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 naturebased upon the procedures origi-

expression "struvite" in honor of H. C. G. von

Stuve, a Russian diplomat and naturalist (17721851)

[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 1124]. 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,

00852538/78/00130372 $02.20

1978, by the International Society of Nephrology.

372

373

Struvite stones
Table 1. Urinary stones: Historical contributions
Yr

Contributor

4800 B.C.

Unknown

460370 B.C.

Hippocrates

9801037 A.D.

Avienna

1649
1676
1720
1767

Riolan
van Leeuwenhoek
Boerhaave
Morgani

1797

Wollaston

1806
1817

Bassini
Marcet

1871

1902

G. Simon
Andrew and Callander
Dawson and Baker
W. Heineke
H. Morris
Kummel
Maclntyre
Horton-Smith
Brown
Kuster

1907
1922

Schmorl
Rosenow and Meissner

1923
1925
1926

Rosevig
Hager and Magrath
J.B. Sumner
A. Fleming
G. Domagk

Finding

Bladder stone recovered from Egyptian mummy of this era: "nidus' 'urid acid;
"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."
Noted association of putrefying urine and stones; recommended consumption of large
quantities of water
Noted that when urine was white and limpid (sterile), stones were hard; when urine
was thick and ropy (infected), 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;
introduced concept of ascending infection
Accurately described calcium oxalate, magnesium ammonium phosphate, and cystine
calculi

1872
1874
1879
1880
1889
1896
1897
1901

1929
1935

Introduced concept of cystoscope

1) Described chemical technique for stone analysis, 2) stressed need to examine nidus
and shell of stone, 3) studied solubiity of stone-forming salts in urine, 4) stated, "At
some time before it is discharged, 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."
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; 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, and carbonate (apatite)a stones [68, 11

131.

The report by Brown in 1901 [8] is noteworthy.

Brown collected renal pelvic urine samples from
both kidneys of six patients with unilateral pelvic
stones and urinary infection. Urinary pH and bacterial cultures were performed on each specimen, and
the urea-splitting character of each bacterial isolate
was determined. The stone-containing kidney was
removed surgically, and the stones were analyzed
chemically. The urine from the uninvolved kidney

E. coli communis (one case). The urine harboring the

Proteus and Staph ylococcal infections was alkaline

(as compared to its mate and the E. Co/i-infected

urine) and contained increased quantities of cellular
debris and protein. All strains of Proteus and both
strains of Staphylococcus split urea, and the stones
from these five patients were composed of struvite
and carbonate-apatite. Identical strains of bacteria
were isolated from the center of the stone and urine

in the three cases so studied. The urine from the

kidney infected with E. co/i was acidic, and the stone

was sterile and acidic in each case, whereas the

from this kidney was composed of uric acid and

stone-containing kidney was infected with Proteus

(three cases), Staphylococcus a/bus (two cases), and

urates. 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.

Calcium carbonate has been reinterpreted as carbonate-apatite.

Brown's observation of increased quantities of

374

GrIffith

protein in the urine harboring urea-splitting bacteria

has been subsequently confirmed [1416].
Other investigators have noted the association of
gelatinous or matrix stones and urea-splitting infection [1721]. These matrix stones are composed of
mucoproteins, carbohydrates, cellular debris, and
crystals of struvite and apatite [22, 23]. There has
been an occasional report alluding to calculogenic
properties of bacteria that do not split urea [24, 251;

the accumulated clinical evidence, however,

strongly supports Brown's notions that only ureasplitting bacteria are calculogenic and that such bacteria form struvite and carbonate (apatite) stones.
Stoichiometry. Most authorities believe that urine

must be supersaturated for crystallization to occur

126, 27]. Under physiologic conditions, urinary ammonia increases in response to induced acidity [28].
When urine is physiologically alkaline, ammonia levels are quite low. Increased levels of both alkalinity
and ammonia must be present for urine to be supersaturated with respect to struvite [291; such conditions occur only in the presence of ureolysis (Fig. 1).
Urinary saturation with respect to struvite has been

studied in several laboratories, and all found that

sterile urine was invariably undersaturated with respect to struvite [27, 29321.

Physiologic urine is intermittently supersaturated

with respect to calcium phosphate [33]. Thus, cal-

cium phosphate crystalluria is a common occurrence. Hydroxyapatite stones commonly occur (occasionally in pure forms, but more commonly mixed
with calcium oxalate) in conditions associated with
sterile urine and increased urinary alkalinity, i.e.,

renal tubular acidosis, hyperparathyroidism, etc.

Under physiologic and sterile pathologic conditions,
the urinary excretion of bicarbonate andlor carbonate is low or nonexistenttoo low to result in the
formation of carbonate-apatite. 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

63
56

80
75
70
65
60

40.5
37.8

50
045

27.0
24.3

o40

C 42
E
E 35
28

0 35
30
25
20

21

15

14

10

49

35.1

32.4
29.7'

55

21.6
18.9 5

/ HC03
.1

/ 14

Co3 pM/mi

1705.5
1591.8
1478.1
1364.4

909.6

795.9 8
682.2 2
454.8

8.1

341.1

5.4
4.7

113.7

tallization of carbonate-apatite occur only in the

presence of ureolysis.

Urease splits urea according to the following

equation:

0
H2NCNH2

urease
> 2NH3 + CO2.
H2O

Further hydrolysis yields:

NH3 + H2O NHt + OH-,

and CO2 + H2O H2CO3 H + HCO3 COT,
where pK of NH3 9.03, pK of HCOi = 6.33, and
pK of CO = 10.1 (?). Thus, stoichiometric considerations are in agreement with the clinical observations, namely that struvite and carbonate-apatite
stones form only as a consequence of urease-induced

hydrolysis of urea. It is of interest that urease was

suggested to be the pathogenic basis of infection
stones by Hager and McGrath in 1925 [11]. In 1926,
J.B. Sumner isolated urease from the jackbean and
identified the enzyme as a protein [341. This was the

first enzyme to be isolated in pure form. For this

major achievement in enzyme chemistry, Sumner
received the Nobel prize in biochemistry in 1946.

Experimental data. Experimental data from in

vivo and in vitro models from several laboratories
support the clinical observations and stoichiometry.
In vitro studies from our laboratory show that both
urea and urease must be present for bacteria to form
stones [29]. Urease inhibitors prevent struvite crystallization in the presence of both urea and urease.
Struvite crystals form only in the presence of alkalinity induced by urease or ammonium hydroxide. Alkalinity induced in urine by sodium hydroxide brings

about crystallization of apatite but not struvite.

Thus, our data is in complete agreement with similar
in vitro studies reported by Elliot et al [31, 32].
Several investigators have shown experimentally
that urease-producing bacteria are the primary (if not

the sole) bacteria involved in infection-induced

1250.7 .
1137.0
1023.3 .:

16.32
13.6 8
10.8 i

environment. Concentrations of bicarbonate and carbonate and alkalinity sufficient to bring about crys-

568.5

227.4

5.0 5.45.8 6.2 6.6 7.07.4 7.8 8.2 8.69.0 9.4

pH

Fig. 1. The biochemical changes occurring during a two-hour

period following the addition of urease to normal human urine.

stones [30, 35, 361. Experimental investigations in

vitro and in vivo suggest that sterile urine which is
undersaturated with respect to struvite may dissolve
struvite stones [29, 30, 32, 3739]. Elliot [40] and
Stamey [41] have reported the dissolution of human
renal calculi. There is good clinical evidence to suggest that Stamey's case was an infection-induced

stone that dissolved during prolonged antibiotic

treatment [41].
Experimental investigations by Braude, Sie mien-

375

Struvite stones

ski, and Shapiro [421 suggest that not only does

urease cause struvite stones, but urease contributes

to the virulence of Proteus species. 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. Both phe-

nomena occur in the absence of infection. Experimental investigations from several laboratories con-

edge, available. Staphylococcus albus, however, is

thought to commonly produce urease. Bacterial fragments (L-forms) may also produce urease [46].
Vicious cycle. Several reports attest to the difficulty (and oftentimes impossibility) of eradicating
urinary infection in the presence of a stone [41, 47].
Residual stones and/or residual or persistent infec-

tion set the stage for recurrent stone formation.

Thus, a vicious cycle is created, whereby infection

firmed Braude's work by showing that urease

causes growth of the stone, 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.
Thus, clinical, experimental, and stoichiometric
evidence supports specific answers to the three questions posed at the outset. Namely, struvite and carbonate-apatite stones form only as a consequence of
the hydrolysis of urea by urease. Only bacteria that

normally induced by Proteus urinary infection [43

451. In these experiments, urease-inhibited Proteus

colonize the urinary tract without inducing pathologic change.

The clinical observation that urea-splitting infection is associated with increased quantities of urinary

colloids has not, to my knowledge, been studied

experimentally. The source of these mucoproteins
and their role in calculogenesis is incompletely

produce urease form such stones. Ureolysis by

very rarely [24, 251. Data concerning the urease-

urease increases urinary levels of ammonia, bicarbonate, carbonate, and pH. These chemical changes
bring about urinary supersaturation with respect to
struvite and carbonate-apatite, which results in crystal formation. These changes are associated with an
increase in urinary proteins, which may also play a
role in calculogenesis. Elimination of the infection

producing capability of various bacterial species has

been accumulated by Analytab Products, Inc. (200
Express Street, Plainview, N.Y. 11803). Examination of more than 120,000 bacterial isolates indicates

and/or inhibition of urease may reverse the pathological process. Dissolution of infection stones is theoretically possible.
The role of non-urease-producing bacteria in the

that E. coli rarely, or never, produces urease,

pathogenesis of other types of urinary stones (i.e.,

whereas Proteus species virtually always do so (Table 2). Data concerning the incidence of urease pro-

calcium oxalate, hydroxyapatite, etc.) is incompletely defined. There is no compelling evidence,

delineated.
Urease producers. The bacterial species Proteus,

Staphylococcus, Pseudomonas, and Klebsiella are

most commonly implicated clinically in calculogenesis. E. coli has been associated with stone formation

duction by gram-positive bacteria is not, to my knowl-

however, to suggest that such bacteria are

calculogenic.
Clinical manifestations

Table 2. Urease producers

Organism

P. vulgaris
P. mirabilis
P. morganii

P. rettgeri
Providencia al cahfaciens
Providencia stuarti
Kiebsiella pneumoniae
Pseudomonas aeruginosa
Serratia marcescens
Serratia liquefaciens
Enterobacter aerogenes
Citrobacterfreundii
E. coli

% positives
99.6
98.7
91.8
99.0
99.0
97. 1

63.6
32.6
29.0

5.0
2.6
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.
(API), 200 Express Street, Plainview, N.Y. 11803. The percentages are based on more than 120,000 bacterial isolates accumulated by API.

Infection stones account for 15 to 20% of all urinary stones. Infection stones may occur as the primary event, or infection may induce further stone
formation on a pre-existing stone. Infection stones
commonly manifest as renal or bladder calculi but
infrequently as ureteral calculi.
Staghorn renal calculi (so-called because of their
branched configuration) are commonly (though not
always) infection-induced. Infected staghorn calculi
can grow rapidly. Such calculi often form with few, if

any, symptoms. Typically, a female presents with

recurrent symptoms of cystitis, and subsequent radio-

graphs demonstrate the asymptomatic renal calculus. Persistent and/or recurrent symptoms of pyelonephritis may also herald development of the stone.
Bladder stones of struvite and carbonate-apatite
occur commonly in association with the long-term

376

Griffith

use of indwelling urethral catheters. Patients maintained on long-term catheter drainage are commonly
treated with various antimicrobial agents in a futile
attempt to sterilize their urine. The most antibioticresistant organisms are ultimately selected by such
treatment, which all too often are urease-producing
Proteus or Pseudomonas.
Patients with spinal cord injury and/or neurogenic
vesical dysfunction seem particularly prone to the
development of infection stones [4852]. Comarr,
Kawaichi, and Bors note an 8% incidence of renal
stones in more than 1,000 patients treated for spinal

tive surgical techniques have been developed to facilitate surgical success. These include: regional re-

nal hypothermia [64], operative radiography,

operative nephroscopy [65], coagulum pyelolithotomy [66, 67], and postoperative renal irrigations with
stone solvents [6873]. Complete surgical removal
of all stone material, however, is not always possible
in even the most expert hands (Table 3). The operative mortality from such procedures is less than 1%,
and the surgical morbidity is small.

Surgical removal of the renal calculus, however,

may not be curative, for recurrent stone formation is
relatively common. There are few statistics available

cord injury; all stones analyzed contained struvite

[48]. 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. Patients undergoing ileal conduit diversion for benign or malignant
disease also tend to form struvite stones [50, 53].

between infected and aseptic renal stones. Likewise,

no valid statistics are available to compare the prevalence of renal loss (nephrectomy). Table 3 summa-

Management

rizes the mortality and prevalence of stone recurrence of a number of clinical series. Each series
contains both infection-induced and aseptic stones.

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, 2) bacteriological evaluation of the urine to ascertain the type of organism and its antimicrobial sensitivities, 3) radiographic documentation
of the number, size, and location of the stones, and
4) radiographic documentation of anatomical abnormalities. If an infection-induced stone is suspected,
bacterial localization studies may be warranted.
Treatment is directed toward 1) surgical removal

of all of the stone and correction of anatomical

abnormalities, 2) eradication and/or long-term
suppression of urinary infection, and 3) specific
treatment of any underlying metabolic disorder. 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. This series is composed primarily of sterile

stones. Williams concludes that though the recurrence rate was high (80%) during twenty years of
follow-up, the morbidity was relatively low. Most of
these patients passed their stones spontaneously or

else tolerated their recurrent renal calculi without

significant mortality or morbidity.

Table 4 summarizes the incidence of recurrent

stones and persistent postoperative infection in series with predominantly infection-induced renal calculi. These are selected series which, in many cases,

are an abstracted portion of larger series. 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. The recalculated data

kidney [54, 55]. 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. Persistent infection can be

within ten years [541.

Surgical treatment. A review of the surgical tech-

expected in 40% of cases, and recurrent stone formation can be expected in about 30% of cases within six

niques involved in the removal of bladder and/or

years. There is little data available on the fate of

residual and/or recurrent infection stones. If recurrent infection stones are similar to untreated infection stones, then a nephrectomy rate greater than

ureteral calculi is beyond the scope of this text.

Renal calculi are commonly removed through a
parenchymal renal incision (nephrolithotomy) [56] or
through an incision into the renal pelvis (pyelolithotomy). Removal of large branched calculi may be

facilitated by use of an extended pyelolithotomy

[57]. The surgical goal is removal of all stone fragments; some surgeons also advocate removal of localized segments of the renal parenchyma that are
obviously pyelonephritic [5863]. Numerous adjunc-

stone will result in "cure" of the infection in approxi-

50% is to be anticipated [54, 55]. It is also unclear as

to how many of those patients with persistent post-

operative infection ultimately develop recurrent

stones. Likewise, little information is available concerning the morbidity of persistent infection and/or
stone recurrence. Review of these series leaves the

impression that nephrectomy and/or azotemia are

377

Struvite stones

Table 3. Unselected series of reports of renal lithotomy operations (pyelolithotomy and/or nephrolithotomy) for removal of renal stones

No. of
Author

Yr
1915

operations

Mortality
%

66

3.2

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

5.7

141

7.1

23

86
340
348

Williams [851

554
50

138

Cabot and Crabtree

[75]

1922
1924
1924
1937
1937
1939
1949
1949
1954
1963
1965

1971

Marshall, Lavengood,
and Kelly [86]
Smith and Boyce [56]
Myrvold and Fritjofs-

1971

Singh, Tresidder, and

1968

195

1974

1974
1974

Williams [74]
Mahmood and Morales [891
Wickham, Coe, and
Ward [64]
Boyce and Elkins [901
Wojewski and Taraszkiewiez [91]

Total

Average
follow-up

49

40
30
40
25
39
38

21

3.0

15

17

50"

25
46
60
9.5

26

56

5.4

54

22

146

33

[631
1972
1973

Total
recurrent
stonesa
%

Blondy [881

Barzilay and Kedar

True
recurrent
stones
%

65

son [87]
1972

Residual
stones
%

yr

5
10b

10
18

4.8
6.2
9)
7b

98
24

13

100

24

100
1729

15

20b

22

10b

80

20

14

10

3229

a Recurrent stones = 1011/3229 = 31% within ten years (from recalculation of authors' data).
b
Values are estimated from author's data.

Values are calculated from author's data.

infrequent sequelae of sterile renal stones, whereas

these are rather frequent sequelae of infection-induced renal stones.

Medical treatment. Traditional medical therapy

plays an adjunctive role to surgery in the management of infection stones, 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. Underlying
metabolic abnormalities must be recognized and cor-

rected. Antibiotics are given preoperatively and

postoperatively in an attempt to eradicate the attendant infection. Long-term (perhaps lifetime), lowdose, culture-specific antibiotics are probably indicated so long as cessation of such agents results in
reestablishment of the urinary infection. Periodic and
routine bacteriologic and radiographic follow-up is
mandatory.
The Shorr regimen (restriction of dietary phosphorus, supplemented with Basaijel to further reduce
intestinal phosphorus absorption) is of some success

in preventing recurrence and/or growth of infection

stones [951. This treatment presumably works by
reducing phosphaturia, which thereby reduces urinary saturation with respect to struvite and calcium
phosphate.
Spec jfic antimicrobial therapy. The experimental
studies previously cited suggest that physiologic ur-

ine, which is undersaturated, should not support

stone growth and might bring about stone dissolution. Pharmacologic treatment, so as to render urine
undersaturated with struvite and calcium phosphate,
is therefore a desirable therapeutic goal. 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.
In 1972, I initiated a clinical protocol using anti-

biotics to attempt the dissolution of infection-induced renal calculi associated with chronic ureaseproducing bacterial infection. In 1975, clinical inves-

Griffith

378

Table 4. 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, Tresidder, and
Blondy [88]
Wojewski and Taraszkiewicz [91]

wickham, Coe, and

ward [64]

No. with
persistent

Infected
postopa
%

Recurrent
stone5
%

No. 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

63

27

10

3
7

84

64

54

be

74

14

18

11

56
69
15

200
49
80

26

32

68

22
36
63
60
=
C Persistent postop infection = 129/315 41% (recalculated from authors' data).
Recurrent stones = 118/435 = 27% within 6.3 yr (recalculated from authors' data).
Values are estimated from authors' data.
Values are recalculated from authors' data.

1974

No. with
recurrent
stone"

Boyce and Elkins [90]

tigations using acetohydroxamic acid (AHA), an effective inhibitor of urease, were added to the ongoing
study. Experimental and preliminary clinical investi-

15c
4U

31
11
11

be
6.2
9C

3.9

several cases in which previous treatment with anti-

biotics failed to achieve sterile urine. Several pa-

elsewhere [29, 30, 34, 43, 96].

tients have been treated for as long as 30 months with

AHA without adverse side effects. 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. Eight of 31 patients developed and maintained sterile urine (while on antibiot-

of treatment. 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. Side effects have been minimal. Headache is relatively common during the first two days

ics) for six months or longer. Partial or complete

stone dissolution occurred in five of these eight pa-

tients. The radiographic size of the stone has remained unchanged in the other three patients.
Acetohydroxamic acid (AHA). The twenty-three
patients with recalcitrant urea-splitting infections
and renal stones were treated with AHA at a dose of
0.5 to 1.0 g per day in divided doses. Details of this
clinical trial are being published elsewhere [97]. Every patient treated with AHA sustained a reduction

in his urinary alkalinity and ammonia (Figs. 24). Tn

cv

100
E

a,
C,

a
C,

ax
0
V
cv,

E
E
5,

a,
C)

several patients, treatment with AHA was used before and after surgical removal of staghorn renal
calculi (Fig. 5). Reductions in urinary alkalinity and
ammonia were significantly greater when obstructing

stones were removed and pockets of infection

drained. Combinations of AHA and culture-specific

antibiotics resulted in sterilization of the urine in

Time, hr

Fig. 2. Dose response af uriaary ammonia (..) in a 26-yr-old

paraplegic with an ileal conduit (creatinine clearance, 68 mI/mm)
following a single 500-mg dose of acetohydroxamic acid (AHA).

379

Struvite stones

3000

'5

' 2000
E

0
E
E

C,

. 1000
4,000

3,000
2,000
1,000
Urinary ammonium, mg/24 hr

Fig. 3. Changes in urinary pH and ammonia induced in 23 patients during long-term treatment with acetohydroxamic acid
(AHA), 500 mg per os, twice daily. Open circles denote Proteusinfected patients on no treatment; closed circles denote Proteusinfected patients on AHA; rectangle enclosure mean values SD
of patient controls (N = 20) with sterile urine.

Control

Duration of treatment, months

Fig. 4. Urinary ammonia excretion in ten patients treated with

acetohydroxamic acid (AHA) at a dose of 500 mg twice daily.
Solid lines indicate patients with artificial collecting devices, i.e.,
Foley catheters, ileal conduits, or suprapubic tubes. Broken lines
indicate patients with intact urinary tracts.

in response to mild analgesics. A hemolytic anemia

occurred in three patients (all with reduced renal

beyond the scope of this review. It seems likely,

function) treated with 1.0 to 2.0 g per day of AHA.

These patients are now on treatment with 500 to 750
mg of AHA per day without ill effect. Three other
patients with pre-existing varicose veins developed
superficial phlebitis in their lower extremities. None
sustained any emboli. The phlebitis resolved follow-

however, that AHA or some other inhibitor of urease

will become clinically useful in the management of
patients with infection stones. Urease inhibitors may
also be of clinical use in the management of hepatic
insufficiency (hyperammonemia) [104106] and perhaps in other disease processes as well.
In conclusion, the association of putrefying urine

ing cessation of AHA and has not recurred since

reinstitution of AMA.

To date, significant stone dissolution has not occurred in any patient receiving AHA. Stone recurrence and/or stone growth also has not occurred.
Longer periods of observation and additional investigations of the pharmacokinetics and biologic tolerance of AHA are warranted.
Our clinical investigations with antibiotics and
AHA support Elliot [40] and Stamey's [41] contention that struvite stones, in many instances, may be

preventable and, in some instances, dissolvable.

Our investigations lend further support to the widely
held hypothesis that stones form primarily as a con-

sequence of urinary supersaturation. Therapy that

achieves sustained undersaturation will not support
calculogenesis and may facilitate stone dissolution.
Other urease inhibitors. In 1962, Kobashi, Hase,
and Uehara [98] noted that the hydroxamic acids
inhibit urease. Numerous hydroxamates have been
synthesized [37, 99101]. All inhibit urease. Of the
hydroxamates studied biologically, AHA seems to
have the greatest pharmacologic potential [102]. Hydroxyurea and thiourea also effectively inhibit urease
[45, 103]. A complete review of urease inhibitors is

and stones has been known since antiquity. The

accumulated clinical and experimental evidence
points to the bacterial enzyme urease as the primary
calculogenic mechanism. The hydrolysis of urea by

urease increases urinary ammonia and alkalinity.

These substances damage tissue and thereby contrib-

ute to bacterial invasion and virulence. Increased

8,000
6,000

4,000
2,000
C

Nelithotorny
Control

AHA
preop

Postop

control

A HA

Normals

POStOP

Fig. 5. Urinary ammonia in three patients with staghorn renal

calculi and chronic Proteus urinary infection who were treated

with acetohydroxamic acid (AHA) pre- and postoperatively. Bac-

tenuria persisted postoperatively in all three patients (two with

ileal conduits) despite radiographic absence of stones. Postoperative treatment with AHA results in near normal levels of ammonia
excretion.

380

GrfJith

levels of urinary pH, ammonia, bicarbonate, and

auf grund neunundzwanjigjahriger erfahrung. Z Urol Chir

carbonate bring about supersaturation of urine with

subsequent crystallization of struvite and carbonateapatite. It is likely that these crystals are formed by

9. FLEMING A: On the antibacterial action of cultures of a

no mechanism other than the hydrolysis of urea.

These pathological processes are accompanied by an
increased urinary excretion of colloids which may
also contribute to calculogenesis.
Bacteria that do not make urease do not contribute

to the formation of struvite and carbonate-apatite.

The role of such bacteria in the pathogenesis of other
types of stones is unclear but seems unlikely.
Surgical removal of infected renal calculi with or
without removal of focal areas of pyelonephritis is

practical and successful in most cases. 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. The long-term practicality, safety, and effi-

cacy of these agents, however, has not yet been

confirmed. Antimicrobial agents and/or urease inhib-

itors may contribute to the clinical dissolution of

infection stones in selected instances; this concept
also awaits further clinical confirmation.
Acknowledgments

This work was supported in part by research

grants from the Veterans Administration, the ValeAsche Foundation, Don McMillian, the Urolithiasis
Laboratory, and NIH Grant #1RO1AM-19313. Appreciation is acknowledged to Charles Mansfield,
Ph.D., who provided insight and references pertaining to the origin of the term struvite.
Reprint requests to Dr. Donald P. Griffith, Associate Professor
of Surgery/Urology, Baylor College of Medicine, 1200 Moursund
Avenue, Houston, Texas 77030, U.S.A.

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