Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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Chapter 17 / Struvite Stones 317

compared with only one receiving placebo, required a decrease in dosage or cessation

of treatment because of adverse medication effects (46).

When administered orally, AHA is readily absorbed from the gastrointestinal tract and

reaches peak serum levels after approximately 1 hour (47). Although a portion of the

orally administered drug is metabolized to carbon dioxide and acetamide, 20–48% is

excreted intact in the urine (48). The recommended dosing regimen for AHA is an initial

dose of 250 mg twice daily by mouth for 3–4 wk, and if tolerated, an increase in the

dosage to 250 mg three times daily (36). AHA is contraindicated in patients with renal

insufficiency (serum creatinine greater than 2 mg/dL) because therapeutic urinary con-

centrations are unlikely to be achieved and the risk of toxicity is increased (7). Use of

AHA is also contraindicated in pregnant women as AHA has been shown to be teratoge-

nic in animals (49). Use of AHA is relatively contraindicated in patients with poor function

in the stone-bearing kidney because of potential increased excretion of AHA on the con-

tralateral side and sub-therapeutic levels within the kidney requiring treatment (50).

Use of AHA and urease inhibitors in general is limited because of toxicity. Major side

effects including hemolytic anemia, deep venous thrombosis, gastrointestinal symp-

toms, headache, tremulousness, hallucinations, loss of taste, and teratogenesis have been

reported (4). Although these side effects are transient and resolve upon discontinuation

of treatment, they occur in 20–30% of patients (36). Consequently although AHA may

serve a palliative role in a select patients, urease-inhibitors play a relatively limited

overall role in clinical practice.

Urinary Acidification

Because the formation of struvite stones depends on an alkaline urinary environment,

urinary acidification has the potential to increase urinary solubility of struvite and car-

bonate apatite, thereby preventing stone formation and potentially dissolving existing

stones. A variety of acidification agents have been investigated for their dissolution or

preventative potential. Ascorbic acid has been used in an attempt to decrease urinary pH,

but this has not been successful clinically. In a two-phase, randomized, placebo-con-

trolled, cross-over trial, 12 normal subjects and 12 calcium stone formers received 2 g

of ascorbic acid or placebo daily for 6 d while maintained on a controlled metabolic diet.

No difference in urinary pH was found between the placebo and ascorbic acid phases in

either the normal subjects (6.02 vs 6.02, respectively) or stone formers (6.0 vs 6.0,

respectively) (51).

Ammonium chloride has been noted to successfully lower urine pH immediately after

initiation, but after 6 d of treatment urinary ammonia excretion increases, counteracting

the acidification effect (52). Ammonium sulfate and ammonium nitrate used in combi-

nation were shown to be more effective than ammonium chloride for urinary acidifica-

tion in 24 patients treated over 2 yr (53). Combination-treated patients experienced a

reduction in urinary saturation of calcium phosphate and stone formation. However,

ammonium sulfate is poorly tolerated due to its cathartic effect, and ammonium nitrate

is potentially explosive. As such, neither drug achieved widespread use in Europe or the

United States (4).

Lavage Chemolysis

The concept of dissolving a stone in situ was particularly attractive when open

stone surgery offered the only treatment option for stone removal. With current mini-

318 Johnson and Pearle

mally invasive and non-invasive treatment modalities, the morbidity of surgical stone

removal has been greatly reduced and reliance on chemolysis has substantially

decreased. Chemolysis is now primarily used in patients who are not considered sur-

gical candidates or as an adjunct to surgical treatment to eliminate small residual

fragments (54).

In the 1930s initial attempts at lavage chemolysis for phosphate-containing calculi

involved urinary antiseptics and acidifying agents, typically citric acid (55,56). At acid

pH, primary and secondary citrates of calcium are formed that are weakly dissociated,

resulting in a reduction of free calcium ions in solution (3). Although effective in vitro,

dissolution therapy in vivo was successful in only one of four patients during early

treatment attempts (56). Moreover, citric acid was found to be irritating to bladder

mucosa. The later addition of magnesium ions reduced mucosal irritation, and led to the

formulation of what is currently known as Suby’s solution G. Direct renal irrigation with

solution G resulted in partial or complete dissolution of phosphate-containing stones in

all six patients treated in the initial report by Suby and Albright (57).

In vitro dissolution of struvite stones was later accomplished with hemiacidrin

(Renacidin), a citric acid and magnesium solution similar to solution G (58). Early

clinical use of Suby’s G solution and hemiacidrin were associated with frequent cases

of hypermagnesemia, with four reported deaths caused by magnesium toxicity (59,60),

prompting the Food and Drug Administration to remove these solutions from clinical use

at that time. However, other investigators attributed these deaths to urosepsis caused by

infusion into the infected collecting system, rather than due to the direct effects of the

irrigating solution itself, and they suggested that irrigating solutions should only be used

in culture-verified sterile urine with close monitoring of intra-renal pressures (61). With

these precautions, they noted no complications and successfully treated stones with

hemiacidrin irrigation in eight patients.

Recent use of citric acid (also known as Solution R) irrigation for the treatment of

refractory infection stones has also been reported (62). Among 23 patients treated,

however, six required termination of irrigation because of complications. Overall, 7

patients were radiographically cleared of stone with irrigation alone and 13 patients were

rendered stone free after irrigation in combination with surgical intervention such as

PCNL and ureteroscopy. At a mean follow-up of 2.4 yr, however, only 4 of the 23

patients remained free of stones.

Current recommendations for the use of irrigating solutions include the following: (1)

maintain sterile urine, (2) ensure unobstructed renal inflow and outflow, (3) maintain

intrapelvic pressure below 30 cm H

O, (4) confirm absence of extravasation, and (5)

frequently monitor serum magnesium levels during treatment (7).

Despite limited success with chemolysis for treatment of infection stones, the proce-

dure is rarely used in clinical practice today because of the prolonged treatment times and

lengthy hospital stays associated with this therapy. Indeed, Tiselius and colleagues

treated 118 patients with infection staghorn calculi with shockwave lithotripsy (SWL)

followed by chemolysis via a percutaneous nephrostomy tube with Renacidin or THAM

solution (tri-hydroxylmethyl-aminomethan) and achieved a stone free rate of only 60%,

with a mean of 3.4 SWL treatments per patient, an average hospital stay of 32 days and

a 4.2% incidence of sepsis (63). With effective minimally invasive surgical therapy that

is associated with high stone free rates, low complication rates and short hospital stays,

the role of chemolysis even for treatment of residual calculi has been relegated to his-

torical interest only.

Chapter 17 / Struvite Stones 319

SURGICAL MANAGEMENT

Before 1980, open surgical stone removal, in conjunction with antibiotics and pos-

sibly irrigation with chemolytic agents, constituted the optimal therapy for infection

stones. Conservative, nonoperative therapy was advocated by some (64), but evidence

suggested that this approach was best reserved for poor surgical candidates due to the

high risk of renal failure, sepsis and death. In a retrospective review of patients with

staghorn stones treated from 1927 to 1940, the survival rate among 234 patients with

unilateral stones was 81% for those undergoing surgical treatment vs 41% for those

managed conservatively (65). Likewise, Blandy and Singh compared 60 patients man-

aged conservatively with 125 treated surgically and found a 10-yr mortality rate in the

conservative group of 28% vs 7.2% in the surgical group (66). Rous and Turner also

reported a 30% mortality rate due to stone-related complications in 95 consecutive

patients hospitalized with staghorn stones and managed conservatively (16). Thus,

conservative management of staghorn calculi is discouraged in all but the highest risk

surgical candidates.

Achieving a stone-free state presents a significant challenge even when open surgical

treatment is employed. The AUA Nephrolithiasis Clinical Guidelines Panel reviewed

110 articles containing abstractable data regarding the management of staghorn calculi

and found a median stone free rate of 81.6% (95% confidence interval 56.6–95.7%) for

open surgical treatment (67). Based on their findings, they deemed that open surgery

should not constitute first line therapy for treatment of these stones because of a higher

morbidity compared with less invasive treatment approaches. However, open surgery is

an appropriate treatment alternative in unusual circumstances where a struvite staghorn

calculus is not expected to be expeditiously treated within a reasonable number of

percutaneous and/or SWL procedures.

Percutaneous Nephrolithotomy (PCNL)

The introduction of percutaneous endoscopic techniques for stone removal provided

a less invasive alternative to the often morbid open stone procedures such as anatrophic

nephrolithotomy for treatment of staghorn calculi. Snyder and Smith compared 75

patients treated with percutaneous nephrolithotomy (PCNL) with 25 patients undergo-

ing anatrophic nephrolithotomy for staghorn calculi and found a superior stone free rate

in the open group (100% vs 86.7%, respectively), but at the expense of higher morbidity

and longer convalescence compared with the PCNL group (68). On the other hand,

Patterson and associates reported a 91% stone free rate after PCNL in 74 patients with

struvite stones, with 89% of stone free patients remaining free of stones after 3 yr (69).

The AUA Nephrolithiasis Clinical Guidelines Panel found a median stone-free rate of

73.3% (95% confidence interval 54.7–87.4%) for PCNL management of staghorn cal-

culi in their meta-analysis, although outcomes were not stratified by infection stones

versus metabolic stones (67).

Shockwave Lithotripsy (SWL)

With the advent of SWL investigators turned to this new technology in an effort to

reduce the morbidity associated with open surgical treatment of staghorn calculi. Unfor-

tunately, these larger, branched stones were not as readily amenable to SWL treatment

as smaller, less complex stones, and success rates were inferior to those seen with the

320 Johnson and Pearle

treatment of smaller stones. Published stone-free rates for SWL monotherapy are incon-

sistent and often unacceptably low, varying from 23–86% (21). Moreover, complication

rates and need for secondary procedures are approx 31% and 42%, respectively (67).

Beck and Riehle reported a 47% stone free rate after SWL monotherapy in 33 patients

(38 kidneys) at a mean follow-up of 27 mo (70). Likewise, Michaels and Fowler achieved

a stone free state in 45% of patients and an infection-free rate of 86% in 22 patients

treated with SWL monotherapy followed by 2 wk of oral antibiotics (71). The AUA

Nephrolithiasis Clinical Guidelines Panel reported a median stone-free rate of 50%

(95% confidence interval 25.6–74.4%) for SWL monotherapy of staghorn calculi (67).

Ultimately, they recommended that SWL monotherapy should not constitute first-line

therapy for staghorn calculi.

Combination Therapy

In an effort to combine the effectiveness of PCNL with the lower morbidity of SWL,

combination therapy consisting of initial PCNL debulking followed by SWL treatment

of residual stones usually followed by percutaneous retrieval of fragments was intro-

duced. In a series of 90 patients treated with combination therapy, Schulze and col-

leagues observed a stone-free rate of 76.7% (72). However, after approx 2 yr of

follow-up, only 55% of patients remained stone free, which the authors attributed to

inadequate medical follow-up. Streem and co-workers evaluated 100 patients with

large, extensively branched calculi treated over a 10-yr period and reported a stone free

rate of only 63% at 1-mo follow-up. However, among the last 25 patients in the series,

a 70% stone free rate was achieved (73). The AUA Nephrolithiasis Clinical Guidelines

Panel reported a median stone-free rate of 80.9% (95% confidence interval 67.8–90.5%)

for combination therapy, and consequently recommended PCNL, with or without SWL,

as first line therapy for struvite staghorn calculi (67). A subsequent prospective, ran-

domized trial comparing SWL monotherapy with combination therapy reinforced this

recommendation, demonstrating a significantly greater stone-free rate in the combina-

tion therapy group (74). Despite these recommendations, however, there has been a

decreasing reliance on adjuvant SWL for treatment of residual fragments after PCNL

and an increase in the use of second look flexible nephroscopy to retrieve these small

fragments (75).

Ureteroscopy

With recent advances in ureteroscopic instrumentation and ureteroscope design along

with the introduction of the Holmium:YAG laser, ureteroscopic treatment of large,

complex stones in the kidney has been made possible. In one early study of 34 patients

with partial or complete staghorn calculi, a 50% stone free rate was achieved using 10.3–

13.3 Fr flexible ureteroscopes (76). A more recent study of 45 patients with large (>2 cm)

renal calculi including staghorn stones treated with smaller caliber 7.5–10 Fr

ureteroscopes and the Holmium:YAG laser revealed a 76% success rate (stone free or

2-mm fragments) with a single procedure and a 91% success rate after second look

ureteroscopy in 33% of patients (77). Likewise, El-Anany treated 30 patients with >2-

cm renal calculi with ureteroscopy and laser lithotripsy and achieved a success rate

(stone free or <2-mm residual fragments) of 77% with a 10% incidence of minor com-

plications (78). These studies demonstrate the feasibility of the ureteroscopic approach

to complex stones, although stone-free rates are decidedly lower than those achieved

Chapter 17 / Struvite Stones 321

with PCNL. Thus ureteroscopy may be appropriate only in select patients with a modest

stone burden who are not suitable candidates for other treatment modalities.

PROGNOSIS

Patients with infection stones remain at high risk for stone recurrence and re-infection

even after appropriate surgical treatment because of persistence of the underlying con-

ditions that initially predisposed the patient to infection. Furthermore, the presence of

residual fragments after therapy increases the likelihood of continued stone growth and

repeated infection. A meta-analysis of the literature from 1924 to 1974 evaluating open

surgical treatment of infection stones revealed a 27% incidence of recurrent stones and

a 41% incidence of persistent infection within 6.3 yr of treatment, although many of the

studies analyzed were completed before the era of widespread antibiotic use (1).

Several investigators have evaluated current long-term stone free and infection-free

rates after SWL therapy for infection stones. In a series of 33 patients (38 renal units)

treated with SWL monotherapy for staghorn calculi, Beck and Riehle reported an initial

stone free rate of 47%. At a mean follow-up of 27 mo, however, 78% of 9 kidneys with

large residual fragments and 20% of 20 kidneys initially rendered stone free demon-

strated stone re-growth (70). Furthermore, among 16 stone free patients, only one patient

experienced a recurrent infection compared with 47% experiencing recurrent infections

among the 17 patients with stable or progressive residual fragments. This study empha-

sizes the importance of a stone free state after surgery to reduce the occurrence of new

stone growth and repeated infection.

Interestingly, Michaels and Fowler suggested that prolonged treatment with antibi-

otics after SWL therapy for struvite stones in patients with preoperative Proteus mirablis

infection could result in sterilization of the urine despite the presence of residual stone

fragments. Indeed 86% of the 22 patients treated remained free of infection despite a

stone free rate of only 53%. Among the three patients with recurrent infection, all

experienced new or progressive stone growth (71). Likewise, Pode and co-workers

found that small infection stones could be treated with SWL with a reasonable likeli-

hood of remaining stone free and infection-free (79). Among 94 patients with stones

and recurrent infections treated with SWL, 67% of 59 patients with stones <2 cm in size

remained stone free and 76% remained infection free at a mean of 6.4 mo post-SWL.

In contrast, only 26% and 35% of patients with stones >2 cm remained free of stones

and infections, respectively. Among the 12 patients with staghorn calculi, 42% each

remained free of stones and infection.

Despite superior stone free rates with PCNL compared with SWL, Streem and col-

leagues noted a substantial risk of recurrent stones and infection in 44 patients with

infection stones treated with PCNL with or without adjuvant SWL followed for a mean

of 42 mo post-treatment (80). With an overall stone free rate of 73%, the authors reported

a 28% incidence of recurrent stones: 25% in patients initially rendered stone free and

33% in patients with residual fragments. By Kaplan Meier estimation, the 5-yr recur-

rence rate after aggressive endourological treatment for infection stones was 36.8%.

Furthermore, at a mean follow-up of 42 mo, 41% of patients experienced recurrent

urinary tract infections. Interestingly, statistical analysis did not show infection to be an

independent risk factor for stone recurrence.

Overall, although prolonged antimicrobial use post-treatment may sterilize the small

residual fragments associated with SWL, the best chance of remaining stone free and

322 Johnson and Pearle

infection free after surgical stone treatment appears to be associated with complete stone

clearance at the time of surgery.

CONCLUSIONS

Urinary infection with urease-producing organisms provides unique urinary condi-

tions of alkaline pH and high ammonia levels that promote the crystallization of struvite

and the formation of infection stones. Although most commonly associated with

P. mirabilis, urease can be synthesized by a variety of microorganisms. Although they

account for a small fraction of the overall stone population, infection stones, with their

high risk of recurrence, are a significant source of morbidity and expense in susceptible

patients. These stones may be suspected based on symptoms of renal colic or infection,

and the diagnosis is readily apparent with current imaging techniques. Treatment of

infection stones remains a challenge; current medical therapies are rarely effective and

are often accompanied by significant side effects. Surgical approaches are highly effec-

tive for stone removal, and procedure-related morbidity has dropped substantially in

recent years. Consequently, the role of chemolysis is limited at best and surgery consti-

tutes first line therapy. However, despite effective initial therapy, recurrent stones and

infections are common. The best outcomes are achieved in patients rendered stone free,

and prolonged antimicrobial therapy after surgical intervention may improve the out-

look for recurrent infection.

REFERENCES

1. Griffith DP. Struvite stones. 1978; Kidney Int 13: 372.

2. Griffith DP, Osborne CA. Infection (urease) stones. Miner Electrolyte Metab 1987; 13: 278.

3. Gleeson MJ, Kobashi K, Griffith DP. Noncalcium nephrolithiasis. Disorders of Bone and Mineral

Metabolism, (Coe FI, Favus MJ, eds.). Raven, New York, NY, 1992; p. 801.

4. Wong HY, Riedl CR, Griffith DP. Medical Management and Prevention of Struvite Stones. Kid-

ney Stones: Medical and Surgical Management. Lippincott-Raven, Philadelphia, PA, 1996.

5. Elliot JS, Sharp RF, Lewis L. J Urol 1959; 81: 366–368.

6. Griffith DP, Musher DM, Itin, C. Urease. The primary cause of infection-induced urinary stones.

Invest Urol 1976; 13: 346.

7. Wang LP, Wong HY, Griffith DP. Treatment options in struvite stones. Urol Clin North Am 1997;

24: 149.

8. Silverman DE, Stamey TA. Management of infection stones: the Stanford experience. Medicine

(Baltimore) 1983; 62: 44.

9. Peacock M, Robertson WC. The Biochemical Aetiology of Renal Lithiasis. Urinary Calculous

Disease, (Wickham JEA, ed.). Churchill Livingstone, Edinburgh, 1979; p. 69.

10. Rodman J S. Struvite stones. Nephron 81 Suppl 1999; 1: 50.

11. Sarmina I, Spirnak JP, Resnick MI. Urinary lithiasis in the black population: an epidemiological

study and review of the literature. J Urol 1987; 138: 14.

12. Resnick MI. Evaluation and management of infection stones. Urol Clin North Am 1981; 8: 265.

13. Kohri K, Ishikawa Y, Katoh Y, et al. Epidemiology of urolithiasis in the elderly. Int Urol Nephrol

1991; 23: 413.

14. DeVivo MJ, Fine PR, Cutter GR, Maetz HM. The risk of renal calculi in spinal cord injury patients.

J Urol 1984; 131: 857.

15. Gettman MT, Segura J W. Struvite stones: diagnosis and current treatment concepts. J Endourol

1999; 13: 653.

16. Rous, S. N. and Turner, W. R.: Retrospective study of 95 patients with staghorn calculus disease.

J Urol, 1977; 118: 902.

17. Vargas AD, Bragin SD, Mendez R. Staghorn calculis: its clinical presentation, complications and

management. J Urol 1982; 127: 860.

Chapter 17 / Struvite Stones 323

18. Wasserstein AG. Nephrolithiasis: acute management and prevention. Dis Mon 1998; 44: 196.

19. Grenabo L, Claes G, Hedelin H, Pettersson S. Rapidly recurrent renal calculi caused by Ureaplasma

urealyticum: a case report. J Urol 1986; 135: 995.

20. Rose GA, Rosenbaum TP. Recurrent infection stones with apparently negative cultures. The case

for blind antibacterial treatment. Br J Urol 1992; 69: 234.

21. Segura JW. Staghorn calculi. Urol Clin North Am 1997; 24: 71.

22. Liberman SN, Halpern EJ, Sullivan K, Bagley DH. Spiral computed tomography for staghorn

calculi. Urology 1997; 50: 519.

23. Mostafavi MR, Ernst RD, Saltzman B. Accurate determination of chemical composition of urinary

calculi by spiral computerized tomography. J Urol 1998; 159: 673.

24. Shorr E. The possible usefulness of estrogens and aluminum hydroxide gels in the management

of renal stone. J Urol 1945; 53: 507.

25. Shorr E, Carter AC. Aluminum gels in the management of renal phosphatic calculi. JAMA 1950;

144: 1549.

26. Lavengood RW Jr, Marshall VF. The prevention of renal phosphatic calculi in the presence of

infection by the Shorr regimen. J Urol 1972; 108: 368.

27. McCarrison R. Causation of stone in India. BMJ 1931; 1: 1009.

28. Higgins CC. Urinary lithiasis: experimental production and solution with clinical application and

end results. J Urol ; 36: 168.

29. Griffith DP, Bragin S, Musher DM. Dissolution of struvite urinary stones. Experimental studies

in vitro. Invest Urol 1976; 13: 351.

30. Griffith DP, Moskowitz PA, Carlton CE Jr. Adjunctive chemotherapy of infection-induced stag-

horn calculi. J Urol 1979; 121: 711.

31. Feit RM, Fair WR. The treatment of infection stones with penicillin. J Urol 1979; 122: 592.

32. Fowler JE Jr. Bacteriology of branched renal calculi and accompanying urinary tract infection. J

Urol 1984; 131: 213.

33. Cohen TD, Preminger GM. Struvite calculi. Semin Nephrol 1996; 16: 425.

34. Rao PN, Dube DA, Weightman NC, Oppenheim BA, Morris J. Prediction of septicemia following

endourological manipulation for stones in the upper urinary tract. J Urol 1991; 146: 955.

35. McAleer IM, Kaplan GW, Bradley JS, Carroll SF. Staghorn calculus endotoxin expression in

sepsis. Urology 2002; 59: 601.

36. Griffith DP, Gleeson MJ, Lee H, Longuet R, Deman E, Earle N. Randomized, double-blind trial

of Lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary cal-

culi. Eur Urol 1991; 20: 243.

37. Kobashi K, Hase J, Uehara K. Specific inhibition of urease by hydroxamic acid. Biochem Biophys

Acta 1962; 65: 380.

38. Fishbein WN, Daly JE. Urease inhibitors for hepatic coma. II. Comparative efficacy of four lower

hydroxamate homologs in vitro and in vivo. Proc Soc Exp Biol Med 1970; 134: 1083.

39. Hase J, Kobashi K, Kawaguchi N, Sakamoto K. Antimicrobial activity of hydroxamic acids. Chem

Pharm Bull (Tokyo) 1971; 19: 363.

40. Dixon NE, Gazzola C, Watters JJ, Blakely RL, Zerner B. Inhibition of Jack Bean urease (EC

3.5.1.5) by acetohydroxamic acid and by phosphoramidate. An equivalent weight for urease. J Am

Chem Soc 1975; 97: 4130.

41. Kobashi K, Takebe S, Numata A. Specific inhibition of urease by N-acylphosphoric triamides. J

Biochem (Tokyo) 1985; 98: 1681.

42. Fishbein WM, Carbone PP. Urease Catalysis: II. Inhibition of the enzyme by hydroxyurea, hy-

droxylamine, and acetohydroxamic acid. J Biol Chem 1965; 240: 2407.

43. Fishbein WN, Winter TS, Davidson JD. Urease Catalysis: I. Stoichiometery, Specificity, and

Kinetics of a second substrate: Hydroxyurea. J Biol Chem 1965; 240: 202.

44. Griffith DP, Moskowitz PA, Carlton CE Jr. Adjunctive chemotherapy of infection-induced stag-

horn calculi. J Urol 1979; 121: 711.

45. Martelli A, Buli P, Cortecchia V. Urease inhibitor therapy in infected renal stones. Eur Urol 1981;

7: 291.

46. Williams JJ, Rodman JS, Peterson CM. A randomized double-blind study of acetohydroxamic acid

in struvite nephrolithiasis. N Engl J Med 1984; 311: 760.

324 Johnson and Pearle

47. Putcha L, Griffith DP, Feldman S. Disposition of 14C-acetohydroxamic acid and 14C-acetamide

in the rat. Drug Metab Dispos 1984; 12: 438.

48. Putcha L, Griffith DP, Feldman S. Pharmacokinetics of acetohydroxamic acid in patients with

staghorn renal calculi. Eur J Clin Pharmacol 1985; 28: 439.

49. Bailie NC, Osborne CA, Leininger JR, et al. Teratogenic effect of acetohydroxamic acid in clini-

cally normal beagles. Am J Vet Res 1986; 47: 2604.

50. Rosenstein I. Therapeutic applications of urease inhibitors. J Antimicrob Chemother 1982; 10:

159.

51. Traxer O, Adams-Huet B, Pak CYC, Pearle MS. Risk of calcium oxalate stone formation with

ascorbic acid ingestion (abstract). J Urol 2001; 165: 243.

52. Rector FC, Seldin DW, Copenhaver JH. The mechanism of ammonia excretion during ammonium

chloride acidosis. J Clin Invest 1955; 34: 20.

53. Pizzarelli F, Peacock M. Effect of chronic administration of ammonium sulfate on phosphatic

stone recurrence. Nephron 1987; 46: 247.

54. Rodman JS, Vaughn JED. Chemolysis of urinary calculi. AUA Update Series 1992; 11: 1.

55. Hellstrom J. The significance of staphylococci in the development and treatment of renal and

ureteric stones. Br J Urol 1938; 10: 348.

56. Albright F, Sulkowitch HWCR. Nonsurgical aspects of the kidney stone problem. JAMA 1939;

113: 2049.

57. Suby HI, Albright F. Dissolution of phosphatic urinary calculi by the retrograde introduction of

citrate solution containing magnesium. N Engl J Med 1943; 228: 81.

58. Mulvaney WP. A new solvent for certain urinary calculi: a preliminary report. J Urol 1959; 82:

546.

59. Kohler FP. Renacidin and tissue reaction. J Urol 1962; 87: 102.

60. Fostvedt GA, Barnes RW. Complications during lavage therapy for renal calculi. J Urol 1963; 80:

329.

61. Nemoy NJ, Staney TA. Surgical, bacteriological, and biochemical management of “infection

stones”. JAMA 1971; 215: 1470.

62. Joshi HB, Kumar PV, Timoney AG. Citric acid (solution R) irrigation in the treatment of refractory

infection (struvite) stone disease: is it useful? Eur Urol 2001, 39: 586.

63. Tiselius HG, Hellgren E, Andersson A, Borrud-Ohlsson A, Eriksson I. Minimally invasive treat-

ment of infection staghorn stones with shock wave lithotripsy and chemolysis. Scand J Urol

Nephrol 1999; 33: 286.

64. Libertino JA, Newman HR, Lytton B, Weiss RM. Staghorn calculi in solitary kidneys. J Urol 1971;

105: 753.

65. Priestly JT, Dunn JH. Branched renal calculi. J Urol 1949; 61: 194.

66. Blandy JP, Singh M. The case for a more aggressive approach to staghorn stones. J Urol 1976; 115:

505.

67. Segura JW, Preminger GM, Assimos DG, et al. Nephrolithiasis Clinical Guidelines Panel sum-

mary report on the management of staghorn calculi. The American Urological Association Neph-

rolithiasis Clinical Guidelines Panel. J Urol 1994; 151: 1648.

68. Snyder JA, Smith AD. Staghorn calculi: percutaneous extraction versus anatrophic nephrolitho-

tomy. J Urol 1986; 136: 351.

69. Patterson DE, Segura JW, LeRoy AJ. Long-term follow-up of patients treated by percutaneous

ultrasonic lithotripsy for struvite staghorn calculi. J Endourol 1987; 1: 177.

70. Beck EM, Riehle RA Jr. The fate of residual fragments after extracorporeal shock wave lithotripsy

monotherapy of infection stones. J Urol 1991; 145: 6; discussion 9–10.

71. Michaels EK, Fowler JE Jr. Extracorporeal shock wave lithotripsy for struvite renal calculi:

prospective study with extended followup. J Urol 1991; 146: 728.

72. Schulze H, Hertle L, Kutta A, Graff J, Senge, T. Critical evaluation of treatment of staghorn calculi

by percutaneous nephrolithotomy and extracorporeal shock wave lithotripsy. J Urol 1989; 141:

822.

73. Streem SB, Yost A, Dolmatch B. Combination “sandwich” therapy for extensive renal calculi in

100 consecutive patients: immediate, long-term and stratified results from a 10-year experience.

J Urol 1997; 158: 342.

Chapter 17 / Struvite Stones 325

74. Meretyk S, Gofrit ON, Gafni O, et al. Complete staghorn calculi: random prospective comparison

between extracorporeal shock wave lithotripsy monotherapy and combined with percutaneous

nephrostolithotomy. J Urol 1997; 157: 780.

75. Lam HS, Lingeman JE, Mosbaugh PG, et al. Evolution of the technique of combination therapy

for staghorn calculi: a decreasing role for extracorporeal shock wave lithotripsy. J Urol 1992; 148:

1058.

76. Aso Y, Ohta N, Nakano M, Ohtawara Y, Tajima A, Kawabe K. Treatment of staghorn calculi by

fiberoptic transurethral nephrolithotripsy. J Urol 1990; 144: 17.

77. Grasso M, Conlin M, Bagley D. Retrograde ureteropyeloscopic treatment of 2 cm. or greater upper

urinary tract and minor Staghorn calculi. J Urol 1998; 160: 346.

78. El-Anany FG, Hammouda HM, Maghraby HA, Elakkad MA. Retrograde ureteropyeloscopic

holmium laser lithotripsy for large renal calculi. BJU Int 2001; 88: 850.

79. Pode D, Lenkovsky Z, Shapiro A, Pfau A. Can extracorporeal shock wave lithotripsy eradicate

persistent urinary infection associated with infected stones? J Urol 1988; 140: 257.

80. Streem SB. Long-term incidence and risk factors for recurrent stones following percutaneous

nephrostolithotomy or percutaneous nephrostolithotomy/extracorporeal shock wave lithotripsy

for infection related calculi. J Urol 1995; 153: 584.

Chapter 18 / Cystine Stone Disease 327

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From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Cystine Stone Disease

Bijan Shekarriz, MD

CONTENTS

INTRODUCTION

HISTORY

EPIDEMIOLOGY

RENAL AND INTESTINAL TRANSPORT OF CYSTINE AND DIBASIC

AMINO ACIDS

MOLECULAR AND GENETIC BASIS OF CYSTINURIA

CLINICAL PRESENTATION

DIAGNOSIS

MANAGEMENT

FUTURE PERSPECTIVES

REFERENCES

Key Words: Cystinuria; urolithiasis; calculus; urinary; stone; genetic.

INTRODUCTION

Cystinuria is an autosomal recessive disease characterized by defects in renal and

intestinal transport of dibasic amino acids including cystine, ornithine, lysine, and argi-

nine (1). The relative insolubility of cystine results in supersaturation of urine with

cystine and recurrent stone formation, which is the hallmark of the disease.

Recent advances in molecular biology have greatly improved our understanding of

the pathophysiology of this disease. However, current medical management is often

disappointing and many patients continue to suffer from recurrent stone formation

despite adequate medical management. Fortunately, with the introduction of minimally

invasive techniques, the role of open surgery for management of cystine stones has

significantly decreased.

The correct diagnosis and an understanding of the pathophysiology and clinical fea-

tures of cystinuria are important for therapeutic decision making. In the following, we