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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 metabolism 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 disorder 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 children4 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 inelude: diet, hydration, oral and parenteral dissolution, catheter irrigation, endoscopic, pereutaneous, and extraeorporeal lithotripsy. A successful outcome usually requires a creative 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 overwhelmingly complex and demands a scrutinized selection of available treatment options.
322
Case Relz
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
UROLOGY
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1991
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~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).
FmU~E 2. (A) Recurrent cystine calculi in left kidney lower pole calices (KUB); (B) stone-free after chemolysis
(KtTB).
8 Surgical removal of the calculi was decided. riiedistal end of the calcified stent was sheared ifl Under cvstoseooic vision using a lithotrite. ~hepatien(was then explored through a dorsal ~t~tbotomyincision. The upper end of the stent !eriS61yembedded in the pelvic calculi was re~i0ved through a vertical pyelotomy. As the :~leffied stent was extracted, the three distal :.i~!}~teralcalculi remained attached to the en~rUstation a r o u n d the stent and egressed;~'ithout difficulty. ~Ostoperatively, the patient maintained a ~!!ghurine output by drinking 3 to 4 L of fluids O~ily.Her urine was alkalinized to pH 7.5 using ~%0C¥
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APRIL 1991
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VOLUME XXXVII, NUMBER 4
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 ureferal 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 titrated 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).
i~ i~ili ¸ ii
":~:
Case 2 A fifty-two-year-old Caucasian woman had a left pyelolithotomy for a staghorn eystine calculus. Postoperatively the urine was alkalinized with oral sodium bicarbonate to pH 7.5. During the next sixteen years, the patient passed several eystine calculi. She was prescribed 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, mierohematuria, and intermittent baeteriuria. Twenty-four-hour urine cystine excretion was 426 mg/day. Subsequently, the patient was recommended for bilateral total hip arthroplasty for degenerative 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. After 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 extended 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-
324
~!ii~ • i i: i
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 dearly 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:~
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1991
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pressures during therapy. Reported times of complete stone eradication have ranged from five to one hundred twenty days using ehemoly-
in oecond. Oral dissolution requires several ~ 0 thsto years under 1deal circumstances..7 12-24 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 sponta1~~0The reason for poor fragmentation is )mpletely understood. Cystine calculi are ~helastudied 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~fcystine 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 en3ie electrohydraulie lithotripsy (EHL), ul1316lithotripsy (USL), and pulsed dye lasers ihave limited efficacy in pulverizing eysaleuli.33-3~ However, if partial fragmentadan be accomplished, the surface area of !alCuli may be sufficiently increased so that etive measures for dissolution can be subehtly 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 fragmentation was achieved with ~WLI Similarly, pereutaneous chemolysis ~y have been considered if ultrasonic litho~y had fragmented the calculus in the seci~ patient. Irrigation solutions that have been utilized [th and without alkalinizers include N-acex [%vsteine,37-39tromethamine-E (Tham-E), phaiMPG,43 and D-penicillamine.44 Chemolis through a retrograde ureteral catheter or ¢Cutaneous nephrostomy has significantly reteed 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-42It is essential to eradite infections an(i maintain low irrigation •
•
sis, 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 consumption 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 receiving 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 indicated, KUB film and ultrasound are done to identify recurrent calculi. Recurrence of calculi was arrested in both our patients by strict adherence to hydration and oral alkalinization. Similar to the treatment of existing calculi, a stepwise approach to prophylaxis is just as prudent. Frequently, the addition of one of the oral therapies is employed if a stable situation cannot 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 challenging 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.
~i~
Naval Hospital Roosevelt Roads Ceiba, Puerto Rico 34051 (DR. SINGER)
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i~qi~)LOGy
/ APRIL
1991
/ VOLUME
XXXVII,
NUMBER
References 1. Thier SO, and Halperin EC: Cystinuria, in Coe FL (Ed): Nephrolithiasis, vol 5, New York, Churchill Livingstone, 1980, p 208.
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325
2. Caldwell BJ, Towsend JI, and Smith MJV: Genetics of eystinuria in an inbred population, J Urol 119:531 (1978). 3. Malek RS, and Kelalis PP: Pediatric nephrolithiasis, J Urol 113:545 (1975). 4. MitchellJP: Lithiasis in children (editorial), Eur Urol 7:121 (1981). 5. Dahlberg P], et al: Clinical features and management of cystinuria, Mayo Clin Proc 52:533 (1977). 6. Bostrom H, and Hambraeus L: Cystinuria in Sweden. VIII. Clinical, histo-pathological, and medico-social aspects of the disease, Acta Med Scand (Suppl) 411:1 (1964). 7. Evans WP, Resnick MI, and Boyce WH: Homozygous cystinuria evaluation of 35 patients, J Urol 127:707 (1982). 8. Dent CE, and Senior B: Studies on the treatment of cystinuria, Br ] Urol 27:317 (1955). 9. Drach GW: Urinary lithiasis, in Walsh PC, Gittes ItF, Perlmutter AD, and Stamey TA (Eds): Campbell's Urology, 5th ed, Philadelphia, WB Saunders, 1986, vol 1, pp 1094-1190. 10. Dent CE, Friedman M, Green H, and Watson LCA: Treatment of eystinuria, Br Med J 1:403 (1965). 11. Freed SZ: The alternating use of an alkalizing salt and aeetazolamide in the management of eystine and uric acid stones, J Urol 113:96 (1975). 12. Crawhall JC, Seowen EF, and Watts RWE: Effect of penieillamine on cystinuria, Br Med J h 588 (1963). 13. Lotz M, et al: D-penicillamine therapy in cystinuria, J Urol 95:257 (1966). 14. MacDonald WB, and Fellers FX: Penieillamine in the treatment of patients with cystinuria, JAMA 197:396 (i966). 15. King JS Jr: Treatment of cystinuria with a-mereapto propionylglyeine: a preliminary report with some notes on column chromatography of mereaptans, Proe Soe Exp Biol Med i29:927 (1968). 16. Hautmann R, Terhorst B, Stuhlsatz HW, and Lutzeyer W: Mercaptopropionylglycine: a progress in cystine stone therapy, ] Urol 117:628 (1977). 17. Koide T, et aI: Conservative treatment of cystine calculi: effect of oral alpha-mercaptopropionylglycine on cystine stone dissolution and on prevention of stone recurrence, J Urol 128:513 (1982). 18. MulvaneyVCP, Quilter T, and Mortera A: Experiences with acetylcysteine in cystinuric patients, J Urol 114:107 (1975). 19. Stokes GS, Ports JT Jr, Lotz M, and Bartter FC: Mechanisms of action of D-penicillamine and n-acetyl D-penicillamine in the therapy of cystinuria, Clin Sci 35:467 (1968). 20. Sloand JA, and Izzo JL Jr: Captopril reduces urinary cysfine excretion in cystinuria, Arch Intern Med 147:1409 (1987). 21. Lux B, and May P: Long-term observation of young cystinuric patients under ascorbic acid therapy, Urol Int 38:91
(1983). 22. Singh A, Marshall FF, and Chang t/: Cystine calculi: clinical management and in vitro observations, Urology 31:207 (1988). 23. Miyagi K, Nakada 17, and Ohshiro S: Effect of glutamine on cystine excretion in a patient with cystinuria, N Engl J Med 301:196 (1979). 24. Skovby F, Rosenberg LE, and Thief SO: No effect of Lglutamine on eystinuria (Letter to the Editor), N Engl J Med 302: 302 (1980). 25. Lewis HB: Cystinuria: a review of some recent investigations, Yale J Biol Med 132:4:437 (1932). 26. Weinberg SR, and Tabenkin PA: Observation on therapy of cystine calculus disease, Arch Intern Med 9 0 : 8 5 0 (1952).
326
27. Pahira JJ: Management of the patient with eYs:muria, IJ~ Clin North Am 14:339 (1987). 28. Kolb FO, Earll JM, and Harper HA: DisaLppear., ~ceceat tinuria in a patient treated with prolonged methion neIthe~"~'~ tabolism 16:378 (1967). • " "~ 29. Leroy AJ, Segura JW, Williams HJ Jr, and Pal:ersor. DI~ Percutaneous renal calculus removal in an extraeo.';×m,al ~ . ~ wave lithotripsy practice, J Urol 138:703 (1987). -~g 30. Burns JR, Shoemaker BE, Gauthier JF, and l'ir.la~on~ Hardness testing of urinary calculi, in Smith LH, Rel~.rts~;nI ~ and Fiulayson B (Eds): Urolithiasis: Clinical and Ba.qc I 1 ~ New York, Plenum, 1981, pp 703-706. -~_ 31. Dretler SP: Stone fragility--a new therapeutic d i - ~ t i r ~ J Urol 139:1124 (1988). "i~' 31a. Bhatta KM, Prien EL, and Dretler SP: Cys~inccal6il~ rough and smooth: a new clinical distinction, ] I'ml 14~i-~'
(1989).
,
~,
32. Chaussy CG, and Fuehs GJ: Extracorporea, shock ~ . . lithotripsy, in Stamey TA (Ed): 1987 Monographs in t.'mlo~]~ search Triangle Park, North Carolina, Custom Publishing ~ . ices, 1987, vol 8, pp 86-87. .~.: :, 33. Vallancien G, et al: Piezoelectric by ultrashort waves with the EDAP Lt ( (1988). 34. Dretler SP: Management of uret, series, 1988, p 8. 35. Segura JW, et al: Percutaneous i review of 1,000 cases, J Urol 134:1077 36. Schmeller NT, et aI: Combinatim wave lithotripsy in the treatment of ey~ 131:434 (1984). 36a. Kachel TA, Vijan SR, and E management of cystine stones in the er~ 152, J Urol 141: 207A (1989). 37. Smith AD, Lange PH, Miller RP, and R( tion of cystine calculi by irrigation with aeet,. pereutaneous nephrostomy, Urology 23:422 (1 38. Dretler SP, Pfister RC, Newhouse JH, Pereutaneous catheter dissolution of eystine e," 216 (1984). 39. Burns JR, and Hamrick LC Jr: In vitro tine urinary calculi, J Urol 136:850 (1986). 40. Berkhoff WBC, Van Haga JJW, and Roo, tient percutaneous chemolitholysis of cystine st~ 180 (1987). 41. Tseng CH, et al: Dissolution of cystine c liceal irrigation with tromethamine-E, J Urol 42. Hayase Y, Fukatsu H, and Sagawa A: ' cystine stones by irrigated tiopronin solution. (1980). "~ ~ , 43. Stark H, and Savir A: Dissolution of cystine caleb', ~,,it, _~,~ vioealiceal irrigation with D-penicillamine, J Urol l~t*~° (1980). -~,~,~,,! 44. Crissey MM, and Gittes RF: Dissolution of cystine qO~Z~ calculus by irrigation with tromethamine, J Urol 111~811 (1979). , ~,-~i~]d.. 45 ' Harbar JA ' Cusworth DC ' Lawes LC ' and ~,~ro~ :. a' L~¢' Comparison of 2-mereaptopropionylglyeine and D-pc in the treatment of cystinuria, J Urol 136:146 (1986). i~ ~_~ 46. Kinoshita K, et al: Treatment of cystinuria with 2 - ~ topropionylglycine (MPG) in. Proceedings of the S e c o n d . ' ~ tional Symposium on Thioia, Osaka,Japan Santen p ~ U cal Co., 1972, p 50.
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VOLUME xXXVII. N ~ l ~ i
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 metabolism 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 disorder 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 children4 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 inelude: diet, hydration, oral and parenteral dissolution, catheter irrigation, endoscopic, pereutaneous, and extraeorporeal lithotripsy. A successful outcome usually requires a creative 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 overwhelmingly complex and demands a scrutinized selection of available treatment options.
322
Case Relz
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
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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).
FmU~E 2. (A) Recurrent cystine calculi in left kidney lower pole calices (KUB); (B) stone-free after chemolysis
(KtTB).
8 Surgical removal of the calculi was decided. riiedistal end of the calcified stent was sheared ifl Under cvstoseooic vision using a lithotrite. ~hepatien(was then explored through a dorsal ~t~tbotomyincision. The upper end of the stent !eriS61yembedded in the pelvic calculi was re~i0ved through a vertical pyelotomy. As the :~leffied stent was extracted, the three distal :.i~!}~teralcalculi remained attached to the en~rUstation a r o u n d the stent and egressed;~'ithout difficulty. ~Ostoperatively, the patient maintained a ~!!ghurine output by drinking 3 to 4 L of fluids O~ily.Her urine was alkalinized to pH 7.5 using ~%0C¥
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APRIL 1991
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VOLUME XXXVII, NUMBER 4
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 ureferal 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 titrated 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).
i~ i~ili ¸ ii
":~:
Case 2 A fifty-two-year-old Caucasian woman had a left pyelolithotomy for a staghorn eystine calculus. Postoperatively the urine was alkalinized with oral sodium bicarbonate to pH 7.5. During the next sixteen years, the patient passed several eystine calculi. She was prescribed 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, mierohematuria, and intermittent baeteriuria. Twenty-four-hour urine cystine excretion was 426 mg/day. Subsequently, the patient was recommended for bilateral total hip arthroplasty for degenerative 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. After 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 extended 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-
324
~!ii~ • i i: i
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 dearly 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:~
UROLOGY
/
APRIL
1991
/
VC
pressures during therapy. Reported times of complete stone eradication have ranged from five to one hundred twenty days using ehemoly-
in oecond. Oral dissolution requires several ~ 0 thsto years under 1deal circumstances..7 12-24 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 sponta1~~0The reason for poor fragmentation is )mpletely understood. Cystine calculi are ~helastudied 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~fcystine 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 en3ie electrohydraulie lithotripsy (EHL), ul1316lithotripsy (USL), and pulsed dye lasers ihave limited efficacy in pulverizing eysaleuli.33-3~ However, if partial fragmentadan be accomplished, the surface area of !alCuli may be sufficiently increased so that etive measures for dissolution can be subehtly 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 fragmentation was achieved with ~WLI Similarly, pereutaneous chemolysis ~y have been considered if ultrasonic litho~y had fragmented the calculus in the seci~ patient. Irrigation solutions that have been utilized [th and without alkalinizers include N-acex [%vsteine,37-39tromethamine-E (Tham-E), phaiMPG,43 and D-penicillamine.44 Chemolis through a retrograde ureteral catheter or ¢Cutaneous nephrostomy has significantly reteed 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-42It is essential to eradite infections an(i maintain low irrigation •
•
sis, 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 consumption 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 receiving 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 indicated, KUB film and ultrasound are done to identify recurrent calculi. Recurrence of calculi was arrested in both our patients by strict adherence to hydration and oral alkalinization. Similar to the treatment of existing calculi, a stepwise approach to prophylaxis is just as prudent. Frequently, the addition of one of the oral therapies is employed if a stable situation cannot 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 challenging 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.
~i~
Naval Hospital Roosevelt Roads Ceiba, Puerto Rico 34051 (DR. SINGER)
~
i~qi~)LOGy
/ APRIL
1991
/ VOLUME
XXXVII,
NUMBER
References 1. Thier SO, and Halperin EC: Cystinuria, in Coe FL (Ed): Nephrolithiasis, vol 5, New York, Churchill Livingstone, 1980, p 208.
4
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