Homozygous Cystinuria—Evaluation of 35 Patients

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HOlVIOZYGOUS CYSTINURIA--EVALUA WILLIAM P. EVANS, MARTIN I. RESNICK*

AND

I\ rr,IEl"'FTIQ P ft.l .i.'i l u

WILLIAM H. BOYCE

From the Department of Surgery, Section of Urology, Bowman Gray School of Medicine, Winston-Salem, North Carolina

ABSTRACT

We discuss the characteristics of 35 patients with cystinuria, which is a medically treatable disease. A successful stone dissolution rate of 55 per cent was observed. Most treatment failures were related to urinary tract infection, poor patient compliance or the presence of associated nondissolvable stones. Surgical intervention usually was required in these patients. Cystinuria is an autosomal recessive inherited disorder that affects amino acid transport of the epithelial cells of the renal tubule and gastrointestinal tract. 1 Cystine, lysine, arginine and ornithine are present in increased amounts in the urine, and were it not for the low solubility of cystine the disorder would be of no clinical import. Approximately 1 in 20,000 of the general population are affected with the disorder and, although patients in whom cystine stones form comprise only 1 to 4 per cent of all patients with urinary stones, cystinuria remains a dilemma to the clinician because of management problems and frequency of recurrent disease.2· 3 In an effort to assess our experience in patients with homozygous cystinuria all individuals with this disorder evaluated at our hospital from 1965 to 1980 were reviewed. Data obtained were related to the characteristics of the patient population, previous therapy, and effectiveness of medical and surgical treatment programs.

patients (45.7 per cent). Of this group all but 1 had a history of stone disease in either a brother or a sister. The father of the remaining patient was known to have had cystine stones. Two patients had children who had had stones. Both of these patients had been evaluated previously and had been found to have had calcium oxalate stones. At evaluation 15 patients (43 per cent) had roentgenographically confirmed urolithiasis. Of these 15 patients 3 had bilateral disease. One patient with a solitary kidney had a complete staghorn calculus. Staghorn calculi were present in 6 patients, 2 of whom had bilateral disease. Of the 35 patients routine urinalyses were abnormal in 23 (65.7 per cent), with the most common finding being that of microscopic hematuria or pyuria. Cystine crystalluria was relatively uncommon and was present in only 6 patients (17.1 per cent). Proteinuria based on urinary dipstick testing was present in more than half of the patients evaluated but its presence usually was associated with urinary tract infection and pyuria. Quantitative amino acid analysis of 24-hour urine specimens demonstrated elevated urinary excretion of cystine, arginine, ornithine and lysine. Cystine excretion averaged 884.2 mg_/24 hours (range 551 to 2,200) for male and 1,100.9 mg./24 hours (range 675 to 1,922) for female patients. Most patients excreted between 500 and 1,000 mg. cystine per day (72 per cent for male and 64.7 per cent for female patients) and only a minority excreted > 1,000 mg. per day (28 per cent for male and 35.3 per cent for female patients). No patient excreted <500 mg. cystine per day. All patients underwent stone analyses. Of the 35 stones analyzed 19 were pure cystine; 9 were a combination of cystine and magnesium ammonium phosphate; 4 were cystine, calcium oxalate and calcium phosphate, and 3 were cystine, magnesium ammonium phosphate, calcium oxalate and calcium µ11,u,c,µ1J.cwe. Urine bacteriologic studies showed that a third of the patients (34 per cent) had associated tract infection at evaluation (table 1). Gram-negative organisms in male and female patients, and >50 per cent of these were nonlactose-fermenting organisms (Proteus and Pseudornonas). All stone analyses of those patients with infections caused urease-producing organisms showed a combination of cystine and magnesium ammonium phosphate. Those patients with a mixture of struvite in the stones and negative cultures were presumed to have had such an infection at one time. Renal function was assessed by creatinine clearance in all patients and averaged 83.9 ml. per minute (range 44 to 116) in male and 74.1 ml. per minute (range 26 to 86) in female patients. Only 2 male and 1 female patient had clearances <50 ml. per minute. No patient was in or approaching renal failure. Only 3 male patients had other metabolic abnormalities that could be related to urinary stone disease. Of these patients 2 had had hypercalciuria (>300 mg. calcium per 24 hours) and 1 had had hyperuricosuria (>800 mg. uric acid per 24 hours). Interestingly, the 2 patients with hypercalciuria had stones composed of cystine, calcium oxalate and calcium phosphate.

MATERIALS AND METHODS

Hospital and office records of all patients with the diagnosis of homozygous cystinuria evaluated between 1965 and 1980 were reviewed. After hospitalization all patients underwent a complete metabolic evaluation in an effort to confirm the diagnosis of homozygous cystinuria and to identify the presence of other metabolic disorders that may be associated with urinary stone disease.4 In addition to urinary studies that have been reported previously, at least 2, 24--hour urine specimens were obtained for creatinine clearance. Stone analyses were done by chemical and/ or crystallographic analysis. Quantitative urinary amino acid analysis was done by liquid chromatography. Information relating to the onset and family history of stone disease, and type and number of prior surgical procedures for stone disease also were obtained from each patient. Office and hospital charts were reviewed to assess the results of treatment programs. RESULTS

Eighteen white male and 17 white female ""''""''"'" underwent evaluation and treatment. The average patient age at the time of initial stone formation was 21.3 years (range 7 to 71) for male and 16.6 years (range 11 to 70) for female patients. Interestingly, the average age at which the diagnosis of homozygous cystinuria was established conclusively was significantly higher: 28 years (range 11 to 71) for male and 22.5 years (range 7 to 46) for female patients. Only 5 male and 5 female patients had the diagnosis of cystinuria established at the time of initial stone formation. The average delay in diagnosis was 6. 72 years (range 0 to 23) for male and 5.94 years (range O to 27) for female patients. A positive family history of stone formation was elicited in 16 Accepted for publication July 10, 1981. Read at annual meeting of American Urological Association, Boston, Massachusetts, May 10-14, 1981. * Requests for reprints: Division of Urology, Case Western Reserve School of Medicine, University Hospitals of Cleveland, 2065 Adelbert Rd., Cleveland, Ohio 44106.

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708

EVANS, RESNICK AND BOYCE

The analysis of prior surgical procedures for stone removal performed on these patients is most interesting (table 2). On the average, 3.38 and 2.82 surgical procedures were done in each male and female patient, respectively. Bilateral procedures were done in 9 male and 10 female patients. The range in the number of surgical procedures is great and all but 2 patients had at least 1 operation before evaluation; 5 patients underwent 17 procedures each for stone removal. In most instances these procedures were done before the presence of cystinuria was established as a causative factor in stone formation and recurrence. A total of 109 operations was done in this group, 78 of which were either pyelolithotomies or nephrolithotomies. Nephrectomies were done in 3 patients and partial nephrectomies were done in 4. All 3 patients who required cystolithotomy for removal of bladder stones were in the pediatric age group. Treatment programs include adequate fluid intake, urinary alkalization and use of penicillamine to effect stone dissolution. All patients were instructed to maintain a urine output of at least 2 l. daily, and urinary alkalization to a pH of 7.5 was accomplished with oral administration of sodium bicarbonate and occasionally, acetazolamide. Penicillamine was used only in ~n attempt to dissolve a stone and cystine excretion was monitored so that levels were reduced to approximately 200 mg./24 hours. Stone dissolution, using a combination of increased fluid intake and urinary alkalization plus penicillamine administration, was attempted in 15 patients and was successful in 8. Of the 7 failures 5 were owing to the presence of persistent urinary tract infection with urease-producing bacteria and subsequent deposition of magnesium ammonium phosphate on an already existent cystine stone. Two patients did not respond to dissolution because of the deposition of calcium oxalate/calcium phosphate on the central cystine stone. All 7 patients in this group required surgical removal of the stone. Six patients had penicillamine allergies and dissolution with alkalization and fluid therapy alone was unsuccessful. These 6 patients required surgical removal of the stones. Finally, all of the remaining 14 patients were free of stones at evaluation and were maintained on a program of increased fluid intake and urinary alkalization. Average followup was 4.89 years (range 1 to 15) and 3.65 years (range 1 to 7) for male and female patients, respectively. Followup data revealed that stones recurred in 6 patients. Previous successful stone dissolution was done in 3 patients and all had failed to adhere to a good medical maintenance program. After reinstitution of increased fluid intake urinary alkalization and short-term penicillamine therapy dissolution again were accomplished, and all of these patients have remained free of stones for >2 years. Three additional patients had recurrent TABLE

No growth Proteus species Pseudomonas Staphylococcus aureus Enterobacter Escherichia coli Klebsiella Totals

TABLE

1. Urine culture Male Pts.

Female Pts.

13

10 3

2 0

1 0

1 1 18

2 1 1 0 0

17

2. Prior surgical procedures

Pyelolithotomy Nephrolithotomy Stone manipulation Partial nephrectomy Ureterolithotomy Cystolithotomy Nephrectomy Totals

Male Pts.

Female Pts.

31

30

8

9

12

0

2

2

5 3 0

4 0 3

61

48

disease related to recurrent urinary tract infection with ureaseproducing organisms; all have only small caliceal recurrences that are being followed and none has shown progressive growth. DISCUSSION

The first and most important aspect of management of the patient with cystinuria is recognizing the presence of the disorder. It is interesting that in our series the average delay in diagnosis in these patients was approximately 6 years after the initial stone episode, and many patients had had multiple surgical procedures before establishment of the correct diagnosis. The combination of an early age of onset, a positive family history and significant recurrent stone formation unresponsive to the usual forms of therapy should raise the suspicion of the diagnosis. Routine stone analysis often will identify the presence of cystine in a surgically removed or spontaneously passed stone and the cyanide-nitroprusside test offers a rapid screening procedure that will detect concentrations of cystine in the urine of 75 mg./mg. creatinine. 5 More precise quantitation of total urinary cystine arginine, ornithine and lysine excretion may be done by chromatographic methods. Successful medical management of the patients in whom cystine stones form is based on 3 principles: 1) decreasing urinary cystine concentration, 2) increasing urinary solubility of cystine and 3) decreasing urinary cystine excretion. Fluid diuresis long has been the cornerstone of medical management in these patients. Dent and Senior have demonstrated that a urinary output of 2 cc per minute (3,000 cc/24 hours) is adequate for the patient with mild to moderate cystinuria (;;;iel,000 mg./ 24 hours) 6 and Drach has stated that an output of 3 to 4 1. per day in addition to urinary alkalization can prevent stone formation successfully in most patients with cystinuria who have a daily cystine excretion of 300 to 800 mg. per day. 7 Generally, a regimen of 2 glasses of water every 2 hours while awake, plus 2 glasses before bedtime and 2 glasses during the night is sufficient to maintain this volume of urinary output. Unfortunately, compliance with such a regimen is difficult, and Dent and associates attributed the 33 per cent recurrence rate of cystine stones to this factor. 8 Similar problems were noted in our review and 50 per cent of the recurrences (3 of 6) were owing to poor patient compliance to a regimen of increased fluid intake and urinary alkalization. Fortunately, re-establishment of the regimen in addition to the use of penicillamine therapy was successful in dissolving the newly formed stones. Increasing urinary solubility of cystine is related directly to the establishment of an alkaline urinary pH, since it has been demonstrated that the solubility of cystine in the urine can be doubled (>800 mg./1.) simply by increasing urinary pH to 7.5. 6 Either sodium bicarbonate or sodium potassium citrate can be used. However, sustained urinary alkalization throughout the day often is difficult to maintain. Doses of up to 15 to 20 gm. sodium bicarbonate per day may be necessary to achieve adequate alkalization. Caution must be exercised because it must be remembered that a high sodium load can result in cardiac or renal failure in the elderly compromised patient. Decreasing urinary cystine excretion may be achieved by the use of D-penicillamine, a derivative of the penicillin molecule. 9• 10 Penicillamine binds with cysteine in the urine, forming a more soluble penicillamine-cysteine complex that is 50 times more soluble than cystine. The objectives of this therapy are to decrease urinary cystine excretion, prevent stone formation and effect stone dissolution. Doses of 1 to 2 gm. penicillamine per day often are successful in dissolving already formed stones within 6 to 12 months. Individual successes with this drug are well documented and clinical studies have demonstrated that the agent is effective in preventing new stone formation and, in selected cases, of dissolving already existent stones. 3• 9- 12 In our series 7 of 15 patients (46. 7 per cent) treated with penicillamine failed treatment and required surgical removal of the stones. The most common factor related to failure

709 was the caexistence of magnesium ammonium phosphate in association with urinary tract infection and urease-producing bacteria" Two patients had deposition of calcium oxalate and calcium phosphate on a pre-existing stone and, interestingly, both had hypercalciuria" Indications for surgical intervention include urinary obstruction, infection and the presence of associated calcium or struvite stones that are not amenable to dissolution" In our series 7 patients required an operation for this reason" An additional 6 patients with large stones and associated penicillin allergies also required an operation because of the failure of urinary alkalization and increased fluid intake to dissolve the stones" It is interesting to note that a third of our patients had associated urinary tract infection and 34 per cent had some struvite component in the stone" As already mentioned all the medical failures were related to infection and/or associated nondissolvable stones" Furthermore, 50 per cent (3 of 6) of the recurrences were attributed to reinfection and presumed struvite stone formationo REFERENCES

L Thier, So 00 and Halperin, K Co: Cystinuriao In: Nephrolithiasiso Edited by Fo L Coe" New York: Churchill Livingstone, po 208, 19800 20 Crawhall, Jo Co and Watts, R WOK: Cystinuriao Amero Jo Medo, 45: 736, 1968a 30 Dahlberg, Po Jo, Van Den Berg, Co Jo, Kurtz, So R, Wilson, Do Mo and Smith, LR: Clinical features and management of cystinuriao Mayo Clino Proco, 52: 533, 19770 4" Boyce, W" R and Resnick, Mo L: Biochemical profiles of stoneforming patients: a guide to treatment J" UroL, 121: 706, 19790 50 Kachman, Jo Fo: Proteins and amino acids: cystine and cysteineo In: Fundamentals of Clinical Chemistry" Edited by No W. Tietz" Philadelphia: WO R Saunders Coo, po 248, 19700 6" Dent, C" K and Senior, R: Studies on the treatment of cystinuria" Brito Jo UroL, 27: 317, 19550 70 Drach, Go Wo: Urinary lithiasiso In: Campbell's Urology, 4th edo Edited by Jo Ho Harrison, R Fo Gittes, An Perlmutter, To k Stamey and Po Co Walsho Philadelphia: WO R Saunders Coo, voL l,chapto 22,po 779, 19780 80 Dent, Co K, Friedman, Mo, Green, ff and Watson, Lo Co A: Treatment of cystinuriao Brit Medo Jo, 1: 403, 19650 90 Crawhall, Jo Co, Scowen, K Fo and Watts, R WO K: Effect of penicillamine on cystinuriao Brito Medo Jo, 1: 588, 19630 100 Lotz, Mo, Potts, Jo T, Jro, Holland, Jo Mo, Kiser, WO Fo and Bartter,

F. C.: D-penicillarn_ine therapy in cystinuria. J. Urol.) 95~ 257, 19660 lL MacDonald, WO Rand Fellers, Fo XO: Penicillamine in the treatment of patients with cystinuriao JOAJVLAO, 197: 396, 19660 120 Bartter, Fo Co, Lotz, Mo, Thier, So, Rosenberg, Lo Kand Potts, Jo T., JL: Cystinuriao Anno Intern" Med", 62: 796, 19650

EDITORIAL COMMENT Since the first suggestion of D-penicillamine for the treatment of homozygous cystinuria in 1956 a large body of evidence has accumulated on the use of DL-penicillamine, later of D-penicillamine, for the prevention and dissolution of cystine stones" This evidence attests to the effectiveness and relative safety of D-penicillamine" D-penicillamine acts by forming a mixed disulfide with cysteine in extracellular fluid, the renal tubules and, possibly, the urine" This disulfide is about 50 times more soluble in urine than cystine" Whereas D-penicillamine causes excretion of a large percentage of half-cystine as the mixed disulfide it has been observed that total halfcystine excretion decreases with D-penicillamine therapy in patients with cystinuria" In normal individuals total half-cystine excretion increases significantly and this has not been explained" This finding suggests an additional effect of D-penicillamine in the patients to lower the gastrointestinal absorption of methionine" Some patients treated with DL-penicillamine for cystinuria or Wilson's disease had sensitivity reactions, including the nephrotic syndrome" However, there is no convincing evidence that D-penicillamine, as opposed to DL-penicillamine, produces the nephrotic syndrome" This paper is a timely summary of the experience in 35 patients with homozygous cystinuria, 15 of whom had cystine stones" Of these patients 55 per cent showed dissolution of stones with D-penicillamine therapy" No complication of D-penicillamine therapy is reported for this short series" The value and shortcomings of the time-honored therapy with forced fluids and alkalization of urine are discussed from the perspective of 198L a-Mercapto-proprionyl-glycine was introduced for the treatment of cystinuria in 1973" This agent, which adds importantly to our armamentarium for the treatment of this troublesome disease, acts by precisely the same mechanism as D-penicillamine" Whereas, a-mercapto-proprionyl-glycine is reported to show fewer complications than D-penicillamine the experience to date is too brief to allow for a definitive comparison of the 2 agents" Frederic G Bartter Research Service Audie L Murphy Memorial Veterans Hospital and the University of Texas Health Science Center San Antonio, Texas