Citrates in nephrolithiasis

10 Jul
2011

Citrates in nephrolithiasis

Introduction and physiological elements

Nephrolithiasis is a multisystem disease arising from the siner- gic effects of enviromental, hormonal and genetic factors. The annual incidence of renal stones is between 0.1 and 0.4% and nephrolithiasis shows wide geographical variations. In Eu­rope an incidence of 2000 stones per million of population has been reported. The lifetime risk of stone formation ranges between 5 and 10% with an expected recurrence rate of almost 50%. Up to 70-80% of patients have calcium-containing stones with a predominance of calcium oxalate (CaOx), with or without calcium phosphate (CaP). cialis professional cheap generic drugs online

Citrate is a weak acid, with a molecular weight of 189 KDa, that is synthesized in the Krebs cycle starting from the condensa­tion of acetyl-CoA and oxalacetate, or that may derive from ex­ogenous intake. In plasma and in urine (although to a lesser degree) citrate is present mainly as a trivalent anion citrate-3; whereas, when the pH becomes more acidic the divalent form of anion citrate-2, increases significantly. The mean daily intake of citrate with the diet is 4 grams and its intestinal absorption is rapid and almost complete. Plasma citrate is filtered by the kidney and then reabsorbed, in the proximal tubule mainly in the convoluted and straight seg­ments; in contrast tubular reabsorption does not seem to be present either in the thick ascending tract of Henle limb or in the cortical collecting duct. Citrate proximal tubular reab- sorption involves a sodium dependent dicarboxylate trans­porter that permits the reabsorption across the apical mem­brane where the citrate is reabsorbed mainly as dicarboxylate anion, although the tricarboxylate is the more common form. Furthermore, experimentally in cell culture, a new sodium dependent saturable citrate transport was observed involving a trycarboxylate transporter; in vivo, this trycarboxylate citrate transporter may be located on the basolateral membrane. A rate of 10-35% of the filtered load is excreted in the urine. The citrate reabsorbed from the proximal tubule and a small quota deriving from peritubular vessels contribute to the energy sup­ply of the kidney. In fact this ion, via a complete oxidation in the mitochondrial Krebs cycle, participates in the production of ATP. Another destiny of citrate is cytosolic metabolization into Acetyl-CoA and oxalacetate by means of the enzyme ATP cit­rate lyase. The small intestine presents a citrate transporter similar to the sodium dependent dicarboxylate carrier observed in the proximal renal tubule; at least experimentally, entero- cytes seem to present a secretion mechanism of citrate. Af­ter oral intake of alkaline salts, citrate undergoes intestinal ab­sorption and is metabolized inducing an alkaline load that in­creases the urinary citrate excretion.

A reduced intestinal alkali absorption may cause a hypocitraturia condition. Hypocitraturia is one of the main factors associated with idio­pathic kidney stone disease. Moreover citrate has been widely studied for its action in preventing renal stones and it has showed a very high efficacy against calcium nephrolithiasis. Many physiological conditions, several drugs and some diseases modulate urinary citrate excretion as shown in table I. Acid-base state is one of the main regulators of urinary citrate excretion, with metabolic acidosis inducing hypocitraturia. Also potassium depletion plays an important role in de­creasing urinary citrate excretion. Both these conditions en­hance ATP citrate lyase activity in the cytosol of renal cortex cells, thus leading to a decreased intracellular citrate concen­tration and, ultimately, to an increased reabsorption of this ion at the brush border membrane level. One of the hor­mones that exerts an important modulating effect on urinary cit­rate excretion is estrogen. Several authors, in fact, have described a reduction in urinary citrate excretion in healthy post- menopausal women, as well as a lower citraturia in males than in premenopausal females.

Table I – Effect of different factors on urinary citrate excretion.

Factor

Citraturia

t
Glomerular filtration rate

t

Acidosis

Alkalosis

t

Starvation

t
Carbohydrates

t
Sodium chloride

1
Potassium

1
Magnesium

1
Calcium

t
Animal proteins

1
Gastrointestinal alkali absorption

Estrogen

t

Parathyroid hormone

Calcitonin

t

Insulin

Growth Hormone/Insulin-like growth factor-1

t

Vitamin D3/Calcitriol

t

Acetazolamide/ACE-inhibitors/Topiramate/Zonisamide

Ethacrinic acid/Thiazides/Glucocorticoids

Transport competitors (succinate, malate, fumarate)

t

Metabolic inhibitors (fluorocitrate, malonate, maleate)

t

Distal renal tubular acidosis

Chronic renal failure

Inflammatory bowel diseases

By-pass or ileal resection

Diarrhea and/or malabsorption

Strenous exercise (lactic acidosis)

1

Urinary citrate directly inhibits stone formation by forming high­ly soluble complexes with calcium in the renal tubule. The first effect of this complex is to reduce urinary levels of supersatura- tion with CaOx and CaP. Moreover citrate reduces the spontaneous nucleation, the agglomeration, the aggregation and the crystal growth of CaOx and CaP. It could be said that citrate acts as a “poison” on renal stones.

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