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

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Chapter 16 / Uric Acid Urolithiasis 307

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Chapter 17 / Struvite Stones 309

309

From: Current Clinical Urology, Urinary Stone Disease:

A Practical Guide to Medical and Surgical Management

Edited by: M. L. Stoller and M. V. Meng © Humana Press Inc., Totowa, NJ

Struvite Stones

D. Brooke Johnson, MD and Margaret S. Pearle, MD, PhD

CONTENTS

INTRODUCTION

COMPOSITION

PATHOGENESIS

BACTERIOLOGY

EPIDEMIOLOGY

CLINICAL PRESENTATION

NONSURGICAL TREATMENT

SURGICAL MANAGEMENT

PROGNOSIS

CONCLUSIONS

REFERENCES

Key Words: Struvite stone; urinary infection; urease; staghorn.

INTRODUCTION

The occurrence of urinary infection in patients with nephrolithiasis is not uncommon.

Although stones of any composition may occur in patients who experience urinary tract

infections owing to a variety of urinary pathogens, the term “infection stone” is reserved

for calculi that form as a direct consequence of infection with urease-producing bacteria

and the urinary environment they promote. This chapter will focus on current concepts

regarding infection stones, including their pathogenesis, clinical diagnosis and treat-

ment.

COMPOSITION

Infection calculi are composed primarily of magnesium ammonium phosphate

hexahydrate (MgNH

 6H

O) but may, in addition, contain calcium phosphate in

the form of carbonate apatite (Ca

[PO

]

 CO

) (1,2). Because infection calculi are

310 Johnson and Pearle

composed of three different cations (Ca

, Mg

, and NH

) in combination with one

anion (PO

3–

) the term “triple-phosphate stones” has been applied as well (1,2). Magne-

sium ammonium phosphate hexahydrate is also known as “struvite,” a moniker denoted

by the German chemist George Ludwig Ulex who first identified the mineral and was a

student of the Russian diplomat and naturalist Heinrich Christian Gottfried von Struve

(3). Hence the term “struvite stone” is often used interchangeably with “infection stone.”

Likewise, the term “urease stone” is also used to describe these calculi, because the

presence of urease-producing bacteria is requisite to their formation.

PATHOGENESIS

Calcium, magnesium, phosphate, and urea are normal constituents of urine at concen-

trations sufficient for stone formation. On the other hand, ammonia, bicarbonate, and

carbonate achieve concentrations sufficient for stone formation only during the process

of ureolysis (see below) (4). In order for crystallization to occur, not only must the

constituent ions and ammonia be present in adequate concentration, but urinary pH must

be 7.2 or greater also (5).

The process of ureolysis provides the alkaline urinary environment and necessary

carbonate and ammonia concentrations to induce infection stone formation. Because

urease is not present in sterile human urine, infection with urease-producing bacteria is

a prerequisite for the formation of infection stones (6). A cascade of chemical reactions

generates the conditions conducive to the formation of infection stones (Fig. 1). First,

urease catalyzes the enzymatic breakdown of urea to ammonia and carbon dioxide:

(NH

)

CO + H

O 2NH

+ CO

Fig. 1. Schematic depicting concurrent events leading to struvite stone formation.

Chapter 17 / Struvite Stones 311

Ammonia then accepts a hydrogen ion from water to form ammonium:

O NH

+ OH

–

pK = 9.0

Under physiologic conditions, alkaline urine contains low levels of ammonia. However,

the presence of urease enables the generation of additional ammonia despite an alkaline

urine, thereby further increasing urinary pH. In an alkaline environment, carbon dioxide

is hydrated to carbonic acid that then dissociates into bicarbonate and hydrogen ion.

Bicarbonate further dissociates into carbonate and two hydrogen ions:

+ H

O H

pK = 4.5

+ HCO

–

pK = 6.3

HCO

–

+ CO

2–

pK = 10.2

At the same time, the alkaline urinary conditions promote the dissociation of phosphate:

–

+ HPO

2–

pK = 7.2

HPO

2–

+ PO

3–

pK = 12.4

This chemical cascade occurring within physiologic urine leads to sufficient concentra-

tions of magnesium, ammonium, and phosphate for precipitation of struvite, and ulti-

mately the formation of struvite stones. In addition, the concentrations of calcium,

phosphate and carbonate allow precipitation of carbonate apatite and hydroxyapatite,

thus accounting for the triad of mineral constituents of human infection stones.

BACTERIOLOGY

Infection of the urinary tract with urease-producing organisms is required for the

formation of infection stones in humans. Although the species Enterobacteriaceae com-

prises the majority of urease-producing pathogens, a variety of gram-positive and gram-

negative bacteria and some yeasts and mycoplasma species have the capacity to

synthesize urease (Table 1) (3). In all, over 200 species of bacteria have been shown to

have urease activity (4) which they use to provide a nitrogen source by incorporating the

produced from urea into glutamate and glutamine (7). The largest population of

urease-producing bacteria resides within the gastrointestinal tract, and in this setting, the

organisms are symbiotic. However, a pathologic urinary tract infection may be derived

from the gastrointestinal urease-producing flora (4). The most common organism asso-

ciated with infection stones is Proteus mirablis (8).

EPIDEMIOLOGY

Historically infection stones have been thought to account for 7–31% of urinary

calculi in the Western world (9). However, a search of the database of a large stone

analysis laboratory revealed only a 2.1% (795 of 37,400) incidence of struvite-contain-

ing stones among the specimens (10). In contrast, struvite/carbonate apatite was found

to comprise the most common composition of stones in a study of urinary lithiasis in

African American patients in Ohio, accounting for a third of stones in males and nearly

50% in females in this population (11). Infection stones are most likely to occur in

patients who are pre-disposed to frequent or persistent urinary tract infections. Struvite

stones occur more often in women than men by a ratio of 2:1, most likely because of the

higher incidence of urinary tract infections in women compared with men (12). New-

312 Johnson and Pearle

borns, especially those born prematurely or with congenital urinary tract malformations,

are also at increased risk for infection stones (7). Both elderly men and women are prone

to developing infection stones because susceptibility to urinary tract infections increases

with age (13).

Urinary stasis associated with urinary tract obstruction, urinary diversion or neuro-

logic disorders also pre-disposes to urinary tract infection and infection stones. Spinal

cord injury patients are at increased risk for both infection and metabolic stones due to

neurogenic urinary tract dysfunction and hypercalciuria related to immobility. Patients

with a functionally complete cord transection are at highest risk of developing a staghorn

calculus (14). Patients with diabetes mellitus or those consuming excessive amounts of

laxatives or analgesics are at increased risk for struvite stone formation as well (15).

Lastly conclusion, a foreign body or a calcium stone nidus may become colonized with

bacteria leading to the formation of struvite stones in conjunction with existing calcium

stone disease (10).

Table 1

Organisms Commonly Associated

With Urease Production

Category Organism

• Gram Negative Proteus mirabilis

Proteus morganii

Proteus rettgeri

Proteus vulgaris

Providencia stuartii

Haemophilus influenzae

Bordetella pertussis

Bacteroides corrodens

Yersinia enterocolitica

Brucella spp.

Flavobacterium spp.

• Gram Positive Corynebacterium hofmanii

Corynebacterium ovis

Corynebacterium renale

Corynebacterium ulcerans

Micrococcus varions

Staphylococcus aureus

• Mycoplasma T-strain Mycoplasma

Ureaplasma urealyticum

• Yeast Cryptococcus humicola

Cryptococcus

Sporobolmyces

Rhodotorula

Trichosporon cutaneum

Adapted from Gleeson, Kobiashi, et al. (3).

Chapter 17 / Struvite Stones 313

CLINICAL PRESENTATION

Signs and Symptoms

A variety of clinical signs and symptoms have been associated with infection stones,

although up to 25% of patients may be asymptomatic (16,17). In many patients, symp-

toms are not due to the stone itself, but rather are attributable to the underlying conditions

predisposing to stones, such as recurrent urinary tract infections or neurogenic bladder.

When symptoms due to the stone are present they are typical of urinary tract infection

and/or renal calculi, such as flank pain, fever, dysuria, urgency, frequency, and hema-

turia. A palpable mass, hydronephrosis, acute pyelonephritis and sepsis may develop in

severe cases and may progress to acute pyonephrosis or intrarenal or perirenal abscess.

In some patients, particularly those with diabetes mellitus, xanthogranulomatous pyelone-

phritis may occur in which renal parenchyma is replaced with lipid-laden macrophages.

Progression to pyonephrosis, end-stage hydronephrosis, and xanthogranulomatous pyelo-

nephritis is usually associated with complete obstruction (17).

Laboratory Testing

Because it is nearly impossible to eradicate bacteria from infection stones, patients

commonly present with bacteriuria and/or pyuria. An abnormal urinalysis may provide

the first evidence suggesting struvite stones. Infection with a urease-positive organism

will be associated with an alkaline urine, and on microscopic examination bacteria,

leukocytes and “coffin lid-shaped” crystals may be evident (18). A urine culture is

essential for identification of the urease-producing organism and for obtaining antibi-

otic sensitivities to guide treatment prior to surgery. In cases where the urine culture

is negative but the suspicion of a struvite stone is high, infection with atypical organ-

isms such as Ureaplasma urealyticum (19), Corynebacterium urealyticum or fungal

species should be considered (20). If cultures are positive only for a non-urease-pro-

ducing organism (e.g., Escherichia coli) and a staghorn stone is present, the stone is

likely composed of a material other than struvite (21).

An elevated serum creatinine may suggest loss of renal function as a result of obstruc-

tion or parenchymal scarring due to recurrent urinary tract infections and pyelonephrits.

The urinary conditions predisposing to struvite stones place both kidneys at risk,

although involvement of only one kidney is common. Determination of differential

renal function may be necessary to establish the utility of kidney salvage versus nephre-

ctomy.

Although the urine of patients with struvite stones is usually chronically infected,

symptoms of systemic disease may be intermittent. A complete blood count can indicate

ongoing pyelonephritis or early sepsis. In some elderly or debilitated patients typical

signs of infection, such as fever, may be absent.

Radiographic Studies

Because of their characteristic appearance, struvite calculi may be suspected based on

radiographic imaging studies. Struvite stones typically grow rapidly and may fill the

entire collecting system, giving the appearance of a “staghorn”, before causing symp-

toms. The majority of staghorn stones are composed of struvite despite the relative

infrequency of struvite stones compared to calcium calculi (21). Approximately 75% of

staghorn stones are composed of a mixture of struvite, carbonate apatite and matrix (3).

314 Johnson and Pearle

Although most infection stones are radiopaque, they appear less dense than calcium

stones on plain radiographs due to their lower mineral content (3).

Although a plain abdominal radiograph will identify most staghorn calculi, an intra-

venous urogram is advisable to determine the degree of obstruction and to clarify renal

anatomy in anticipation of surgery (Fig. 2). Surprisingly, many staghorn calculi are

associated with minimal obstruction despite their large size.

Determination of renal function is prudent if the possibility of surgical intervention

is entertained. Although global renal function can be determined by serum creatinine or

creatinine clearance, differential renal function should be assessed by nuclear reno

graphy if contrast imaging studies such as intravenous urogram or contrast computerized

tomography (CT) suggest equivocal unilateral renal function (21).

Helical CT, with its multiple overlapping images, can provide precise 3-dimensional

reconstruction of the stone and collecting system that can be used to assist in surgical

planning. However, CT imaging has not been shown to be superior to plain films and

intravenous urograms solely for this purpose, and consequently CT is not currently

recommended for routine pre-operative use (22). In vitro studies have suggested that

thin-cut CT may be capable of differentiating struvite from other stone compositions

which could help treatment planning (23); unfortunately, the overlapping ranges of

Hounsfield units for stones of different compositions currently precludes use of this

technology in vivo for the definitive preoperative diagnosis of struvite stones.

NONSURGICAL TREATMENT

The treatment of struvite stones involves removal of the urinary calculus and eradi-

cation of infection with urease-producing bacteria. Only by accomplishing both these

goals is the risk to renal function eliminated and the prevention of recurrent struvite

stones assured. Without removing the stone, eradication of infections associated with

struvite stones is virtually impossible, as the stones harboring bacteria cannot be pen-

etrated by systemic antibiotics. Once a patient is rendered stone free, prevention of

further infection is critical to prevent future stone formation. Consequently, treatment of

struvite calculi requires a multi-modal approach, utilizing both medical and surgical

therapy to achieve the optimal results.

Fig. 2. Plain abdominal radiograph and intravenous urogram depicting a complete right staghorn

calculus associated with minimal obstruction.

Chapter 17 / Struvite Stones 315

Diet

Early investigators attempted to treat struvite and other phosphate-containing stones

with dietary modification based on a low calcium, low phosphorus, high fluid (3 L/d)

diet, along with aluminum gel supplementation (24,25). The aluminum gel served to

bind phosphate in the intestinal lumen, thereby reducing intestinal phosphate absorption

and subsequent urinary phosphate excretion. Retrospective evaluation of stone formers

maintained on this regimen demonstrated a reduced stone recurrence rate, particularly

when the dietary regimen was combined with antimicrobial sterilization of the urine

(26). However, compliance with this diet was difficult as it was cumbersome,

constiptating and somewhat unpalatable (26).

In the 1930s, dietary deficiency of vitamin A was thought to contribute to the forma-

tion of struvite calculi (27,28). However, vitamin A dietary supplementation is now

thought to provide little benefit in stone prevention (3).

Antimicrobial Agents

Antimicrobial treatment is directed at eradicating the causative organism, thereby

eliminating urease-production and alkaline urine. Earlier in vitro studies showed dis-

solution of struvite crystals when they were perfused with sterile, undersaturated urine

(29), and in vivo studies demonstrated at least partial dissolution of infection calculi in

urine that had been rendered sterile (30,31). However, sterilization of the urine is im-

peded by the protection from antibiotics afforded bacteria that dwell within the inter-

stices of the stone (32). Even if sterile urine can be maintained for a time, cessation of

antibiotic therapy usually results in re-infection of the urine by the organisms residing

within the stone, re-establishing the conditions conducive for struvite stone formation.

Moreover, long-term suppressive antibiotic therapy may lead to colonization with more

virulent, resistant organisms (33). Consequently, antibiotic therapy alone does not pro-

vide definitive treatment for struvite calculi.

Antimicrobial agents do, however, play an important role in the overall treatment

regimen of infection stones. Preoperative and perioperative antibiotics are essential for

preventing sepsis associated with surgical manipulation of the stone (4). Unfortunately,

the results of urine cultures obtained preoperatively do not always correspond to the

organism isolated from the stone obtained at the time of surgery (32). Preoperative

treatment with antimicrobial agents directed at culture-documented organisms and that

provides broad-spectrum coverage as well, particularly against common urease-produc-

ing bacteria, is advisable and should be initiated 1–2 wk before planned surgical inter-

vention.

Even patients without documented bacteriuria may develop bacteremia, endotoxemia

and enhanced release of tumor necrosis factor after endourologic manipulation for stone

removal, placing them at risk for sepsis syndrome (34). A recent report of death due to

sepsis in a child undergoing percutaneous stone removal for a staghorn calculus was

attributed to severe endotoxemia even though bacterial colony counts from the urine

obtained in the immediate post-operative period were remarkably low (35).

In the long term, antimicrobials may be used to reduce the severity of urinary infec-

tion despite the persistence of the organism. In addition, culture-specific antibiotics can

be effective against those organisms that are present in the urine and on the surface of

the stone, which comprise the majority of bacteria. This treatment leads to a significant

reduction in colony count, and, since the production of urease is directly proportional

316 Johnson and Pearle

to the number of organisms present, the quantity of urease decreases accordingly. A

reduction in colony count from 10

to 10

per milliliter reduces urease production by

99%, thereby limiting the rate of stone growth (2).

In patients rendered stone free by surgery, suppressive antibiotics should be admin-

istered in order to maintain sterile urine, thereby preventing the morbidity of recurrent

infection and further stone formation. One group of investigators recommended prophy-

lactic treatment until the urine is confirmed sterile by monthly cultures for three consecu-

tive months (4). Long-term, low-dose, culture-specific suppressive antibiotics may also

be the best course of therapy for those patients who are not considered surgical candi-

dates (4).

Urease Inhibitors

Ureolysis catalyzed by urease is essential for the production of struvite stones in

humans. As such, inhibition of urease should abolish the conditions that promote struvite

stone formation. Although there is ample clinical and experimental evidence demon-

strating the effectiveness of urease-inhibiting drugs such as acetohydoxamic acid, wide-

spread use of urease-inhibitors has not occurred in clinical practice due to the high

incidence of side effects including hemolytic anemia, deep venous thrombosis, neuro-

logical symptoms (headache, malaise, and nervousness/tremulousness), gastrointestinal

symptoms (anorexia, diarrhea, nausea, and vomiting), alopecia, muscle aches, rash, and

leg pain or swelling (36). Even with strict compliance, urease inhibitors only reduce the

size of the stone rather than completely eliminate the stone. In light of this information

these agents should be viewed as palliative rather than therapeutic.

The molecular structure of the R-CONHOH group, which characterizes the

hydroxamic acids, is similar to that of urea. This molecular similarity leads to specific

inhibition of urease at low concentrations (37). Aromatic hydroxamic acids inhibit

urease competitively, whereas fatty acyl hydroxamic acids inhibit noncompetitively

(3). Among the four simplest aliphatic compounds, potency decreases and side effects

increase as the carbon chain (R-) lengthens; consequently, acetohydoxamic acid, with

its short carbon chain, has the greatest pharmacologic potential (38). Phosphotriamide

derivatives have been reported to be most effective against urease derived from plants

and bacteria (39–41).

Although many urease inhibitors have been evaluated, no single agent has been shown

to inhibit urease within bacterial cells where the vast majority of urease is found and also

to have a high renal clearance and a favorable long-term safety profile (3). Currently, the

only two FDA-approved urease inhibitors are acetohydroxamic acid (AHA) and hydrox-

yurea (10). Hydroxyurea has been shown in vitro to be less effective than AHA as a

urease ihhibitor. Although hydroxyurea is an irreversible urease inhibitor, a fraction of

urease enzyme activity persists in the presence of hydroxyurea, unlike the case with

AHA (42). In addition, hydroxyurea is broken down by urease thereby liberating ammo-

nia, while AHA is inactive as a substrate (43).

AHA is the most commonly used and best-studied urease inhibitor. It has been shown

to effectively lower urinary pH and ammonia levels and to cause stone dissolution

(44,45). AHA has also been shown to retard stone growth in a placebo-controlled trial.

In a randomized, double-blind study of 37 patients with actively growing stones (18

receiving AHA and 19 controls), none of the AHA patients and seven control patients

demonstrated a doubling in size of the stone. However, nine patients receiving drug,