therapeutic dilemmas in management ofcystine calculi

THERAPEUTIC DILEMMAS IN MANAGEMENT OF

CYSTINE CALCULI

ADAM SINGER, M.D.

SAKTI DAS, M.D.

From the Naval Hospital, Oakland, and the Kaiser Permanente Hospital, Walnut Creek, California

ABSTRACT--The appropriate management o] patients with cystine calculi: mental understanding of the pathophysiology o] cystinuria and a working knr able therapeutic modalities. The .following case reports and review o] the lit~ trate that successful treatment involves a multidimensional approach to eradi~ long-term follow-up aimed at prevention.

Cystinuria is an inherited inborn error of me- tabolism characterized by abnormal transport of eystine, ornithine, lysine, and arginine in the renal tubules and the intestinal tract. Of these amino acids, only eystine is poorly soluble in urine.1 The morbidity of this metabolic disor- der results from the formation of urinary calculi. Cystine represents 1-6 percent of urinary calculi. 2,3 Quantitative eystine excretion and propensity for stone formation varies among eystinuries. Stone formation occurs with urinary levels as low as 76 rag/day in children 4 and 400 mg/day in adults2 Interestingly, up to 43 percent of eystinuries with stones will have calculi of mixed composition and 9 percent will have calculi devoid of eystine. 6 Urinary tract infection occurs in approximately one third of these patients, v Stone-forming eystinuries are difficult to treat. Therapeutic regimens in- elude: diet, hydration, oral and parenteral dissolution, catheter irrigation, endoscopic, pereutaneous, and extraeorporeal lithotripsy.

A successful outcome usually requires a crea- tive combination of available modalities with careful monitoring and close follow-up to prevent recurrence of calculi. As illustrated in the following ease reports, dealing with urinary calculi in patients with eystinuria can be over- whelmingly complex and demands a scruti- nized selection of available treatment options.

Case Rel z

Case 1

A nineteen-year-old Ca referred for recurrent epis eostovertebral pain. An showed a large calculus ii (Fig. 1A). Serum ereatini: twenty-four-hour urinary 324 mg.

After placement of a l stent into the left ureter, tt with extraeorporeal shc (ESWL). No fragmenta noted after 3,200 shocks. shock-wave lithotripsy on, unsuccessful in fragment: 1B).

Three weeks later, t h e nant. The stent remaine~ obstructive complication She had an uncomplicatec

Excretory urogram on, demonstrated three previ~ the renal pelvis and three tal ureter. The urine wa~ weeks in an attempt to dis resulted in dense caleifice no change in the existing

322 UROLOGY / APRIL 1991 / VO

~i~ i. (A) Cystine calculus in left renal pelvis (KUB); (B) calculus unchanged after stenting and ESWL 1~); (C) calcification of ureteral stent and newly formed cystine calculi one month post partum (KUB).

8

Surgical removal of the calculi was decided. riie distal end of the calcified stent was sheared ifl Under cvstoseooic vision using a lithotrite. ~he patien(was then explored through a dorsal ~t~tbotomy incision. The upper end of the stent !eriS61y embedded in the pelvic calculi was re- ~i0ved through a vertical pyelotomy. As the :~leffied stent was extracted, the three distal :.i~!}~teral calculi remained attached to the en- ~rUstation a round the stent and egressed- ; ~'ithout difficulty.

~Ostoperatively, the patient maintained a ~!!gh urine output by drinking 3 to 4 L of fluids O~ily. Her urine was alkalinized to pH 7.5 using

~%0C¥ / APRIL 1991 / VOLUME XXXVII, NUMBER 4

FmU~E 2. (A) Recurrent cystine calculi in left kidney lower pole calices (KUB); (B) stone-free after chemolysis (KtTB).

sodium bicarbonate. Urinary excretion of cystine was 322 mg/day.

A follow-up plain x-ray film of the abdomen at six months revealed recurrent calculi in the left kidney (Fig. 2A). Chemolytic dissolution was done by infusing tromethamine-E (36 rng/ L) in normal saline through a retrograde ure- feral catheter. Complete dissolution of the calculi was evident after four days of irrigation (Fig. 2B). The patient remains free of calculi at two years follow-up with continued attention to hydration and alkalinization of urine with ti- trated doses of oral sodium bicarbonate and home monitoring of urine pH.

323

FICURE 3. (A) Coralli]orm cystine calculus in left kidney (KUB); (B) stone-]ree two years after surgery (KUB).

Case 2

A fifty-two-year-old Caucasian woman had a left pyelolithotomy for a staghorn eystine calculus. Postoperatively the urine was alkalinized wi th oral sodium bicarbonate to pH 7.5. During the next sixteen years, the pat ient passed several eystine calculi. She was pre- scribed penieillamine prophylaxis. She was lost to follow-up until five years later when x-ray film of kidney-ureter-bladder (KUB) showed a 4 cm x 2 em eoralliform calculus in the left renal pelvis (Fig. 3A). She declined intervention for two years. Urinalysis revealed pyuria, mi- erohematuria, and intermittent baeteriuria. Twenty-four-hour urine cystine excretion was 426 mg/day.

Subsequently, the patient was recommended for bilateral total hip arthroplasty for degenera- tive osteoarthritis. Consensus was to remove the calculus prior to prosthetic surgery to eradicate this potential source of infection. The patient declined any irrigation dissolution therapy due to the possible length of necessary treatment and duration of hospital stay.

A single-stage percutaneous nephrostomy and ultrasonic lithotripsy were attempted. Af- ter a prolonged trial this calculus could not be pulverized. A 20F nephrostomy was placed. The patient again declined irrigation ehemolysis. The calculus was removed through an ex- tended pyelolithotomy.

Postoperatively the patient continues her high fluid intake and urinary alkalinization. A KUB and renal ultrasound reveal no recurrence of calculi at two-yea r follow-up (Fig. 3B).

Comment

The elinieal eourse and therapeutie outeome of our 2 patients highlight the available metho-

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dologies in the treatment of cystinuria. attempts at stone dissolution usually begi~ hydration, s-l° alkalinization, 9-11 and oral eal therapy. 7,12-~4,15-24 Maximum insolubi eystine is at the isoeleetrie point (pH 3 Solubility increases slightly at pH 6.0 1: creases 50 percent and 1,400 pereent at t and 9. 25,2° Biearbonate, citrate, and aec amide are sufficient to alkalinize the while the patient is further instructed crease solubility by drinking at least 3 L I ter daily. T M Over-alkalinization can be ei productive since calcium erystalizatioi preeipitate on existing eateuli when uril exceeds 8. 27 A low methionine diet ( the acid precursor of eystine) is infreqi adhered to since it is generally eonsidefi palatable. 28 Oral medical regimens incl~ penieillamine, 12-14 alpha-MPG, 15-17 aeet tine, is N-aeetyl penicillamine, x° eapti vitamin C, 21,22 and glutamine. 2a'24 The ii nism of action of vitamin C and glutai not dear ly defined; however, the effectii other medical therapies are based on a dl exehange reaetion with eystine. Cystin! dueed to eysteine by cleavage of the dl bond. Cysteine bonds to the sulfhydryl of the oral agent employed. Our first i formed new calculi along her stelat though she was vigorously hydrating ag! fully alkalinizing her urine. Howe~ calcareous debris precipitation along fl: was not completely unexpected owing t¢ tion as a nidus for stone preeipitationi second patient recurrent calculi develo~ lowing a similar protocol in addition toi famine prophylaxis. Further oral di~ therapy was not chosen for either pati~i cause of the enerusted ureteral stent i~} patient and the need for expedient hipii: ~

3 2 4 U R O L O G Y / A P R I L 1 9 9 1 / V C

in oecond. Oral dissolution requires several ~ 0 • • 7 12-24 thsto years under 1deal circumstances.. itracorporeal and pereutaneous lithotripsy b o t h unsuccessful. Our experience has similar to others who report poor success :with these modalities alone. ESWL is rela- ,ineffective in fracturing cystine calculi ~mall fragments that will pass sponta- 1~ ~0 The reason for poor fragmentation is )mpletely understood. Cystine calculi are ~hela studied in vitro, 3° but highly resistant ,W ,due in part to its uniform crystal aUtri;n~without circumferential or radial ij ).31 Variability of fragmentation by

may be related to two different popula- ~f cystine crystal structural arrangement ave been described as having either rough ~oth texture. 31" Localization of eystine i for ESWL can be problematic since the de compound makes eystine semiopaque ~gy films. 32 Some clinical investigators /lemonstrated that pereutaneous and en- 3ie electrohydraulie lithotripsy (EHL), ul- 1316 lithotripsy (USL), and pulsed dye lasers ihave limited efficacy in pulverizing eys- aleuli.33-3~ However, if partial fragmenta- dan be accomplished, the surface area of

!alCuli may be sufficiently increased so that

~i~ etive measures for dissolution can be sub- ehtly employed. 36 Kaehel, Vijan, and

!il~P~a have reported success using percuta- !~s debulking of very large cystine calculi ~ uitrasonic lithotripsy followed by ESWL

ehemolysis, while suggesting ESWL inotherapy for renal calculi less than i cm in ~; In our first patient, dissolution by ureteral illeter irrigation may have been attempted if ~tial fragmentat ion was achieved with ~WLI Similarly, pereutaneous chemolysis ~y have been considered if ultrasonic litho- ~y had fragmented the calculus in the sec- i~ patient. Irrigation solutions that have been utilized [th and without alkalinizers include N-ace x [%vsteine, 37-39 tromethamine-E (Tham-E), - phaiMPG, 43 and D-penicillamine. 44 Chemol- is through a retrograde ureteral catheter or ¢Cutaneous nephrostomy has significantly re- teed the number of open surgical proeedures. ith the exception of Tham-E these agents act exchange resins identical to the mechanism of :~ton when administered orally. Tham-E ~ anees cystine solubility by virtue of its high alinity (pH 10 6) 3s-42 It is essential to eradi-

te infections an(i maintain low irrigation

pressures during therapy. Reported times of complete stone eradication have ranged from five to one hundred twenty days using ehemolysis, 37-44

Follow-up in cystinuric patients is critical to prevent the growth and propagation of urinary calculi. Patient compliance is most important if prophylaxis is to be effective. Each patient keeps a personal diary of their water consump- tion and twenty-four-hour urinary output. A total of 3 L of urine production a day is usually satisfactory. Urine pH is monitored three times a day and once during sleeping hours so that alkalinization can be adjusted accordingly since urinary pH can fluctuate widely. The desired urine pH should range between 7.2 and 7.5. A more basic urine may incite the deposition of calcium stones.

Bimonthly visits insure that the patient is re- ceiving the maximum benefits of treatment. A review of their diary, urinalysis, urine pH, twenty-four-hour creatinine clearance, and cystine excretion with serum electrolytes, blood urea nitrogen (BUN), and creatinine are recommended. A semiannual, or when otherwise in- dicated, KUB film and ultrasound are done to identify recurrent calculi. Recurrence of calculi was arrested in both our patients by strict ad- herence to hydration and oral alkalinization. Similar to the treatment of existing calculi, a stepwise approach to prophylaxis is just as pru- dent. Frequently, the addition of one of the oral therapies is employed if a stable situation can- not be attained with hydration, and alkalinization. In general the adverse side effects of MPG appears less than penicillamine, 16,17,45,48 while the experience with captopril, acetyl cysteine, glutamine, and vitamin C is limited.

The management of eystine calculi is chal- lenging and filled with frustration. Treatment must be carefully selected and individualized based on each observed therapeutic response. A reasonable understanding of the pathophysiology of calculus disease in cystinurics, as well as the pharmacokinetics of the available agents helps in the pragmatic planning of therapy.

Naval Hospital Roosevelt Roads

Ceiba, Puerto Rico 34051 (DR. SINGER)

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i~qi~)LOGy / APRIL 1991 / VOLUME XXXVII, NUMBER 4 325

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326 UROLOGY / APRIL 1991 / VOLUME xXXVII. N ~ l ~ i

therapeutic dilemmas in management ofcystine calculi

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