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Allopurinol for Stones: Right Drug—Wrong Reasons

      Controversy and confusion have been the hallmarks of attempts to clarify the basis of allopurinol administration in reducing the recurrence of calcium oxalate (CaOx) urinary calculi. Hyperuricosuria has not been unequivocally demonstrated as a common reproducible finding in CaOx stone-formers,
      • Grover P.K.
      • Ryall R.L.
      Urate and calcium oxalate stones: from repute to rhetoric to reality.
      and the drug reduces stone recurrences even in normouricosurics.
      • Coe F.L.
      Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria or no metabolic disorder.
      The 2 theories cited to explain the association between urate excretion and urolithiasis, namely epitaxy
      • Coe F.L.
      • Lawton R.L.
      • Goldstein R.B.
      • Tembe V.
      Sodium urate accelerates precipitation of calcium oxalate in vitro.
      • Pak C.Y.C.
      • Arnold L.H.
      Heterogeneous nucleation of calcium oxalate by seeds of monosodium urate.
      and glycosaminoglycans-depletion,
      • Robertson W.G.
      • Knowles F.
      • Peacock M.
      Urinary acid mucopolysaccharide inhibitors of calcium oxalate crystallization.
      are steeped in controversy and are not physiologically pertinent.
      • Grover P.K.
      • Ryall R.L.
      Urate and calcium oxalate stones: from repute to rhetoric to reality.
      This suggested that perhaps the beneficial effect of the drug is attributable not to its reduction in urate output, but that of some other urinary metabolite which effects CaOx crystallization. This theory spawned contradictory studies investigating the effect of alloupurinol on excretion of calcium, oxalate, inhibitors of mineralization, and direct effect of the drug or its metabolites on CaOx crystallization.
      • Grover P.K.
      • Ryall R.L.
      Urate and calcium oxalate stones: from repute to rhetoric to reality.
      These must be balanced against consistent reports that administration of allopurinol does reduce urinary excretion of urate and recurrence of CaOx stones.
      • Coe F.L.
      • Kavalach A.G.
      Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis.
      • Ettinger B.
      • Tang A.
      • Citron J.T.
      • Livermore B.
      • Williams T.
      Randomized trial of allopurinol in the prevention of calcium oxalate calculi.
      Given such empirical but persuasive evidence, it would be unreasonable to deny the existence of some connection between urate excretion and urolithiasis. But how? As early as the 1970s, Kallistratos et al
      • Kallistratos G.
      • Timmermann A.
      • Fenner O.
      Zum Einfluss des Aussalzeffektes auf die Bildung von Calciumoxalat-Kristallen im menschlichen Harn.
      suggested that the connection rests on the principle of “salting-out.” They did not provide any evidence, though, and the concept was virtually ignored. It has now been unequivocally documented that hyperuricosuria, simulated by the addition of soluble urate to urine, does indeed promote CaOx crystallization and that this effect cannot be explained by epitaxy and glycosaminoglycans-depletion theories. More recent studies
      • Grover P.K.
      • Marshall V.R.
      • Ryall R.L.
      Dissolved urate salts-out calcium oxalate in undiluted human urine in vitro: Implications for calcium oxalate stone genesis.
      revealed that the promotory effect of dissolved urate is attributable to its ability to salt-out CaOx from solution. It has also been shown
      • Grover P.K.
      • Marshall V.R.
      • Ryall R.L.
      Dissolved urate salts-out calcium oxalate in undiluted human urine in vitro: Implications for calcium oxalate stone genesis.
      that the urate’s effect depends upon the prevailing concentrations of urinary calcium and oxalate. Thus, in addition to lowering urinary urate, the management of hyperuricosuric CaOx stone-formers also should include taking steps to reduce their calcium and oxalate excretion. It also follows that excretion of urate might be responsible for CaOx urolithiasis in normouricosuric patients who have relatively high urinary concentrations of calcium and oxalate. This explains why the drug reduces stone recurrences even in normouricosurics and excretion of urate does not have to be in hyperuricosuric range to exhibit its promotory effect on the crystallization. Taken together, allopurinol administration reduces urinary urate, and this reduces recurrence of CaOx urolithiasis, not as suggested by epitaxy
      • Coe F.L.
      • Lawton R.L.
      • Goldstein R.B.
      • Tembe V.
      Sodium urate accelerates precipitation of calcium oxalate in vitro.
      • Pak C.Y.C.
      • Arnold L.H.
      Heterogeneous nucleation of calcium oxalate by seeds of monosodium urate.
      and glycosaminoglycans-depletion
      • Pak C.Y.C.
      • Arnold L.H.
      Heterogeneous nucleation of calcium oxalate by seeds of monosodium urate.
      theories but as suggested by salting-out
      • Kallistratos G.
      • Timmermann A.
      • Fenner O.
      Zum Einfluss des Aussalzeffektes auf die Bildung von Calciumoxalat-Kristallen im menschlichen Harn.
      • Grover P.K.
      • Marshall V.R.
      • Ryall R.L.
      Dissolved urate salts-out calcium oxalate in undiluted human urine in vitro: Implications for calcium oxalate stone genesis.
      theory. This indeed is an interesting example of fortuitousness, doing the right thing for the wrong reasons.

      References

        • Grover P.K.
        • Ryall R.L.
        Urate and calcium oxalate stones: from repute to rhetoric to reality.
        Miner Electrolyte Metab. 1994; 20: 361-370
        • Coe F.L.
        Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria or no metabolic disorder.
        Ann Intern Med. 1977; 87: 404-410
        • Coe F.L.
        • Lawton R.L.
        • Goldstein R.B.
        • Tembe V.
        Sodium urate accelerates precipitation of calcium oxalate in vitro.
        Proc Soc Exp Biol Med. 1975; 149: 926-929
        • Pak C.Y.C.
        • Arnold L.H.
        Heterogeneous nucleation of calcium oxalate by seeds of monosodium urate.
        Proc Soc Exp Biol Med. 1975; 149: 930-932
        • Robertson W.G.
        • Knowles F.
        • Peacock M.
        Urinary acid mucopolysaccharide inhibitors of calcium oxalate crystallization.
        in: Fleisch H. Robertson W.G. Smith L.H. Vahlensieck W. Urolithiasis Research. Plenum Press, New York1976: 331-334
        • Coe F.L.
        • Kavalach A.G.
        Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis.
        N Engl J Med. 1974; 291: 1344-1350
        • Ettinger B.
        • Tang A.
        • Citron J.T.
        • Livermore B.
        • Williams T.
        Randomized trial of allopurinol in the prevention of calcium oxalate calculi.
        N Engl J Med. 1986; 315: 1386-1389
        • Kallistratos G.
        • Timmermann A.
        • Fenner O.
        Zum Einfluss des Aussalzeffektes auf die Bildung von Calciumoxalat-Kristallen im menschlichen Harn.
        Naturwissenschaften. 1970; 57: 198
        • Grover P.K.
        • Marshall V.R.
        • Ryall R.L.
        Dissolved urate salts-out calcium oxalate in undiluted human urine in vitro: Implications for calcium oxalate stone genesis.
        Chem Biol. 2003; 10: 271-278