Infeksi Dan Bsk

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Jurnal tahun 2003 tentang hubungan infeksi saluran kemih dengan kejadian batu saluran kemih.
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  Current Pharmaceutical Design, 2003  , 9,  975-981975 1381-6128/03 $41.00+.00© 2003 Bentham Science Publishers Ltd. Infections and Urinary Stone Disease  Nadeem U. Rahman, Maxwell V. Meng, and Marshall L. Stoller  *  Department of Urology, University of California School of Medicine San Francisco, California Abstract: The relationship between urinary infections and stone formation has been recognized since antiquity and it has been over a century since bacterial degradation of urea was postulated to cause struvite stones. Specific therapy for urease-producing bacteria, such as urease-inhibitors and antibiotics, has allowed for treatment for this subset of urinarystones. Future directions for research include development of novel urease-inhibitors and chemicals to enhance the protective glycosaminoglycan layer.An improved understanding of the pathogenesis of calcium-based stones has led to the discovery of potential roles for nanobacteria and Oxalobacter formingenes . Methods of altering intestinal regulation of oxalate by reintroduction of lacticacid bacteria may significantly impact the treatment of calcium oxalate stones.The use of catheters, both urethral and ureteral, is common in the urinary tract and is associated with significantmorbidity, primarily from associated infections. Catheters to prevent bacterial colonization and formation of biofilms have been created using various coatings, including ciprofloxacin, hydrogel, and silver. Use of these types of catheters mayminimize infections and encrustation inherent with their placement in the urinary tract. STRUVITE CALCULI Urinary tract calculi have plagued humans since the beginning of civilization and associated infections have long been thought to play a critical role in their lithogenesis. In387 B.C., Hippocrates first documented an association between urinary tract infections, loin abscesses, and urinarystones. Over two thousand years later, in 1817 Alexander Marcet noted that there was a relationship between urinaryinfections and an alkalotic urine contributing to theformation of phosphate stones [1]. This was further eluciated in 1901 by T. R. Brown who suggested that alkalotic urineand stone formation was a consequence of bacterial splittingof urea and subsequent ammonia production. In addition, asthree of the six patients in his case series were infected with Proteus , this was the first time that Proteus  species wereimplicated in stone formation [2]. In 1925, T.B. Magath and B.H. Hagar suggested that a bacterial protein, urease, must be responsible for the breakdown of urea [3]; this wasconfirmed one year later upon the isolation of urease by J. B.Sumner. For isolating the first enzyme in its pure form, hewas awarded the Nobel Prize in Chemistry in 1946 [4].Bacterial urease, which is normally intracellular, isreleased into the urine after bacterial cell lysis [5].Subsequently, it catalyzes the hydrolysis of urea at a rate 10 4 times that of spontaneous urea hydrolysis [6]. The followingequations summarize the conversion of urea to ammonia,ammonia to ammonium, and acidification from carbondioxide:H 2  NCONH 2 + H 2 0 à  2NH 3  + CO 2 *Address correspondence to this author at the Department of Urology, U-575, University of California, San Francisco, San Francisco, CA 94143-0738, USA; Tel: (415) 476-1611; Fax: (415) 476-8849;E-mail: mmeng@urol.ucsf.edu 2NH 3 + H 2 O à  2NH 4+  + 2OH - (increase pH>7.2) and CO 2  + H 2 O à  H +  + HCO 3-   à  2H +  + CO 32- The hydrolysis of urea increases the local concentrationof ammonia and increases urinary pH. The alkaline urinaryenvironment favors the formation of trivalent phosphate(PO 43- ), normally present in uninfected, non-alkalotic urineas   univalent    phosphate   (HPO 42- ).   It   is the presence of trivalent phosphate along with the ammonium ion in an alkaline urine(pH >7.2) which allows the formation of magnesium ammo-nium phosphate crystals (MgNH 4 PO 4 . 6H 2 O) [7-9]. Themineral was termed “struvite” in 1920 by the Swedishgeologist Ulex, who named it after his mentor, the Russiandiplomat H.C. von Struve. Typically these stones areadmixed with carbonate apatite, Ca 10 (PO 4 ãCO 3 ãOH) 6. (OH) 2 .Hence, the term triple phosphate comes from association of the trivalent phosphate anion with the three cations, calciumfrom carbonate apatite and magnesium + ammonium fromthe magnesium ammonium phosphate crystal [10].Under physiological conditions, urinary ammonia levelsare maintained at an approximate concentration of 100mEq/L. However, as the chemistry of the urine is altered byinfection, the urinary ammonia, hydroxide, and carbonatelevels become significantly elevated. The pathologicalsupersaturation of these ions leads to particle formationwhich aggregate to form crystals and eventually stones. Thisstone propogation is enhanced because ammonia alsodamages the normally protective urothelial mucopoly-saccharide (glycosaminoglycan) layer. The struvite crystalsare thus thought to adhere to the damaged glycosamino-glycan layer, allowing for adhesion to the urothelium and accelerated growth of the stone. Overall, it is a combinationof the supersaturation of the ions along with increased crystal adhesion that accounts for the large sizes and rapid growth rates of struvite stones [11].  976 Current Pharmaceutical Design,  2003,  Vol. 9, No. 12Stoller et al. Attempts have been made to develop inhibitors of ureaseto aid in the treatment of struvite calculi. Acetohydroxamicacid (AHA) has been used as such an inhibitor. It has both ahigh renal clearance and is able to penetrate the bacterial cellwall. Clinical studies have demonstrated that AHA decreasesthe urinary alkalinity and ammonia levels even in the presence of infection. A double-blind study of AHA versus placebo revealed that none of the 20 patients taking AHAdoubled the size of their stones, the predetermined endpointin the study, compared to 7 of 19 patients receiving placebo[12]. Furthermore, when one of these patients previouslytaking placebo started taking AHA, the stone burdendramatically decreased after one month of therapy [13].Unfortunately, the side effects of AHA, including phlebitis,deep venous thrombosis, and hemolytic anemia, limit itsclinical utility. In addition, many patients with struvite stoneshave concomitant impairment in renal function, which notonly increases AHA toxicity but makes the drug lesseffective. It is recommended that AHA not be given to patients with a serum creatinine greater than 2.5 mg/dL. Theclinical utility of urease inhibitors will thus remain limited until drugs with fewer side effects are developed [14]. ANTI-INFECTIVES Antibiotics alone are unlikely to sterilize the urine of  patients with struvite stones, as the interstices of the stoneharboring bacteria are not adequately penetrated by drugs.Thus, treatment for struvite stones requires intervention toreduce or remove the stones. Chronic suppressive antibiotictherapy is sub-optimal but may have a role in patients withresidual stone fragments at risk for chronic urinary tractinfections. It must be kept in mind that certain anti-infectivesthemselves are considered lithogenic and may be responsiblefor as many as 2% of all patients with stones. For instance,ceftriaxone may induce kidney stones in high dosages,especially in children. The calculi may be composed of thedrug itself or result from changes in the urinary mileau [15].Indinavir, a human immunodeficiency viral protease inhibi-tor, is another common medication known to cause urinarycalculi. It is suspected that indinavir stones are composed of the un-metabolized drug, indinavir monohydrate. Theincidence of indinavir stones varies in the literature from 3 -13.1% [16]. Morbidity associated with indinavir therapy isnot affected by treatment duration, as patients who do and donot develop stones had similar mean treatment times [17].Other protease inhibitors, such as saquinavir and ritonavir,have not been reported to result in urinary precipitation and stones. Recently, medical treatment with another HIV protease inhibitor, nelfinavir, resulted in urinary stoneformation [18]. Awareness of the association between certainmedications and urinary stones is important for earlyidentification, cessation of the drug, and initiation of conservative management, as the majority of these calculiwill pass spontaneously. GLYCOSAMINOGLYCANS As mentioned previously, ammonia significantlydamages the urothelium and enhances stone formation by promoting crystal retention. Semi-synthetic sulfated glyco-saminoglycans are hypothesized to prevent crystal retentionand thus may inhibit stone formation. In a study by Senthil et al ., ammonium oxalate was used to induce stone formationin rats [19]. The glycosaminoglycan sodium pentosan polysulphate (Elmiron®) was administered and was shownto significantly reduce urinary stone forming constituents.However, in a trial using another synthetic glycosamino-glycan, pentosan polysulphate, the effects as a stone inhibitor were equivocal. In this study, 121 patients were followed over a period of three years both before and after treatment.The study demonstrated that there were no differences in thestone episode and stone operation rates [20]. Although theuse of glycosaminoglycan for stone inhibition seems feasibletheoretically, restoration of the glycosaminoglycan layer hasnot yet been shown to be of use clinically.Bacteria that produce urease are usually in the  Enterobacteriacae  family, with the most common pathogen being Proteus mirablis  (Table 1 ). Another common pathogenincludes Ureaplasma urealyticum , which requires urea as anobligate growth factor. All these urease-producing organismsderive their nitrogen requirements from the breakdown of urea. It should be noted that  Escherichia coli , the mostubiquitous uropathogen, rarely produces urease.The gastrointestinal tract harbors the largest urease- producing bacterial population, including  Helicobacter  pylori  in the stomach. The discovery of  H. pylori  hasrevolutionized the treatment of peptic ulcer disease [21].Implicating  H. pylori  in the etiology of peptic ulcer diseasegenerated tremendous excitement, because for the first timeit became possible to cure and prevent ulcers with the simpleuse of antimicrobial agents to eradicate the bacteria. It is now believed that  H. pylori  is the cause of 80% of all gastriculcers and 90% of all duodenal ulcers [22]. If we look to thecurrent situation in kidney stones, release of bacterial ureaseand the subsequent formation of struvite stones has beenthought to be the only mechanism for formation of infection-associated kidney stones. Yet struvite stones represent lessthan 15% of all urinary stone disease. Could there be other  pathogens involved in the formation of kidney stones and what would be the role of anti-microbials in their  prevention? An analogous change in the traditional paradigms of stone pathogenesis may be required tosignificantly impact future work on urolithiasis. NANOBACTERIA Kajander et al . suggested that not only struvite stones, but calcium based stones, may have an infectious srcin – nanobacteria [23]. These unconventional, cytotoxic bacteriawere discovered within the past decade in human blood and  blood products, as well as in urine. They are thought to bethe smallest living organism, nearly 100-fold smaller thanmost common bacteria. Some forms of nanobacteria mayexist in a calcified state, with a spherical coating of the cellwall made of carbonate apatite, similar to the commoncomponent thought to be the nidus for most stones. Nanobacteria have been shown to cause mineralization invitro  under physiologic concentrations of calcium and  phosphate. Furthermore, the kidney is thought to play a rolein the clearance of nanobacteria. Akerman et al . published a   Infections and Urinary Stone DiseaseCurrent Pharmaceutical Design,  2003,  Vol. 9, No. 12 977 report in which viable, radioactively labeled nanobacteriawere injected into rabbits and appeared in urine withinfifteen minutes [24]. Hjelle et al . reported that nanobacteriaor its antigens were present in polycystic kidneys and in theurine, implicating them as a potential microbial pathogenresponsible for the disease [25]. In another study byKajander et al ., fibroblasts were infected with nanobacteriaand later analyzed with electron microscopy, which revealed intra- and extracellular crystal deposits that resembled thosefound in stone disease. Additional work demonstrated thatnanobacterial antigens were present in 70 of 72 humankidney stones analyzed [26]. Also, injecting nanobacteriainto rat kidneys suggested that kidneys stones may developin a nanobacteria-inoculum dependent manner. Given thisdata, it was thought that nanobacteria acted as a nidus to promote apatite nucleation and crystal growth, representing anovel mechanism by which bacterial infections relate tostone formation [27].However, much of the data regarding nanobacteria have been disputed. Cisar et al . have proposed that biominerali-zation of calcium apatite, previously attributed to nanobac-teria, may in fact have been a contaminant. In their study,examination of the biomineralization culture failed to revealany nucleic acid or protein. Also, it was not inhibited bysodium azide. They have explained Kajander’s results bysuggesting that the DNA sequences attributed to thenanabacterium species were in fact a contaminant from a Phyllobacterium  species present in the environment [28].Thus, the crystallization thought to result from nanobacteriamay in fact arise from the culture medium itself. Moreimportantly, critics have pointed out that there have been nostudies which confirm the presence of nanobacteria in humancalculi or human urine. Chan et al . as well as Low et al . wereunable to duplicate the results of Kajandar and could notdetect nanobacterial antigens in human calculi [29-30].Although the controversy remains and has become publiclyheated, it appears unlikely that nanobacteria represent a pathogen responsible for the development of human kidneystones [31]. OXALOBACTER FORMIGENES Oxalobacter formigenes  is known to affect oxalatemetabolism and has recently been implicated in calciumstone formation. The majority of endogenous oxalateformation srcinates from the metabolism of glycine,glyoxylate and ascorbic acid. As much as 20% of oxalate isderived from oral ingestion and colonic absorption.Increased absorption of oxalate can occur in patients withhigh oxalate intake or in those with intestinal disorders,including small bowel resection, inflammatory boweldisease, steatorrhea, jejeno-ileal bypass surgery, and cysticfibrosis [32-34]. The resultant hyperoxaluria has been shownto be a significant risk factor for calcium oxalate stonedisease. In 1985, Allison et al . first isolated Oxalobacter  formigenes  from human feces, showing it to be an obligateanaerobic gram negative rod that was able to degrade oxalicacid. Humans have no known endogenous enzyme capableof degrading oxalate. Thus, O. formigenes  plays animportant symbiotic role with its vertebrate host by reducingenteric absorption of oxalate and regulating oxalatehomeostasis [35]. Allison et al . later examined bacterialoxalate degradation rates in normal humans and compared them to those who had undergone a jejuno-ileal bypass. Thelatter group had a much slower rate of degradation, and thusit was postulated that the decreased rate of oxalate breakdown resulted in greater oxalate absorption and associated hyperoxaluria. This hyperoxaluria is thought to bethe main risk factor for the development of calcium oxalatestones in these patients [36].Intestinal colonization by O. formigenes  begins ininfancy and by age eight, nearly all children are colonized with the bacteria. However, antibiotic use affects the abilityof this bacteria to colonize the gut [37]. Prolonged use of antibiotics by patients with cystic fibrosis may either  preclude natural colonization of O. formigenes  or destroy theexisting colonies. Sidhu et al . examined O. formigenes  incystic fibrosis patients, another group of patients at risk for hyperoxaluria and calcium oxalate stone formation. These Table 1.Common Urease Producing Organisms (Data from[8-9]) Urease Producing OrganismsType of OrganismOrganism Gram PositiveBacteria Staphylococcus aureusStaphylococcus epidermidisCorynebacterium species ( C .ulcerans, C. renale, C. ovis,C. hofmanii, C. murium, C. equi)) Mycobacterium rhodochrous group  Micrococcus varians Bacillus speciesClostridium tetaniPeptococcus asaccharolyticus Gram NegativeBacteria  Bacteroides corrodens Helicobacter pylori Bordetella pertussis Bordetella bronchiseptica Haemophilius influenzae Haemophilus parainfluenzaeProteus species ( P. mirabilils, P. morganii, P. rettgeri)Providencia stuartiiKlebsiella species ( K. penumoniae, K. oxytoca ) Pasteurella  species Peseudomonas aeruginosa Aeromonas hydrophiliaYersinia enterocolitica Brucella species Flavobacterium species Serratia marcescens Mycoplasma Ureaplasma urealyticum Mycoplasma  T-strainYeast Cryptococcus species  Rhodotorula species Sporobolmyces species Trichosporon cutaneumCandida humicola  978 Current Pharmaceutical Design,  2003,  Vol. 9, No. 12Stoller et al.  patients were shown to have decreased levels of intestinal O. formigenes . Stool samples and 24-hour urine collectionsfrom 43 patients with cystic fibrosis and 21 healthy controlswere analyzed for O. formigenes  and oxalate, respectively.Only seven of the 43 cystic fibrosis patients (16%) werecolonized with O. formigenes , compared to 15 of 21 (71%)of healthy controls. In addition, none of these sevencolonized patients had elevated urinary oxalate levels, while19 of 36 uncolonized cystic fibrosis patients (53%) had hyperoxaluria. Thus, the regulation of urinary oxalateexcretion was directly correlated with colonization of O. formigenes  in the intestine [38].   Absence of this bacteriafrom the gut flora is associated with an increased suscep-tibility to hyperoxaluria, which can lead to calcium oxalatestones in the urinary tract. An epidemiological studysuggested an association between recurrent urinary lithiasisand the lack of intestinal O. formigenes  [39]. Thirty-three of 44 control patients (75%) had detectable O. formigenes  instool samples. In contrast, in patients with calcium oxalatestones, there was a direct correlation with the number of stone episodes and the lack of intestinal O. formigenes colonization. Twelve of 15 (80%) with only one episode of urolithiasis were colonized with O. formigenes , while 8 of 21(38%) with 2-episodes and 3 of 23 (13%) with more than 5episodes had O. formigenes  detected in their stool. Thesedata have been confirmed by other investigators. Tunaguntla et    al .   also   correlated    urinary   oxalate   levels   with O. formigenes colonization in gut. Absence of O. formigenes  wasassociated with hyperoxaluria and an increased risk of recurrent oxalate stone disease [40]. Sidhu et al . further documented this in an in vivo  rat model. Sprague Dawleyrats not colonized with O. formigenes  developed hyper-oxaluria when fed oxalate-rich diets. After introduction of O. formigenes  into these rats in sufficient concentrations tocause bowel colonization, there were significant reductionsin urinary oxalate levels. In 2001, Sidhu et al . elaborated ontheir previous study where male Sprague Dawley rats were placed on a diet to induce a state of severe hyperoxaluria.These rats were then treated with O. formigenes  for a two-week period. The rats with hyperoxaluria showed decreased levels of urinary oxalate within two days of initiating bacterial probiotic therapy; the amount of decrease was proportional to the dose of bacteria. These rats tolerated thetherapy, without adverse affects on health [41]. Feeding ratsother oxalate-degrading factors, including the enzymeoxalyl-coenzyme A decarboxylase, reduced urinary oxalatelevels and, more importantly, decreased formation of urinarytract stones compared to controls [42].In summary, O. formigenes  is likely an importantcomponent in human oxalate degradation and urinary oxalatelevels. Its absence from the gut can increase the intestinalabsorption of oxalate, increasing the risk for hyperoxaluriaand subsequent kidney stone disease. Novel therapeuticstrategies involving oxalobacteria, including recolonizationin the intestine, require further investigation and humantrials. LACTIC ACID BACTERIA Campierti et al . evaluated the role of other oxalate-degrading bacteria in stone formation [43]. They postulated that oral supplementation with probiotic, freeze dried lacticacid bacteria may also affect the urinary oxalate excretion, asmany of these bacteria have oxalate consuming metabolic pathways. Six patients with known mild hyperoxaluria (> 40mg/24 hr) were administered a mixture of freeze dried lacticacid bacteria (4 gm slurry, with each gram containing 2 x10 11  bacteria). The specific strains of bacteria are shown inTable 2 .In addition to the probiotic treatment, each patient wasencouraged to maintain a urine output of at least 1.5 L per day and restrict consumption of high oxalate foods. In all six patients, significant reductions in 24-hour urinary oxalatewere noted after 8 weeks of treatment. Fecal excretion of oxalate was evaluated in two patients and both were found tohave a large reduction of fecal oxalate levels after 30 days of treatment. Other urinary paramaters, including 24-hour volume, phosphate, citrate, and calcium excretion, were notsignificantly affected. The various bacterial strains differed in their abilities to degrade oxalate as well as to grow inmedia containing different oxalate levels. For example,  L.acidophilus  and S. thermophilus  degraded oxalate but their growth was inhibited by the presence of oxalate; conversely,  L. brevis  and  L. plantarum  had only a modest ability todegrade oxalate yet was able to grow in an oxalate medium.Only  B. infantis  showed a significant ability to degradeoxalate and grow rapidly in an oxalate rich medium (Table Table 2.In Vitro Growth and Degradation of Oxalate by Different Strains of Lactic Acid Bacteria Lactic Acid Bacteria for Probiotic TreatmentBacteriaDegradation (%)in low oxalateGrowth in low oxalate(Time zero: end point)Degradation (%)in high oxalateGrowth in high oxalate(Time zero: end point)  Lactobacillus acidophilus 11.825: 1303.425: 52  Lactobacillus plantarum 1.432: 2700.032: 230 Streptococcus thermophilus 2.32.5: 283.12.5: 9  Bifidobacterium infantis 5.336: 3002.236: 230  Lactobacillus brevis 0.927: 1300.727: 120
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