You are on page 1of 11

Kidney International, Vol. 13 (1978), PP.

372 —382

Struvite stones
DONALD P. GRIFFITH
The Urology Service of the Verterans Administration Hospital, the Roy and Li/lie Cut/en Department of Urologic Research,
the J. Say/es Leach Laboratory, and the Urolithiasis Laboratory, Division of Urology, Baylor College of Medicine,
Houston, Texas

Struvite, a crystalline substance first identified in
the 18th century, is composed of magnesium ammonium phosphate (MgNH4PO4 6H20). Ulex, a Swedish geologist, is generally credited with introduction
of the term struvite in 1845; he coined the geological

itinerant lithotomists, though he did not perform the

operation himself (perhaps because the mortality
was so high). Hippocrates is believed to have been
the first to recognize that high fluid intake increases
urine volume, which he also recognized as favorable
therapy. Marcet (1817) was perhaps the first to note
the association of ammonia-producing putrefaction
and urinary stones [2]. At the end of the 19th century, the observations of Horton-Smith [5], Brown
[6], Kuster [7], and Rosevig [8] established the
cause and effect relationship between urinary infection and stones. Modern therapy has been primarily
surgical in nature—based upon the procedures origi-

expression "struvite" in honor of H. C. G. von
Stuve, a Russian diplomat and naturalist (1772—1851)

[11. Von Stuve had published one of the earliest
scholarly geological works in 1807 entitled "Mineralogical Memoirs."

Struvite urinary stones have also been referred to
as "infection stones" and "triple phosphate" stones.
The term triple phosphate stems from early chemical
analyses of the stones which demonstrated the presence of calcium, magnesium, ammonium, and phosphate (i.e., three cations and one anion). Carbonate
ions were also commonly identified; they were as-

nally described by Simon, Heineke, Morris, and
Kummel [2, 4]. The discovery of penicillin and sulfanilamide [9, 10] and the widespread use of antimicrobial agents have markedly reduced the morbidity and mortality previously associated with surgical
therapy.

sumed to be associated with calcium as calcium
carbonate (CaCO3). Modern crystallographic analy-

ses have shown that human "struvite" stones are a
mixture of struvite (MgNH4PO4 6H20) and carbonate-apatite (Ca10[P04]45 C03). Calcite (CaCO3) is ex-

Patho genesis

There are five primary types of commonly encoun-

tremely rare (we have found one calcite stone in
20,000 stone analyses) and may be an artifact. In

tered urinary stones, i.e., calcium oxalate, calcium
phosphate, magnesium ammonium phosphate, uric
acid, and cystine. Calcium phosphate stones may
have variable molecular configurations. For exam-

some stones, struvite may be more abundant,
whereas in other stones apatite may predominate.
There is good evidence (to be reviewed) to link the
formation of struvite and carbonate-apatite stones to
urinary infection. For the purpose of this review,
infection-induced stones are synonymous with struvite and carbonate-apatite.

ple, calcium phosphate may exist as brushite
(CaHPO4), hydroxyapatite [Ca10(P04)6 (OH)2] or
carbonate-apatite [CalO(PO4)E C03]. Numerous
strains of bacteria cause clinically significant infection in the urinary tract. The pathogenesis of infection-induced urinary stones can be more clearly de-

Historical background (Table 1)

lined by three questions; namely 1) what type of
stones are formed in the presence of bacteria, 2)

Hippocrates was well aware of the association of
putrefying urine and stones 112—4]. He encouraged
the surgical drainage of perinephric abscesses by

what types of bacteria cause stones to form, and 3)
what is the biochemical mechanism of infection-induced stones.
Clinical observations. Numerous clinical reports
attest to the association of urea-splitting bacteria,

0085—2538/78/0013—0372 $02.20

© 1978, by the International Society of Nephrology.

372

recommended consumption of large quantities of water Noted that when urine was white and limpid (sterile). "At some time before it is discharged. Brown collected renal pelvic urine samples from both kidneys of six patients with unilateral pelvic stones and urinary infection. and the stones were analyzed chemically. and the stone was sterile and acidic in each case. Brown's observation of increased quantities of . The urine from the kidney infected with E. Co/i-infected urine) and contained increased quantities of cellular debris and protein. Urinary stones: Historical contributions Yr Contributor 4800 B. Hippocrates 980—1037 A.D. stones were soft Described branched renal calculus Discovered bacteria Discovered urea in urine Described purulent urine in pelvis and ureter in association with vesical calculus. 2) stressed need to examine nidus and shell of stone. 4) stated. The report by Brown in 1901 [8] is noteworthy. Sumner A. and the stones from these five patients were composed of struvite and carbonate-apatite. The stone-containing kidney was removed surgically. and carbonate (apatite)a stones [6—8. All strains of Proteus and both strains of Staphylococcus split urea. whereas the from this kidney was composed of uric acid and stone-containing kidney was infected with Proteus (three cases). Domagk Finding Bladder stone recovered from Egyptian mummy of this era: "nidus' '—urid acid. Calcium carbonate has been reinterpreted as carbonate-apatite. urine must always become alkaline as a result of the ammonia evolved when the process of putrefaction began and that the alkalinization thus produced is unavoidably attended with the precipitation of the phosphates contained in urine. Simon Andrew and Callander Dawson and Baker W. co/i was acidic. he suggested that crystalline salts were deposited on the organic material Described matrix concretions associated with urinary infection Demonstrated experimentally that certain bacteria have a specific stone-forming ability Stressed importance of urea-splitting bacteria in calculous formation Suggested that urease was basis of infection-induced stones Isolated and crystallized urease enzyme from jackbeans Discovered antimicrobial properties of penicillin Discovered antimicrobial properties of prontosil (sulfanilamide) struvite. stones were hard. and cystine calculi 1872 1874 1879 1880 1889 1896 1897 1901 1929 1935 Introduced concept of cystoscope 1) Described chemical technique for stone analysis. Fleming G. Brown concluded from his studies that struvite and carbonate-apatite formed as a consequence of alkalinity and the increased ammonia that resulted from the splitting of urea. The urine from the uninvolved kidney E. 11— 131. "shell' '—carbonate-apatite and struvite "I will not cut persons laboring under stone but will leave this to be done by men who are practitioners of this work. and urates.C. 3) studied solubiity of stone-forming salts in urine. The urine harboring the Proteus and Staph ylococcal infections was alkaline (as compared to its mate and the E. Unknown 460—370 B.C. when urine was thick and ropy (infected). Heineke H. coli communis (one case). Staphylococcus a/bus (two cases).B. magnesium ammonium phosphate.373 Struvite stones Table 1. and the urea-splitting character of each bacterial isolate was determined." Performed first nephrectomy for calculus Electively incised pyonephritic kidneys and removed stones. all three patients expired Performed first successful pyelolithotomy Performed first successful nephrolithotomy Performed partial nephrectomy for stones First demonstrated renal calculi with X-ray Described Proteus species in urine Demonstrated coexistence of "triple phosphate stones" and urea-splitting bacteria Noted that urinary infection increased the organic content of urine. Urinary pH and bacterial cultures were performed on each specimen." Noted association of putrefying urine and stones. introduced concept of ascending infection Accurately described calcium oxalate. Avienna 1649 1676 1720 1767 Riolan van Leeuwenhoek Boerhaave Morgani 1797 Wollaston 1806 1817 Bassini Marcet 1871 1902 G. Identical strains of bacteria were isolated from the center of the stone and urine in the three cases so studied. Morris Kummel Maclntyre Horton-Smith Brown Kuster 1907 1922 Schmorl Rosenow and Meissner 1923 1925 1926 Rosevig Hager and Magrath J.

2 2 454. the accumulated clinical evidence. carbohydrates. 29—321. 1.5 37. cellular debris. This was the first enzyme to be isolated in pure form.4 7. stones [30.1 / 14 Co3 pM/mi 5 1705. ammonia levels are quite low. When urine is physiologically alkaline. Urease splits urea according to the following equation: 0 H2N—C—NH2 urease > 2NH3 + CO2.2 8. Elliot [40] and Stamey [41] have reported the dissolution of human renal calculi. where pK of NH3 9.1 1364. Increased levels of both alkalinity and ammonia must be present for urine to be supersaturated with respect to struvite [291.6 8 10. Urease inhibitors prevent struvite crystallization in the presence of both urea and urease.9 8 682.7 . 23]. Thus. Thus. In 1926.7 113.6 8 795. Experimental investigations in vitro and in vivo suggest that sterile urine which is undersaturated with respect to struvite may dissolve struvite stones [29. Stoichiometry. It is of interest that urease was suggested to be the pathogenic basis of infection stones by Hager and McGrath in 1925 [11]. These matrix stones are composed of mucoproteins..8 i environment.5 227. The carbonate ions that exist in carbonate-apatite come from the conver- sion of bicarbonate into carbonate in an alkaline 112 105 98 91 84 77 70 S 63 56 80 75 70 65 60 40.0 1023. the urinary excretion of bicarbonate andlor carbonate is low or nonexistent—too low to result in the formation of carbonate-apatite. and pK of CO = 10. Other investigators have noted the association of gelatinous or matrix stones and urea-splitting infection [17—21]. For this major achievement in enzyme chemistry. and all found that sterile urine was invariably undersaturated with respect to struvite [27. renal tubular acidosis. etc.8 8.4 29.1 32.8 6.45.6 7. Alkalinity induced in urine by sodium hydroxide brings about crystallization of apatite but not struvite. 30.3 o40 C 42 E E 35 28 0 35 30 25 20 21 15 14 10 C 49 7 35.5 1591.7 tallization of carbonate-apatite occur only in the presence of ureolysis.0 5. 251.B.7' 55 21. Hydroxyapatite stones commonly occur (occasionally in pure forms. 27].8 8. Experimental investigations by Braude. 361. and crystals of struvite and apatite [22.6 18.8 50 045 27.4 909. Experimental data.07. 32. Thus. 32]. Experimental data from in vivo and in vitro models from several laboratories support the clinical observations and stoichiometry. Under physiologic conditions.4 pH Fig.2 6. Under physiologic and sterile pathologic conditions.33. urinary ammonia increases in response to induced acidity [28]. i.0 9.374 GrIffith protein in the urine harboring urea-splitting bacteria has been subsequently confirmed [14—16]. Physiologic urine is intermittently supersaturated with respect to calcium phosphate [33]. J. Several investigators have shown experimentally that urease-producing bacteria are the primary (if not the sole) bacteria involved in infection-induced 1250.4 5. our data is in complete agreement with similar in vitro studies reported by Elliot et al [31. Sumner received the Nobel prize in biochemistry in 1946. pK of HCOi = 6. but more commonly mixed with calcium oxalate) in conditions associated with sterile urine and increased urinary alkalinity. and CO2 + H2O H2CO3 H + HCO3 COT. however. Concentrations of bicarbonate and carbonate and alkalinity sufficient to bring about crys- 568. There has been an occasional report alluding to calculogenic properties of bacteria that do not split urea [24. 35.3 . stoichiometric considerations are in agreement with the clinical observations. Sumner isolated urease from the jackbean and identified the enzyme as a protein [341. strongly supports Brown's notions that only ureasplitting bacteria are calculogenic and that such bacteria form struvite and carbonate (apatite) stones.32 13.4 4. 1).69. Struvite crystals form only in the presence of alkalinity induced by urease or ammonium hydroxide. Most authorities believe that urine must be supersaturated for crystallization to occur 126.03.1 5. 37—39]. Urinary saturation with respect to struvite has been studied in several laboratories. Sie mien- . The biochemical changes occurring during a two-hour period following the addition of urease to normal human urine. 1137.e.: 16. H2O Further hydrolysis yields: NH3 + H2O NHt + OH-. There is good clinical evidence to suggest that Stamey's case was an infection-induced stone that dissolved during prolonged antibiotic treatment [41]. namely that struvite and carbonate-apatite stones form only as a consequence of urease-induced hydrolysis of urea.0 24.9 5 / HC03 .8 1478. cal- cium phosphate crystalluria is a common occurrence.1 341. hyperparathyroidism. In vitro studies from our laboratory show that both urea and urease must be present for bacteria to form stones [29]. such conditions occur only in the presence of ureolysis (Fig.1 (?).

Thus. available.6 98. There is no compelling evidence.6 32. pathogenesis of other types of urinary stones (i. Plainview. Inc. Clinical manifestations Table 2. (API). 1 63. which results in crystal formation. whereby infection firmed Braude's work by showing that urease causes growth of the stone. The source of these mucoproteins and their role in calculogenesis is incompletely produce urease form such stones.8 99.Y. Typically. Urease producers Organism P. and subsequent radio- graphs demonstrate the asymptomatic renal calculus.0 99. delineated.) is incompletely defined. however. Pseudomonas. Data concerning the urease- urease increases urinary levels of ammonia. N.0 2.375 Struvite stones ski. produces urease. Infection stones account for 15 to 20% of all urinary stones. to suggest that such bacteria are calculogenic.000 bacterial isolates accumulated by API. and Shapiro [421 suggest that not only does urease cause struvite stones. E. is thought to commonly produce urease. In these experiments. carbonate. rettgeri Providencia al cahfaciens Providencia stuarti Kiebsiella pneumoniae Pseudomonas aeruginosa Serratia marcescens Serratia liquefaciens Enterobacter aerogenes Citrobacterfreundii E. Only bacteria that normally induced by Proteus urinary infection [43— 451. Infected staghorn calculi can grow rapidly. which may also play a role in calculogenesis. Such calculi often form with few. Examination of more than 120. Staphylococcus albus. The clinical observation that urea-splitting infection is associated with increased quantities of urinary colloids has not. and the presence of inhibition will prevent the pyelonephritic changes the foreign body (stone) harbors and perpetuates the infection and blunts the effectiveness of antimicrobial therapy. coli rarely. The bacterial species Proteus. if any. Persistent and/or recurrent symptoms of pyelonephritis may also herald development of the stone. mirabilis P. The percentages are based on more than 120. but urease contributes to the virulence of Proteus species. N. 11803). experimental. Infection stones commonly manifest as renal or bladder calculi but infrequently as ureteral calculi. symptoms. Ureolysis by very rarely [24. been studied experimentally.6 0 0 aThe percent positive indicates the percent of bacterial isolates that gave positive indication of urease activity when utilizing the standardized assay system developed by Analytab Products Inc. Several reports attest to the difficulty (and oftentimes impossibility) of eradicating urinary infection in the presence of a stone [41. coli has been associated with stone formation duction by gram-positive bacteria is not.000 bacterial isolates indicates and/or inhibition of urease may reverse the pathological process. Urease producers. 47].0 97. Bacterial fragments (L-forms) may also produce urease [46].7 91.0 5. whereas Proteus species virtually always do so (Table 2). Namely. Bladder stones of struvite and carbonate-apatite occur commonly in association with the long-term . Elimination of the infection producing capability of various bacterial species has been accumulated by Analytab Products. hydroxyapatite. Vicious cycle. These changes are associated with an increase in urinary proteins. The role of non-urease-producing bacteria in the that E. to my knowledge. Data concerning the incidence of urease pro- calcium oxalate. clinical. and pH. coli % positives 99.Y. Infection stones may occur as the primary event. Both phe- nomena occur in the absence of infection. bicarbonate. Thus. vulgaris P.e. Plainview. urease-inhibited Proteus colonize the urinary tract without inducing pathologic change. and Klebsiella are most commonly implicated clinically in calculogenesis. Braude et al have shown that intrarenal injections of urease in rats produces struvite renal stones within 24 hr and that histological evidence of pyelonephritis occurs following intravascular injection of urease. Staghorn renal calculi (so-called because of their branched configuration) are commonly (though not always) infection-induced. 251. (200 Express Street. 200 Express Street. to my knowl- however. or infection may induce further stone formation on a pre-existing stone. 11803. and stoichiometric evidence supports specific answers to the three questions posed at the outset.6 29. a female presents with recurrent symptoms of cystitis.. These chemical changes bring about urinary supersaturation with respect to struvite and carbonate-apatite. Staphylococcus. struvite and carbonate-apatite stones form only as a consequence of the hydrolysis of urea by urease. a vicious cycle is created. Residual stones and/or residual or persistent infec- tion set the stage for recurrent stone formation. morganii P. Experimental investigations from several laboratories con- edge. Dissolution of infection stones is theoretically possible. or never. etc.

This series is composed primarily of sterile stones. If an infection-induced stone is suspected. Diagnostic evaluation of the patient with urinary stones and infection is directed toward 1) biochemi- cal evaluation of blood and urine to ascertain the presence of an underlying physiologic or metabolic abnormality. may not be curative. size. no valid statistics are available to compare the prevalence of renal loss (nephrectomy). The surgical goal is removal of all stone fragments. and Bors note an 8% incidence of renal stones in more than 1. Treatment is directed toward 1) surgical removal of all of the stone and correction of anatomical abnormalities. 53]. is not always possible in even the most expert hands (Table 3). Table 4 summarizes the incidence of recurrent stones and persistent postoperative infection in series with predominantly infection-induced renal calculi. It is also unclear as to how many of those patients with persistent post- operative infection ultimately develop recurrent stones. Renal calculi are commonly removed through a parenchymal renal incision (nephrolithotomy) [56] or through an incision into the renal pelvis (pyelolithotomy). Review of these series leaves the impression that nephrectomy and/or azotemia are . If recurrent infection stones are similar to untreated infection stones. in many cases. There are few statistics available cord injury. I have taken the liberty of recalculating the original author's data in several instances in an attempt to gain insight into the effectiveness of modern management of infection-induced renal stones. 67]. Each series contains both infection-induced and aseptic stones. then a nephrectomy rate greater than ureteral calculi is beyond the scope of this text. 2) bacteriological evaluation of the urine to ascertain the type of organism and its antimicrobial sensitivities. and recurrent stone formation can be expected in about 30% of cases within six niques involved in the removal of bladder and/or years. some surgeons also advocate removal of localized segments of the renal parenchyma that are obviously pyelonephritic [58—63]. however. Williams concludes that though the recurrence rate was high (80%) during twenty years of follow-up. 55]. and postoperative renal irrigations with stone solvents [68—73]. The most antibioticresistant organisms are ultimately selected by such treatment. Patients with infected staghorn calculi who receive no treatment have about a 50% chance of losing the The series by Williams [74] is perhaps most notewor- thy. and location of the stones. These include: regional re- nal hypothermia [64]. for recurrent stone formation is relatively common. 3) radiographic documentation of the number. 2) eradication and/or long-term suppression of urinary infection. Numerous adjunc- stone will result in "cure" of the infection in approxi- 50% is to be anticipated [54. Kawaichi. which all too often are urease-producing Proteus or Pseudomonas. however. and the surgical morbidity is small. Patients undergoing ileal conduit diversion for benign or malignant disease also tend to form struvite stones [50. Patients with untreated bilateral infected staghorn calculi are reported to have a 25% suggest that surgical removal of an infected renal mortality within five years and a 40% mortality mately 60% of cases. The operative mortality from such procedures is less than 1%. Comarr. A review of the surgical tech- expected in 40% of cases. coagulum pyelolithotomy [66. Surgical treatment. Table 3 summa- Management rizes the mortality and prevalence of stone recurrence of a number of clinical series. between infected and aseptic renal stones. are an abstracted portion of larger series. Persistent infection can be within ten years [541. the morbidity was relatively low. The recalculated data kidney [54. Most of these patients passed their stones spontaneously or else tolerated their recurrent renal calculi without significant mortality or morbidity. all stones analyzed contained struvite [48]. 55]. There is little data available on the fate of residual and/or recurrent infection stones. Complete surgical removal of all stone material. and 4) radiographic documentation of anatomical abnormalities. Patients maintained on long-term catheter drainage are commonly treated with various antimicrobial agents in a futile attempt to sterilize their urine. operative nephroscopy [65]. These are selected series which. Surgical removal of the renal calculus.000 patients treated for spinal tive surgical techniques have been developed to facilitate surgical success. bacterial localization studies may be warranted. Patients with spinal cord injury and/or neurogenic vesical dysfunction seem particularly prone to the development of infection stones [48—52]. little information is available concerning the morbidity of persistent infection and/or stone recurrence. and 3) specific treatment of any underlying metabolic disorder. The basis for the increased incidence in these patients may be in part related to the antimicrobial by means of which to compare the prevalence of recurrence and/or the morbidity of the recurrence management described previously. operative radiography. Likewise. Likewise.376 Griffith use of indwelling urethral catheters. Removal of large branched calculi may be facilitated by use of an extended pyelolithotomy [57].

Long-term (perhaps lifetime).7 — — — — — 8 141 7. b Values are estimated from author's data. In 1972. and 1968 195 1974 1974 1974 Williams [74] Mahmood and Morales [891 Wickham. Pharmacologic treatment. Lavengood. The experimental studies previously cited suggest that physiologic ur- ine. In 1975. Underlying metabolic abnormalities must be recognized and cor- rected. infrequent sequelae of sterile renal stones.0 — — — 1—5 7 17 — — 50" 25 46 60 9. culture-specific antibiotics are probably indicated so long as cessation of such agents results in reestablishment of the urinary infection. Unselected series of reports of renal lithotomy operations (pyelolithotomy and/or nephrolithotomy) for removal of renal stones No. Traditional medical therapy plays an adjunctive role to surgery in the management of infection stones. This treatment presumably works by reducing phosphaturia.2 — Barney [76] Brongersma [77] Rovsing [78] Twinem [79] Oppenheimer [80] Spence and Baird [811 Priestly and Dunn [82] Hellstrom [83] Sutherland [84] 35 100 109 202 5. Medical treatment. supplemented with Basaijel to further reduce intestinal phosphorus absorption) is of some success in preventing recurrence and/or growth of infection stones [951.8 6. Tresidder.1 23 86 340 348 0 Williams [851 554 50 4 138 4 Cabot and Crabtree [75] 1922 1924 1924 1937 1937 1939 1949 1949 1954 1963 1965 1971 Marshall. Coe. clinical inves- . Antibiotics are given preoperatively and postoperatively in an attempt to eradicate the attendant infection.4 — 54 — 22 5 5 146 — — — 33 [631 1972 1973 — Total recurrent stonesa % — Blondy [881 Barzilay and Kedar True recurrent stones % 65 son [87] 1972 Residual stones % yr 4 — 5 10b 10 18 4. I initiated a clinical protocol using anti- biotics to attempt the dissolution of infection-induced renal calculi associated with chronic ureaseproducing bacterial infection. Values are calculated from author's data.377 Struvite stones Table 3. is therefore a desirable therapeutic goal. of Author Yr 1915 operations Mortality % 66 3. The Shorr regimen (restriction of dietary phosphorus. lowdose. and Kelly [86] Smith and Boyce [56] Myrvold and Fritjofs- 1971 Singh. should not support stone growth and might bring about stone dissolution.2 9) 7b 9 98 24 — — 0 13 — — — 100 0 24 7 7 100 1729 0 15 20b 3 22 10b — 5 — — 80 20 — 1—4 10 3229 a Recurrent stones = 1011/3229 = 31% within ten years (from recalculation of authors' data). Spec jfic antimicrobial therapy. so as to render urine undersaturated with struvite and calcium phosphate.5 — — 26 — — — — 56 9 9 5. which thereby reduces urinary saturation with respect to struvite and calcium phosphate. which is undersaturated. Periodic and routine bacteriologic and radiographic follow-up is mandatory. whereas these are rather frequent sequelae of infection-induced renal stones. Elimination of bacteria with antibiotics and/or inhibition of bacterial urease can be expected to render urine undersaturated with respect to struvite and should significantly reduce (though not always to undersaturated levels) the calcium phosphate saturation. though Libertino et al have suggested recently that medical therapy may be preferable to surgical therapy in patients with infected staghorn calculi in solitary kidneys [941. and Ward [64] Boyce and Elkins [901 Wojewski and Taraszkiewiez [91] Total — Average follow-up — 49 — — 40 30 40 25 39 38 — — — — — — — 21 3.

Partial or complete stone dissolution occurred in five of these eight pa- tients. Coe. Recurrent stones = 118/435 = 27% within 6. C) several patients. . 2—4). 30.0 g per day in divided doses. Side effects have been minimal. Experimental and preliminary clinical investi- — 15c 4U 31 11 11 be 6. Selected series of reports of renal lithotomy operations (pyelolithotomy and/or nephrolithotomy) for removal of infected renal stones Yr 1924 1924 1937 1937 1939 1943 1949 1954 1968 1971 1971 1971 1971 1973 1974 Author Brongersma [77] Rovsing [78] Oppenheimer [801 Twinem [79] Higgins [92] Chute and Suby [131 Hellstrom [831 Sutherland [84] Smith and Boyce [56] Myrvold and Fritzjofsson [87] Pedersen [58] Nemoy and Stamey [93] Singh.—. and ward [64] No. The twenty-three patients with recalcitrant urea-splitting infections and renal stones were treated with AHA at a dose of 0. Details of this clinical trial are being published elsewhere [97]. Several pa- elsewhere [29. with persistent % Infected postopa % Recurrent stone5 % — — — — — — — — — — — — No.Griffith 378 Table 4. Patients with reduced renal function (creatinine clearance 30 ml! Thirty-one patients who had renal stones but no detectable underlying metabolic abnormalities with urea-splitting urinary infection were treated with culture-specific antibiotics. an effective inhibitor of urease. 96]. Every patient treated with AHA sustained a reduction E in his urinary alkalinity and ammonia (Figs. Eight of 31 patients developed and maintained sterile urine (while on antibiot- of treatment.) in a 26-yr-old paraplegic with an ileal conduit (creatinine clearance.9 several cases in which previous treatment with anti- biotics failed to achieve sterile urine. 43. 2. C a E ax 0 V cv. Reductions in urinary alkalinity and ammonia were significantly greater when obstructing stones were removed and pockets of infection drained. Values are recalculated from authors' data. treatment with AHA was used before and after surgical removal of staghorn renal calculi (Fig. 1974 No. and Blondy [88] Wojewski and Taraszkiewicz [91] wickham. 0 C a. Values are estimated from authors' data. 68 mI/mm) following a single 500-mg dose of acetohydroxamic acid (AHA). C. Combinations of AHA and culture-specific antibiotics resulted in sterilization of the urine in Time. Acetohydroxamic acid (AHA). of Sterile postop operations infection" Average follow-up yr 48 — — 129 69 23 31 — — — — — — — — 40 77 20 52 68 56 40 80 73 37 64 9 42 50 14 36 27 92 73 36 — 8 1 0 0 63 27 10 3 7 84 — — 64 54 be 74 — 0 0 1—4 18 11 3 — 56 69 15 200 49 80 26 32 68 22 36 63 60 = C Persistent postop infection = 129/315 41% (recalculated from authors' data). were added to the ongoing study.3 yr (recalculated from authors' data). 34. Tresidder. tients have been treated for as long as 30 months with AHA without adverse side effects. Symptoms disappear spontaneously or gations of AHA by our group have been reported mm) have been treated for longer than 18 months with a dose of 250 mg of AHA taken two or three times daily. Headache is relatively common during the first two days ics) for six months or longer. E E 5. a C. with recurrent stone" Boyce and Elkins [90] tigations using acetohydroxamic acid (AHA). hr Fig. Dose response af uriaary ammonia (.2 9C 3. The radiographic size of the stone has remained unchanged in the other three patients.5 to 1. Tn cv 100 E a. 5).

and Uehara [98] noted that the hydroxamic acids inhibit urease. may be preventable and. Our clinical investigations with antibiotics and AHA support Elliot [40] and Stamey's [41] contention that struvite stones. Therapy that achieves sustained undersaturation will not support calculogenesis and may facilitate stone dissolution.379 Struvite stones 3000 '5 ' 2000 E 0 E E C. None sustained any emboli. The phlebitis resolved follow- however. Control 4 2 Duration of treatment. Open circles denote Proteusinfected patients on no treatment. in many instances. rectangle enclosure mean values SD of patient controls (N = 20) with sterile urine.000 6. ileal conduits. Of the hydroxamates studied biologically.0 g per day of AHA. Urinary ammonia excretion in ten patients treated with acetohydroxamic acid (AHA) at a dose of 500 mg twice daily.000 2.000 4. These patients are now on treatment with 500 to 750 mg of AHA per day without ill effect. 3.000 C Nelithotorny Control AHA preop Postop control A HA Normals POStOP Fig. in response to mild analgesics.and postoperatively. Changes in urinary pH and ammonia induced in 23 patients during long-term treatment with acetohydroxamic acid (AHA).000 3. 99—101]. Bac- tenuria persisted postoperatively in all three patients (two with ileal conduits) despite radiographic absence of stones. The accumulated clinical and experimental evidence points to the bacterial enzyme urease as the primary calculogenic mechanism. Urinary ammonia in three patients with staghorn renal calculi and chronic Proteus urinary infection who were treated with acetohydroxamic acid (AHA) pre. closed circles denote Proteusinfected patients on AHA. significant stone dissolution has not occurred in any patient receiving AHA. function) treated with 1. Solid lines indicate patients with artificial collecting devices. dissolvable. twice daily. A complete review of urease inhibitors is and stones has been known since antiquity. It seems likely. 1000 4. These substances damage tissue and thereby contrib- ute to bacterial invasion and virulence. Kobashi. A hemolytic anemia occurred in three patients (all with reduced renal beyond the scope of this review.0 to 2. . AHA seems to have the greatest pharmacologic potential [102]. Hydroxyurea and thiourea also effectively inhibit urease [45. Other urease inhibitors. 500 mg per os. that AHA or some other inhibitor of urease will become clinically useful in the management of patients with infection stones. Increased 8. 4. In conclusion. Postoperative treatment with AHA results in near normal levels of ammonia excretion.. the association of putrefying urine ing cessation of AHA and has not recurred since reinstitution of AMA.000 Urinary ammonium. To date. in some instances. In 1962. months Fig.000 1. mg/24 hr 0 Fig. Broken lines indicate patients with intact urinary tracts. The hydrolysis of urea by urease increases urinary ammonia and alkalinity. Stone recurrence and/or stone growth also has not occurred.000 2. All inhibit urease. Our investigations lend further support to the widely held hypothesis that stones form primarily as a con- sequence of urinary supersaturation. Foley catheters. Hase. i. . Longer periods of observation and additional investigations of the pharmacokinetics and biologic tolerance of AHA are warranted. or suprapubic tubes. Three other patients with pre-existing varicose veins developed superficial phlebitis in their lower extremities. Numerous hydroxamates have been synthesized [37.e. 5. 103]. Urease inhibitors may also be of clinical use in the management of hepatic insufficiency (hyperammonemia) [104—106] and perhaps in other disease processes as well.

JAMA 36:1395—1397. bicarbonate. 1929 4. HELLSTROM J: The significance of Staphylococci in the de- velopment and treatment of renal and ureteral stones. Long-term treatment with antimicrobial agents and/or urease inhibitors can be expected to reduce the incidence of stone recurrence and/or the growth of residual stones. Surgical removal of infected renal calculi with or without removal of focal areas of pyelonephritis is practical and successful in most cases. BROWN TR: On the relation between the variety of microorganisms and the composition of stone in calculous pyelone. Thomas Co. BRUNS P. LEWIS U: Mineralogic studies of urine: The relationship of apatite. the Urolithiasis Laboratory. Matrix calculi. BOSHAMER K: Staphylokokkensteine de nieren. FLEMING A: On the antibacterial action of cultures of a no mechanism other than the hydrolysis of urea. ELLIOT JS. Bacteria that do not make urease do not contribute to the formation of struvite and carbonate-apatite. 1897 6. Don McMillian. J Urol 95:284—290. who provided insight and references pertaining to the origin of the term struvite. in The Urologic Clinics of North America. 1896—1902. NEUMANN A: Uber bakteriensteine iM nierenbecken.S. BEAL HW: Fibrinous calculi in the kidney. FINLAYSON B: Renal lithiasis in review. The role of such bacteria in the pathogenesis of other types of stones is unclear but seems unlikely. M0GG RA: Matrix calculi.380 GrfJith levels of urinary pH. Hirschwald. SPENCE }{M: Matrix stones. SuBY HI: Prevalence and importance of ureasplitting bacterial infections of the urinary tract in the formation of calculi. 54 31. influenzae. 1976 30. DOMAGK G: Em beitrag zur chemotherapie der bakteriellen infektionen. Verlag von Ferdinand Enke. the ValeAsche Foundation. 1976. Springfield. p. GARVEY FK: The amount and nature of the organic matrix in urinary calculi: A review. ELLIOT JS. Texas 77030. 1973. Chas. der harnleiter und der nebennieren. ILLYES G: Des calculs renaux recidivants.D. DANA ES: Descriptive Mineralogy. American Physiological Society. BOYCE WH. 1901 7. 1968 24. 806 2. Br J Urol 10:348—372. MARSHALL RW. 1964 21. Chas. Antimicrobial agents and/or urease inhib- itors may contribute to the clinical dissolution of infection stones in selected instances. Proc Roy Soc Med 57:935—937. J Pathol 4:210—215.. #52B 8. 1972 5. Philadelphia. Isr J Med Sci 7: 1230—1234. Gains- ville. 1929 10. discovered in the urine of a patient suffering from cystitis. 1911 18. brushite and struvite to urinary pH. ammonia. WILLIAMS DI. 1972 28. J Urol 81:366—368. Appreciation is acknowledged to Charles Mansfield. Dtsch Med Wochenschr 61:250—253. William Wood and Co. 1959 33. 35:411—415. zugleich zur behandlung der akuten. SHARP RF. Munch Med Wochenschr 79: 1951—1953. BUTT AJ: Etiologic factors. W.A. J Urol 80:269—271. 1974. in Dtsche Chirurgie. 1935 11.. Ph. MUSHER DM.B. C. however. HAGER BH. and auf grund neunundzwanjigjahriger erfahrung. JAMA 85:1352—1355. 1973 26. BrJ Urol. ROSEVIG T: Uber diagnose und behandlung der nierensteine 12:358. phritis. pp. Clin Sci 43:499-506. Urology 2:627—633. Houston. 1956 23. 1920. PEACOCK M: Calcium oxalate crystalluria and inhibitors of crystallization in recurrent renal stoneformers. Acknowledgments This work was supported in part by research grants from the Veterans Administration. Baylor College of Medicine. The long-term practicality. 1943 14. LEWIS L: The solubiity of struvite in urine.. U. SHARP RF. Reprint requests to Dr. eitrigen nephritis. in Renal Physiology. J Urol 76:213— 227. 1958 32. edited by BERGMAN E. JAMA 34:643—647. 1932 17. and effi- cacy of these agents. Washington. p. New York. MUSHER DM: Pathogenesis of infection stones. It is likely that these crystals are formed by 9.. edited by ORLOFF J. Thomas Co. 1938 13. GRIFFITH DP. 1923 Penicillium with special reference to their use in the isolation of B. ADAMS F: The Genuine Works of Hippocrates. edited by FINLAYSON B. GRIFFITH DP. 1908 19. safety. p. Springfield. 1956 3. Am J Med 45:673—683. Associate Professor of Surgery/Urology. Br J Exp Pathol 10:226—236. ALLEN TD. HANIS ML: Renal calculi. MAGRATH TB: The etiology of incrusted cystitis with alkaline urine. in Renal Lithiasis. Dtsch Med Wochenschr 37:1473—1476. Invest Urol 13:346—350. THOMAS WC. These pathological processes are accompanied by an increased urinary excretion of colloids which may also contribute to calculogenesis. Griffith. QUAIDE WL. BERLINER RW. Berlin. C. 1901 15. Stuttgart. Ann Surg 48:378—387. 1934 25. 1200 Moursund Avenue. STAMEY TA: Bacteriology of infected stones. HODGKINSON A. CHUTE R. 1925 12. 1971 . ISRAEL J: Chirurgische Klinik der Nierenkrankheiten. in Proceedings of International Colloquium on Urinary Stones. University of Florida. Prrrs RF: Production and excretion of ammonia in relation to acid-base regulation. KUSTER E: Die chirurgie der nieren. ITIN C: Urease: The primary cause of infection-induced urinary stones. Saunders Co. edited by BOYCE WH. John Wiley and Sons. Z Urol Chir carbonate bring about supersaturation of urine with subsequent crystallization of struvite and carbonateapatite. 1966 20. Donald P. MURPHY UT: The History of Urology. THOMPSON RB. 1963 22. 455 29. New York. vol 1. BOYCE WH: Organic matrix of human urinary concretions. COCHRAN M: Diurnal variations in calcium phosphate and calcium oxalate activity products in normal and stone-forming urines. this concept also awaits further clinical confirmation. References 1. J Urol Nephrol (Paris) 38:419—432. 1900 16. has not yet been confirmed. 181—212 27. HORTON-SMITH P: On bacillus Proteus urinae: A new variety of the Proteus group. chapter 15. and NIH Grant #1RO1AM-19313.. GAGE H. ROBERTSON WG. J Urol 44:590—595.

SINGH M. 1971 59. COMARR AE. J Urol Nephrol (Paris) 18:157—166. J Urol 87:647—656. 69—88 43. RATHMORE A. magnesium. 1960. GOETZ R: Experimental urolithiasis: IX. in Urinary Infections. 1975 38. Paraplegia 12:98—110. 1976 66. GIL VERNET J: New surgical concepts in removing renal calculi. 1960 69. Williams and Wilkins Co. mt Surg Abstr 91:209—240. edited by QUINN EL. Conduit study. GELLMAN AC. KELLY D: Complete longitudinal nephrolithotomy and the Shorr regimen in the . mt Urol Nephrol 5:249—260. WOJEWSKI A. pp. RovsING CM: On infection as a cause of recurrence following operations for kidney stone. COMARR AE: Dissolution of renal stones by Renacidin in patients with spinal cord injury. 1962 49. BARNES RW: Complications during lavage therapy for renal calculi. 1949 83. PRIESTLEY iT. GOETZ R: Ex- perimental urolithiasis: III. Br J Urol 21:9—16. 1957 50. J Urol 87:657—661. DUNN JH: Branched renal calculi. Am JSurg 44:348—357. MUSHER DM. BRONGERSMA H: Remote results of operations for kidney calculi. RIES SW. Nephron 12:94—114. TRESIDDER GC. 1962 73. GRIFFITH DP. 1922 77. South Med J. WILLIAMS RE: The results of conservative surgery for stone. 1969 48. Paraplegia 10:56—63. Br J (Irol 44:292—295. SHAPIRO AP: The role of bacte- rial urease in the pathogenesis of pyelonephritis. Surg Gynecol Obstet 65:829—837. BUSCHER HK: Formation of staghorn calculi and their surgical implications in paraplegics and tetraplegics. J Urol 72:331—336. ZAJACZKOWSKI T: The treatment of bilateral staghorn calculi of the kidneys. Influence of infection on Stone growth in rats. J Urol 87:102— 105. LERMAN S: Partial nephrectomy versus 381 pyelolithotomy and nephrolithotomy in the treatment of localized calculous disease of the kidney. GROVE WJ. BRAUDE Al: Production of bladder stones by L-forms. 1974 72. GRIFFEL B: Prevention of ascending pyelonephritis in mice by urease inhibitors. WRIGHT JD. Prevention and dissolution of calculi by alteration of urinary pH. VERMUELEN CW. Ann NYAcad Sci 174:896—902. J Urol 37:259—267. bacteriology and experimental production. RAGANS HD. BARZILAY BI. III. 1965 58. J Urol 111:7—8. J Urol 116:8— 10. BOYCE WH: Anatrophic nephrotomy and plastic calyrhaphy. Prevention. Br J Surg 60:230. 1962 74. 1924 78. CABOT H. GRIFFITH DP: Ileal loop urinary diversion. PEDERSEN JF: Partial nephrectomy for nephrolithiasis. ELVEHJEM CA: Prevention of urinary calculi formation in mink by alteration of urinary pH. ELLIOT iS: Spontaneous dissolution of renal calculi. in press 51. COE N. 1972 53. KENT MW. 1938 82. J Urol 72:761— 769.. Br J Urol 45:581. mt Surg 46:555—566. J Urol 112:702—705. 1968 57. SUMNER JB: The isolation and crystallization of the enzyme urease. Urol mt 20:255—288. Surg Gynecol Obstet 35:743—748. NIELSEN IM: Urolithiasis in mink: Pathology. II. 1970 47. SPENCE HM. J Urol 84:206—212. MULVANEY WP: The clinical use of Renacidin in urinary calcifications. ROCHA H. ABESHOUSE BS. BRANTLEY RG. 1974 55. CRABTREE EG: Frequency of recurrence of stone in the kidney after operation. 1966 62. ScandJ Urol Nephrol 5:171—176. FOSTVEDT GA. BARNEY JD: The question of recurrent renal calculi. ANDERSEN TA: Benureastat. VERMUELEN CW. YAWN D. invest Urol 12:146— 149. J Med Micorbiol 2:372—376. J Infect Dis 131:177—181. Surg Gynecol Obstet 21:223— 225. MEDALIA 0. KAWAICHI GK. MACLAREN DM: The influence of acetohydroxamic acid on experimental Proteus pyelonephritis. J Urol 75:602—614. 1937 81. WARD JP: One hundred cases of nephrolithotomy under hypothermia. 1974 52. J Urol 116:148—152. BRAUDE Al. 1963 86. 1972 75. STAMEY TA: Infection Stones. 1974 65. 1960 60. MARSHALL VF. Br J Urol 32:392—413. 1924 79. WICKHAM JA. KOHLER FP: Renacidin and tissue reaction. Proc Soc Exp Biol Med 85:42—44. 1971 71. Br J Urol 26:22—45. SUTHERLAND JW: Recurrence following operations for upper urinary tract stone. SHIRLEY SW: U-tube nephrostomy: An aid in the postoperative removal of retained renal stones. a urease inhibitor for the therapy of infected ureo]ysis. HELLSTROM J: Aetiological and therapeutic experiences concerning kidney and ureteric stones. 1975 44. 1973 63. 1949 84. SMITH MJB. HANI5ON JH: Coagulum pyelolithotomy using autogenous plasma and bovine thrombin. ARONSON M. Boston. BORS E: Renal calculosis of patients with traumatic cord lesions. LAVENGOOD RW JR. STEWART HH: The surgery of the kidney in the treatment of renal stone. Invest Urol 12:381—386. 1972. GITTES RF: Operative nephroscopy. CHAPMAN R. BLANDY J: The fate of the unoperated staghorn calculous. 1972 64. 1973 68. Acta Ghir Scand 57:387— 395. 1954 41. Proc Veterans Admin Spinal Cord Injury Goof 18:174. BrJ Urol 35:416—437. Urology 1:355—358. 1973 56. Urol Surv 7(3): 177—250. 1951 40. KASS EH. DRETLER STEPHEN P: The pathogenesis of urinary tract calculi occurring after ileal conduit diversion: I. with a report of 17 partial nephrectomies. J Urol 89:329—331. TWINEM FP: A study of recurrence following operations for nephrolithiasis. 213—229 42. BURR RG: Urinary calcium. 1954 39. J Biol Chem 69:435—441. J Urol 66:1—5. KEDAR SS: Surgical treatment of staghorn calculus by lower partial nephrectomy and pyelocalicolithotomy. ROSSEN RD: The role of urease in pyelonephritis resulting from urinary tract infection with Proteus. 1956 36. BAIRD SS: Recurrent renal and ureteral calculi: Management and prevention. MALAMERT M: Partial nephrectomy in renal calculus disease. OPPENHEIMER GD: Nephrectomy versus conservative oper- ation in unilateral calculous disease of the upper urinary tract. Baltimore. WILLIAMS RE: Long-term survey of 538 patients with upper urinary tract stone. pp. SIEMIENSKI J. J Urol 61:194—203. PATEL VT: The coagulum pyelolithotomy. Bogs E: Neurogenic bladder. 196 70. MALAMENT M: Renacidin: A urinary calculi solvent. PUIGVERT A: Partial nephrectomy for renal lithiases: Experience with 208 cases. 1937 80. 1954 37. 1973 54. SANT05 LCS: Relapse of urinary tract infection in the presence of urinary tract calculi: The role of bacteria within the calculi. Clinical study. Little Brown and Co. J Urol 109:204— 209.. 1945 85. KRACHT H. 1960 61. 1915 76. 1974 46. 1976 67. LEOSCHKE WL. crystals and stones in paraplegia. J Urol 99:521—527. 1926 35. 1974 45.Struvite stones 34. in Biology of Pyelonephritis. J Urol 108:689—694.

DALY JE: Urease inhibitors for hepatic coma: II. Biochern Med 1:111— 128. TAIS. SUMMERSKILL WHJ. 1967 YALE HL: The hydroxamic acids. urease by hydroxamic acid. 1970 103. patients with staghorn renal calculi. BLONOY J: The long-term results 383. Biochim Biophys Acto 65:380— 1971 88. 1971 100. BOYCE WH. 105. FRITJOFSSON A: Late results of partial ne- 98. Biochim Biophys of removal of staghom calculi by extended pyelolithotomy withoul cooling or renal artery occlusion. Jot Urol Nephrol 6:54—60. 1939 93. MARSHALL VF: The prevention of renal phosphatic calculi in the presence of infection by the Shorr regimen. 1973 90. TRE5IDDER GC. bacteriological and bio- infection stones. NEWMAN HR. Gostroeoterology 54:20—26. Chem Rev 33:209—256. acid. SUMMERSKJLL WHJ: Synthe- sis and metabolism of labeled acetohydroxamic acid. Scond J Urol Nephrol 5:57—62. MAHMOOD P. FI5HBLIN WN. Proc Soc Exp Blot Med 136:592—598.Griffith 382 tohydroxamic acid: Clinical studies of a urease inhibitor in management of staghorn calculi. LYTTON B. Br J Urol 43:658— 664. J Urol 109:772—774. 1978 1965 87. 1968 WOLPERT E.AszKiEwicz 5: On recurrences after surgical removal of renal calculi. HOFMANN AF. GIBsON JR. JAMA 113:1460—1465. GRIFFITH DP. 1971 HAsE J. Kow&sni K. MYRVOLD H. J Urol 108:368—371. Proc Soc Exp Blot Med 134:1083—1090. . chemical management of 215:1470—1476. J Urol. JBiol Chem 240:2407—2414. GRIFFITH DP. 1943 102. UEHARA K: Specific inhibition of phrectomy for renal lithiasis. NEMROY JJ. 1974 91. HASF J. 1975 97. 1971 . 1962 99. ELKINS IB: Reconstructive renal surgery fol- lowing anatrophic nephrolithotomy: Follow-up of 100 consecutive cases. 119:9—15. W0JEw5KI A. KoBAsru K. CARBONE PP: Urease catalysis: II. HASE JI: Effect of acyl residues on hydroxamic acids on ureasc inhibition. Methodology: Acetohydroxamic acid. J Urol 111:307—312. 89. LIBERTINO LAvENGOOO RW JR." JAMA 101. FEINBERG HG. KUMAKI K.4on Surg 162:366—373. 1967 1971 95. THORSELL F. MORALES PA: Extended pyelolithotomy (Gil Vernet's pyelotomy). K0BA5HI K: Inhibition of Proteos vulgoris urease by hydroxamic acids. 94. FI5HBEIN WN. hydroxylamine. SINGH M. CLINTON C. ALDRETE 35: Effects of urease inhibition in hyperammonemia: Clinical and experimental studies with acetohydroxamic 106. J Urol 105:753—757. HIGGiNS CC: Factors in recurrence of renal calculi. Comparative efficacy of four lower hydroxamate homologs in vitro and in vivo. 1974 92. Urology 5:299—302. Acto 227:429—441. a urease inhibitor. MUSHER DM: Ace- FISUBEIN WN: Urease inhibitors for hepatic coma: Inhibition of 14C-urea hydrolysis in mice by alkyl hydroxamates: I. Inhibition of the enzyme by hydroxyurea. WEIss RM: Staghorn calculi in solitary kidneys. 1965 104. MUSHER DM: Acetohydroxamic acid: Potential use in urinary infection caused by urea-splitting bacteria. J Biocheos 62:293—299. STAMEY TA: Surgical. 1971 JA. and acetohydroxamic acid. 1972 96.