I63

METABOLIC DISORDERS AND RENAL STONEBy A. R. HARRISON, M.D., M.R.C.P.

Institute of Urology

IntroductionResearch into the aetiology of calculus disease

has failed to reveal the fundamental cause of stoneformation, but it is apparent that various factorspredispose to their development. Renal calculiare likely to occur in most diseases in which thereis an increased urinary excretion of crystalloidstone-forming substances. Calcium phosphateand oxalate stones are particularly liable to arisein disorders leading to hypercalcuria such ashyperparathyroidism, cystine calculi seem onlyto occur in those patients with cystinuria whoexcrete large amounts of this amino-acid, and thereis some evidence that diseases causing a raisedexcretion of uric acid predispose to uric acidstones.

In this short review an attempt will be made topresent the main diagnostic features of some ofthese diseases, particularly those in which patientsmay first seek advice because of symptoms ofstone in the upper urinary tract.

Increased Urinary Excretion of CalciumNormal Values

Precise figures cannot be given, for even whenallowances are made for age, body-weight anddietary intake, there seems to be a considerablevariation in urinary calcium output amonghealthy individuals (Knapp, 1947). However,when no attempt is made to standardize diets,healthy adults rarely excrete more than 300 mg.per day, and when low calcium diets are taken thelimit of output is about 150 mg. per day.

Disorders Causing HypercalcuriaHypercalcuria will occur in any condition in

which calcium is lost from the skeleton, e.g.hyperparathyroidism, diseases causing local des-truction of bone such as osteolytic metastases andmultiple myelomatosis, and the various forms ofosteoporosis including those due to immobilizationand Cushing's syndrome.

In these the raised urine calcium reflects thetransfer of calcium from the skeleton into the bodyfluids, but in vitamin D intoxication and possibly

in some cases of sarcoidosis (Anderson, Harper,Dent and Philpott, I954) there is increased alimen-tary absorption of calcium.

In various forms of acidosis, including renaltubular acidosis and that which may followuretero-sigmoidostomy, excessive calcium is ex-creted with other bases of the body.

Finally, in idiopathic hypercalcuria it is possiblethat there is diminished renal tubular re-absorptive capacity for calcium.

HyperparathyroidismMany descriptions of this disorder, such as that

of Albright and Reifenstein (1948), have beenpublished and only a brief account of the clinicalfeatures need be given here. Skeletal symptomsrange from solitary swellings to the generalizedbone pains, deformities, multiple swellings andpathological fractures of osteitis fibrosa cystica.Renal calculi and nephrocalcinosis are common,as is some degree of renal failure. Indeed, insevere cases with extensive nephrocalcinosis,renal failure may be irreversible and progressiveeven after parathyroidectomy. Hypercalcaemiaitself may give rise to muscular hypotonicity andweakness, anorexia and constipation.As this disorder was first recognized by its

effects on the skeleton, it was inevitable that caseswith skeletal lesions predominated in earlyreports. However, Albright and his colleagues,in a series of papers (1934, 1937, 1948), demons-trated that renal calculi and nephrocalcinosis aremore frequent consequences of hyperparathy-roidism than skeletal lesions. Widespread recog-nition of this was slow to develop, but it has nowbeen abundantly confirmed. Norris (I947) in areview of the 314 cases then published showedthat only 17 of these had renal lesions alone, andin IOxI there were renal and skeletal lesions.Pyrah and Raper (1955) stated that of 266 casespublished after I947, I36 had renal lesions aloneand a further 66 had renal and skeletal lesions.

In the past i8 motrths the diagnosis has beenmade in i I patients admitted to our metabolicward. In eight of these the diagnosis has been

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confirmed at operation, but the remaining threestill await surgical exploration. I-n these hospitals-there will obviously be a bias towards cases withstone or nephrocalcinosis, but in none of the iopatients who displayed such lesions was there anyevidence of bone disease. The remaining patienthad osteitis fibrosa cystica and no renal lesion.

DiagnosisWhen osteitis fibrosa cystica is present, diagnosis

is not difficult, but it is evident that many patientswith hyperparathyroidism will present at urologicalclinics as caseg of calculus disease. In these,diagnosis is not easy, for clinical and 'routineexaminations of the urinary tract will not dis-tinguish them from other patients with calciumphosphate or calcium oxalate stones. Hyper-parathyroidism is more likely when stones arebilateral or recurrent or when nephrocalcinosis ispresent, but none of'these features is pathog-nomonic of the disease, and all may be absent' inits early stages. The diagnosis can only be estab-lished by biochemical investigations.

Biochemical FeaturesThe mode of action of parathormone may still

be controversial, but there is no disagreementregarding the biochemical changes it produces;elevation of the plasma calcium, lowering of theplasma inorganic phosphate (phosphorus) andincreases in the urinary excretion of calcium andphosphorus.Plasma Cakium.-The normal range is 9-I I mg./

100 ml. In hyperparathyroidism values vary fromthose which are obviously high, e.g. i6 or 17 mg./ioo ml., to those which are only slightly elevated.In'one of our confirmed cases, who had normalplasma proteins, the highest reading obtained was11.4 mg./ioo ml. and the average of four readingswas II.I mg./Ioo ml. Laboratory techniquescannot be discussed here, but if such cases are tobe diagnosed a consistently high standard ofaccuracy in assays is essential. Since part of thecalcium'is bound to protein, hypoproteinaemiamay mask hypercalcaemia and, therefore, plasmaproteins should always be estimated. Conversely,the total plasma calcium may rise because ofhyperproteinaemia. Occlusion of the arm veins,particularly if combined with repeated clenchingof t'he hand, may occasionally lead to local con-centration of the plasma protein and'its boundcalcium and, therefore, it is advisable to withdrawblood samples without using a tourniquet.Plasma Phosphorus.-The average normal value

is 3.5 mg./Ioo ml., but in health there may beappreciable fluctuations throughout the day andestimations'should preferably be made on fastingblood specimens. The values obtained in this

Patients withHyperparathyroidism

Stone patients withoutX Hyperparathyroidism

24 6810 24 6 8 10 121416182022

FIG. I.-Daily urinary calcium output in 33 patientson a low calcium intake. Note that I5 of the 22patients without hyperparathyroidism exhibit hyper-calcuria (more than I50 mg. per day).

disease vary from those which are obviously low,e.g. 2.0 mg./Ioo ml., or less, to those which do notdiffer much from low ' normals,' e.g. 3.0 mg./IOO ml. If renal failure is present an increasedrenal clearance of phosphate cannot occur and theplasma level will not fall.Plasma Alkaline Phosphatase.-It is only in

patients with bone lesions that the alkaline phos-phatase is raised beyond the normal range (3-13King-Armstrong units).

Urinary Calcium Output.-An increased urinarycalcium excretion is not pathognomonic of hyper-parathyroidism, for in other disorders there maybe hypercalcuria even when calcium intake is low(Fig. I). On the other hand, if the urine calciumis low then hyperparathyroidism is virtually ex-cluded.The Sulkowitch test provides a rough but quick

method of estimating the urinary calcium contentand when the extremes of reaction are encounteredis of value for screening purposes. A faint pre-cipitate in a concentrated urine specimen denotesa low calcium content, and makes hyperpara-thyroidism unlikely, whereas a heavy precipitatein a dilute specimen calls for more precise inves-tigations. More information can be achieved byestimating the calcium in 24-hr. urine specimens.When the patient is taking a normal diet, levelsof over 300 mg. are suspiciously high. WVhenestimations are made after the patient has beentaking'a neutral-ash low-calcium diet for five or

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March I958 HARRISON: Metabolic Disorders and Renal Stone I65

six days, values of 150 mg./24 hr. are suspiciouslyhigh and of 200 mg. or more abnormal. Thistest, although elaborate, is of value in mild caseswhen the blood changes are only slight.

Urinary Phosphate Output.-Since this fluc-tuates appreciably with variation in dietary intake,estimations are rarely utilized in diagnosis. Nordinand Fraser (1956) evolved a test which relates theurinary phosphate output to plasma phosphatelevels and the renal clearance of creatinine; ahigh phosphate/creatinine clearance ratio beingfound in hyperparathyroidism. This proceduremay be of help in doubtful cases, thoughMcGeown and Bull (I957) found it of onlylimriited value.

It must be appreciated that the diagnosis ofhyperparathyroidism may not be easy. No singlelaboratory investigation will provide absolute.proof of the diagnosis, which can only be estab-lished after careful interpretation of a number ofinvestigations which may need to be performedrepeatedly.

TreatmentSurgical removal of the adenoma is the only

successful form of treatment.

Differential DiagnosisOccasionally nephrocalcinosis and lithiasis asso-

ciated with hypercalcaemia and hypercalcuriaoccur in sarcoidosis (Longcope and Freiman,I952). Confusion with hyperparathyroidism ispossible, but the plasma phosphorus is not low;other signs of sarcoidosis may be present, and ifdoubt still exists cortisone may be administered,for this reduces the hypercalcaemia in sarcoid(Anderson et al., I954).

Osteolytic metastases and multiple myeloma-tosis can cause extensive destruction of bone, withan outpouring of calcium. When this is rapid theplasma as well as the urine calcium may rise andthe picture mimic hyperparathyroidism.

Renal Tubular AcidosisA disorder characterized by hyperchloraemic

acidosis and nephrocalcinosis may first becomeapparent in infancy, adolescence or adult life. In1936 Butler, Wilson and Farber described theinfantile form, in I940 Albright, Consolazio,Coombs, Sulkowitch and Talbott reported asimilar condition in an adolescent girl whopresented with rickets and dwarfism, and in I945Baines, Barclay and Cooke described it in an adultwho presented with renal colic.Although the infantile type differs in its course

from that appearing in later life the essentialmetabolic disturbance appears to be the same ineach. Following the pioneer work of Albright et

al. (1940) it is now believed that the disorder isdue to inability of the kidney tubules to manufac-ture ammonia and to acidify the urine by theformation of free H + ions. Other renal functions,e.g. the excretion of urea, remain relatively intact.As a result of this tubular defect, excess base,notably potassium and calcium, is lost in the renalexcretion of acid metabolites, and low potassiumsyndromes and osteomalacia may arise. Further-more, the high urinary calcium output and thecontinual neutrality of the urine favour the pre-cipitation of calcium salts within the kidney andurinary tract, so producing nephrocalcinosis or,less commonly, calculi.

Laboratory investigations show a low plasmaC02-combining power, a high chloride and,unless there has been secondary renal damage, anormal blood urea. Plasma calcium is normal orlow, and the phosphorus low; the alkaline phos-phatase is raised if there is osteomalacia. Thediagnosis is established by demonstrating thepatient's inability to excrete an acid urine after theadministration of ammonium chloride.

It is important to recognize this condition, forfurther renal calcification and stone formationmay be prevented by the regular administration ofalkaline salts such as sodium bicarbonate orcitrate.

Idiopathic HypercalcuriaFlocks (I939) found a high urinary calcium

output in a large proportion of his patients withcalcium-containing renal stones. None of thesepatients had a raised plasma calcium or anydemonstrable metabolic abnormality which couldaccount for the increased urinary calcium.Similar findings have been reported by others(Sutherland, 1954; Pyrah and Raper, 1955;Cottet and Vittu, 1955) and it would seem that alarge number of such cases are revealed wheneverurinary calcium estimations are performed as aroutine investigation in stone patients.

Fig. 2a shows the readings obtained in our ownmetabolic department on a consecutive series ofstone patients who did not appear to be sufferingfrom metabolic disorders such as hyperparathy-roidism. If allowance is made for the inclusion ofpatients with renal failure, whose urinary calciumis low, it will be seen that over 50 per cent. excretemore than 300 mg. calcium per day. The availableevidence suggests that only a small proportion ofnormal individuals excrete such an amount, andit was exceeded only once in our few healthycontrols. (Fig. 2b.)The mechanism of this disorder is unknown,

but the association of a high urinary calciumoutput with normal blood levels suggests adiminished capacity of the renal tubules to re-

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i66 POSTGRADUATE MEDICAL JOURNAL March 1958

hrs.600

400

5 lO 15 20 25 30 35 40 246 8 10 12 14 16 1820222426

FIGS. 2A and 2B.-Daily urinary calcium output in 46 stone patients on normal diets (2A) contrasted with a6 healthycontrols (2B). None of the 46 patients had hyperparathyroidism. Cases 23, 24, 32 and 34 had renal failure.

absorb calcium from the glomerular filtrate. Ifan abnormal urinary calcium loss is the only ab-normality, then at least some patients with thisdisorder should be in a state of negative totalcalcium balance and eventually develop osteoma-lacia. Yet although the condition is common inpatients with stone, osteomalacia is not. Possiblythere is an increased absorption of dietary calciumwhich compensates for the high urinary loss, butit seems unlikely that overabsorption of dietarycalcium is the primary dysfunction for, even whencalcium intake is low, the urinary output is stillabnormally high (Fig. i).The distinction between this condition and

hyperparathyroidism may be very difficult anddepends entirely on the blood chemistry-particu-larly on the blood calcium levels.No satisfactory treatment is available. Reduc-

tion of calcium intake will diminish the urinaryoutput in some of these cases, but this measuremay induce a negative total calcium balance withall its attendant dangers. Maintenance of a waterdiuresis will reduce the concentration of calciumin the urine, and this, perhaps, is the only form oftherapy that can be freely advised.

CystinuriaNormally the urine contains only small quan-

tities of cystine, but it has long been recognizedthat certain individuals, often members of thesame family, excrete markedly excessive quantitiesof this sulphur-containing amino-acid and thatsome of them form cystine stones.

Until recently this disorder was thought to bedue to an inborn error, or block, in the metabolismof cystine, which, therefore, accumulated in the

body fluids and spilled over into the urine. How-ever, Dent and his colleagues investigated thisdisorder with new chemical methods, notablypaper chromatography, and have shown that thedefect lies in the renal tubules (Dent, i949; Dentand Rose, I951; Dent et al., 1954a, b). Thetubules are unable to reabsorb cystine and certainother amino-acids from the glomerular filtrate.These other amino-acids are lysine and, in severergrades of the disorder, arginine and ornithine.There is considerable variation in the amounts

of cystine excreted by different individuals withthis disorder, variation which can perhaps beexplained on a genetic basis. Genetical studies(Harris and Warren, I953; Harris, Mittwoch,Robson and Warren, I955) suggest that the dis-order is inherited as a Mendelian recessivecharacteristic and that those individuals whoinherit two abnormal genes, i.e. the recessivehomozygotes, excrete the greatest amounts ofcystine and also the three other amino-acids.Those who are heterozygous either are normal orexcrete smaller quantities of cystine and lysineonly.These studies have also thrown light on the

problem of calculus formation, for it would appearthat stones only form in individuals excretinglarge quantities of cystine, i.e. the homozygotes.Indeed, the work of Dent and Senior (I955) sug-gests that stones only form when the urine issupersaturated with cystine and, furthermore,that when supersaturation is present the in-cidence of calculi is very high.The diagnosis is suggested when there is a

history of bilateral recurrent calculi, oftenbeginning at an early age, or when there is a

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1IarcIh 1958 hI ARRISON: Metatbolic Disorders and Rfnal Stone 167

..S< . ...

-*... .... :...

io I-I N F''

*: JH, | - '

FIG. 3. Spontaneous change in plain X-ray appearances in a patient wsith cystine calculi wNho developed renal failure.(a) October 1951: Blood urea 68 mng. per lo ml. (h) June 1957: Blood urea 120 mg. per ioo ml.

history of calculus formation in siblings. All butthe smallest cystine stones are radio-opaque,though their density to X-rays is less than that ofcalcium-containing stones. Large staghorn cal-culi may form, as well as multiple small stones,and not infrequently they occur together. Whenthere is no stone available for analysis, cystinecan be detected in the urine by the simple cyanide-nitroprusside test of Brand, Harris and Biloon(1930).

7TreatmentDent and Senior, arguing from their simple

theory of the pathogenesis of stones in cystinuria,suggest that further calculus formation will beprevented, and existing stones perhaps dissolve,if the urine can be kept undersaturated withcystine. Cystine output cannot be reduced, butundersaturation can be achieved if the urinevolume is maintained at over 3 1. per day by meansof an increased water intake. It is, of course,necessary to obtain the secretion of a dilute urineby night as well as by day, and this requires thatthe patient cooperate by drinking about I pt. ofwater on retiring. In our own patients the pre-liminary results of this treatment are encouraging,but follow-up periods are too short for any finalassessment to be made.As pointed out by Denit and Seniior, this concept

of calculus formation and treatment is favoured bythe observation that stones may diminish in sizeonce renal failure supervenes, for then not onlywill less cystine be excreted by the glomeruli but,in addition, the kidney will be unable to form aconcentrated urine. This was seen in one of ourpatients (Fig. 3).

In addition to a high-fluid intake, urinaryalkalinizing agents may be given, for cystine ismore soluble in alkaline solutions.

It is generally believed that causal metabolicfactors will be found in only a small proportion ofpatients with nephrolithiasis and, if idiopathichypercalcuria is excluded, this is probably true.Nevertheless, the incidence of such factors mightwell prove higher if biochemical investigationswere invariably part of routine urological examina-tion. It must be admitted that the more elaboratebiochemical tests are time consuming and may callfor the facilities of a large laboratory or even ametabolic ward, but much information can begained from those which are well within the scopeof any general hospital with adequate laboratoryfacilities.

Plasma calcium and phosphorus determinationsshould always be carried out in patients withcalcium-containing stones; the cyanide-nitro-prusside test for cystine can be performed in a few

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minutes in the out-patient department, and evenurine calcium estimations are not too difficult toorganize.

BIBLIOGRAPHYALBRIGHT, F., BAIRD, P. C., COPE, O., and BLOOMI3ER(;,

E. (I934), Amer. J. med. Sci., 187, 49.ALBRIGHT, F., CONSOLAZIO, W. V., COOMBS, F. S.,

SULKOWITCH, H. W., and TALBOTT, J. H. (1940),Bull. Johns Hopk. Hosp., 66, 7.

ALBRIGHT, F., and REIFENSTEIN, E. C. (1948), 'The Para-thyroid Glands and Metabolic Bone Disease,' London: Bailliere,Tindall and Cox.

ALBRIGHr, F., SULKOWITCH, H. W., atnd BLOOMBERG;,E. (I937), Amer. Y. med. Sci., I93, 8io.

ANDERSON, J., DENT, C. E., HARPER, C., and PHILPOTT,G. R. (I954), Lancet, ii, 720.

IBAINES, C. H., BARCLAY, J. A., and COOKE, W. 'F. (1945),Quart. Y. Med., 14, II 3.

13RAND, E., HARRIS, M. M., and BILOON, X. (I930), Y. biol.Chenm., 86, 315.

BUTLER, A. M., WILSON, J. L., and FARBER, S. (1936),Y. Paediat., 8, 489.

COTTET, J., and VITTU, C. (1955), Presse mdd., 63, 878.DENT, C. E. (I949), Symp. Biochem. Soc., No. 3, 34.DENT, C. E., HEATHCOTE, J. G., and JORON, Gi.E. (i54.p0),

Y. clin. Invest., 33, I2I0.DENT, C. E., and ROSE, G. A. (I951), Quart. 7. Med., 20, 205.I)ENT, C. E., and SENIOR, B. (I955), Brit. Y. Urol., 27, 3I7DENT, C. E., SENIOR, B., and WALSHE, J. M. (1954b),Y. c/lin.

Invest., 33, 12I6.FLOCKS, R. H. (1939), Y. Amer. med. Ass., 113, 1466.HARRIS, H., MITTWOCH, U., ROBSON, E. B., and WVARREN,

F. L. (I955), Ann. Human Genetics, I9, I96.HARRIS, H., and WARREN, F. L. (I953), Ann. Eugen. (Camb.),

I8, 125.

KNAPP, E. L. (1947), Y. clin'. Invest., 26, 182.LONGCOPE, W., and FREIMAN, D. G. (1952), Medicine, 31, 1.McGEOWN, M. G., and BULL, G. M. (I957), Brit. med. Butll.,

I3, 53-NORDIN, B. E. C., and FRASER, R. (1956), 'Ciba Foundation

Symposium on Bone StruLcture and Metabolism,' London:Churchill.

NORRIS, E. H. (I947), Int. Abstr. Suirg., 84, 1.PYRAH, L. N., and RAPER, F. P. (09S5), Brit.Y. Urol., 27, 333.SUTHERLAND, J. WV. (09s5), [bid., 26, 22.

UNIVERSITY OF GLASGOW AND ROYAL FACULTY OF PHYSICIANS AND SURGEONSPOSTGRADUATE MEDICAL EDUCATION COMMITTEE

CONFERENCE ON NEOPLA SLAA specialist conference on Neoplasia will b- held in the Royal Faculty of Physicians and Surgeons, 242 St.

Vincent Street, Glasgow, C.2, from the 26th to the 28th of March, 1958. The conference is open to all medicalpract.tioners. The programme is as follows:

WEDNESDAY, 26th MARCH, 1958 Speakers Choir9.45 a.m. Inauguration10.00 a.m. FUNDAMENTAL BIOLOGY AND CONCFPTS J. N. Davidson, P. R. Peacock, R. J. C. Harris Protessor S. Alstead

OF NEOPLASIA (London)2.00 p.m. ENDOGENOUS CANCER B. D. Pullinger Mr. Arthur Jacobs2.45 p.m. OCCUPATIONAL CANCER A. T. Doig

THURSDAY, 27th MARCH, 195810.00 a.m. MEDICAL PROBLEMS IN NEOPLASIA A\. R. Curric, R. I. Shaw Duinn, A. Brov n 'rtoessor L.. .l. l)avis

HORMONES IN NEOPLASIA2.00 p.m. (a) Breast cancer A. P. M. Forrest l'rolessor- T. Syninlgtio2.45 p.m. (b) Prostatic malignancy W. B. Stirling

FRIDAY. 28th MARCH. 1958REGIONAL NEOPLASIA

10.00 a.m. (a) Carcinoma of liver J. W. Orr (Birmingham) Protessor W. A. Mackey11.15 a.m. (b) Carcinoma of stomach C. F. W. Illingworth2.00 p.m. (c) Carcinoma of thyroid E. M. McGirr Professor E. J. Wayne2.45 p.m. (d) Carcinoma of lung R. S. Barclay

There is no fee for the course. There will be an informal Conference Dinner on Thursday, 27th March, at7.00 p.m. for 7.30 p.m. Tickets, inclusive of wine, are £1. Further particulars may be had from the Registrar,Royal Faculty of Physicians and Surgeons, 242 St. Vincent Street, Glasgow, C.2.

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