Editorials first diagnosed, it has become obvious that determined efforts must be made to detect the disease before symptoms occur, but the problems of introducing screening for mammary cancer on a national scale are formidable. There is no doubt, however, that careful clinical examination combined with mammography can detect very- small cancers. The accuracy of mammography is improving at such a rate that it is now possible to detect lesions deep in the breast well below 1 cm in size and completely impalpable. Cancer of the breast is an all too common disease and its incidence is increasing. Diagnosing it earlier than hitherto offers the most realistic hope for the immediate future. Fortunately this need has been recognized and a number of carefully planned pilot studies are in progress which are examining all the many aspects and problems of mammary screening. The conclusions of these studies are awaited with great interest. IAN BURN
Surgeon in Charge of the Breast Clinic, Charing Cross Hospital, London W6
Biochemical Aspects of Urinary Stones Although urinary stone formation occurs all over the world it is not a uniform condition. In the under developed countries bladder stones in boys are still common (Van Reen & Valyasevi 1974) as was the case in this country a century or so ago (Batty Shaw 1970). Often these stones are mixtures of oxalate and urate, but this is not always so; in Rwanda they are made of calcium oxalate and phosphate (Popelier et al. 1976), and in Indonesia they are largely composed of ammonium urate, probably because of a low phosphate content in the diet (Thalut et al. 1977). In the developed countries -upper urinary tract stones are common and apparently getting more so, and these are most often made of calcium oxalate and/or phosphate. Uricacid stones are more common in Israel and West Germany than in the other developed countries, and in the latter case a rise in incidence of these stones since the Second World War (Schneider & Hesse 1976) has been linked with increasing affluence and dietary intake of purine-rich foods (Griebsch & Zollner 1973). Nevertheless, the calcium-rich urinary stone is clearly predominant in developed societies at the present time and is, therefore, the subject of considerable research. It is the calcium-rich stone with which this article is concerned.
517
That certain basic physicochemical laws controlling the solubility of compounds in aqueous solutions apply to the formation of urinary stones cannot be denied. Thus, stone formation can only occur when the urine becomes supersaturated with a particular chemical. If the urine is under saturated then stone formation cannot occur, but stone dissolution may occur. These principles have been convincingly demonstrated for cystine and uricacid stones. Thus, the solubility of cystine has been measured in water and in urine, and it was established by Dent & Senior (1955) that a flow rate of about 2 ml/min (2880 ml/24 h) is sufficient to avoid supersaturation of urine with cystine in a cystinuric. Above this flow rate cystine stones can be dissolved. It has also been shown (Frank & De Vries 1966) that stone formation rate in a hot climate can be dramatically reduced by increasing urine volume through advising all those at risk of the importance of increasing fluid intake. The concentration of uric acid in urine is greatly reduced by alkalinization which converts uric acid to urate ions, and such simple treatment has been shown to permit dissolution of uric-acid stones (Uhlir 1970). Even in these simple cases, however, certain basic questions remain unanswered. First, supersaturation is not synonymous with stone formation; urine may be supersaturated without any precipitation occurring. Furthermore, many normal individuals frequently pass crystals in their urine, proving that it is supersaturated, without developing stones. If stone formation proceeds by crystal aggregation, and this is not certain, what determines whether or not crystals aggregate? What causes a crystal aggregate to stick high up in the renal tract so that it can grow into a visible stone? How do stones grow? Do whole crystals become added on or is it a process of molecular accretion? What is the role of the matrix that is found within all renal stones? All these questions need to be answered before we can claim to understand stone formation. Pursuing the physicochemical methods of investigation, groups in Leeds (Robertson et al. 1968) and in the USA (Pak 1969) have tried to study the state of saturation of urine with regard to calcium oxalate and calcium phosphate. For this purpose they needed to know the ionic activity products of these compounds and also the formation products. However, whereas the concept of solubility is relatively simple, the concept of supersaturation for a salt such as calcium oxalate is extremely difficult to understand. The degree of supersaturation that can be obtained is not precise since it is affected by inhibitors of crystal nucleation which undoubtedly occur in urine, by the presence of colloidal particles and even by mechanical impacts (Young 191 1). Hence, it may be impossible to define the formation product as a
518
Proc. roy. Soc. Med. Volume 70 August 1977
single numerical value as these authors have tried to do; The attempts that have been made to measure the ion activity products of calcium oxalate and phosphate in urine have been hampered by a lack of certain basic information required to calculate activity factors which enter the calculations. Even the use of computers cannot compensate for such a lack of basic information; urine is too complicated a solution to be susceptible to this mathematical approach at the present time. Perhaps it is for this reason that work in this direction has not yielded information of great practical value. One point has emerged from these studies, however, namely that oxalate concentration is more critical than calcium concentration (Robertson et al. 1972) and this point will be considered further below. Fortunately, a new technique has been developed which is a much simpler and more reliable method for showing that a urine sample is supersaturated. It is really the old technique, brought up to date, of looking at crystals in the urine and this enables us to bypass the whole question of calculating ionic strengths and activity factors and of considering all the inhibitors of crystal nucleation. The presence of crystals in urine reveals that the first requirement for stone formation exists, namely the ability of the urine to throw a substance out of solution. It is remarkable that although clinical pathologists have been looking at urinary crystals ever since the invention of the microscope it was only recently that it was pointed out (Dyer & Nordin 1967) that observation of crystals in urine was only of value when made on fresh urine that had been kept at 37°C. When this is done it is found that while both normal subjects and stoneformers may pass calcium oxalate and phosphate crystals, albeit the stone-formers do so more frequently, there is a striking difference between the two groups in that aggregates of calcium oxalate crystals occur frequently in the stone-formers and almost never in the normal subjects (Robertson et al. 1969, Hallson & Rose 1976). This seems to suggest that the ability of crystals to aggregate in urine may indeed be an important factor, which determines whether or not stone formation occurs. If these observations are correct then we would seem to be provided with a way of recognizing whether or not patients are at risk of further stone formation, and this could be an important advance. The role of the organic matrix of renal calculi remains obscure. It was established by Boyce and his coworkers that stone matrix is made of mucoproteins (King & Boyce 1959), but unfortunately further work on this subject has been slow and relatively unhelpful. This is perhaps because of the great technical difficulties of such work. Stone matrix is obtained by dissolving away the mineral
portion of the stone in a suitable aqueous medium (alkaline EDTA in the case of calcium-rich stones), so leaving behind the insoluble uromucoid. In order to study this material further it must be got into solution and the methods required to do this necessarily disrupt the molecular structure which one wishes to study. The alternative is to study the mucoproteins present in the urine but progress here has also been hindered by technical difficulties, and advances in these directions must presumably await new analytical techniques. The investigation of a patient suffering from urinary stones should begin with consideration of the chemical composition of the stone. If the stone has been passed or removed it should be analysed. This may be by wet chemistry (Hodgkinson et al. 1969, Westbury & Omenogor 1970) or by physical methods such as infra-red spectroscopy (Bellanato et al. 1973), X-ray crystallography (Sutor & Scheidt 1968), or thermogravimetric analysis (Rose & Woodfine 1976). Quantitative analysis alone should now be considered as unacceptable as an old-fashioned Sulkowitch test for urinary calcium, and clinicians should insist that hospital laboratories which are measuring calcium, phosphate, magnesium and urate every day should also measure these ingredients in stones. If the stone is still in situ then the chemical composition may be assessed by the radiodensity (Rose 1976a). The mineral content of a large proportion of calciumrich stones is calcium oxalate and phosphate, usually with the former predominating. Often calcium oxalate is the only mineral that can be detected by ordinary chemical or physicochemical methods. This strongly suggests that calcium oxalate may be the more important mineral, with phosphate added on afterwards in some way. This view was supported by a study of the stone-central core by Elliot (1973) which showed that calcium oxalate was by far the most common mineral to occur in these central cores, i.e. in what appeared to be the original area of stone formation. Others, however, have taken a different view. Thus, Pak et al. (1971) thought that brushite (CaHPO4. 2H20) initiated calcium stone formation, while Meyer et al. (1975) convincingly demonstrated that hydroxyapatite seed crystals could induce growth of calcium oxalate monohydrate epitaxially from a metastable supersaturated solution ofcalcium oxalate. Later, however, Meyer et al. (1977) went on to show that epitaxy could operate in the reverse direction and that calcium oxalate monohydrate crystals could induce growth of brushite. Every urinary-stone case should be subjected to a small but important group of laboratory investigations which have recently been reviewed elsewhere (Rose 1976b) and will, therefore, not be considered further here. The most likely diagnosis to emerge, especially in males, is idiopathic hyper-
519
Editorials
calcuria, a condition that gives rise to many questions, not the least of which is how to define normal urinary calcium. This undoubtedly varies in different areas of the world, but even in individual areas the limits of normality are hard to define because the distribution curve is non-gaussian with considerable tailing. Furthermore, as is the case for plasma urate levels in gout, there is an overlap in ranges for normal and abnormal individuals. It is therefore probably better, and certainly more practical, to set acceptable upper limits for the urinary calcium in cases of stone formation; for this purpose I use 350 mg/24 h in adult males and 300 mg/24 h in adult females. Idiopathic hypercalcuria is sometimes due to high calcium intake and calcium-rich foods should therefore be avoided. This is not too difficult since they mainly comprise milk and its products. Avoiding these foods will lower the urinary calcium to acceptable levels in some patients, but not in others who may have either a primary over absorption of dietary calcium, or a primary renal leak for calcium resulting in secondary over absorption of dietary calcium. One would expect that the plasma parathyroid hormone and urinary cyclic AMP levels would be reduced in the case of primary over absorption and elevated in the case of primary renal leak, and attempts have been made to distinguish between the two cases in this way. Unfortunately the findings have been conflicting. Pak et al. (1974; Pak et al. 1975) in Texas where there is a lot of sunshine found the majority of cases to show a lowered plasma parathyroid hormone and urinary cyclic AMP, while Coe et al. (1973) working in Chicago where the climate is cooler found the opposite. Nevertheless, there are now several ways of lowering the urinary calcium when diet alone proves unsatisfactory. First, thiazide diuretics can lower urinary calcium by direct action on renal tubules and may be used for long periods of time for this purpose (Yendt et al. 1970, Yendt & Cohanim 1973, Harrison & Rose 1974). Secondly, sodium cellulose phosphate lowers urinary calcium (and magnesium) by exchanging dietary calcium for sodium in the gastrointestinal tract and may also be used for long periods of time (Harrison & Rose 1974, Blacklock & Macleod 1974). One of these drugs can usually be found to work without producing side-effects (Harrison & Rose 1974). Thirdly, inorganic phosphate may be administered in the form of one of its sodium/potassium/hydrogen salts (Ettinger & Kolb 1973). Patients should also be advised to restrict the intake of oxalate-rich foods, and if Robertson et al. (1972) are correct (see above), this is more important than restricting calcium intake. Urinary oxalate varies with season of the year (Hallson et al. 1977) presumably because certain oxalate-rich foods are seasonal, e.g. beetroot, spinach, nuts,
rhubarb and strawberries, and undoubtedly these foods should be restricted. However, much of the exogenous urinary oxalate that is nonseasonal comes in this country from tea (Zarembski & Hodgkinson 1962), and a case could be made for advising restriction of this beverage. An entirely different therapeutic approach is the use of allopurinol to lower urinary urate (Coe & Raisen 1973). Two quite distinct propositions have been put forward to support this idea. First, it has been suggested that urate can 'salt out' calcium oxalate (Kallistratos et al. 1970, Kallistratos 1974). However, the actual evidence for this theory is unconvincing, and it has not been confirmed by others. Secondly, calcium oxalate may grow epitaxially on uric acid crystals (Lonsdale 1968) so that reducing the latter may prevent crystal growth of the former. This is probably theoretically sound, but there is no convincing evidence that this is actually the way in which oxalate aggregates develop. Although attempts have been made to assess some of the various therapies now available, they all suffer from certain defects. First, the trials have not been properly controlled; at best pre-treatment findings have been compared with the same patients on treatment. Secondly, all patients with renal stones are quite properly advised to increase fluid intake, and often to reduce calcium intake, and it is, therefore, hard to determine whether therapeutic success is due to the specific therapy or to the water. G ALAN ROSE
Consultant Chemical Pathologist, St Peter's Hospitals & Institute of Urology, London WC2 REFERENCES Batty Shaw A (1970) Medical History 14, 221-259 BeUlanato J, Delatte L C, Hidalgo A & Santos M (1973) Urinary Calculi, International Symposium on Stone Research, Madrid 1972. Ed. L C Delatte, A Rapado & A Hodgkinson. Karger, Basel; pp 237-246 Blacklock N J & Macleod M A (1974) British Journal of Urology 46, 385-392 Coe F L, Canterbury J M, Firpo J J & Reiss E (1973) Journal of Clinical Investigation 52, 134-142 Coe F L & Raisen L (1973) Lancet i, 129-131 Dent C E & Senior B (1955) British Journal of Urology 27, 317-332 Dyer R & Nordin B E C (1967) Nature (London) 215, 751-752 Elliot J S (1973) Journal of Urology 109, 82-83 Ettinger B & Kolb F 0 (1973) American Journal of Medicine 55, 32-37 Frank M & De Vries A (1966) Archives of Environmental Health 13, 625-630 Griebsch A & Z6l1ner N (1973) Zeitschrift fur klinische Biochemie 11, 346-356 Halison P C, Kasidas G P & Rose G A (1977) British Journal of Urology 49, 1-10 Hallson P C & Rose G A (1976) British Journal of Urology 48, 515-524
520
Proc. roy. Soc. Med. Volume 70 August 1977
Harison AR & Rose GA (1974) British Journal of Urology 46, 343-350 Hodgio A, Peacock M & Nicholson M (1969) Investigative Urology 6, 549-561 Kallistratos G (1974) In: Pathogenese und Klinik der Harnsteine II. Ed. W Vahlensieck & G Gasser. Darmstadt; pp 56-80 Kalistratos G, Tumnerman A & Fenner 0 (1970) Die Naturwissenchaften 57, 198 King J S jr & Boyce W H (1959) Archives of Biochemistry 82, 455-461 Lonadale K (1968) Science 159, 1199-1207 Meyer J L, Bergert J H & Smith L H (1975) Clinical Science and Molecular Medicine 49, 369-374 Meyer J L, Bergert J H & Smith L H (1977) Clinical Science 52, 143-148 Pak C Y C (1969) Journal of Clinical Investigation 48, 1914-1922 Pak C Y C, Eanes E D & Ruskin B (1971) Proceedings of National Academy of Sciences of USA 68, 1456-1460 Pak C Y C, Kaplan R, Bone H, Townsend J & Waters 0 (1975) New England Journal of Medicine 292, 497-500 Pak C Y C, Ohata M, Lawrece E C & Snyder W (1974) Journal of Clinical Investigation 54, 387-400 Popelier G, Van den Eeckhour E & Dekeyser W (1976) British Journal of Urology 48, 317-322 Roberton W G, Peacock M & Nordin B E C (1968) Clinical Science 34, 579-594 Robertson W G, Peacock M & Nordin B E C (1969) Lancet ii, 21-24
Robertson W G, Peacock M & Nordin B E C (1972) In: Urolithiasis, Physical Aspects. Ed B Finlayson, L L Hench & L H Smith. National Academy of Sciences, Washington; p 88 Rose G A (1976a) In: Recent Advances in Urology. Ed W F Hendry. Churchill Livingstone, Edinburgh; chapter 2 (1976b) In: Scientific Foundations of Urology. Ed. D I Williams & G D Chisholtn. Heinemann, London; 1, 329-331 Rose GA & Woodfie C (1976) British Journal of Urology 48, 403-412 Schneider H J & Heme A (1976) Therapiewoche 26, 5881-5889 Sutor D J & Scheidt S (1968) British Journal of Urology 40, 22-28 Thalut K, Rizal A, Brockis J G, Bowyer R C, Taylor T A & Wisniewski Z S (1977) British Journal of Urology 48, 617-621 Uhlir K (1970) Journal of Urology 104, 239-247 Van Reen R & Valyasevi A (1974) Public Health Reviews 3, 57-71 Westbury E J & Omenogor P (1970) Journal of Medical Laboratory Technology 27, 462-474 Yendt E R & Cohanim M (1973) Transactions of the American Clinical and Climatological Association 85, 65-75 Yendt E R, Guay F G & Garcia D A (1970) Canadian Medical Association Journal 102, 614-620 Young S W (1911) Journal ofthe American Chemical Society 33, 148-162 Zarembski P M & Hodgkinson A (1962) British Journal of Nutrition 16, 627-634
Surgeon in Charge of the Breast Clinic, Charing Cross Hospital, London W6
Biochemical Aspects of Urinary Stones Although urinary stone formation occurs all over the world it is not a uniform condition. In the under developed countries bladder stones in boys are still common (Van Reen & Valyasevi 1974) as was the case in this country a century or so ago (Batty Shaw 1970). Often these stones are mixtures of oxalate and urate, but this is not always so; in Rwanda they are made of calcium oxalate and phosphate (Popelier et al. 1976), and in Indonesia they are largely composed of ammonium urate, probably because of a low phosphate content in the diet (Thalut et al. 1977). In the developed countries -upper urinary tract stones are common and apparently getting more so, and these are most often made of calcium oxalate and/or phosphate. Uricacid stones are more common in Israel and West Germany than in the other developed countries, and in the latter case a rise in incidence of these stones since the Second World War (Schneider & Hesse 1976) has been linked with increasing affluence and dietary intake of purine-rich foods (Griebsch & Zollner 1973). Nevertheless, the calcium-rich urinary stone is clearly predominant in developed societies at the present time and is, therefore, the subject of considerable research. It is the calcium-rich stone with which this article is concerned.
517
That certain basic physicochemical laws controlling the solubility of compounds in aqueous solutions apply to the formation of urinary stones cannot be denied. Thus, stone formation can only occur when the urine becomes supersaturated with a particular chemical. If the urine is under saturated then stone formation cannot occur, but stone dissolution may occur. These principles have been convincingly demonstrated for cystine and uricacid stones. Thus, the solubility of cystine has been measured in water and in urine, and it was established by Dent & Senior (1955) that a flow rate of about 2 ml/min (2880 ml/24 h) is sufficient to avoid supersaturation of urine with cystine in a cystinuric. Above this flow rate cystine stones can be dissolved. It has also been shown (Frank & De Vries 1966) that stone formation rate in a hot climate can be dramatically reduced by increasing urine volume through advising all those at risk of the importance of increasing fluid intake. The concentration of uric acid in urine is greatly reduced by alkalinization which converts uric acid to urate ions, and such simple treatment has been shown to permit dissolution of uric-acid stones (Uhlir 1970). Even in these simple cases, however, certain basic questions remain unanswered. First, supersaturation is not synonymous with stone formation; urine may be supersaturated without any precipitation occurring. Furthermore, many normal individuals frequently pass crystals in their urine, proving that it is supersaturated, without developing stones. If stone formation proceeds by crystal aggregation, and this is not certain, what determines whether or not crystals aggregate? What causes a crystal aggregate to stick high up in the renal tract so that it can grow into a visible stone? How do stones grow? Do whole crystals become added on or is it a process of molecular accretion? What is the role of the matrix that is found within all renal stones? All these questions need to be answered before we can claim to understand stone formation. Pursuing the physicochemical methods of investigation, groups in Leeds (Robertson et al. 1968) and in the USA (Pak 1969) have tried to study the state of saturation of urine with regard to calcium oxalate and calcium phosphate. For this purpose they needed to know the ionic activity products of these compounds and also the formation products. However, whereas the concept of solubility is relatively simple, the concept of supersaturation for a salt such as calcium oxalate is extremely difficult to understand. The degree of supersaturation that can be obtained is not precise since it is affected by inhibitors of crystal nucleation which undoubtedly occur in urine, by the presence of colloidal particles and even by mechanical impacts (Young 191 1). Hence, it may be impossible to define the formation product as a
518
Proc. roy. Soc. Med. Volume 70 August 1977
single numerical value as these authors have tried to do; The attempts that have been made to measure the ion activity products of calcium oxalate and phosphate in urine have been hampered by a lack of certain basic information required to calculate activity factors which enter the calculations. Even the use of computers cannot compensate for such a lack of basic information; urine is too complicated a solution to be susceptible to this mathematical approach at the present time. Perhaps it is for this reason that work in this direction has not yielded information of great practical value. One point has emerged from these studies, however, namely that oxalate concentration is more critical than calcium concentration (Robertson et al. 1972) and this point will be considered further below. Fortunately, a new technique has been developed which is a much simpler and more reliable method for showing that a urine sample is supersaturated. It is really the old technique, brought up to date, of looking at crystals in the urine and this enables us to bypass the whole question of calculating ionic strengths and activity factors and of considering all the inhibitors of crystal nucleation. The presence of crystals in urine reveals that the first requirement for stone formation exists, namely the ability of the urine to throw a substance out of solution. It is remarkable that although clinical pathologists have been looking at urinary crystals ever since the invention of the microscope it was only recently that it was pointed out (Dyer & Nordin 1967) that observation of crystals in urine was only of value when made on fresh urine that had been kept at 37°C. When this is done it is found that while both normal subjects and stoneformers may pass calcium oxalate and phosphate crystals, albeit the stone-formers do so more frequently, there is a striking difference between the two groups in that aggregates of calcium oxalate crystals occur frequently in the stone-formers and almost never in the normal subjects (Robertson et al. 1969, Hallson & Rose 1976). This seems to suggest that the ability of crystals to aggregate in urine may indeed be an important factor, which determines whether or not stone formation occurs. If these observations are correct then we would seem to be provided with a way of recognizing whether or not patients are at risk of further stone formation, and this could be an important advance. The role of the organic matrix of renal calculi remains obscure. It was established by Boyce and his coworkers that stone matrix is made of mucoproteins (King & Boyce 1959), but unfortunately further work on this subject has been slow and relatively unhelpful. This is perhaps because of the great technical difficulties of such work. Stone matrix is obtained by dissolving away the mineral
portion of the stone in a suitable aqueous medium (alkaline EDTA in the case of calcium-rich stones), so leaving behind the insoluble uromucoid. In order to study this material further it must be got into solution and the methods required to do this necessarily disrupt the molecular structure which one wishes to study. The alternative is to study the mucoproteins present in the urine but progress here has also been hindered by technical difficulties, and advances in these directions must presumably await new analytical techniques. The investigation of a patient suffering from urinary stones should begin with consideration of the chemical composition of the stone. If the stone has been passed or removed it should be analysed. This may be by wet chemistry (Hodgkinson et al. 1969, Westbury & Omenogor 1970) or by physical methods such as infra-red spectroscopy (Bellanato et al. 1973), X-ray crystallography (Sutor & Scheidt 1968), or thermogravimetric analysis (Rose & Woodfine 1976). Quantitative analysis alone should now be considered as unacceptable as an old-fashioned Sulkowitch test for urinary calcium, and clinicians should insist that hospital laboratories which are measuring calcium, phosphate, magnesium and urate every day should also measure these ingredients in stones. If the stone is still in situ then the chemical composition may be assessed by the radiodensity (Rose 1976a). The mineral content of a large proportion of calciumrich stones is calcium oxalate and phosphate, usually with the former predominating. Often calcium oxalate is the only mineral that can be detected by ordinary chemical or physicochemical methods. This strongly suggests that calcium oxalate may be the more important mineral, with phosphate added on afterwards in some way. This view was supported by a study of the stone-central core by Elliot (1973) which showed that calcium oxalate was by far the most common mineral to occur in these central cores, i.e. in what appeared to be the original area of stone formation. Others, however, have taken a different view. Thus, Pak et al. (1971) thought that brushite (CaHPO4. 2H20) initiated calcium stone formation, while Meyer et al. (1975) convincingly demonstrated that hydroxyapatite seed crystals could induce growth of calcium oxalate monohydrate epitaxially from a metastable supersaturated solution ofcalcium oxalate. Later, however, Meyer et al. (1977) went on to show that epitaxy could operate in the reverse direction and that calcium oxalate monohydrate crystals could induce growth of brushite. Every urinary-stone case should be subjected to a small but important group of laboratory investigations which have recently been reviewed elsewhere (Rose 1976b) and will, therefore, not be considered further here. The most likely diagnosis to emerge, especially in males, is idiopathic hyper-
519
Editorials
calcuria, a condition that gives rise to many questions, not the least of which is how to define normal urinary calcium. This undoubtedly varies in different areas of the world, but even in individual areas the limits of normality are hard to define because the distribution curve is non-gaussian with considerable tailing. Furthermore, as is the case for plasma urate levels in gout, there is an overlap in ranges for normal and abnormal individuals. It is therefore probably better, and certainly more practical, to set acceptable upper limits for the urinary calcium in cases of stone formation; for this purpose I use 350 mg/24 h in adult males and 300 mg/24 h in adult females. Idiopathic hypercalcuria is sometimes due to high calcium intake and calcium-rich foods should therefore be avoided. This is not too difficult since they mainly comprise milk and its products. Avoiding these foods will lower the urinary calcium to acceptable levels in some patients, but not in others who may have either a primary over absorption of dietary calcium, or a primary renal leak for calcium resulting in secondary over absorption of dietary calcium. One would expect that the plasma parathyroid hormone and urinary cyclic AMP levels would be reduced in the case of primary over absorption and elevated in the case of primary renal leak, and attempts have been made to distinguish between the two cases in this way. Unfortunately the findings have been conflicting. Pak et al. (1974; Pak et al. 1975) in Texas where there is a lot of sunshine found the majority of cases to show a lowered plasma parathyroid hormone and urinary cyclic AMP, while Coe et al. (1973) working in Chicago where the climate is cooler found the opposite. Nevertheless, there are now several ways of lowering the urinary calcium when diet alone proves unsatisfactory. First, thiazide diuretics can lower urinary calcium by direct action on renal tubules and may be used for long periods of time for this purpose (Yendt et al. 1970, Yendt & Cohanim 1973, Harrison & Rose 1974). Secondly, sodium cellulose phosphate lowers urinary calcium (and magnesium) by exchanging dietary calcium for sodium in the gastrointestinal tract and may also be used for long periods of time (Harrison & Rose 1974, Blacklock & Macleod 1974). One of these drugs can usually be found to work without producing side-effects (Harrison & Rose 1974). Thirdly, inorganic phosphate may be administered in the form of one of its sodium/potassium/hydrogen salts (Ettinger & Kolb 1973). Patients should also be advised to restrict the intake of oxalate-rich foods, and if Robertson et al. (1972) are correct (see above), this is more important than restricting calcium intake. Urinary oxalate varies with season of the year (Hallson et al. 1977) presumably because certain oxalate-rich foods are seasonal, e.g. beetroot, spinach, nuts,
rhubarb and strawberries, and undoubtedly these foods should be restricted. However, much of the exogenous urinary oxalate that is nonseasonal comes in this country from tea (Zarembski & Hodgkinson 1962), and a case could be made for advising restriction of this beverage. An entirely different therapeutic approach is the use of allopurinol to lower urinary urate (Coe & Raisen 1973). Two quite distinct propositions have been put forward to support this idea. First, it has been suggested that urate can 'salt out' calcium oxalate (Kallistratos et al. 1970, Kallistratos 1974). However, the actual evidence for this theory is unconvincing, and it has not been confirmed by others. Secondly, calcium oxalate may grow epitaxially on uric acid crystals (Lonsdale 1968) so that reducing the latter may prevent crystal growth of the former. This is probably theoretically sound, but there is no convincing evidence that this is actually the way in which oxalate aggregates develop. Although attempts have been made to assess some of the various therapies now available, they all suffer from certain defects. First, the trials have not been properly controlled; at best pre-treatment findings have been compared with the same patients on treatment. Secondly, all patients with renal stones are quite properly advised to increase fluid intake, and often to reduce calcium intake, and it is, therefore, hard to determine whether therapeutic success is due to the specific therapy or to the water. G ALAN ROSE
Consultant Chemical Pathologist, St Peter's Hospitals & Institute of Urology, London WC2 REFERENCES Batty Shaw A (1970) Medical History 14, 221-259 BeUlanato J, Delatte L C, Hidalgo A & Santos M (1973) Urinary Calculi, International Symposium on Stone Research, Madrid 1972. Ed. L C Delatte, A Rapado & A Hodgkinson. Karger, Basel; pp 237-246 Blacklock N J & Macleod M A (1974) British Journal of Urology 46, 385-392 Coe F L, Canterbury J M, Firpo J J & Reiss E (1973) Journal of Clinical Investigation 52, 134-142 Coe F L & Raisen L (1973) Lancet i, 129-131 Dent C E & Senior B (1955) British Journal of Urology 27, 317-332 Dyer R & Nordin B E C (1967) Nature (London) 215, 751-752 Elliot J S (1973) Journal of Urology 109, 82-83 Ettinger B & Kolb F 0 (1973) American Journal of Medicine 55, 32-37 Frank M & De Vries A (1966) Archives of Environmental Health 13, 625-630 Griebsch A & Z6l1ner N (1973) Zeitschrift fur klinische Biochemie 11, 346-356 Halison P C, Kasidas G P & Rose G A (1977) British Journal of Urology 49, 1-10 Hallson P C & Rose G A (1976) British Journal of Urology 48, 515-524
520
Proc. roy. Soc. Med. Volume 70 August 1977
Harison AR & Rose GA (1974) British Journal of Urology 46, 343-350 Hodgio A, Peacock M & Nicholson M (1969) Investigative Urology 6, 549-561 Kallistratos G (1974) In: Pathogenese und Klinik der Harnsteine II. Ed. W Vahlensieck & G Gasser. Darmstadt; pp 56-80 Kalistratos G, Tumnerman A & Fenner 0 (1970) Die Naturwissenchaften 57, 198 King J S jr & Boyce W H (1959) Archives of Biochemistry 82, 455-461 Lonadale K (1968) Science 159, 1199-1207 Meyer J L, Bergert J H & Smith L H (1975) Clinical Science and Molecular Medicine 49, 369-374 Meyer J L, Bergert J H & Smith L H (1977) Clinical Science 52, 143-148 Pak C Y C (1969) Journal of Clinical Investigation 48, 1914-1922 Pak C Y C, Eanes E D & Ruskin B (1971) Proceedings of National Academy of Sciences of USA 68, 1456-1460 Pak C Y C, Kaplan R, Bone H, Townsend J & Waters 0 (1975) New England Journal of Medicine 292, 497-500 Pak C Y C, Ohata M, Lawrece E C & Snyder W (1974) Journal of Clinical Investigation 54, 387-400 Popelier G, Van den Eeckhour E & Dekeyser W (1976) British Journal of Urology 48, 317-322 Roberton W G, Peacock M & Nordin B E C (1968) Clinical Science 34, 579-594 Robertson W G, Peacock M & Nordin B E C (1969) Lancet ii, 21-24
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