Citrates in nephrolithiasis: Citrate salts in the treatment of nephrolithiasis

23 Jul
2011

Several studies have pointed out that alkaline citrate is one of the most efficient therapeutic regimens in the treatment of idio- pathic calcium nephrolithiasis. In 2001 the Advisory Board of European Urolithiasis Research recommended alkaline citrate, thiazides and fluid intake as the corner-stones in preventing calcium stone formation. Oral citrate administration results in an alkali load that, in turn, increases urinary citrate excretion by means of a reduction in the tubular reabsorption of this ion. The consequent high urinary citrate concentration and the alkalinization of the urine cause several effects that struggle against CaOx and CaP crystallization. The increased intra- luminal pH induces a dissociation of citrate and the inhibitory macromolecules, resulting in an enhanced inhibiting power. For example, it has been suggested that Tamm-Horsfall protein (THP) shows a dichotomous behaviour on stone formation, act­ing either as promoter or as an inhibitor of crystallization processes. When urinary citrate increases and luminal pH ris­es, THP viscosity decreases and its inhibitory effect on calcium oxalate aggregation is enhanced. On the contrary in the ab­sence of citrate THP promotes calcium oxalate aggregation. As far back as 1985 Preminger et al. demonstrated that new stone formation continued in 39% of the patients during conser­vative or placebo trials and 69% of untreated stone formers however, needed at the end surgical treatment. On the other hand only 2% of the patients receiving alkaline citrate required further surgical treatment. In the last two decades alkaline salts have been widely used in patients with recurrent calcium stone disease and in several other pathological conditions asso­ciated or not with calcium stones (Table III). The most common­ly used salts are potassium citrate, sodium-potassium citrate, potassium-magnesium citrate and calcium citrate, although potassium citrate is usually the preferential treatment. Both potassium citrate and sodium-potassium citrate, in fact, can ameliorate urinary composition, but the sodium load in­duced by the latter can increase calcium excretion or a less pronounced reduction of calciuria. In fact citrate has shown to be able to reduce urinary calcium excretion. Furthermore, in patients with hypertension, sodium intake must be restricted, as well as in patients with calcium oxalate lithiasis treated with thiazide. In fact, sodium load induces a hypercalciuria that is uncontrollable with thiazide. cialis professional discount drugs online

Magnesium is and inhibitor of CaP crystal growth and the com- plexing of magnesium and oxalate induces a decrease in the supersaturation with respect to CaOx. Nevertheless it has been observed that also magnesium excretion is associated with an increased calcium excretion, thus reducing the inhibiting effect of potassium-magnesium citrate on stone formation. Moreover long-term studies on potassium-magnesium citrate administra­tion are still lacking. However this alkaline citrate appears to enhance thiazide effect on urinary calcium reabsorption when this drug is co-administered. Long-term thiazide therapy, in fact, may result in decresead plasmatic and urinary magnesium and in this very case magnesium supplements appear to be of value. Finally promising results have come from Ettinger et al. which found that potassium-magnesium citrate is effective in preventing calcium oxalate stone recurrence. Calcium citrate is generally prescribed as a calcium supple­ment in the treatment of osteoporosis, while it is not usually used for calcium lithiasis therapy. Calcium citrate increases both urinary citrate and calcium excretion. Notwithstanding the growth of calciuria, this compound provides an alkali load, which in turn counteracts the increased calcium excretion. Thus the risk of stone formation does not appear to be en­hanced. Therefore calcium citrate seems to induce a lower risk of stone formation than all the other calcium supplements. Most of the studies on renal stone prevention have been con­ducted using potassium citrate as alkaline salt. A decrease in urinary calcium concentration has been well documented with this drug. In a previous work we were able to demon­strate the ability of potassium citrate to decrease urinary calci­um excretion after 9 months of therapy, but the same re­sult was not confirmed in a successive paper, where the follow up period was extended to 48 months. In fact, after an increase in urinary calcium excretion during the first year of therapy, calciuria began to decrease slowly, but progressively, in the follow up.

Table III – Indications for alkali citrate therapy in different diseases and conditions

–  Idiopatic calcium oxalate stone disease (with or without hypoci- traturia)
–  Uric acid nephrolithiasis
–  Mixed nephrolithiasis (hyperuricosuric calcium nephrolithiasis)
–  Cystine nephrolithiasis
–  Primary or secondary hyperoxaluria
–  Hypocitraturia in distal renal tubular acidosis
–  Hypocitraturia associated with inflammatory bowel diseases
–  Hypocitraturia associated with by-pass or ileal resection
–  Hypocitraturia associated with chronic diarrhea syndrome
–  Drug-induced hypocitraturia
–  Hypocitraturia associated with potassium depletion
–  Hypocitraturia associated with excessive dietary acid load
–  Residual renal stone fragments after extracorporeal shock wave lithotripsy
–  Osteoporosis

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