CROATICA CHEMICA ACTA CCACAA 53 (2) 381-388 (1980)

CCA-1215: -YU -fSSN 0011-1643

ubc 612.461 :547.461.2 :546.41 Conference• A.bstract

Mechanisms 9f .the Influence of Uric Acid on the Precipitation of Ca-Oxalate Crystals out of Metastabi'e · ·

Solution (Urine)*

R. Hartung, P. Leskovar, and M. Kratzer

Urologische Klinik und Poli klinik rechts der Isar der Technischen Universitii.t Miinchen, Miinchen, BR Deutschland · ·

Received September 6, 1979

INTRODUCTION

One of the very actual problems in the urolithiasis research is, the ,question whether and in what way raised uric acid can influence the formation of

_ Ca-oxalate stones. There are many clinical observations indicating an interrelation between

uric acid and oxalate lithiasis. Since the early reports of P rfen and Pri~n1 as well as Gutman and Yii2 in 1968 about the surprisingly high occurrence of oxalate stones in gouty patients, additional observations indicated that oxalate stone-formers were often characterized by a raised uriC acid level in serum respectively in urine. This observation, made by S!l1ith and Boyce in 1969,3 was confirmed by later clin,ical studies by Coe,4 Coe and Raisen,5' Hartung,6, Braun, May and BirteF as well as Eisen, Dosch, Altwein and Hohenfellner.8 The hyperuricosuria was partly accompanied by hypercalciuria, a correlation firstly observed by Dent and Sutor9 in 1971.

Here, the possible mechanisms of the oversecreted uric acid on the facilit­ated precipitation of Ca-oxalate crystals in urine will be discussed in some detail. In addition, own experiments giving a new explanation for the uri.c acid: oxalate interaction will be presented briefly.

MECHANISMS OF URIC ACID INFLUEN,CE ON Ca-OXAL ATE PRECIPITATION

Lonsdale10 in 1968 published his' theory that uric acid respectively sodium urate crystals facilitate the precipitation and growth of Ca-oxalate crystals by epitaxis. Robertsorr11 in his early publication in .1971 also a ssumed an epitactic growth of Ca-oxalate crystals on preformed uric acid crystals:

The expitaxis between uric acid and Ca-oxalate ·crystals is however called in question· by mineralogists working in this field.

Coe, Lawton, Goldstein and Tembe12 as well as Pak and Arnold13 in 1975 published their hypothesis that sodium urate induces the oxalate precipitation. Pak and Coe, carrying out experiments with · radioactive labelled sodium

* .Based on an invited lecture prese1;1ted at the 5th »Ruder Boskovic« Insti­tute's International Summer Conference Chemistry of Solid/Liquid · Int erfaces, Cav­tat/Dubrovnik, Croatia, Yugoslavia, June · 1979.

382 R . HARTUNG ET AL.

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Figure 1.

oxalate, also could show that concentrations of monosodium urate as low as 20 mg/1, occurring physiologically in urine, were able to accelerate essentially the Ca-oxalate precipitation so that the latent time before the start of the precipitation could be reduced from 50 to 10 minutes. In this way, the crystal­lization times became comparable with the passage time of urine in the upper urinary tract (3 to 5 minutes), as calculated by Brown and Britton.

Robertson however, studying the influence of sodium and ammonium urate, couldn't confirm the theory of Pak. He, in the first line couldn't observe in urine the corresponding urates respectively the high uric acid oversaturat­ions leading to the formation of monosodium urate. The role of uric acid in the facilitated oxalate precipitation Robertson saw in the binding of acid mucopolysaccharides as potent inhibitors by the semicolloidal uric acid. The same effect, the reduced activity of inhibitors in presence of uric acid, we also observed.

In addition, the so called »salting-out« effect of uric acid on Ca-oxalate crystals, reported by Kallistratos and Fenner14 in 1971, should be mentioned. Kallistratos, adding uric acid to urinary samples with increasing pH values, found that at pH= 5.5 uric acid, at pH= 6.0-6.5 oxalate and at pH= 7.0 phosphate precipitated. This »Salting-out« effect of urk acid led to repeated

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URIC ACID AND PRECIPITATION OF Ca-OXALATE

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383

discussions because of the problematic use of the term »salting-out« in this connection.

Evaluating the own experiments to this problem, we could define the facilitated Ca-oxalate precipitation in presence of uric acid as a special case of a more general phenomenon, the induction of heterogeneous precipitation from metastable urine by preformed crystals of accompanying scarcely soluble urinary salts.

METHODS

Our experiments were carried out by means of the Coulter Counter/Size Distribution Analyzer (P 128)-technique and should be presented in the following

figures. RESULTS

In Figure 1, the promotion of phosphate precipitation out of a metastable solution by uric acid crystal seeds is demonstrated. Curve 1 represents the metastable Ca-phosphate solution, curve 2 the suspension of uric acid crystals and the curve 3 the metastable Ca-phosphate solution incubated with uric acid crystals.

384 R. HARTUNG ET AL.

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Figure 3.

In Figure 2, the same metastable phosphate solution was incubated with powdered uric acid stone. Again, the comparison of curve 3 and curve 1 shows the clear promotion of phosphate precipitation by the crystalline material of uric acid stone.

In Figure 3, the facilitated Ca-oxalate precipitation out of metastable solution by uric acid crystal seeds is presented. Curve 1 represents the meta­stable oxalate solution without and curve 3 that one with uric acid crystal seeds added. The acceleration of the precipitation process by uric acid crystals is obvious.

The comparison of curve 1 and curve 3 in Figure 4 shows that the crystal­line material of disintegrated uric acid stones is also efficaceous in promoting the nucleation and growth of Ca-oxalate crystals out of metastable solution . Curve 2 represents the suspension of powdered uric acid stone used.

In Figure 5, the influence of uric acid crystal seeds on the precipitation of Ca-oxalate crystals out of a highly oversaturated, instable solution is de-

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URIC ACID AND PRECIPITATION OF Ca- OXALATE

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INCREASED FORMATION OF Ca-OXALATE -CRYSTALS IN PRESENCE Of

POWDERED URIC -AC ID - CALCULUS

..... SUSPENSION OF POWDERED URIC-ACID-STONE (BLANK)

2 . . .. METASTABLE Ca -OXALATE- SOLUTION

l ...... .. .METASTAIH E Ca-OXALATE-SOLUTION +SU SPEN SION OF

POWDERED URIC - ACI D - STONE

Figure 4.

385

monstrated. The comparison of curve 2 and 3 shows that even at such a over­saturation crystal seeds accelerate the precipitation of oxala;e crystals. Curve 1 represents the uric acid suspension used.

In addition, the high positive correlation between urinary calcium and uric acid we calculated on the basis of data from single urinary samples, collected during 6 weeks in the group of recurrent oxalate stone patients and their controls, should be demonstrated (Figure 6). This parallelism in the uric acid and calcium excretion we found with recurrent oxalate stone-formers is a support of our hypothesis that uric acid, especially if overproduced , leads to

R. HARTUNG ET AL.

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INFLUENCE 0~ URIC - ACID - SUSPENSION ON MARKED OVERSATU •

RATED Cg- OXALATE - SOLUTION

........ . URIC - ACID - SUSPENSION (BLANK)

.. .. ..... OVERSA TURA TED Co -OXALATE - SOLUTION OVERSATURATED Co-OXALATE-SOLUTION+

URIC -A Ci D - SUSPENSION

Figure 5.

a latent metabolic acidosis and mediately to the mobilisation of the bone base reserve. In this way, the bone calcium occurs in urine.

CONCLUSION

From our experimental data it can be concluded that uric acid promotes the precipitation of Ca-oxalate crystals out from metastable solutions like urine, the mechanism being the induced heterogeneous precipitation. An additional result is the high positive correlation between urinary calcium and uric acid, supporting our hypothesis that overproduced uric acid mobilises the bone calcium.

URIC ACID AND PRECIPITATION OF Ca -OXALATE

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REFERENCES

I. 5 mMOL/I

1. E . L . Pr i en and E. L. Pr i en, Am.er. J. Med. 45 (1968) 654. 2. A. B. Gutman and T. F . Yu, Am.er. J . Med. 45 (1968) 756. 3. M. J. V. Smith and W. H. Boyce, J. Ural. 102 (1969) 750 . 4. F. L. Co e, Clin. Res. 20 (1972) 589. 5. F . L. Coe and L. Raise n, Lancet 1 (1973) 129. 6. R. Hartung, Miinch. med. Wschr. 117 (1975) 387.

387

7. S . J. Br au n, P. May, and R. Birt e 1, Nieren und Hochdruckkrankheiten 3 (1974) 116.

8. M. Eisen, W. Dosch, J. E. A 1 t we in, and R. Hoh en f e 11 n er, Nieren und Hochdruckkrankheiten 4 (1975) 174.

9. C. E. Dent and D . J. Sutor, Lancet 2 (1971) 775. 10. K. Lons d a 1 e, Nature (London) 217 (1968) 56. 11. W. G . Robertson, M. Pe a cock, and B. E. C. N ordin, C lin. Sci. 40

(1971) 365. 12. L . F. Coe, R. L. Lawton, R. B. Go 1 d stein, and V. Te m be, Proc. Soc.

Exp. Biol. Med. 149 (1975) 926. 13. C. Y. C. Pak and L. H. Arno 1 d, Proc. Soc. Ex p. Biol. M ed. 149 (1975) 930. 14. G. Ka 11 is tr at o s and 0. Fenner, Miinch. med. Waschr. 113 (1971) 1131.

388 R. HARTUNG ET AL.

SAZETAK

Mehanizmi utjecaja urinske kiseline na talozenje kristala kalcijeva oksalata iz metastabilnih otopina (uriri.a)

R. Hartung, P. Leskovar i M : Kratzer

Potaknuti opafanjem da pacijenti sa hiperurikemijom i hiperurikozurijom cesto pokazuju pojave stvaranja bubreznih oksalatnih kamenaca, provedena su ispitivanja mehanizama utjecaja urinske kiseline na talozenje kalcijeva oksalata. Raspravlja se i o pojavama induciranog, odnosno ubrzanog talozenja kalcijeva oksalata u prisut­nosti kristala urinske kiseline.

UROLOGISCHE KLINIK UND POLIKLINIK RECHTS DER !SAR

TECHNISCHE UNIVERSITAT MDNCHEN MUNCHEN, B. R. DEUTSCHLAND

Prispjelo 6. rujna 19'i9.