The Management of Cystinuria and Cystine-Stone Disease

THE JOURNAL OF UROLOGY

·Vol. 81, No. I, January 1959 Printed in U.S.A.

THE MANAGEMENT OF CYSTINURIA AND CYSTINE-STONE DISEASE DONALD R. SMITH, FELIX 0. KOLB AND HAROLD A. HARPER From the Departments of Surgery (Urology), Medicine, the Metabolic Unit for Research in Arthritis and Allied Diseases, and the Surgical Research Laboratories, University of California School of Medicine, San Francisco, Cal.

Cystinuria is a renal tubular defect that occurs in 0.2 per cent (1: 500) of the population (Lewis). Cystine stone disease is rare, however, and accounts for only 2 per cent of all renal calculi. N everthdess, stone formation in patients with cystinuria (and in their relatives) is quite common (Harris and Warren). Stones that develop in children are often composed of cystine. If these calculi continue to form, the eventual outcome may be loss of renal function from infection, hydronephrosis or the formation of staghorn stones. N ephrectomy may then become necef'sary. In contrast to the older concept that cystinuria is due to an "inborn error of metabolism" (Brand and associates, 1935; Freudenberg) (fig. 1), it is now generally believed that in patients with cystinuria the renal tubule is congenitally defective, insofar as the reabsorption of cystine, lysine, arginine and ornithine is concerned. All other amino acids, however, are handled in normal fashion (Dent and Rose; Dent and associates, 1954; Kolb and Harper; Stein and associates) (fig. 2). This is quite different from the rare (1 :40,000) Lignac-Fanconi syndrome (Bickel and associates, 1952; Bickel and Thursby-Pelham) in which generalized amino-aciduria is found (Harper, Grossman, Henderson and Steinbach). Other signs of this latter disease include glycosuria, phosphaturia, loss of base, rickets, nephrogenic diabetes insipidus and, finally, the storage of cystine in tissues (cystinosis). There is no evidence that cystinuria and cystinosis are related; the latter, however, is a stage in the FanconiLignac disease (Bickel and associates, 1952; Bickel and Thursby-Pelham) (fig. 3). Since cystine is the only amino acid that is insoluble at the normal pH ranges of urine, formation of stones can occur; only then does cystinuria become clinically important. The higher the cystine excretion, the more likely it is that stones will form (Harris and Warren; Harris and Robson, 1957). Attempts to increase Read at annual meeting of Western Section of Ameri()an Urological Association, Inc., Palm Springs, Cal., February 3-6, 1958.

solubility of cystine by alkalinization, or to decrease its concentration by forcing fluids, have not been entirely satisfactory, especially in patients with severe cystinuria (Dent and Senior). The results of measures designed to decrease cystine output by chemical means, such as choline (Coxon and Kolb; Zinsser) or by low protein diets (Dent and Senior; Doolan and associates, 1957) have not been too encouraging. The demonstration that methionine in dietary proteins is the principal source of exogenous cystine (Brand and associates, 1934 and 1935) has led us to the trial of a low-methionine diet in 2 patients with severe cystinuria in whom simpler measures had failed to stop stone formation. Our experience with the problems relating to the diagnosis and treatment of a group of cystinuric patients forms the basis for our observations and conclusions concerning the management of cystinuria. DIAGNOSTIC CONSIDERATIONS

History. Any patient who has passed renal stones in childhood, who has many recurrences, or who has a family history of renal stones should be investigated for cystinuria. All relatives of a patient with cystinuria, as far as possible, should also be screened, since new and unsuspected cases of this defect may be found. The disorder is inherited as a recessive (complete or incomplete) trait; yet if the trait is present on two sides of the family, several members will form stones (Harris and associates, 1953 and 1955). One of our patients had 11 relatives with cystinuria (fig. 4); only those with strongly positive tests, however, are likely candidates for stone formation and must be watched. There are no physical stigmata in the cystinuric; apart from formation of renal stones, he lives a perfectly normal life, and does not suffer deficiencies from the urinary losses of cystine, lysine, arginine or ornithine. Examination of the 11.rine. Search for cystine crystals: The presence of typical, hexagonal, "benzene-ring" crystals is diagnostic of the disease. These crystals are often difficult to find 61

62

SMITH, KOLB AND HARPEH OXIDATION

METHIONI N E""7HOMOCYSTEINE~ CYSTATH ION IN E~CYSTEI N E-t+H> SULFATE

L

CYSTINE BRAND !935 FREUDENBERG /949

~

/

CYSTINURIA

CYSTINOSIS

(ADULTS)

(CHILDRE.N)

''METABOLIC" THEORY OF CYSTINURIA AND CYSTI NOSIS

FIG. 1 2050

0 1000

800

URINE

MG/24°

600

400

Pt. J.Q NORMAL UM/TS

FIG. 2. Patient J.Q. Note normal plasma levels of all amino acids, with greatly increased urinary excretion of arginine, cyst(e)ine, and lysine (cystine and cysteine are determined together). Ornithine is not measurable by this method.

in dilute or alkaline urine. If glacial acetic acid is added (which drops the pH to about 4) and the urine is allowed to stand in a wide-bottomed flask in the icebox overnight, crystals can often be found in the centrifuged sediment. If cystine crystals are found in the microscopic examination of a specimen of alkaline urine, the patient must be extremely cystinuric. The nitroprusside test on urine: This simple office test is most helpful as a screening proce-

dure. * It is not entirely specific for cystine (acetone, and certain drugs may give positive results) but if the results are found to be strongly positive in a stone-former, cystinuria is strongly suggested. vVeakly positive reactions, or reac-

* To about 5 cc urine add a few drops of concentrated ammonium hydroxide, then acid 2 cc of a freshly prepared 5 per cent sodium cyanide solution and mix. Wait for five to ten minutes, then add by drops a freshly prepared solution of 5 per cent sodium nitroprusside. A deep purplish color is a positive result for cystine.

CYS1'INUilL\. .AND CYSTINE-STONE DISKlcSE

1: 500 RENAL DEFECT

I: 40,000 RENAl + '? METABOLJC DEFIIH::r

sJ,, CYSTINURIA

"'

NO

LYSINURIA ARGININURIA ORNITHINURIA

~ANC:ONI - llGNAC GEN. AMINO-ACIDURIA

GLYCOSURIA PHOSPHATURIA LOSS OF BASE

-z. 0

I CYSTINE

2° RENAL

ACIDOSIS NEPHROGENIC DIABETES INSIPIDUS

CALCULUS

l

(AlKALl/\1£ URINE.)

NO IM PAIRMENl' --H+-~

--·--i

CVSTIINOS!S CYST!:_ STORAGE

MECHANISM Fm. 3. Present arc entirely different

OF

AMINO -ACIDURIAS

of mechanism of amino-acidurias. Cystinuria ,md Lignac-Fanconi syJ1drome

FAMILY

8

D~SEA5E-

@

STRONGLY POSITIVE WEAKLY POSITIVE

0

NEGATIVE

TREE

OF

H. S .

NT NOT TESTED + DECEASED

:FxG. 4. Family tree of one of om· paLients. Eleven relatives were fonlll! to excrete ahnonrrnl n.rnouni.s of cystiJJe.

tions 1Yith fading colorn, must be confirmed by chemical procedures. Paperchromatogrnphy has been employed extensively by others (Dickel and associates,

Hl52; Dent and 1054) 1Ye havt'. J1ot used it in our cases, since otlwr wen, available to us. Quantitative tt·sts: The treatment of the

64

SMITH, KOLB AND HARPER

cystinuric depends on the severity of his rnnal defect. We believe, therefore, that a quantitative assay of the cystine excretion is essential. We have used the estimation of the amount of alphaamino nitrogen, found in a 24-hour specimen of urine, as an assay of the degree of aminoaciduria, and the microbiologic assay for cystine (Harper, Hutchin and Kimmel) as a specific and quantitative test for cystine output. Others have utilized the nitroprusside reaction (Coxon and Kolb), column chromatography (Stein; Yeh and associates) or polarography (Dent and associates, 1954; Dent and Senior). These procedures are not simple but they are essential in the evaluation of the efficacy of therapeutic measures. 1) Alpha-amino-nitrogen (Van Slyke and associates). This test is performed on a 24-hour specimen of urine; a few thymol crystals arc added to the bottle to prevent bacterial contamination. Normal people excrete about 1 mg. per pound (up to 150 mg. per 24 hours). If the results of this test are positive, we do a cystine assay as well. 2) Cyst(e)ine assay (Harper, Hutchin and Kimmel; Hutchin and associates). (Cystine and cystcine are determined together in this method.) TABLE

,V

c perform the rnicrobiologic assay on a 24hour spe6mcn of urine. The patient should not be taking antibiotics, since the test depends upon bacterial growth. One ml. of concentrated hydrochloric acid per liter of urine is added as a preservative. Thymol or other chemicals must be avoided. Normal people excrete up to 80 mg. of cystine in 24 hours. ::VIilcl cystinurics excrete about 200 to 400 mg.; moderate cystinurics excrete 400 to 1000 mg. Two of our patients, each of whom had a kidney removed because of the formation of staghorn stones, usually excreted between 2000 and 3600 mg. of cystine a day! The amounts of lysine and arginine roughly parallel the amounts of cystine found in the urine (table 1). Roentgenologic examination. Despite many reports to the contrary, cystine stones do cast shadows that are visible on roentgenograms (fig. 5,:1). This is not due to contamination by calcium, since most cystine stones are pure (vVatson) but to the content of sulfur, and to the fact that the specific gravity of these stones is greater than that of surrounding soft tissues. Cystine stones arc smooth; are often multiple and faceted; and may coalesce to form staghorn masses. They

1. Laboratory findings beforn lrea,tmenl in four patients with cyslinuria

---------~--------------------··----------Urinary Excretion in mg. per 24 Hrs.

Crystals Observed

Case Case Case Case

1 2 3 4

Q.U.I... C.A.W .. R.O.S .. S.C.H ..

Yes Yes No Yes

N itroprussidl' Test

Positive Positive Positive Positive

Alp~ia amino I Cystine mtrogen --~~ ---~-

444 444 185 220

2880 2740 586 1472

Lysine

Arginine - - · - -

3070 2050

4386 1672

3180

708

---~--

Fm. 5. A, plain film. Typical, multiple, homogeneous, faceted cystine calculi, which resemble gallstones. B, plain film. Stone in lower pole is homogeneous, round, and has low density typical of cystine. Staghorn calculus has a core of pure cystine and calcific deposits on its periphery.

CYSTTN1:IUA AND CYSTINFJ-STON1, DISEASE

hek the lamination of cakimn-phosphatc calculi, which also comnwnl.,- form coralifonn storws. Cystine stones are not as de11sc as stones composed or calcium phosphate and calcium oxalate, but seconda.r_l' clqiosition of calcium on c:ystim: can at tinws be seen (fig. 5, B). Stones composed of magncsimn ammonium phosphate may at times umse confusion ])Pc:.tuse thC'ir density is closer to L:ystinc than to that of calcimn. The rndiogrn1n is a valuable guide to therapy, since cystine stone's may decrease: i11 size or even disappear if dfoctive therapy is instituted (Crowd!; Dent and Senior) in our c:mw C.A.W.). Formation of calcium stones that may be caused by snperimposl:cl infr:ction may also be detected. stones may reform very rapidly in seve,rc cystinurics. J1,':wm1:nati:on of stones. 1Yhcn stones an, avail11hlc for examination, tlic diagnosis is simple. The typical )'Cllowish, smootL, multifaceted stone permits diagnosis at a glanc:e,. We urge our patients to bring in any stones previously. A roentgenogram is then taken of them on dental film in order to evaluate the clensit)' and homogeneity of the stom· ..\ portion of the stone is tlwn dissolved in strong ammonium hydroxide and the nitroprussidc test ic; clone. Once dissolved, crystals can also he produced by l0vvering the pH to 4 with glacial acetic: (not hydrol·hloric !) and placing the urine in the icebox overnight. Alt.hough auy one of the foregoing proc:eclures ma)· gin: the correct diagnosis, we do all of them so tlmt we c.an classify the patieut with regard to the SC\"erity of his tubular ddect ..-\ppropria.te tlwrnpy cn11 thr11 he institnteel. These, tests are nlso u:,ecl to rheck upon the lefficac:y of treatment. TfIJSHAPJ,UTTC COK.SI DERATJONS

Although removing an obstructing stone is import.ant, cn,u more· important is the need for institution of measures clesig1wd to pre,-ent the formation oJ new stones Urologic treatment. If a patient lms a stone that is causing ureteral obstruction, lw should be treated 1.u:c;ording to urologic. principles. Almost all un,teml stones will pass spontaneously but a few will require manipulation or surgicnl removal. It is wise to postpone the surgical removal of asymptom:i.tic e:ystine stones until an dfoc:t.ive tlwrapeutic reginwu Jin$ bP(-;t1 instituted, sine;;

the patient with uncontrolled eystiunria can form new stones rapidly.

Cystoscopic manipulation carries the ri~k ol introducing infoction by urea-splitting which may cncol!l'agc the eoprccipitation of calcium or magnesium salts. Ultraconservatism is further i11clicatcd beca11sc in a few instances it has lwe,n observed tlwt cystiuc stones may dPu·ea.sc· in sizu wit] 1 effcc.tivL· treatment, or may pass spontaneously, 01· c,-eu dissolve. J{edical treatment. :\Iedicul rneasmw,, apart from routine treatment for stones and nrinary tract infoction, that are dr:signecl to help th(' patient with cystinuria must either I) decrease the cystine c:onccntrntion, 2) increas<, the wiJn .. bility of c.\'Stinc: or :3) dec:rease the nrinary rxcrc., tion of cystine. At times all three steps are required to treat a patiC'nt with ,c;evere adequately. l\Iany measures han: lJ,:cn in the past wliich have had variable success (Dmt and Senior; Weinberg ancl Tabenkiu) Of t.lwse, only forcing fluids and alkalinization hav(: tmquestionabk merit (Dent and Senior; Hanis and Robson, 1957). ,Ve will relate onr with dietary mcastues as well. Since the daily output of eyst.inc: in the, incli vidu:tl patient fluctuates wide:l.r (Coxon :ind Kolb; Dent ancl Se:nior), therapeutic. claims mi.wt be preceded by sevcn.11 clctermirmtions of cystirn: exnetion before thernpy is beguu. This pnwcdttn· will e:stablish the patient's case as one of mild, modcrn.te or severe cystinmia and will nmkc rational treatment possible. 1) :\foasures clcsignecl to rc·clucc cvstinc conc.entrntion: Forcing of fluicls: As in the treatment u r all types of stones, forcing of fluids rnmains the most effective way of treating patients who form cystine stones, and for preventing stone fornmtiou in the patient with asymptomatic cystirrnria. The studies of W
66

SMITH, KOLB AND HARPER

patients with cystine outputs of much more than 1000 mg. (e.g. our cases Q.U.I.and C.A.W.),merely forcing fluids alone, then, is not sufficient. \Ve advise our patients to have fluids available at all times and to increase the intake during periods of fever or dehydration, when parenteral fluids may have to be added. Drinking two glasses of water at bedtime and again between bedtime and arising is also helpful, although inconvenient (Dent and Senior). 2) Measures designed to increase the solubility of cystine: a) Alkalinization: The known solubility of cystine at alkaline pH ranges is the basis for the use of alkali. Inspection of the solubility curve demonstrates that to be effective, alkalinization must be raised to a pH of 7 .5 or more to increase the solubility materially (from about 400 mg. to 600 mg. per liter) (fig. 6). It is perhaps more important to avoid prolonged acid pH ranges. The use of alkali in the form of 50 per cent sodium citrate, sodium bicarbonate, or the sodium-potassium citrate solution designed by Eisenberg and associates is feasible.* Alkalinization at night again is a problem; an extra dose of alkali must be taken with extra fluid at 2 a.m. by the severe cystinuric. There are potential hazards in therapy with alkalines. The high sodium intake may be dangerous in patients with cardiac or renal failure; a high potassium intake may be contraindicated in renal failure. Furthermore, a constantly alkaline urine predisposes to the formation of calcium or magnesium-phosphate stones. When we institute alkalinization we restrict milk and cheese in the diet, and check the calcium and phosphate excretion. \Ve prescribe amphogel, when necessary, to reduce phosphaturia. Alkalinization by the use of diamox has been unsuccessful, since this drug cannot maintain an alkaline pH for a prolonged period of time (Leaf). b) Other measures: Although the presence of large amounts of cystine is a necessary factor in the formation of stones, it is not the only one. At times, in spite of large amounts of cystine in the urine, stones do not form. Dent and Senior cite as an example a species of wild cat that excretes large amounts of cystine without ever * Citric acid 70 Sodium citrate 98 Potassium citrate 108 Syrup base, non-alcoholic, q.s. ad 1000 Sig: 20-30 ml. q.i.d.

1,000

800

600

400 >-

~

>-

u

200

5. 0

6.0

7.0

8 .0

pH

Fm. 6. Solubility curve of cystine in urine depending upon pH (from Harris, H. and Robson, E. B.: Cystinuria, Am. J. Med., 22: 774, 1957).

producing stones. Sonie type of complexer must be present to prevent its precipitation. We have tried salicylamide in 2 patients for reasons used by Prien and Walker in patients with calcium phosphate stones, but like Pricn we cannot evaluate its effectiveness with certainty. \Ve have no personal experience with such agents as naphthalene and ascorbic acid (Dent and Senior). If cystine could be converted into cysteine or into a soluble complex, formation of stones might well be prevented. 3) Measures designed to decrease the urinary excretion of cystine: Lack of a clear understanding of the exact nature of the defect causing cystinuria has made practical approaches designed to decrease the cystine output difficult. For many years a "metabolic block" in cystine metabolism was postulated by Brand to explain the fact that cystine itself, fed to a cystinuric would not increase his excretion of cystine in the urine, though methionine and cysteine would do so. \Ve have repeated these experiments in one of our patients (Q.U.I.) and have had similar results (fig. 7). A better explanation of this peculiarity, however, is based upon the insolubility of cystine in the gastrointestinal tract. This is confirmed by our observation that after feeding cystine to a patient the amount of cystine in the blood did not increase although it did increase after feeding cysteine, which is quite soluble (Kolb and Harper).

CYS'rINUIUA AND CYST[NE-STONE DISEASFi Pt.

.I. Q

CYSTINUR.IA 0

D-L METHION!NE 6GM

1- CYSWNE 5GM

1-CYSTINE SGM

'1'

~

t

3000

0

¼ __

10/\6-17

--=

--=

II~

_A\:'EJ<~~L CONTROL

- -NORMAL- - -

10/23-24 10/30-31 DAYS

Frn. 7. Patient .T.(~. Average urinary excretion level was 1800 mg. in 24 hours. Effect of feeding methionine, cysteine, and cystine on urinary excretion of cystine is illustrated.

At prcsf,nt the ('.oncqit that the cystinuric has a specific rcmd, tubular, rcabsorptive defect of varying degree for lysine, arginine and ornithim· seems to explain most of the findings. Since the defeet seems to be: virtually complck for eystinc, approaching the c:learance of creatinine (Doolan and associates, 1956 and 1957), it is unlikely that any practical measure can hr found that will enhance tubular reabsorption of cystine and thus prevent stone formation. The cystinuric, most likely "cures" his defect only when, with advancing renal failure, the glomernbr filtration of diminishes. Yet there arc spontaneous, wide fluctuations in output that am not fully explained, and there an, periods of several years during which the patient may be stone-free . Daily variations in excretion are probably due to differences in intake of dietary proteins that contain methionine (and cysteine). Since the principal precursor of urinary cystine is nwthioni nc (Brnnd ,md J934 and 19:).'i), attempts have: been made to prevent endogenous breakdown of methionine by the use: of such agents as choline and betaine (Doolan and 1957; . These agents have bec:n studied carefully and have shown no signifcant reduction in output (Coxon and Kolb; Doohtn and 1957). Another approach has been the n,strietion of ingested proteins by the use of diets very low in protein, and rice diets. Although advornted often (Andrews; and · ~\Iir,l1els and Engel), the placu of snch diets has not been fully eval-

('""'.'

lll

uatccl. The effect of low-protein as judged by clccrcascs in the amounts of cystiur cxcn-tcd by rnoderatdy severe eystinurics, has not been striking (Dent and Senior; Doolan alld 1957). Restriction of all proteins, espPcially m c,hild (such as Dent's patient), might have C'fr· hanced endogenous breakdown of protein a.ncl thus would have accomplishf'd little in the way of reducing the urinary output of Sine,' in patients with eystinuria the e.,senti:i.l am11H1 acid, lysine, is excreted in large amounts as 1n\l! as is cystine, the long-term use of suc:h lcmprotein diets might be hazardous. A further eonsidcration is the unpalatability of the did. Two of our patients (table 2), who excreted between 3000 and 3600 mg. of per '24 hours, could not be controllr:d by alkalinization and forcing of fluids alone. One of them contimtccl to form stones. ,Ye,, therefore, decided to as
* We are indebted for the design of this ,liet Lo J'\!Irs. IL H. IVIochizuki, B.S., chief tlieLitiau ,\fot.:i bolic Unit, University of Cnliforuia. of

l\1edicine_

68

SMITH, KOLB AND HARPER

TABLE 2. E.f}'ect of low methionine diet on 1,rinary excretion of alpha amino nitrogen, cystine, lysine, and arginine Urinary Excretion in 24 Hrs.

Dietary Regimen

Alpha amino

I

Cystine

nitrogen (normal 40-80 (normallSOmg.). mg.)

Lysine (normal 12-20 mg.)

Arginine (normal 10-15 mg.)

Patient C.A.W. mg.

Regular diet 12-8-55. 7-2-56 2 new stones . Low methionine diet started 8-14-56 9-7-56 3-19-57 stones smaller. 7-31-57 one stone dissolved, one stone passed.

mg.

mg.

mg.

444 400

2740 3600

2050

1672

320

1225 1163 639

1987 3070 1890 2870 1800 2100

1656 4386 1800 1950 2950 3150

Patient Q.U.I. Regular diet 6-3-55 ... 11-4-57 .. Low methionine diet 12-16-57. 12-28-57 .. Regular diet 1-18-58. High fish protein diet 2-2-58. Low methionine diet 2-24-58. SUMMARY vV e have related our experience in the management of patients with cystinuria. The practical measures available for diagnosis and treatment of this disorder have been critically evaluated. We have stressed the importance of seeking potential stone-formers among the relatives of our patients. vVe believe that the treatment of every patient with cystinuria must be individualized, and that the quantitative excretion of cystine is the basis for rational therapy, as well as for judging prognosis. Although mild cases can well be treated by forcing fluids alone or by the addition of alkalinization, in severe cases the institution of dietary measures to reduce the intake of sulfurcontaining amino acids (methionine, cysteine) must be given serious consideration. The results of such treatment are most encouraging. The importance of proper followup observations is stressed. REFERENCES ANDREWS, J.C.: The place of cystinuria in human disease. North Carolina M. J., 13: 186, 1952. BICKEL, H., BAAR, H. s., ASTLEY, R., DOUGLAS, A. A., FINCH, E., HARRIS, H., HARVEY, C. c., HrcKMANs, E. M., PnILPOTT, JVI. G., SMALLwooD, W. C., SMELLrn, J.M. AND TEALL, C.

448 444 335 296 452 424 314

1325 2880 798 520 2380 4172 1010

G.: Cystine storage disease with aminoaci-

duria and dwarfism (Lignac-Fanconi disease). Acta Paediat. (Suppl. 90) 42: 1-237, 1952. BrcKEL, H. AND TnuRsBY-PELHAM, D. C.: Hyperamino-aciduria in Lignac-Fanconi disease, in galactosaemia, and in an obscure syndrome. Arch. Dis. Childhood, 29: 224, 1954. BRAND, E., CAHILL, G. F. AND HARRIS, M. M.: Cystinuria: the metabolism of cystine, cysteine, methionine, and glutathione. J. Biol. Chem., 109: 69, 1935. BRAND, E., CAHILL, G. F. AND HARRIS, M. M.: Metabolism of various sulfur compounds in cystinuria. Proc. Soc. Exper. Biol. & Med., 31: 348-349, 1933-1934. BRAND, E. AND CAHILL, G. F.: Further studies on the metabolism of sulfur compounds in cystinuria. Ibid., p. 1247. CoxoN, V. AND KoLB, F. 0.: The use of oral choline in cystinuria. Metabolism, 3: 255, 1954. CROWELL, A. J.: Cystine nephrolithiasis: report of a case with roentgenographic demonstration of disintegration of stone by alkalinization. Surg., Gynec. & Obst., 38: 87, 1924. DENT, C. E. AND RosE, G. A.: Amino acid metabolism in cystinuria. Quart. J. Med., 20: 205, 1951. DENT, C. E., HEATHCO'l'E, J. G. AND JoRoN, G. E.: The pathogenesis of cystinuria. I. Chromatographic and microbiologic studies of the metabolism of sulphur-containing ammoacids. J. Clin. Invest., 33: 1210, 1954. DENT, C. E., SENIOR, B. AND WALSHE, J.M.: The pathogenesis of cystinuria. II. Polarographic studies of the metabolism of sulphur-containing amino-acids. J. Clin. Invest., 33: 1216, 1954. DENT, C. E. AND SENIOR, B.: Studies on the treat-

CYSTINURIA AND CYSTINE-STONE DISEASE

ment of cystinuria. Brit. ,l. U rol., 27: 317, Hl55. DooLAN, P. D., HARPER, H. A., HuTCHIN, lVl. E. AXD AL PEN, E. L .. The renal tubular response to amino acid loading. ,J Clin. Invest., 35: 888, l\J56. DOOLAN, p D., HARl'J
GU

KmsELL, L. W.: Microbiological deterrnim.1tion of cystine, cysteine, and glutathionc in plasma. J. Biol. Chem., 185: 839, l\l50. KEYSER, L. D. AND SMITH, C. D.· ClinicnJ ma.n-agement of cystine lithiasis. J. Urnl., 62: 807. 1949. KoLB, F. 0. AND HARn:R, H. A.: The amino <1cid pattern i11 cystinuria. Cliu. Res. Proc .. 2: 142, 1954. LEAF, A.: Personal communication. LEWIS, H. B.: The occurrence of cvstinuria in healthy young men and womerr~ J\1111. JnL. Med., 6: 183, 1932. J\'hcHELS, A. G. Al,D ENGJDL, W. J. · na and cystine calculi. Cleveland Clin. Quart., 17: 80. 1950. PRIEN, E.. L. AND WALKER, B. S .. SnJicylamid~, and acetylsalicylic acid in recurrent uruli-thiasis. J.A.lVI.A., 160: :155, Hl56. PRIEN, E. L.: Personal communication. PRAKKEN, H.: A case of congenitnl cystinuriu.. ,J. Pediat., 40: 186, 1952. STEIN, W. H.: Excretion of ami,10 acids in cy,otinuria. Proc. Soc. Exper Biol. & Med.; 'UL 705, 1951. VANSLYKE, D. D., MAcFAY!JEN, D. AND HAM!lr TON, I'. B.: The gasometric determirrntion of amino acids in urine by the ninhnlrin-ca.rbou dioxide method. J. Biol. Chem., 150: 251, 9,i;J WATSON, J. H. L.: Electromicroscopy of a cystme urolith. J. Urol., 75: 940, 1966. WEINBERG, S. R. AND TABENKlN, l'. A. Ob,;er vat.ions on therapy of cystine calculus dis ease. Arch. Int. Med., 90: 860, I\J52. YEH, H. L., FRANKr,, vv., Dt:NN, J\L s., PARKEH, P., HUGHES, B. A.'ID GYiiRGY, P.: The excretion of amino acids bv a cystimnic su ject. Am. J.M. Sc., 214: 507, 1947 ZrnssER, H. H.: The effect of oral choliue in reducing cystine excretion in cystinuriu.: n report of two cases. ,J. Urol., 63; !JW, 1%0.

70

SMITH, KOLB AND HARPER

APPENDIX

Low Methionine Diet Amount

Meal Plan Grams

Sample Menu

Measure

Breakfast 200 100 30 15 25 15 15

1 cup

½ cup 1 slice 1½ pat 2 tsp. 1 tbsp. 1 tbsp.

Fruit juice Fruit Toast Butter Jelly Sugar Beverage Cream

Orange juice Applesauce Whole wheat toast Butter Jelly Sugar Coffee Cream

Lunch 200 85 200 240* 15 15

1 serv. 1 serv. 1 cup 8 oz. 3 tsp. 1 tbsp.

Soup Sandwich Fruit Soy milk Sugar Cream Beverage

Vegetable soup, vegetarian Peanut butter sandwich Canned peaches Soy milk Sugar Cream Coffee or tea

Dinner 60 100 100 100 15 30 200 15 15 15

2 oz. 1 med. ½ cup 1 serv. 1 tbsp. 1 slice 1 serv. 1 tbsp. 1 tbsp. 1½ pat

Meat Starch Vegetable Salad Dressing Bread Dessert Sugar Cream Butter Beverage

Chicken, roast Baked potato Artichoke Sliced tomatoes French dressing Whole wheat bread Fruit ice Sugar Cream Butter Coffee or tea

* Optional-use in children to increase protein intake. Omit if urine calcium is elevated in adults.

CYS'rINURL\ AND CYS'I'IKE-STONJ£ llISK\.SE

-------·-------

-------------- - - - ---- - - - · -----

Foods allowed ----- ---------------------

----------

Salads· Cercmls Breads: ;-,,;-u1.s: Desserts: Concentratecl swcr,ts: Concentrated fats: Miscellaneous.

Any soup made without meat stock or addition of milk Peanut bl1tter sandwich, spaghetti or macnroni clish made "-ithout, adclition of meat, cheese, or milk One scrning per day: chicken, lamb, veal, beef, pork, crab, or bacon (;5 s1 rips) Soy milk, tea, coffee Asparagus, artichoke, beans, beets, ca.rrots, chicor.r, cucumber, eggpla.nC, escarole, lettuce, onions, parnnips, potato, pumpkin, rhubarb, tomaloes, turnips Apples, apricots, banana, berries, cherries, fruit cocktail, grapefruit, grapes, lemon juice, nectarines, oranges, peaches, pears, pine:Lpple, plums, tan gerines, watermelon, cantaloupe Raw or cooked vegetable or fruit salad Macaroni, spaghetti, noodles -whole wheat, rye, white Peanuts Fresh or cooked fruit, ices, fruit pies Sugar, jams, jellies, sirup, honey, hard candies Butter, oleomarga.rine, cream Pepper, mustard, vinegar, garlic, oil, various herbs and spices

Soups: Meat or meat substitute Vegetables: Eggs: Cheese. Nuts: Beverage: Fruits:

Rieb meat soups, broths, canned soups made with meat broth Fish and those not listed above Those not listed above In any form All varieties All varieties, except, peanuts Milk in any form Those not listed above

Soups: J\;leat or meal, substitute:

Bevernges: Vegetables:

Frnits:

Foods not a,llowcd

REFERENCES

R ..J. AND WEISS, K. W.: Amino Acid Handbook. '\fothods and Results of Protein Analysis. Springfield, Ill. - Charles C. Thomas, 1956 . •foHNSON, HARRY J.: Bridges' Dietetics for the Clinician, 5th eel. Philadelphia, Pa.: Lea & Feliiger, J \l--h\l. LY:VIA:>T, C. l'll. AND KuKE1'i, IC A.: The amino acid composition of meat and some other foods. l. ,\r ginine, histidine, iwleucine, leucine, lysine, methionine, phenylalanine, threonine, l,ryp(opkrn a.ncl valine. Texas A.griculiurnl Experimental Station Bulletin No. 708, 1949. WERTZ, A. \V., RUT'l'ENBERG, P. K., :FRJ<~NCH, 0. P., l\1uRPHY, G. H ..'I_ND Gi_;rLn, L. P.: Amino neid contents of food. J. Arn. Dietetic Assn., 32: 926-928, 1956. BLOCK,