hypocalciuria. Hypomagnesaemia is present in many but not all cases.
- Carriers of Gitelman's syndrome-linked mutations are often asymptomatic while some complain of mild muscle cramps or weakness fatigue.
- Bartter's syndrome causes hypocalcaemia, but Gitelman's syndrome causes hypercalcaemia.
- In both Bartter's syndrome and Gitelman's syndrome, NSAIDs in combination with potassium-sparing diuretics usually bring the plasma potassium concentration into the low normal range.
Pseudohypoaldosteronism and Liddle's syndrome
- Pseudohypoaldosteronism and Liddle's syndrome cause abnormal function of the sodium channel in the renal cortical collecting tubule.
- Inherited by either autosomal-recessive or autosomal inheritance.
- Usually presents in infancy with hyponatraemia and hyperkalaemia.
- The lung sodium channel is also impaired leading to lower respiratory tract infections.
- Management consists of a high-salt diet with fludrocortisone.
- Liddle's syndrome:
- A rare autosomal-dominant condition causing an increase in sodium reabsorption and often an increase in potassium excretion.
- It presents with hypertension, hypokalaemia and metabolic alkalosis.
- Management includes sodium restriction and amiloride.
Further reading and references
Zhuo JL, Li XC; Proximal nephron. Compr Physiol. 2013 Jul3(3):1079-123. doi: 10.1002/cphy.c110061.
Fiseha T, Gebreweld A; Urinary Markers of Tubular Injury in HIV-Infected Patients. Biochem Res Int. 20162016:1501785. doi: 10.1155/2016/1501785. Epub 2016 Jul 17.
Bagga A et al; Approach to Renal Tubular Disorders Indian Journal of Pediatrics Volume 72-September, 2005.
Distal renal tubular acidosis; Orphanet, 2014
Rehman HU; A woman with generalised weakness, hypokalaemia, and metabolic acidosis. BMJ. 2012 Apr 12344:e2545. doi: 10.1136/bmj.e2545.
Both T, Zietse R, Hoorn EJ, et al; Everything you need to know about distal renal tubular acidosis in autoimmune disease. Rheumatol Int. 2014 Aug34(8):1037-45. doi: 10.1007/s00296-014-2993-3. Epub 2014 Mar 29.
Renal tubular acidosis; BMJ Best Practice, 2016.
Walsh SB, Unwin RJ; Renal tubular disorders. Clin Med October 1, 2012 vol. 12 no. 5 476-479.
Pereira PC, Miranda DM, Oliveira EA, et al; Molecular pathophysiology of renal tubular acidosis. Curr Genomics. 2009 Mar10(1):51-9. doi: 10.2174/138920209787581262.
Goswami RP, Mondal S, Karmakar PS, et al; Type 3 renal tubular acidosis. Indian J Nephrol. 2012 Nov22(6):466-8. doi: 10.4103/0971-4065.106058.
Haas CS, Pohlenz I, Lindner U, et al; Renal tubular acidosis type IV in hyperkalaemic patients--a fairy tale or reality? Clin Endocrinol (Oxf). 2013 May78(5):706-11. doi: 10.1111/j.1365-2265.2012.04446.x.
Karunarathne S, Udayakumara Y, Govindapala D, et al; Type IV renal tubular acidosis following resolution of acute kidney injury and disseminated intravascular coagulation due to hump-nosed viper bite. Indian J Nephrol. 2013 Jul23(4):294-6. doi: 10.4103/0971-4065.114476.
Prasad N, Bhadauria D; Renal phosphate handling: Physiology. Indian J Endocrinol Metab. 2013 Jul17(4):620-7. doi: 10.4103/2230-8210.113752.
Moutzouri E, Liberopoulos EN, Elisaf M; Life-threatening hypophosphataemia in a cirrhotic patient with jaundice. Arch Med Sci. 2011 Aug7(4):736-9. doi: 10.5114/aoms.2011.24148. Epub 2011 Sep 2.
Coe FL, Worcester EM, Evan AP; Idiopathic hypercalciuria and formation of calcium renal stones. Nat Rev Nephrol. 2016 Sep12(9):519-33. doi: 10.1038/nrneph.2016.101. Epub 2016 Jul 25.
Stechman MJ, Loh NY, Thakker RV; Genetic causes of hypercalciuric nephrolithiasis. Pediatr Nephrol. 2009 Dec24(12):2321-32. doi: 10.1007/s00467-008-0807-0. Epub 2008 Apr 30.
Christensen SE, Nissen PH, Vestergaard P, et al; Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes. 2011 Dec18(6):359-70. doi: 10.1097/MED.0b013e32834c3c7c.
Al Shibli A, Narchi H; Bartter and Gitelman syndromes: Spectrum of clinical manifestations caused by different mutations. World J Methodol. 2015 Jun 265(2):55-61. doi: 10.5662/wjm.v5.i2.55. eCollection 2015 Jun 26.
Boiko N, Kucher V, Stockand JD; Pseudohypoaldosteronism type 1 and Liddle's syndrome mutations that affect the single-channel properties of the epithelial Na+ channel. Physiol Rep. 2015 Nov3(11). pii: e12600. doi: 10.14814/phy2.12600.
hi just looking to see if anyone has any experience with this. My daughter has a swollen kidney from birth shes been on a low dose gradually increasing as she grows everyday for 3 years, the kidney...maryanne44977
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