Aust. 3.2.J. Med. (1979). 9, pp. 718 721

CURRENTCONCEPTS

Nephrolithiasis R. Melick'

From the Royal Melbourne Hospital

Stones form because material crystallises out of solution and becomes caught somewhere in the upper renal tract. The exact place is not known, various theories suggesting a subepithelial plaque (Randall's), a collecting duct or a lymphatic channel. Anatomical abnormalities which favour stasis may predispose to stones. Crystals are frequently seen in samples of urine from normal people, as urine is often supersaturated with respect to calcium, oxalate and phosphate. A supersaturated or metastable state is that where the constituents exceed the solubility product but require some seed for crystallisation to commence. As the concentration increases. spontaneous precipitation occurs and this level is referred to as oversaturation. Renal stones are common' and large series have been described from Australia' and New Zealand.3 In New Zealand, it was estimated that 13.5 patients per 10.000 population per year suffer from urinary stone^.^ The cause of most stones is not known but, where a cause has been definitely identified, it is usually related to an increased concentration of a component of urine. This is seen in its simplest form in water deprivation in hot climates, and stone formation is commoner in hot areas.' In our community, increased excretion causing an increased concentration of a substance is often thought to be responsible, as in cystinuria which gives rise to cystine stones, the very rare hyperoxaluria which causes calcium oxalate precipitation in the kidney, the increased excretion of calcium found in immobilisation, hyperparathyroidism or idiopathically, and increased uric acid excretion found in some patients with gout and uric acid stones. Although studies usually report the excretion of urinary constituents as amounts per 'Reader in Medicine. Correspondence: Dr. Roger Melick, Department of Medicine, Royal Melbourne Hospital PO, Victoria 3050.Australia

24 hours, the important measurement is concentration and not amount. Thus, if the amount IS given, the volume of urine in which this was excreted should also be reported. Decreased solubility of normal constituents may occur with alterations in pH: the triple phosphate stone produced in the highly alkaline urine infected by urea splitting organisms or the uric acid stones of some older patients with a very acid urine. Patients with renal tubular acidosis form calcium phosphate stones because of a combination of increased calcium excretion, alkaline urine and probably diminished citrate excretion. But in most patients the cause is not known and, even in the conditions mentioned, all aspects of stone formation are not understood. As most stones contain calcium, the urinary excretion of calcium has been studied extensively. It is difficult to define hypercalciuria because the normal excretion of calcium varies widely, 25% of normal people excreting over 7 . 8 mM (312 mg) daily and 5% over 10.5 mM (420 mg).4 There is a big overlap between the urinary excretion of calcium by the normal population and recurrent stone formers. Definitions of hypercalciuria include a urinary excretion above 9 mM (360 mg) daily in men and 7 . 5 mM (300 mg) in women (on usual diet), and above 5 mM (200 mg) daily when taking a low calcium (4 mM or 150 mg) diet. Normal urine volume is about 1.5 litres daily, so urinary calcium concentration in normals may reach 6 mM/I. Hypercalciuria is frequently found in stone formers and occurs more often in men.2 Although stone formation is not usually familial, idiopathic hypercalciuria has recently been described in families: in these, men and women were affected equally.' Hypercalciuria has been classified into three types6: absorptive where the primary abnormality is thought to be an increased absorption of calcium from the bowel, resorptive where calcium is derived from bone

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NEPHROLITHIASIS .~

as in hyperparathyroidism or immobilisation, and renal where a renal tubular defect of calcium reabsorption is thought to be present. The commonest is thought to be absorptive. The various types are separated by the response to a low calcium diet (urinary calcium falls in the absorptive but not in the others) and by measuring urinary cyclic AMP levels and plasma parathyroid hormone (these are low in the absorptive group but raised in the renal group).6 Separation of hypercalciuria into these subgroups has some possible therapeutic implications but is mainly of experimental interest at present. As with urinary calcium, the excretion of oxalate by calcium oxalate stone formers resembles that of the normal population, but with the frequency distribution curve shifted slightly to the right.7 However, increased excretion of oxalate has been found in obese patients who have developed calcium oxalate stones after jejuno-colic anastomosis.8 The cause appears to be an increased absorption ofoxalate. The by-pass procedure causes malabsorption of fat which combines with the calcium in the bowel. This allows oxalate, which would normally form an insoluble complex with calcium, to be absorbed more freely. This hypothesis is supported by the fact that feeding calcium to these patients reduces urinary oxalate excretion but, as excretion is not reduced to normal, this mechanism cannot be the only ones8 Increased uric acid excretion has been found in patients who form calcium stones.339As with calcium and oxalate, most values are in the normal range, but the curve is shifted to the right. Coe’ has claimed that treatment with allopurinol of patients with hyperuricosuria has reduced the formation of calcium stones; he has suggested that the increased urate excretion (as monosodium urate at the pH of urine excreted by these patients) acts as a nucleating material for calcium oxalate. Experimental work has shown that urate may indeed act as the seed on which calcium phosphate or calcium oxalate crystals may form.” In fact, heterologous nuclcation of crystals may be a fairly general phenomenon, as crystallographic studies have shown that there may be several mineral components in stones and that the centre may be different from the rest of

719

the stone. Although this heterologous nucleation has been demonstrated in vitro, its role in stone formation in vivo is still uncertain. Because many patients with recurrent renal stones excrete normal amounts of calcium, oxalate and uric acid, attention has turned to factors which may influence the solubility of calcium oxalate or calcium phosphate in urine. That urine is often supersaturated with respect to these substances has already been mentioned. Substances which may increase their solubility include organic constituents such as urea, creatinine and organic acids, but the most important appear to be citrate and pyrophosphate.” Magnesium may also play a part. But, again, measurements of these substances have shown no substantial difference between stone formers and normals, though magnesium deficiency has been claimed to occur in the “stone belt” of the south eastern United States. One of the big unanswered questions is whether there is some unknown inhibitor of precipitability of calcium in urine or whether the known substances provide all the inhibition thought to be present. Howard, from Johns Hopkins, many years ago” described “good” and “evil” urine, the “evil” urine (from stone formers) calcifying rachitic rat cartilage and while the “good” (from controls) did not. He also claimed that “evil” urine caused cement to set more quickly and firmly than “good” urine. However, a long search by his laboratory failed to identify a specific inhibitor and a recent paper from his group suggested that the normal constituents of urine could explain all of its inhibitory ~ r 0 p e r t i e s .They l ~ conclude that stone formation may be the result of small alterations in several normal urinary constituents resulting in either abnormal crystal formation or abnormal growth of crystals once formed. Conversely, investigators have searched for “promoters” of stone formation, but examination of stone matrices showed little difference between stones of different compo~ition.’~ Recently Hallson and Rosei5 reported that the formation of calcium oxalate and calcium phosphate crystals in fresh, rapidly concentrated urine was accelerated by uromucoid. They postulate that precipitation of uromucoid is the first step in stone formation and

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minerals then attach to it. No doubt this study will stimulate new interest in the currently neglected stone matrix. Recent work has attempted to examine these problems of promoters and inhibitors by studying ion activity products in urine, the number and size of crystals and the growth of artificial crystals in diluted urine. Ion activity products are calculated by measuring urinary pH and the concentrations in urine of sodium potassium, calcium, magnesium, ammonium, sulphate. phosphate, citrate. oxalate, urate and ch10ride.l~A computer programme makes the calculations feasible. Simpler methods requiring fewer measurements and using simple calculations and nomograms have been dess ~ r i b e d .From '~ studies such as these oxalate has been identified :is the most important ion in calcium oxalate stone forination. Unfortunately, oxalate is not easy to measure accurately in urine. These calculations have helped to understand more of the physiological aspects of stone formation, though there are few therapeutic implications at present. Robertson18 has measured volumes of crystals in urine and the size profile of crystals using a Coulter counter. Although control subjects excrete crystals in their urine, recurrent calcium oxalate stone formers excrete larger volumes of crystals. Patients with calcium phosphate stones excreted the same volumes of crystals as controls. But stone formers of both types excreted more large crystals than controls. These and other observations suggest that the important factor in stone formation may be, not the formation of crystals, but their aggregation to form large masses. If this is so, the concentration in urine of inhibitors (or promoters) of crystal aggregation becomes important; the currently identified inhibitors of aggregation are citrate, pyrophosphate and proteoglycans. A recent observation has suggested that colloidal monosodium urate may aid stone formation by interfering with the natural inhibitors of calcium oxalate aggregation in urine.I8 Attempts have been made to measure inhibitors of crystallisation by incubating seed crystals of calcium oxalate or brushite (CaHP0,.2H2O) in standard solutions of calcium oxalate or calcium phosphate and

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watching the growth of the crystals. Urine is then added and the alteration in the growth of the crystals observed. Some stone formers have been found to have diminished "inhibitory activity" by these methods.18 This may be due to absorption of inhibitors onto crystal surfaces and may reflect supersaturation rather than lack of inhibitors.16 In addition, the use of diluted urine to inhibit crystal growth has been criticised on physicochemical grounds." Despite these objections, studies of this type may yield valuable information. In idiopathic hypercalciuria, plasma calcium is nonnal. but plasma phosphate is low. Recent studies have shown that many of these patients have elevated levels of the active metabolite of vitamin D, 1,25 dihydroxycholecalciferol ( 1,25 DHCC). in their plasma." This has suggested that the initial lesion may be a renal phosphate leak which lowers plasma phosphate; this increases the formation of 1,25 DHCC which in turn stimulates increased calcium absorption, which raises calcium excretion in the urine. As levels of 1,25 DHCC in plasma may be raised by calcium deprivation, the raised levels found may be the result of the condition or of the diet prescribed rather than the cause. When hyperparathyroidism is found, parathyroid surgery significantly reduces stone formation.2o But a recent report describes patients with hypercalciuria who had mild hypercalcaemia and raised parathyroid hormone levels." Operation revealed parathyroid adenomas or hyperplasia, but removal of abnormal parathyroid tissue, while returning plasma calcium to normal, did not affect the hypercalciuria or stone formation. The authors suggested that the hyperparathyroidism in these patients was due to long standing parathyroid stimulation caused by a renal calcium leak. When the cause is unknown, treatment tends to be unsatisfactory. Water intake should be increased to ensure that urine volume exceeds 2 . 5 litres daily. Various agents have been used to try to reduce recurrent stone formation and each has its advocates. Thiazide administration reduces urinary calcium2* and this appears to occur whether the hypercalciuria is absorptive or renal. A low calcium diet has its supporters and cellulose phosphate has been used to block

calcium absorption by the bowel. Nordin's group has criticised both of these treatments for patients with calcium oxalate stones on the grounds that the reduced calcium in the bowel allows more oxalate to be absorbed; urinary calcium falls but urinary oxalate rises and the activity product of the two ions remains much the same or even increases slightly.' Thus. a low calcium diet should only be used in coiljunction with a low oxalate diet. In this context the content of oxalate in tea and chocolate is often forgotten. Oral phosphate is thought to be effective in preventing stone formation and has been shown to increase the formation of pyrophosphate by the kidney and its excretion in the urine.'3 However, a double blind study has shown little effect of phosphate over placebo on recurrent stone formation.24Coe has produced impressive data guggesting that allopurinol will reduce formation of calcium oxalate stones in hyperuricosuric calcium stone One other study suggesting that this is so has appearedz5. but a double blind trial has not yet been done. As mentioned previously. monosodium urate has been invoked as a nucleating agent for calcium oxalate stones"' and as an antagonist of inhibitors of calcium oxalate crystal aggregation.'8 Although Coe reports that allopurinol is most effective in calcium oxalate stone formers, he claims that it is also useful in patients with other types of calcium stones. Stone dissolution without open surgery has been and is still an elusive objective. Many years ago this was attempted using ureteric catheterisation and citrate solutions. It has recently been described using percutaneous nephrostorny and irrigating the renal pelvis with a citratemagnesium solution.26 Only triple phosphate stones were treated, and with success. Disintegration of stones using ultrasound is also being evaluated at present but is in its early stages (R. Jauernig, personal communication). The evaluation of the results of treatment is difficult. In most subjects, stones form intermittently rather than continuously. A patient will seek treatment after a stone-forming episode. This is likely to be followed by a stonefree period whether specific treatment or placebo is prescribed. One needs observation for at least

three years before one can be confident of the effects of treatment. Water is the simplest, cheapest and safest but even it has not been the subject of a properly controlled investigation. It is likely that there is no one cause for recurrent stone li,rmation. but that the tendency to form stones results from the interaction of several factors which may be peculiar to the patient and his environment. The one thing that all the investigators agree on is that further work is needed.

References I . SOKINK, B. 1. C. (1973): Metabolic bone and stone disease. Churchill 1.ivingatonc. Edinburgh and London.

2. LAVA%. J. N.. NEAI.I.I;. C.and PcxIs. S. (1971): Crinar) calculi. Clinical. biochcmical and radiological studies in 619 paticnls. MI?/. J. AIN. 2. 1049. 1061. 3. BAII,I:Y. K. R..I>ANS. E.. (;NEkhSt.Al)~, s.I:.. 1.11Tl.E. P. I.. MCR4P. C. I:. and U'LFY. W.I.. I,'.(1974): Urinary sluncs. A prospuctive stud? of 35U patients. X Z . nii?l. .I. 7V. 961 Y65. 4. N U K ~ I IB. N , 1,C. (1977): Hypercalciurh. Clin. Sri. .lfd.Ilcd 52. i .X. 5 . Cw. I'. l... PARKS.J . 11. and M o m . . li. S. (1Y79): Fandial idiopathic hyprcalciuria. N i w h ~.J. /Med. . .W. 337.340. 6. PAK. c. Y. C.. O I I A l h . M..I.hWNkh('k. 1;. c. and SSYIXK. W. (1974): 'The h)percalciurias. Caures. parathyroid function and diagnos:iccriteria. J. h i . I ~ ~ ~54.~ 387 N . wo. 7. II~rl~ciK:usos. A. ( 19741: Relations bctnCCII oxalic acid. ualuiun. magnesium and crcatinine excretion in normal mcn and mnlc piiients nkh calcium oialate iidne) stones. Clin. Sci. Md. M i ~ d46. 357 967. 8. WII.LIAX% 11. 1:. (1978): Oxalic acid and the hyparoxaluric syndromes. Kichri Inf. 13. 410-417. 9. COL:1:. L. (1978): Hyperuricosuric calcium oxalate nephrolithiasis. Kidnrj rnr. 13, 418- 426. 10. PAC. c. Y. c., ~iAu.4..lll.Y.and A R w t B . 1.. 11. (1976)): tIeterolcgous nuclcation with urate. calcium phosphate and cnlciom oxalite, Pro,,. Sor. exp. Bid. (S.Y.). 153, 83 -87. 11. (1978): Inhibitors and promoters of stone formation, K;dwj IIII. 11. fi,t:nc~~. 13.361 371. 12. ~IOS'AND. 1. E. (19621: Lrinary stone. Canad. iiiud. ASS. J. 86, 1001 .1007. 13. BARLFK.L.M..PAI.IA~TE. S. L..~1SIiSBEKG.H., Jm1.r:. I. A,. BECKKH. G. 1.. and IiowAnu. J. fi. (1974): Simplc synthetic and ndlurnl urines have equivalent anticalcifying properties. h i t w . Urol. 12, 79 -81. 14. M A x m m . M.(1963): Urinary mucopolysaccharides and calculi, .4nii. Rev. Med. 14. 99 110. 15, IIAI.I.SON,1'. C. and R m k . (i. A. (1979): Lriimucoids and urinary stone formation. Imwr 1. 1000 1002. 16. l'iur.n!uw, B.( I Y i X l : l'byricochcmical a*~tsol'?ir(ilithiasis. Kidiiex Iiir. 13, 344 360. R. W. and ROWKISCIS,W.G. ilY7hi. Nomograms for the 17. MAKSIIALL. estimation of the saturation of urine with calcium oxalate. calcium phosphate. magnesium ammonium phosphate, uric acid, sodium acid urate, ammonium acid uriltc and cystine, Cliir. rliin~..4cfa. 72. 253 -260. 18. RonlrKTsns. W. G. (1976): Physical chmical aspects of calcium stoneformation in the urindry lmct. in: I+o/irhiuTi.s Rrswrch. 11. Flcixh. W.G. Robertson. L. H. Smith and W. Vahlcnsieck (eds.):Pbnum Press. I.ondon and Sew York. pp. 25 29. 19. LIEN1:. H..BAYI.IN~, I>. J.. N e t . S ~ sK. . I..,SHEKKALI>.D. J.. IVEY J. I..and HAI~SI.ER. M. K. (1977): Increased serum 1.25-dihydroxyvita1hin D in idiopathic hypercdlciuria. J. lab. din. Med. 90, 955 ,962. 20. McGmws, M.G. (1961): Elfect of pdriithyroidectomy on the incidencc of renal calculi. Lancer 1, 586--587. P..RYCKEWAKT, A,. GWKIS. J. and RASMLSES.H.11977): On the 21. B~RDIEK. pathopenew of of so-called so-called idiopathic idiopathic hypercalciuria. hypercalcluria. Amer. 4 1 n w J. J Med. Merl 63, 63, pathogenesis 198 409 398. ,409. 12. Y E S ~ I F... and COtIANIW, Y. (1978): Prevention of calcium stones with thiuides. Kidnev B i f . 13. 397- 409. 23. 'rIn.wAs, W.C. (1978): Use of phosphates ill pd;icats with caicdnwus renal calculi. Kidnrj h i / . 13. 3Y0 --396. 24. Ei-risc;uc. B. (1976): Recurrent nephrolithiasis: Katural history and effectof phosphate thcrapy. A double-blind controlled study. Airier. J. MnI. 61, 210. -206. 25. SWTII. M.J. V. (19771: Placebo vcrsus allopurinol for reral calculi. J. L'rd 117,bYO 692. 26. Dnl:.n.EK. S. P.,YrlSl1.R. R. C.and Nt.wIIasE. J. H.(1979): Renal sionc dissolution via percutaneous nephrostomy. :Vru En,g/.J. Mcv/. 300,341 .-343.

Nephrolithiasis.

Aust. 3.2.J. Med. (1979). 9, pp. 718 721 CURRENTCONCEPTS Nephrolithiasis R. Melick' From the Royal Melbourne Hospital Stones form because material...
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