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Disorders of tubular electrolyte handling 

Disorders of tubular electrolyte handling

Disorders of tubular electrolyte handling

Nine V.A.M. Knoers

and Elena N. Levtchenko


May 25, 2011: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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date: 25 March 2017


Physiology—glucose reabsorption in the proximal tubule is carried out by two different pairs of apical Na+-dependent (SGLT1 and 2) and basolateral Na+-independent (GLUT1 and 2) glucose transporters.

Clinical disorders—abnormalities in renal glucose transport can be seen in association with other defects of proximal tubular transport (Fanconi syndrome, see below). Familial renal glycosuria is an autosomal recessive condition caused by mutations in the SGLT2-encoding gene, SLC5A2.

Phosphate-handling disorders

Physiology—the plasma concentration of inorganic phosphate depends on the balance between intestinal absorption, renal excretion, and the internal contribution from bone. Absorption in the small intestine is mainly mediated by the brush border membrane sodium-dependent transporter, isoform NaPi-IIb. In the kidney about 80% of filtered phosphate is reabsorbed in the proximal tubule. In the proximal tubules, phosphate reabsorption is mediated by two members of the SLC34 family, NaPi-IIa and NaPiIIc, which are specifically expressed in the brush border membrane of proximal tubular cells. Renal phosphate excretion is regulated by numerous hormones and other factors, with key regulators being parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), both of which cause phosphaturia.

Clinical disorders—changes of serum phosphate levels can be caused by numerous inherited and acquired conditions (frequently during severe infections). Disorders associated with increased urinary phosphate excretion and low serum phosphate levels produce symptoms that mainly affect the bones: rickets in children and osteomalacia in adults.

X-linked hypophosphataemic rickets (XLH)—this is the most frequent (prevalence 1:20 000) and best-characterized inherited disorder of renal phosphate metabolism. It is caused by inactivating mutations of the cell-surface endopeptidase PHEX, is inherited as an X-linked dominant disorder, and presents with growth retardation, femoral and/or tibial bowing, rickets/osteomalacia, low serum phosphate, and inappropriately normal 1,25-dihydroxycholecalciferol (calcitriol; 1,25(OH)2 D) for the degree of hypophosphataemia. Treatment is with administration of phosphate and calcitriol.

Magnesium-handling disorders

Physiology—normal plasma magnesium concentration is achieved by variation of urinary magnesium excretion in response to altered uptake by the intestine. The main site of magnesium absorption is the small bowel, via paracellular simple diffusion at high intraluminal concentrations, and via active transcellular uptake through the magnesium channel TRPM6 (transient receptor potential channel melastatin 6) at low concentrations. Regulation and fine-tuning of serum magnesium concentration occurs primarily in the kidney: most filtered magnesium is passively reabsorbed in the thick ascending limb of Henle’s loop through the paracellular pathway via claudin proteins; active and modulated reabsorption takes place in the distal convoluted tubule via the epithelial magnesium channel, TRPM6.

Clinical disorders—hypomagnesaemia is common in hospitalized patients, and often an acquired disorder resulting from deficient oral intake or accelerated urinary or intestinal loss. Genetic disorders of magnesium handling include Gitelman’s syndrome, which is an autosomal recessive condition caused by loss-of-function mutations in the SLC12A3 gene that encodes the renal thiazide-sensitive sodium-chloride cotransporter NCCT. Most patients suffer from carpopedal spasms; paraesthaesias are frequent; some experience severe fatigue; a few develop chondrocalcinosis. Most patients remain untreated, but there is an argument for lifelong supplementation of magnesium; hypokalaemia can be treated by drugs that antagonize the activity of aldosterone (e.g. spironolactone) or block the epithelial sodium channel (ENaC) in the distal nephron (e.g. amiloride).

Aminoaciduria and renal Fanconi syndrome

Physiology—most amino acids (except for tryptophan, which is protein bound) are freely filtered by the glomerulus, after which 95% to 99.9% are reabsorbed in the proximal tubules by apical Na+-dependent cotransporters (for neutral amino acids, aromatic neutral amino acids, and anionic amino acids) and Na+-independent cotransporters (H+-cotransporter for glycine and proline; heterodimeric exchanger bo,+AT-rBat for cystine, and cationic amino acids). Aminoaciduria is defined as urinary excretion of more than 5% of the filtered load of an amino acid.

Specific aminoacidurias—these include (1) cystinuria, which manifests with urinary stones (see Chapter 21.14); (2) Hartnup’s disease, associated with defective renal and intestinal absorption of neutral amino acids (see Chapter 12.2); (3) Lysinuric protein intolerance, caused by defective dibasic amino acid transport and progressing to renal failure in some patients (see Chapter 12.2).

Renal Fanconi syndrome—this is characterized by generalized defect of both Na+-coupled and megalin-dependent proximal tubular transport. Symptoms manifest at various ages dependent on the underlying condition and comprise generalized aminoaciduria; glycosuria; renal sodium, potassium, urate and phosphate wasting; proximal tubular acidosis; and low-molecular-weight proteinuria and albuminuria. It can be caused by inherited (e.g. cystinosis) or acquired (e.g. Sjögren’s syndrome, drugs) conditions.

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