There are a variety of 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.

Fanconi's syndrome

Fanconi's syndrome is a disturbance of renal tubular function resulting in:

• Generalised aminoaciduria
• Phosphaturia
• Glycosuria
• Rickets (children) or osteomalacia (adults)
• Renal tubular acidosis (RTA) type 2 (see below)

Causes

• Inherited :
  • Primary idiopathic: sporadic or familial see Renal Fanconi Syndrome article. Occurs in the absence of any identifiable cause, and most cases are sporadic. Some cases are inherited, but the mode of inheritance appears to be variable (autosomal dominant, autosomal recessive, X-linked).
  • Secondary: cystinosis, tyrosinaemia, Wilsons disease, Lowe's syndrome (oculocerebrorenal syndrome: bilateral congenital cataracts, glaucoma, general hypotonia, hyporeflexia, severe mental retardation and Fanconi syndrome), galactosaemia, fructose intolerance, glycogen storage disorders and mitochondrial cytopathies.
• Acquired:
  • Intrinsic renal disease: acute tubular necrosis, interstitial nephritis, hypokalaemic nephropathy, myeloma, amyloidosis, Sjogrens syndrome, rejected transplant
  • Hyperparathyroidism
  • Kwashiorkor
  • Drugs: cisplatin, ifosfamide, gentamicin, valproate¹
  • Toxins: glue sniffing, heavy metals

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 (e.g. Sjögren's syndrome, systemic lupus erythematosus (SLE)), hyperparathyroidism, analgesic nephropathy, renal transplant rejection, obstructive uropathy and chronic urinary tract infections.
• Without treatment, leads to growth retardation and progressive renal failure.
• Presentation:
  • Hyperventilation, muscle weakness, cardiac arrhythmias (hypokalaemia) and bone pain (due to rickets or osteomalacia).
  • Renal calculi, recurrent UTI, renal failure.
• Investigations:
  • Hypokalaemia, hyperchloraemic metabolic acidosis.
  • Urinary pH is above 6, hypercalciuria.
• Treatment:
  • 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 the Fanconi's syndrome.
• Defective secretion of hydrogen ions and bicarbonate reabsorption in the proximal tubule leads to an excess of bicarbonate in the urine.
• Presentation:
  • Polyuria, polydipsia, proximal myopathy.
  • Osteomalacia or rickets.
• Investigations:
  • Hypokalaemia, hyperchloraemic metabolic acidosis.
• Treatment:
  • High doses of bicarbonate are required but the prognosis is good. Correcting acidosis and low potassium levels allows normal growth and prevents bone disease, but vitamin D supplements may also be required.

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: ACE-inhibitors, beta-blockers, potassium sparing diuretics, NSAIDs.
  • Mineralocorticoid deficiency: reduced hydrogen secretion in the distal nephron causes reduced ammonium excretion.
• Presentation:
  • Urinary pH below 5.4.
  • Hyperkalaemia, hyperchloraemic metabolic acidosis.
• Treatment:
  • Fludrocortisone is required if there is acidosis or hyperkalaemia.

Type 3 is not included as it is now thought to be a combination of types 1 and 2.

Glycosuria

• Renal glycosuria occurs when there is failure of tubular mechanisms to reabsorb the entire filtered load of glucose under conditions of normoglycaemia.
• The isolated form of renal glycosuria is familial with a mixed inheritance pattern.
• Abnormalities of glucose transport may be associated with other defects of proximal tubular transport (Fanconi's syndrome).
• Many patients with chronic renal insufficiency of mild to moderate degree exhibit renal glycosuria, usually in combination with other disorders of tubular function.

Nephrogenic diabetes insipidus

Nephrogenic Diabetes Insipidus is discussed in a separate article.

• Caused by renal insensitivity to antidiuretic hormone.
• It may be primary (familial, X-linked) or secondary to a number of causes:
  • Drugs, e.g. lithium, diuretics
  • Metabolic: hypokalaemia, hypercalcaemia
  • Tubulointerstitial disease: partial obstruction, pyelonephritis, cystic diseases, granulomatous diseases, sickle-cell disease
• Presents with polyuria, hypernatraemia and uraemia.

Phosphate-handling disorders

• Kidney is largely responsible for controlling extracellular phosphate levels, under control of parathyroid hormone.
• There are several types of phosphate transport defect causing hypophosphataemia and inappropriate phosphaturia. Commonest forms include:
  • Hereditary hypophosphataemic rickets (Vitamin D-resistant rickets).
  • Hypophosphataemia with rickets or osteomalacia.
• Presents with growth retardation 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 commonest cause of an isolated defect in tubular phosphate reabsorption.²
  • 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.

Calcium-handling disorders

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:
  • Rare disorder associated with proteinuria, nephrocalcinosis, renal stones and frequently renal failure.
• 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 normal range.

Aminoacidurias

There are a variety of aminoacidurias, including Hartnup disease, homocystinuria and cystinuria.

• Hartnup disease:
  • Rare, autosomal recessive disorder resulting in malabsorption of dietary tryptophan, a pellagra-like syndrome with photosensitive skin lesions, ataxia, and neuropsychiatric disturbances, and aminoaciduria with increased renal clearance of neutral aminoacids.
  • Tryptophan malabsorption presents like pellagra, but is less severe.
  • Treatment is with oral nicotinamide.
• Cystinuria:
  • Disorder of intestinal absorption and proximal renal tubular reabsorption of the dibasic amino acids, cystine, ornithine, arginine and lysine.
  • Inheritance is autosomal recessive.
  • Presents with renal calculi causing renal colic, haematuria, urinary obstruction and secondary pyelonephritis, leading to renal failure.
  • Calculi are radiopaque and the cyanide-nitroprusside urine test is positive.
  • Treatment includes a high fluid intake, urinary alkalinisation with bicarbonate, D-penicillamine (which reacts with cystine to form a more soluble compound) and lysine supplementation.

Hereditary hypokalaemic tubulopathies

Examples include:

• Bartter's syndrome: caused by a gene mutation affecting potassium transport at the ascending limb of the tubule.
• Gitelman's syndrome:
  • 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 suffering from 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.
• 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.²

Pseudohypoaldosteronism and Liddle's syndrome²

• Pseudohypoaldosteronism and Liddle's syndrome cause abnormal function of the sodium channel in the renal cortical collecting tubule.
• Pseudohypoaldosteronism:
  • 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:
  • Rare autosomal dominant condition causing an increase in sodium reabsorption and often an increase in potassium excretion.
  • Presents with hypertension, hypokalaemia and metabolic alkalosis.
  • Management includes sodium restriction and amiloride.

Document references

1. Yoshikawa H, Watanabe T, Abe T; Fanconi syndrome caused by sodium valproate: report of three severely disabled children.; Eur J Paediatr Neurol. 2002;6(3):165-7. [abstract]
2. Royal Hospital for Sick Children (Yorkhill Division); Guidelines for the investigation and management of renal tubular disease; November 2005.

Internet and further reading

• Oxford Textbook of Medicine 4th edition; Section 20.22; Renal tubular disorders.
• Bagga A et al; Approach to Renal Tubular Disorders Indian Journal of Pediatrics; Volume 72-September, 2005.

Acknowledgements