Struvite Stones

Nephron 1999;81(suppl 1):50–59

Struvite Stones

John S. Rodman

Division of Clinical Pharmacology, Department of Medicine, Cornell University School of Medicine, and

Division of Nephrology, Department of Medicine, Lenox Hill Hospital, New York, N.Y., USA

John S. Rodman, MD435 East 57th StreetNew York, NY 10021 (USA)

ABCFax + 41 61 306 12 34E-Mail [email protected]

© 1999 S. Karger AG, Basel0028–2766/99/0815–0050$17.50/0

Accessible online at:http://BioMedNet.com/karger

Key WordsStruvite W Kidney stones W Urease

AbstractStruvite stones constitute only about 2–3% of the stones

reaching the laboratory for analysis, but the clinical prob-

lems they create including sepsis and even renal demise

are greater than with any other stone type. This article

reviews the evidence that bacterial urease, usually from

a Proteus species, is responsible for the chemical

changes in urine which result in struvite formation.

Available urease inhibitors and other forms of medical

management of patients with these stones are dis-

cussed. A patient with struvite stones should be as-

sumed to have a progressive disease which cannot be

ignored. Even after seemingly successful elimination of

stones with lithotripsy and/or percutaneous nephrolitho-

tomy, careful medical follow-up is critical. The medical

profession is probably underutilizing postprocedure

hemiacidrin irrigation because of shortsighted financial

considerations. Primary-care physicians need to be edu-

cated in the importance of aggressive management of

Proteus and other urea-splitting infections.

Introduction

Magnesium ammonium phosphate (struvite) calculirepresent only a small percentage of all urinary stones, butthe morbidity and even mortality they cause are dispro-portionate to the small numbers of patients involved. Thetendency for them to recur and the clinical problems theycreate have caused some to refer to them as ‘stone can-cer’ [1].

Data from the 1970s [2] indicated that struvite stonesrepresented about 15% of the specimens sent to a special-ty laboratory for analysis. Clearly, this figure overreportsthe incidence of infection stones, since many small, spon-taneously passed calculi are never caught and certainly donot have their chemical composition determined. Thelaboratory figures are obviously weighted toward speci-mens obtained during surgery and other urological proce-dures. However, I asked Urocor Inc. (Oklahoma City,Okla., USA) [personal commun.] to search their data basefor struvite-containing stones. Of 37,400 specimens, only795 contained some struvite or about 2%. Is the frequencyof infection stones decreasing? Has our management ofurinary tract infections improved, so that infection-induced stone disease is less common? Or, are these fig-ures misleading?

Struvite stones almost always contain admixed carbon-ate apatite. Because three different cations are present,calcium in the apatite, plus magnesium and ammoniumin the struvite, these stones are often called triple phos-phate. When the amorphous mixture of these two miner-

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Struvite Stones Nephron 1999;81(suppl 1):50–59 51

als sends calculus branches into the renal calyces, the term‘staghorn’ calculus may be applied because of the resem-blance to the antlers of a male deer. Staghorns may resultfrom uninfected cystine or uric acid stones, but the amor-phous quality of the triple phosphate mineral mixturemakes it particularly likely to mold into the form of theurinary tract.

Infected stones containing struvite may originate denovo but often form when preexisting stones are colon-ized with Proteus or other bacteria. A not unusual historyis that a somewhat obese woman will have a few episodesof calcium oxalate stones and then present a few years lat-er with a branching calculus containing struvite.

Patients with struvite stones can suffer from frequentepisodes of pyelonephritis; if the amount of intrarenalobstruction is considerable, perinephric abscesses mayform. An episode of stone passage can become life-threat-ening if renal pelvic pressures increase and pyelovenousbackflow occurs. In this situation, there is essentiallydirect infusion of bacteria into the bloodstream withresultant gram-negative sepsis.

As discussed below, struvite stone disease should al-ways be assumed to be progressive. In some cases, particu-larly in paraplegic patients with concomitant resorptivehypercalciuria, a kidney may completely fill with calcu-lous material in only a few months. More fortunatepatients may have indolent disease which seems stagnantfor years. However, if urinary cultures remain positive forthe offending organisms, it is likely that even such pa-tients will eventually lose the affected kidney after suffer-ing from multiple episodes of pyelonephritis. Worse, theopposite kidney may become infected.

Chemistry of Struvite Formation

For struvite to form, the urine must contain the ammo-nium ion and trivalent phosphate at the same time [3].This combination is a nonphysiological condition whichcan only occur when the chemistry of the urine is alteredby infection. The renal tubule makes ammonium onlywhen the organism needs to excrete an acid load. In anacid urine without abnormal bicarbonate losses, the ex-creted acid can be described by the empirical equation:

[H+] exc = [NH+4] + titratable acid (1)

where titratable acid is largely univalent phosphate(HPO–

41). Trivalent phosphate (PO–

43) is virtually nonexis-

tent in an acid urine when the kidney is making ammonia.When the urinary pH is high enough to contain significant

amounts of trivalent phosphate, tubular production ofammonia has ceased.

For struvite to form, nonphysiological conditions gen-erated by urea-splitting infections are required. Hydroly-sis catalyzed by urease at pH 7 is 1014 times as fast as thespontaneous reaction [4]. The bacterial enzyme splits ureainto ammonium and carbamate ions or equivalently intoammonia and carbonic acid:

2HN-CO-NH2 → 2HN-COO– + NH+4 or H2CO3 + 2 NH3. (2)

Ammonia plus water then yields ammonium hydroxide:2 NH3 + 2 H2O → 2 NH+

4 + 2 OH–.

In this alkaline environment, carbonic acid movestoward bicarbonate and carbonate ions. Hence, the ureasereaction causes alkalinization of the urine, favoring trival-ent phosphate, formation of ammonium ion and forma-tion of carbonate ion. These conditions favor the forma-tion of both mineral components of triple phosphatestones, struvite and carbonate apatite.

That the urease reaction is both necessary and suffi-cient to produce struvite is well documented [5]. Simplyadding ammonium hydroxide to normal urine will rapid-ly cause precipitation of amorphous struvite. Proteus spe-cies which virtually always make urease will engenderinfection stones, while Escherichia coli species, which donot split urea, will not. If the ureter of a mink is bandedand the bladder inoculated with Proteus stones form;organisms which do not split urea do not result in stones[6]. Morganella will cause encrustation of a zinc discplaced in the bladder of a rat, but Staphylococcus and E.coli will not [7]. When Proteus is grown in artificial urinefrom which urea has been omitted, struvite does not form.If a urease inhibitor is added to urine infected with Pro-teus, struvite formation is halted [8]. To summarize,duplicating the chemical conditions caused by ureaseforms struvite. Inhibiting the enzyme or removing its sub-strate halts formation of magnesium ammonium phos-phate.

It is possible to generate struvite crystals in vitro insolutions as acidic as pH 6.0, but the morphology of thesecrystals is different from those formed at higher pH values[9]. Theoretically, struvite could form in the absence of aurea-splitting infection. In vivo, no nonurease mechanismhas ever been demonstrated.

Human urine shows no inhibitory activity against jackbean urease [10]. Whether this can be extrapolated to bac-terial urease is uncertain. Crystallization of triple phos-phate seems to vary in the urine of different individualsand is less in human urine than in synthetic solutions sim-ulating urine [11]. Perhaps, therefore, there are inhibitors

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52 Nephron 1999;81(suppl 1):50–59 Rodman

of struvite in human urine, but the in vitro studies precip-itated more apatite than struvite, so the clinical relevanceof these data is unclear. They, nevertheless, could explainthe individual differences in rates of growth of staghorncalculi.

Under physiological conditions, urinary ammonia lev-els do not reach levels much above 100 mEq/l. In urineinfected by Proteus, ammonia levels may be ten times thisvalue. Consider patients who make ammonium acid uratestones. These individuals, often laxative abusers, are de-pleted of phosphate, potassium and bicarbonate as aresult of poor nutrition and lower gastrointestinal losses.They have a large load of acid to excrete to make up forbicarbonate losses and must use the ammonium ion to doso, since there is little phosphate to make titratable acid.Further, hypokalemia further stimulates ammonia forma-tion. Even these patients do not have urinary ammonialevels as high as those found in patients with infectionstones.

Furthermore, the urinary tract is not a large flask in thelaboratory with complete and even mixing. Rather, it hasnooks and crannies where the chemistry of the fluid in agiven renal calyx may be quite different from that of theurine in the rest of the same kidney. If there is a narrowinfundibulum, for example, there may be a heavy infec-tion with a urea-splitting organism and consequent highlevels of ammonia in one small part of a kidney, but muchless concentration of ammonia in the voided urine.

Bacteriology

Most triple phosphate stones are caused by Proteus orProvidencia species. Some changes in the nomenclaturemay be confusing. Proteus rettgeri has been renamed Pro-videncia rettgeri, and Proteus morgani has been assignedits own species Morganella. More than 90% of the aboveorganisms split urea [12]. Proteus mirabilis alone accountsfor more than half of all urease-positive infections. In ourfirst series [13], 31 of 39 patients had a Proteus infectionas the predominant urease-producing organism. Pseudo-monas, Klebsiella and Providencia species accounted forthe remaining 8 cases. Other investigators [14–16] havealso found a preponderance of Proteus infections.

One problem in defining the bacteriology of infectedstones is that cultures of the voided urine may not reflectwhat is present in the upper urinary tract. Surgicallyremoved stones may grow organisms which could not becultured pre-operatively. In one study [17], 14 of 16branched calculi grew bacteria not found in the voided

Table 1. Colony count in voided urine ofurease-positive organisms in patients withstaghorn calculi

Colony count Patients, n Percentage

28 425 ! 104 18 26104 19 29None 2 3

More than a quarter of urease-positiveorganisms would not have been reported bylaboratories which exclude colony counts be-low 50,000, and more than half would bemissed if the cutoff was 100,000.

urine. Stones removed percutaneously or surgicallyshould always be cultured directly.

Another problem is the common practice of bacteriolo-gy laboratories to label colony counts of less than 10,000or 50,000 organisms as ‘not significant’ and then to dis-card them. Such practice may be a practical reality indealing with large numbers of unselected specimens, butit can lead to serious errors in clinical decisions. Even forthe casual episode of cystitis, a low colony count can beimportant in symptomatic patients [18]. When there is alot of upper tract stone material and some intrarenalobstruction, ignoring organisms growing small numbersof colonies can discard critical information (table 1). Ourpolicy with cultures from patients with potentially in-fected stones is to ask the laboratory to: ‘grow and identifyall organisms regardless of colony count!’ If possible, wealso ask the laboratory to tell us if the organism splits urea.In more than a quarter of our cases, the usual laboratoryprocedure of ignoring low colony counts would havefailed to identify the urea-splitting bacterium. The largerthe stone, the more likely is the voided urine culture tomiss the responsible organism.

Biofilm matrix produced by bacteria which formstaghorn calculi tends to create an isolated microenviron-ment which both makes it difficult to eradicate such infec-tions and keeps the organisms from being shed into thesurrounding urine [19]. The presence of such gelatinousmaterial increases the likelihood of intrarenal obstructionand failure of usual culture practices to assess the true sit-uation.

Sometimes, the voided urine culture shows organismswhich are not relevant to the status of the upper urinarytract. One patient in my practice was a 60-year-old diabet-

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ic woman who repeatedly grew Proteus from her urine.She had minimally opaque staghorn calculi in each kid-ney. However, her urinary pH was persistently acid, andthe upper tracts were found to contain sterile uric acidstones. Thus, the physician must place any culture infor-mation in the clinical context.

On occasion, a struvite stone may form, but no urea-splitting bacteria can be cultured. Some of these stonesmay be caused by Ureaplasma urealyticum. Injection ofthese organisms into the renal medulla of a rat will causedeposition of struvite, but the organisms can only rarelybe recultured from the resulting stones [20]. Human urineforms both struvite and whitlockite in the presence ofUreaplasma; urease inhibitors prevent the precipitate[21]. One urease inhibitor, fluorofamide, will inhibit thegrowth of Ureaplasma but not Mycoplasma species [22].Clinical struvite stone disease can clearly be produced byUreaplasma organisms [23], and it is likely that manyseemingly culture-negative cases are caused by these or-ganisms [24]. Since long-term suppression with tetracy-cline may be possible, the distinction is important [25].

Types of Patients

It is useful to separate patients with struvite diseaseinto three different groups; (1) ambulatory patients withgrossly normal renal anatomy; (2) patients with urinarydiversion or other reasons such a neurogenic bladder tohave chronic urinary tract infection, and (3) paralyzedpatients. Obviously, there are patients who defy this neatclassification, but the groups tend to have different mech-anisms for their disease.

Of the 29 patients in one series who were ambulatory,25 were female [13]. Since women are far more likely tohave urinary infections, these data are not unexpected.Struvite stones may originate de novo in women whohave had recurrent urinary infections, but more common-ly complicate preexisting stone disease. A frequent scen-ario is a woman who has had several procedures for cal-cium oxalate stone disease and who then develops a stag-horn calculus. In my experience, many of these womenare obese or have some other form of eating disorder.

Women may form struvite stones in the absence of anunderlying metabolic defect. The stone will likely be freeof calcium-containing minerals, except carbonate apatite[26]. Stone-causing metabolic disorders are uncommon.On the other hand, ambulatory men with normal urinarytracts rarely develop struvite stones without an underly-ing disorder of calcium, urate or cystine metabolism [27].

Sometimes the amount of struvite precipitation willobscure an underlying metabolic disorder. Adding hy-drochloric acid to a collection container preserves cal-cium, oxalate and cystine, but all patients should havetheir metabolic studies done after they are rendered stonefree, if possible.

Patients with urological problems who thus havechronic urinary tract infections may form struvite stoneswithout any underlying metabolic stone-forming process.A patient with an ileal conduit after cystectomy is a primeexample. A flaccid bladder in a diabetic patient requiringcatheter drainage is another. Particuarly, if an infection insuch a patient is shown to be urease positive, aggressiveantibiotic treatment and often long-term suppressivetherapy are appropriate. The older diabetic woman with aneurologically abnormal bladder figures prominently inthe statistics for struvite stone disease.

Anatomic problems in the urinary tract may predis-pose the patient to urinary infection and may particularlymake clearing an infection more difficult. It is not possi-ble to list all such malformations, but some common onesare: stenosis of the infundibulum of a calix, calicectasiswith cyst formation, vesicoureteral reflux and ureteropel-vic dysproportion. One argument for classic surgery forstruvite stones as opposed to many of the newer tech-niques is that intrarenal anatomic defects can be simulta-neously addressed.

Paralyzed patients have the most virulent form ofstone disease. Resorptive hypercalciuria which followsmay cause apatite deposition even if the urine neverbecomes infected [27]. A combination of stones and neph-rocalcinosis may occur. When a urea-splitting infectionbecomes established in such a patient, two different stone-forming processes are operative. The result is often accel-erated stone growth. Male patients with indwelling cathe-ters and functionally complete cord transection are at thehighest risk to develop staghorn calculi [28]. Regimensemploying intermittent catheterization beginning at thetime of injury probably reduce the likelihood of estab-lishing a urinary tract infection. Recurrent stone diseasehas been the most common cause of death in spinal cordinjury patients [28].

Children

While struvite stones were reported to constitute about15% of the stones sent for analysis [2], close to half of thecalculi in children contain this mineral [29]. Anatomicabnormalities of the urinary tract and partial and com-

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plete paralysis are particularly common. Unlike the situa-tion in adults where many more women have struvitestones than do men, in children boys are affected morecommonly than girls [30]. When no anatomic or neurolog-ical abnormality is evident, in my experience, a metabolicproblem always is present in such patients.

The Imperative for Treatment

The notion that an infected staghorn calculus can beleft alone and not cause trouble is best described as wish-ful thinking. There certainly are anecdotal cases of pa-tients who have survived for long periods of time withoutsuffering from their disease. These, however, are theexceptions. Any treatment plan in a patient with a reason-able life expectancy should assume that a struvite stonewill grow.

While it is usually preferable to preserve the renalparenchyma, nephrectomy is usually better than no sur-gery when the other kidney is stone free. Cross-infectionof the good kidney is prevented, and the patient may bespared the misery of repeated infections. One woman inmy practice has clung to a chronically infected, stone-rid-den kidney for psychological reasons, even though theother kidney is normal. She has undergone multiple pro-cedures and required hundreds of courses of antibioticsboth in and out of the hospital. Fortunately, she has sur-vived several septic episodes. One wishes that she hadconsented to a simple nephrectomy years ago.

Intervention

Until the advent of extracorporeal shock wave litho-tripsy (ESWL) and percutaneous nephrolithotomy(PCN), kidney-splitting surgery was the treatment ofchoice for infected staghorn calculi. Even though therewas a recurrence rate of about one third without adjunc-tive modalities, two thirds of the patients were cured oftheir problem [1]. With the addition of hemiacidrin irri-gations [31], the results were certainly better, althoughcomparable statistics were never assembled. Most of usrecommended a protocol where the watertightness of thekidney was first tested by nephrostogram on about the10th postoperative day [32]. Irrigations with hemiacidrinwere then begun with care taken to avoid pressures above25 cm of water in the renal pelvis. Residual fragmentswhich were not removed in the operating room could fre-quently be dissolved, and the kidney rendered stone free

and sterile. So many successful reports appeared thatnephrolithotomy followed by hemiacidrin irrigations be-came the standard of practice [32].

Presently, there is no real consensus as to the best ther-apy for a staghorn calculus. Streem [33] has suggested so-called sandwich therapy for many patients with struvitestones. A primary percutaneous debulking process is fol-lowed by ESWL to break up as much stone material aspossible in inaccessible areas of the kidney. A secondPCN procedure is then used to remove residual stones.Such an approach minimizes the number of percutaneoustracts which must be created and probably leads to lessblood loss than the use of PCN alone. There are, however,about 30% of patients who develop recurrent infections.Other urologists have used various combinations ofESWL and PCN, but we really do not have good long-term data [34].

Choosing which type of intervention is best in a givenpatient is beyond the scope of this paper. However, thequestion as to whether ESWL can render a patient infec-tion free is a critical one. Michaels and Fowler [35]reported that even though only 45% of the patients withstaghorn calculi are made stone free by ESWL monothera-py, infection was eliminated in 86%. It is clear that ESWLwill not sterilize urease-positive bacteria within a stone, soperhaps powdering a staghorn with shock waves permitsconcomitant antibiotic therapy to complete the bacteriakill.

Hemiacidrin irrigations are used much less frequentlytoday than they were a decade ago. To be sure they are notbenign. Improper venting of the irrigation system can leadto sepsis. When irrigations are used in patients with renalfailure, hypermagnesemia has been described [36]. Thesolution itself can cause significant mucosal injury, partic-ularly if the irrigation time is extended [37]. However, onehas to wonder whether the advent of managed care andthe consequent emphasis on shortening hospital stays isnot adversely affecting the management of struvite stonedisease. Certainly, the concept that an irrigation mayremove small fragments that cannot be seen is logical. Itwas obvious to all of us who treated patients with struvitecalculi that the addition of postoperative irrigations tokidney-splitting surgery was improving the long-term curerate, even though the data were not assembled [32]. Somepatients were unquestionably made stone free by irriga-tions when surgery alone would have failed.

We [38] treated one such patient over 15 years ago. Heranatrophic nephrolithotomy left her with small fragmentsin the lower pole, a lateral calix, and the upper pole. Herkidney was irrigated with hemiacidrin first while she was

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seated. The lower-pole fragment dissolved, but the othertwo stone remnants persisted. Subsequent irrigations withthe patient lying on her side and then in Trendelenbergposition eliminated the remaining pieces of struvite. To-day, such fragments might have been first addressed withsecondary ESWL, but at least one such fragment was in atthe end of a calix with a very narrow infundibulum. Onewonders whether ESWL could have worked, since dis-charge of the fragments might have been impaired. Adirect percutaneous tract into this small calix could havebeen tried if the technique had been available but mightnot have been possible. Irrigations worked beautifully,and this patient is still stone and infection free.

Certainly, there is little if any role for hemiacidrin irri-gations, as they were once used [39] as the only therapy forinfected staghorn calculi. On the other hand, should theybe playing a larger role in our management? Are we inap-propriately limiting the use of an effective adjunctivetherapy in the name of cost containment?

Medical Therapy Options

The management of patients with struvite stone dis-ease varies among the different groups of patients. Spinalcord injury victims have been helped immeasurably bythe initiation of intermittent bladder catheterization atthe time of their first hospitalization rather than allowingthe use of an indwelling catheter. Similarly, patients withmultiple sclerosis and others with neurogenic bladdershave avoided struvite stones by not leaving a foreign bodyin their bladders. Mobilization and weight bearing reducethe likelihood of resorptive hypercalciuria which ofcourse predisposes to metabolic stone problems. Certain-ly, these measures have reduced the frequency of infec-tion stones in paralyzed patients.

Those patients with diverted urinary tracts have bene-fited from better ostomy care with less persistent coloni-zation. Suppressive antibiotic therapy may be appro-priate. Repletion of lost base in patients with ileal con-duits decreases the likelihood of a uric acid stone formingand becoming the nidus on which a struvite stone starts.

Most patients with struvite stones have intact urinarytracts and are not neurologically impaired. They have,however, already demonstrated a propensity toward uri-nary infections. Assuming that urological interventionhas rendered the urine sterile, the most important goal ofmedical management is to prevent reinfection. Any sex-ually active female should be taught to void after inter-course and other measures to reduce the chances of cysti-

tis. Many women who have suffered from struvite stonesare overweight and suffer from hygiene problems aggra-vated by groin perspiration. These must be addressed.Older women with postvoiding residual urine may benefitfrom techniques to encourage the completeness of bladderemptying.

Women who have had struvite stones are often un-aware that their urinary tracts have been chronicallyinfected. For this reason, the physician should not rely onsymptoms alone to identify recurrent infection. For sever-al years after a seemingly successful intervention for stru-vite stones, the patient should have a urine culture done atleast every 3 months, even if she professes to having nobladder symptoms. The specimen must be collected withcare to be sure it represents bladder urine. Remember,these patients are frequently overweight and may havesubtle voiding difficulties. The culture request form sentto the laboratory should ask for identification of all organ-isms regardless of colony count. Aggressive treatment ofany identified infection is mandatory as are follow-up cul-tures.

Uncontrolled diabetes undoubtedly contributes tostruvite stone disease. First, monilial vaginitis is commonand makes bladder contamination more likely. Glycosu-ria itself provides a substrate for bacterial growth. Finally,lack of control of blood sugar is frequently part of a gener-al lack of control of diet which, for many reasons some ofwhich are discussed below, makes stone formation morelikely. Of course, the long-term side effects of diabetessuch as papillitis and bladder dysfunction further placethe diabetic patient at risk of infected stones.

Other groups of women who, in my experience, windup with struvite stones are those who overuse either anal-gesics or laxatives or both. Analgesic nephropathy is wellrecognized as an injury to the renal papillae which maypredispose to pyelonephritis. Laxative abusers may ofcourse make ammonium acid urate stones, but they alsoprobably have psychological disorders with excretoryfunction in general and may be bulimic. No treatmentplan will succeed, unless the patient’s total problem isaddressed.

Substrate Depletion

One way to stop an enzyme from working is to removethe substrates on which it acts. This approach has somevalue in the management of patients with infectionstones. In the rat, struvite deposition is easily produced byplacing a foreign body in the bladder along with an inno-

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Fig. 1. Chemical formulas for urea and ace-tohydroxamic acid.

Urea

O

HH

HHC NN

Acetohydroxamic acid

OH

H

OH

HC NCH

culum of Proteus; struvite formation is prevented bydietary depletion of either magnesium or phosphorus[40]. Veterinarians dissolve canine infected stones byfeeding a phosphate-poor diet [41].

The so-called Shorr regimen [42] uses a low-phosphatediet coupled with aluminum hydroxide capsules to reduceintestinal absorption of phosphate and thereby lower uri-nary excretion of phosphate to less than 300 mg/day. Sev-eral reports [43] in uncontrolled trials suggest that thisregimen will reduce struvite formation in patients at risk,but there are important problems with its use. The diet isdifficult to follow, and the aluminum salts are unpleasantand constipating. As some of the patients will developrenal failure, the use of aluminum salts may cause reten-tion of this metal with adverse consequences for bonesand neurological function. Perhaps newer phosphate bin-ders could be used.

Besides being hard to tolerate, the Shorr regimen is oflimited usefulness, because even mild systemic phosphatedepletion can have important side effects, including os-teoporosis and muscle weakness. An underlying propensi-ty toward ammonium acid urate stones will be aggravat-ed, and urinary pyrophosphate will drop, possibly makingcalcium oxalate stone formation more likely. However,although an active attempt to reduce urinary phosphatemay or may not be appropriate, the role of too much phos-phate in aggravating struvite stone disease should not beignored.

As noted above, overeating is a common cause of manydifferent types of stone formation. This paper cannot con-

sider the totality of diet in stone formation. However, pro-tein overconsumption, probably the most important rea-son for metabolic stone formation in general, has a partic-ular relevance to struvite stone formation, because mostdietary phosphate is found in high protein foods. Whilephosphate ‘depletion’ may or may not be desirable, ‘con-trol’ of too much dietary phosphorus is certainly war-ranted. The role of substrate excess is illustrated by whathappened to a patient eventually referred to me. She had asmall, irregularly shaped stone in her left kidney with pos-itive urine cultures for Proteus. Her physician did not rec-ognize her true problem and prescribed sodium phos-phate supplements as a treatment for presumed calciumoxalate stone disease. Within 2 months, the entire kidneywas filled with a staghorn calculus. Substrate excess forthe bacterial urease was undoubtedly responsible for thisexplosive stone growth.

Thus the admonition to calcium oxalate and uric acidstone formers to reduce protein intake and to avoid pro-tein binges is particularly appropriate to patients withstruvite stones; both a potential underlying metabolicproblem and the struvite-forming process are favorablyaffected. Any patient with a creatinine clearance !25 ml/min should certainly be on a reduced phosphate intake tominimize secondary hyperparathyroidism. Since manypatients with struvite stones have considerable renal dam-age, the principles of the Shorr regimen are thus part ofthe management of chronic renal failure for these individ-uals.

Urease Inhibitors

Since the bacterial enzyme urease has been shown tocreate the chemical conditions necessary to cause struvite,attempts have been made to develop a urease inhibitorwhich would be clinically useful. Such a compound musthave a high renal clearance and must penetrate the bacte-rial cell wall, since most of the urease remains intracellu-lar. Only one such compound has been marketed, aceto-hydroxamic acid (AHA; fig. 1).

AHA is effective in reducing and even reversing stru-vite formation. In the rat, ascending pyelonephritis devel-ops if a foreign body infected with Proteus is placed in thebladder. AHA prevents the pyelonephritis and reducesencrustation of the foreign body [44]. Clinical studies [1]showed that AHA reduced urinary alkalinity and ammo-nia in the face of persistent infection. Urinary ammonialevels rose almost immediately, as urinary levels of AHAfell. Thus, the urease inhibition produced by AHA is

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short-lived, and the drug must be given several times aday for maximum effectiveness.

In a double-blind study, we [13] found that 7 of 19patients given placebo doubled the area of their stones ona plain radiograph, while none of 20 patients given theactive drug reached this predetermined end point. One ofthe patients in the placebo group was then given activedrug; her stone which had increased by more than 100%during the double-blind trial was almost invisible on X-ray 1 month later [45]. In this woman, AHA dramaticallyreduced the stone burden which had been increasing with-out urease inhibition. Thus, there is little question thatAHA is an effective drug and that the urease theory ofstruvite formation is established.

Unfortunately, the side effects of AHA limit its useful-ness. In the early study performed by Griffith [1], bothphlebitis and a dose-related hemolytic anemia werenoted. Although we [13] did not find any difference inwhite or red blood cell counts between our controls andpatients treated with active drug, 9 of 20 patients hadimportant side effects. Three patients without predispos-ing causes developed deep vein phlebothrombosis, and 1was diagnosed as having a pulmonary embolus by otherphysicians. As others [46] also reported lower-extremitythrombosis, we began to measure clotting parameters inour patients. Platelet counts fell in 12 of 15 patients froma mean of 311,000 to 250,000/cm3, and fibrinopeptide A,a breakdown product of fibrinogen, rose from 2.0 to4.8 ng/ml. In 5 patients studied intensively, fibrinopep-tide A rose within 24 h of starting the drug [47]. Anothergroup [46] reported a decrease in plasma fibrinogen. Thusthere is strong evidence that AHA induces a low-gradeintravascular coagulation problem [47].

Six of 20 patients in our original paper [13] developedtremulousness or headache requiring at least a dose reduc-tion. Subsequently, we had 3 patients who became quiteconfused when taking AHA and who improved when thedrug was discontinued. We tried to duplicate the apparentneurological toxicity of AHA in rats by loading with AHAand its metabolite acetamide, but without success.

Hydroxamates are effective chelators of iron. Welooked for the possibility of iron depletion occurring inour patients, but could never document this problem.However, if AHA is used, attention should be given to theadequacy of iron stores. If iron supplements are indicated,they should not be given at the same time as AHA, asneither will be absorbed.

Impaired renal function will increase the toxicity ofAHA and will, of course, make it less effective. Patientswith creatinine clearances !40 ml/min or serum creati-

nines 12.5 mg/dl should not be given this drug. While thedevelopment of AHA has provided a major step forwardin our understanding of struvite stone disease, the drug’sside effects should limit its use to those patients in whomthe clinical situation overwhelmingly argues for its use.

Other Urease Inhibitors

Since AHA is so effective, a safe urease inhibitor wouldbe of considerable clinical value. Potential applicationsextend beyond stone disease [48]. Such a drug might beused to control catheter incrustation of chronic indwellingcatheters. Since Ureaplasma is partially dependent onurease for its virulence, one of my colleagues who special-izes in fertility problems tried the drug in several women,a practice I discouraged. However, a safer compoundmight find use in this area. The original studies by Fish-bein and Daly [49] of urease inhibitors were done to find atreatment for hepatic coma. Finally, dental plaque andgastric Helicobacter infections might be other uses for abenign urease inhibitor.

Hydroxyurea was tried [4], but it is not as effective asAHA. Other hydroxamates have been discarded [50]because of either lack of effectiveness or toxicity. Oneinteresting approach was to attach the hydroxamate moi-ety to an analog of creatinine [51]. However, this com-pound did not work well at all, unless it was given with aß-lactam antibiotic. Presumably, this larger molecule didnot reach the intracellular urease of the bacteria.

A nonhydroxamate, flurofamide, is a transition stateanalog of urea and is 1,000-fold more potent than AHA invitro. Unfortunately, it failed clinical trials [52]. How-ever, one hopes that the pharmaceutical industry will notabandon attempts to find a clinically useful urease inhibi-tor.

Antibiotic Treatment

The difficulty in treating struvite stone disease is thatof any infection in the presence of a foreign body. Becausethe organisms may hide in the interstices of a stone [16,17], antibiotics are unlikely to sterilize the urine by them-selves. One study [53] did report that long-term penicillintherapy eliminated Proteus infection in patients with stru-vite stones, but such has not been the general experience.

Chronic suppressive treatment with urinary antisep-tics such as mandelamine or antibiotics undoubtedly hassome value. Such treatment seems to diminish the symp-

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toms of cystitis and probably slows stone growth inpatients who decline or are otherwise unsuitable for inter-vention to rid them of stones. However, to reiterate, boththe physician and the patient should remember that sup-pressing struvite stone disease is suboptimal therapy. Thedecision not to intervene should constantly be reassessed.In patients who have had struvite stone disease and havebeen rendered stone and infection free, suppressive treat-ment is often indicated, if the patient remains prone torecurrent urinary infections.

The Potential for a Medical Emergency

If a stone becomes lodged in the ureter, or part of therenal pelvis becomes obstructed in a patient with struvitestone disease, the potential for a life-threatening situationexists. Urologists, by training, are almost always aware ofthe risk of systemic sepsis or perinephric abscess whenthere is infection behind urinary obstruction; it is amaz-ing how many internists and primary-care physicians arenot. I, therefore, repeatedly counsel my patients withinfected stones about urgently seeking help from a physi-cian versed in stone disease for fever, chills and flankpain.

Conclusions

(1) Infection-associated stone disease is a complicatedproblem with many options for management. These pa-tients should be treated by physicians who are particularlyexperienced with stone disease. The doctor with a general

practice of urology who sees only an occasional suchpatient should consider making a referral to a stone cen-ter.

(2) In this world of increased cost consciousness inmedical care, the physician treating a patient with struvitestones must not let short-term monetary considerationscompromise an adequate initial intervention. Renderingsuch a patient stone-free with a sterile urine is likely tocost the medical care system less in the long run and iscertainly the best outcome for the patient. We may beunderutilizing hemiacidrin irrigations because they oftenrequire prolonging a hospital stay.

(3) In a patient with normal gross anatomy of the uri-nary tract, the goal of intervention must be a sterile urine.Meticulous follow-up is critical including frequent uri-nary cultures even if the patient is asymptomatic [54].Any Proteus or other urea-splitting infection must be giv-en particular attention.

(4) Any woman who has had struvite stone diseaseshould have an urgent urine culture for any symptomssuggesting urinary infection. Particularly if the cultureshows a urease-positive infection, short-term treatmentwith 3 days of antibiotics is inappropriate. At least a weekof therapy with follow-up cultures is mandatory.

(5) In my experience, most of the women with normalurinary anatomy and no neurological problems who de-velop struvite stones are overweight or have some form ofeating disorder. If their dietary problems are not ad-dressed, these women are particularly likely to developmore stones. They defy the usual definition as having ametabolic disorder because their urinary chemistries onlylook lithogenic when they are overeating.

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Struvite Stones

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