Renal Tubular Disease

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 syndrome, or associated with more generalised disease processes.

• Fanconi syndrome is a disturbance of renal tubular function resulting in:
• Generalized aminoaciduria
• Phosphaturia
• Glycosuria
• Rickets (children) or osteomalacia (adults)
• Renal tubular acidosis type 2 (see below)

Causes

• Inherited: cystinosis, galactosaemia, glycogen storage disease type 1, fructose intolerance, Lowe syndrome, tyrosinaemia type 1, Wilson's disease
• Acquired:
• Renal: acute tubular necrosis, hypokalaemic nephropathy, myeloma, Sjogren's syndrome, transplant rejection
• Hyperparathyroidism
• Kwashiorkor
• Drugs: out-of-date tetracycline, iphosphamide
• Heavy metals: lead, mercury, cadmium, uranium

Idiopathic Fanconi syndrome

• Autosomal dominant inheritance
• Presents in adulthood with rickets, osteomalacia, and progressive chronic renal failure
• Presentation:
  • Depends on the underlying cause
• Management:
  • Treatment of the cause
  • Treatment of the effects of tubular dysfunction, e.g. bicarbonate and potassium for RTA type-2, oral phosphate and calcitriol for phosphate wasting

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. Sjogren's, 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 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, e.g.
  • 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.

• 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 is discussed in a separate article.

• Renal insensitivity to vasopressin
• 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

• 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
  • 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
  • Rare disorders 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.

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.

Examples include:

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