CHAPTER 6.4 Nephrotoxic metals 237 of colic, vomiting, tremor, convulsions, and features of Fanconi \200\231s syndrome. Gingiv al red line is seen in adults. On renal biopsy, lead/protein complexes are seen as acid- fa st nuclear inclusion bodies in proximal tubular epithelial cells. Blood levels >0.089 mol/L (1 g/dL), and urine levels >10 g/g creatinine are suggestiv e of toxicity. Urinary excretion is a reliable indicator of total body cad- mium burden. Th e American Conference of Government Industrial Hygienists recommends a value of 5 g/g cre ati- nine in urine as the occupational limit. \200\230Ita -Ita \200\231 or \200\230ouc h-ouch \200\231 disease, seen in Japanese women after World War II, was due to consumption of rice con- taminated with cadmium. Postmenopausal multiparous women developed a waddling gait, with anemia, osteoma- lacia with pseudofractures, and glucosuria. Since binding of ca dmium to metallothionein makes diso- dium edetate ineffective as a chelating agent, there i s no effective treatment. Chronic lead nephropathy It is usually a diagnosis of exclusion. The classic presenta- tion is with a benign urinary sediment with <2 g/day of proteinuria, hyperuricemia, hypertensio n and gout. It should be suspected in all cases of CKD and gout. New- onset hypertension is seen, and the CKD may eventually progress to ESRD. Grossly the kidneys appear contracted w ith a granular surface, and microscopically show features of acellular interstitial nephrit is, with dilated tubules alternating with atrophic tubules. Arteriolar nephrosclerosis sugg ests a role for hypertension in the progression of the disease. Arsenic Exposure to a toxic dose causes a dry burning sensation in the mouth, cramping abdo minal pain, diarrhea with rice- water stools, and circulatory collapse leading to hepatic a nd renal failure. Hemolysis occurs within 4 \200\2236 h followed by jaundice, anemia and he moglobinuria. Acute oliguric renal failure secondary to acute tubular necrosis is seen. Tre atment includes volume expansion, gastric lavage with warm water, and in severe cases whole bowel irrigation using a solution of polyethylene glycol has been recommended. Occasionall y hemodialysis, and chelation therapy with dimercaprol is necessary. Exchange transfusion r emoves the arsenic \200\223hemoglobin complex. Incomplete recovery may lead to chronic tubu lointerstitial nephritis. Lead and hypertension Lead industry workers have been shown to have higher systolic and dia stolic blood pressure. NHANES III data showed an increase in the mean SBP and DBP of 7 mmHg and 5 mmHg respectively, with an increase in the blood lead levels from 0.67 to 1.5 mol/ L (14 \200\22330 g/dL). Treatment Since no effective therapy reverses the long-term conse- quences of lead poisonin g, the best therapy is to prevent further exposure. Individuals should be removed from the work place if a single blood lead level is >1.5 mol/L (30 g/dL), or if two successive b lood lead levels, measured over a 4 week interval are >1 mol/L (20 g/dL). Chelation is preferred if levels are >2.2 mol/L (45 g/dL) in children and >3.4 mol/L (70 g/dL) i n adults. Succimer (DMSA) (and penicillamine) are used as oral drugs in children, and calci um edetate (and dimercaprol (BAL; British anti-lewisite)) are used as parenteral drugs in a dults. The aim of treatment is a lead chelate product that is normal. Such treatment is eff ective in reversing acute toxicity, but there is no evidence that it reverses chronic tubul ointersti- tial disease. It should also be considered that the toxicity of chelating agents in the presence of renal dysfunction has not been fully evaluated. Mercury Mercury is primarily a neurotoxin, although an association with nephrotic syndrome (membranous nephropathy) has been described. It resolves with exposure control, and rarely requires che- lation therapy. Acute exposure with <0.5 g of mercuric chloride causes erosiv e gastritis, hematemesis, and acute tubular necrosis, causing rapidly developing oliguric r enal failure. Early chela- tion therapy with dimercaprol helps. Other rare metal-induced nephropathies Uranium can induce ATN. Copper sulfate can lead to h emolysis/hemoglobinuria. Gold can cause membranous nephropathy. Cadmium This is found in plastics, alloys and electrical equipment (e.g. rechargeable batte ries). Cigarette smoking is a major source of toxicity. After absorption, it binds to album in, and is then complexed with metallothionein in the liver. This complex is \201 ltered in the glomerulus, pinocytosed by prox- imal tubular epithelial cells, and stored in lysoso mes. This accumulation promotes interstitial injury. Cadmium toxicity is known to be associ ated with low molecular weight proteinuria. Persisting Fanconi syndrome, and hypercalciuria leads to kidney stones and osteomalacia. Chronic interstitial nephritis occurs rarely but is progressive. Further reading Ekong EB, Jaar BG, Weaver VM. Lead related nephrotoxicity: a review of the epidemiologic evidence. Kidney Int 2006; 70: 2074 \200\223 2084. Sanchez-Fructuoso AI, Torralbo A, et al. Occult lead intoxication as a cause of hypertensio n and renal failure. Nephrol Dial Transplant 1996; 11: 1775 \200\2231780. Internet resources Poisons information monographs: http://www.inchem.org/pages/pims.html V. STEFANOVIC 238 Balkan nephropathy Balkan nephropathy (BN) is a chronic tubulointerstitial nephropathy, geographically limited to people living in the alluvial plains along the tributaries of the Danube River in Bosni a, Bulgaria, Croatia, Romania and Serbia (Fig. 6.5.1). BN has a familial predisposition. In a single household, several members of one or several generations may be affected. Within the same village, affected and spared households may be found in close proximity. Affected villages are sometimes separated from disease- free villages by only a few kilometers. So f ar the disease has been identi \201 ed in: \200 In the early stages, patients have tubular proteinuria, which includes 2-microglobulin, t he most readily recognizable low molecular weight protein. Urinary 2-microglobulin excret ion increases not only in patients but also in some clinically healthy relatives and can th us serve as a marker for early tubular damage in BN. The urinary sediment is usually normal although a few red and white blood cells per high power \201 eld may be seen. Macroscopi c hematuria usually indicates an associated uri- nary tract tumor. Urate and some other cry stal formations are frequent, especially during summer months. Imaging studies demonstrate normal-sized kidneys in the early stages. When renal failure develops, the kidneys are bila terally, symmetrically small with a smooth outline. BN is characterized by diffuse cortical interstitial \201 brosis, which is hypocellular in the majority of cases, and by tubu- l ar atrophy with both features decreasing from the outer to the inner cortex. In the early s tages the lesions are focal and associated with interstitial edema as well as proximal tubu le epithelial cell degeneration. 142 villages in Bosnia, Croatia, and Serbia with a local prevalence ranging between 0.5 and 4%; 40 settlements in Bulgaria with a local mean morbidity rate of 3%; 40 villages and sma ll towns clustered in a limited south- western territory of Romania (districts of Mehedinti and Caras \200\223Severin), where the prevalence of manifest dis- ease was >2%. A high prevalence of tumors of the renal pelvis and ureter has been described in patients w ith BN and in affected families. The geographic correlation between BN and urinary tract tu mors supports the speculation that these diseases share a common etiology. Table 6.5.1 Epidemiological, clinical and functional characteristics of Balkan nephropathy Etiology The etiology is unknown. However, accumulated evidence indicates that BN is an env ironmentally induced disease produced by chronic intoxication with aristolochia, ochratoxin A, or caused by a long-term exposure to polycyclic aromatic hydrocarbons and other toxic o rganic compounds leaching into the well drinking water from low rank coals in the vicinity of the endemic settlements. Moreover, the risk of developing BN is in \202 uenced by inher - ited susceptibility factors. The impact of environmental triggers on individuals genet- i cally predisposed to BN was demonstrated by the higher frequency of folate-sensitive fragil e sites, and spontaneous and radiation-induced chromosome breakages in blood samples of BN patients compared to controls. Moreover, structural changes were described in the third chr omosome at 3q25-3q26 in patients and in some healthy relatives with initial morphological c hanges peculiar to BN. Some of the rearranged chromosome bands contain oncogenes. Epidemiological characteristics Residence in an endemic settlement Family history of renal disease and of renal deaths Urothelial tumors Occupational history of farming Clinical characteristics Slowly progressive renal insuf \201 ciency Anemia: normochromic o r slightly hypochromic Edema absent Hypertension: rare in early stages of disease, common in advanced renal failure Urothelial tumors: common Abnormalities on urinalysis Reduced kidney size, normal size in e arly stages Functional changes Impaired concentrating capacity Decreased glomerular \201 ltration rate Impaired urinary acidi \201 cation Glycosuria, aminoaciduria Increased uric acid excretion Renal salt wasting Proteinuria of the tubular type Clinical features BN is a chronic tubulointerstitial disease with insidious onset, slow pro gression to end-stage renal failure, and an association with urothelial malignancies. The d isease usually affects adults in their \201 fth decade with the eventual development of e nd-stage renal failure in their sixth decade. Its clinical presentation is that of chronic interstitial nephri- tis of any cause (Table 6.5.1): it is asymptomatic for years or decade s, and becomes clinically apparent only when advanced renal failure ensues. Proteinuria is initially intermittent and mild (up to 1 g/day). Modi \201 ed from Stefanovic (1983). Stefanovic V. (1983): Diagnostic criteria for endemic (Balkan) nephropathy. In: Strahinjic S, Stefanovic V, editors. Current research in endemic (Balkan) nephropathy. Nis University Press, p 351 \200\22363. Diagnosis The diagnosis of BN is made in inhabitants from endemic settlements using: 1. Epi demiologic criteria. 2. Demonstration of: reduced GFR; proteinuria (generally <1 g/24 h); m icroalbuminuria; \200 \200 CHAPTER 6.5 Balkan nephropathy 239 Treatment In the absence of an identi \201 ed etiological factor, effective prevention of BN is not yet possible. As with all causes of CKD, patients with BN must pay close attentio n to cardiovascular risk and stop smoking, eat a healthy and balanced diet, and take regula r exercise. Treatment of BN is similar to that of all chronic interstitial nephropathies. H ypertension should be treated with ACEIs or ARBs. Volume depletion from salt wasting should be avoided, particularly during the summer months. A low protein diet can be used in CKD s tages 3 and 4 . Hemo- and peritoneal dialysis as well as kidney transplan- tation have been used with success. BN does not recur after renal transplantation. With longer survival on renal replacement therapy, patients develop tumors of the renal pelvis, ureter, and urinary bladder and long-term surveillance is required for this. bland urinary sediment; tubular markers of injury (renal glucosuria, increa- sed urinary ex cretion of 2-microglobulin or 1- microglobulin, and N-acetyl-D-glucosaminidase); typica l renal histology showing hypocellular cortical interstitial \201 brosis decreasing from the outer to the inner cortex (if renal biopsy feasible). \200 3. Exclusion of other kidney disease (chronic pyelonephri- tis \200\223 obstructive and at rophic, adult dominant polycystic kidney disease, glomerulonephritis, etc.). Kidney disease outside of the Balkans BN may not be con \201 ned exclusively to the Balkan s but could probably have spread elsewhere in Europe and the world. Outside of the endemic regions, in Europe and overseas, BN should be suspected in any case of chronic interstitial nephritis of unknown etiology. An increased incidence of both BN and urothelial tumors not associated with analgesic abuse should draw attention to the possibility of BN. However, o nly once the etiological factor(s) underlying the development of BN have been identi \201 ed will it be possible to make a \201 rm diagnosis of BN through the use of speci \201 c laboratory tests. Further reading Djukanovic L, Radovanovic Z. Balkan endemic nephropathy. In: De Broe ME, Po rter GA, Portner WM, Ver Poten GA (eds), Clinical nephrotoxins \200\223 renal injury from drugs and chemicals. 2nd edn. Dordrecht: Kluwer Academic Publishers; 2003. pp. 587 \200\223 601. Screening BN is still a major problem in several endemic regions in Bosnia, Croatia and Ser bia. Many patients are not diagnosed until the late stages of disease have developed, since early kidney disease may be asymptomatic. Ideally all adults in endemic villages should be routinely screened for evidence of early BN and associated risk factors. Members of a work ing party for the management of CKD have identi \201 ed several recommendations for the sc reening of patients at risk of CKD. These could be used for the screening of patients at ri sk of BN, with addition of tubular markers. Renal ultrasonogra- phy is usually needed. Stefanovic V, Cosyns JP. Balkan Nephropathy. In: Davison AM, Cameron JS, Grunfeld JP, Ponti celli C, Van Ypersele C, Ritz E, Winearls CG (eds), Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press; 2004. pp. 1095 \200\2231102. Stefanovic V, Toncheva D, Atanasova S, Polenakovic M. Etiology of Balkan endemic nephropath y and associated urothelial cancer. Am J Nephrol 2006; 26: 1 \200\22311. Stefanovic V, Jelakovic B, Cukuranovic R, et al. Diagnostic criteria for Balkan endemic nep hropathy: Proposal by an international panel. Ren Fail 2007; 29: 867 \200\223880. Voice TC, Long DT, Radovanovic Z, et al. Critical evaluation of envi- ronmental exposure ag ents suspected in the etiology of Balkan endemic nephropathy. Int J Occup Environ Health 20 06; 12: 369 \200\223376. See also Aristolochic acid nephropathy ( \200\230Chinese herb nephropathy \200\231) and oth er rare causes of chronic interstitial nephritis, p. 240 Fig. 6.5.1 Map of Balkan nephropathy distribution. J. NORTIER AND J.-L. VANHERWEGHEM 240 Aristolochic acid nephropathy ( \200\230Chinese herb nephropathy \200\231) and other rare c auses of chronic interstitial nephritis Chinese herbs A chronic interstitial nephritis has been reported in patients taking Chinese herbal medicine. Subsequent inves- tigation has shown that aristolochic acids contained in the Chinese plants are the nephrotoxic agent and there is now general agreement that this condition should be named \200\230Aristolochic acid nephropathy \200\231 instead of \200 \230Chinese herb nephropathy \200\231. Ochratoxin may contaminate foods (mainly cereals) des- tined for humans as well as for catt le. Experimentally, ochratoxin is oncogenic and nephrotoxic. Ochratoxin is responsible for chronic nephropathy in pigs. High blood levels of ochratoxin have been reported in associat ion with chronic interstitial nephritis in Tunisia and in France. Ochratoxin has been incri minated in BN as well as in BN- associated urothelial carcinoma. Currently the relative con tribution of AA and ochratoxin to the development of BN is a matter of debate. Aristolochic acid nephropathy Aristolochic acid nephropathy (AAN) is a chronic inter- stiti al nephritis that may be complicated by urothelial carcinoma. Aristolochic acids (AA) are b otanical compounds con- tained in various plants (Aristolochia sp. and others) that are use d mainly in traditional Chinese medicine but also in other forms of herbal medicine such as Japanese Kampo or Ayurvedic medicine. Experimentally AA are nephrotoxic and carcinogenic. The typical clinical presentation of AAN includes renal fail- ure of variable severity, pro found anemia, normal blood pressure, normal urine sediment, mild tubular proteinuria, gluco suria and small and shrunken kidneys on ultrasound examination. Some cases present with Fan coni syndrome. Histologically AAN is characterized by a dense paucice- llular interstitial \201 brosis extending from the outer to the inner cortex. The tubules are atrophic and th e glomeruli are generally preserved. Despite withdrawal of AA exposure, generally renal fun ction progressively declines to end-stage renal disease (ESRD). Exposure of the patient to AA may be demonstrated either by phytochemical analysis of the ingested herbs or by the ide nti \201 cation of speci \201 c AA-DNA adducts in kidney tissue. In patients with ESRD, s ystematic histological examination of the urinary tract has demonstrated a prevalence of ur othelial carcinoma of 40%. Therefore, in dialysed or transplanted patients with AA-related ESRD, it is recommended that the native kid- neys and ureters are removed, and the bladder is examined by cystoscopy every 6 months. Reports have indicated a worldwide distribution of AA nephropathy. AA-containing products have been banned in some coun- tries but are stil l available in others and may be obtained over-the-counter or from the internet. Therefore, in a case of chronic interstitial nephritis of unknown origin, espe- cially when associate d with a urinary tract carcinoma, nephrologists should always search for an exposure to AA (herbal medicine). Recent evidence seems to indicate that AA (Aristolochia clematitis)-cont aminated cereals cultivated in Balkan regions may be the causal agent (as well as ochratoxi n) of the so-called Balkan nephropathy (BN). Ochratoxin nephropathy (and Balkan nephropathy ) Ochratoxin is a mycotoxin produced by various species of Aspergillus and Penicillium. Metals Comparison of the occupational histories of patients with CKD with those of matched controls having normal renal function has shown exposure to mercury, tin, chromium, copper, lead and cadmium can be associated with an increased risk of CKD. Lead Lead nephropathy is a chronic interstitial nephritis associ- ated with diverse routes of chronic lead exposure: children eating lead paint or drinking lead-contaminated water at home; ingestion of lead-contaminated \202 our; drinking of illegal moonshine whiskey; oc cupational exposure in lead- producing industries. Clinical manifestations of lead nephropa thy are arterial hypertension, gout and renal dysfunction. Hyperuricemia is an early promin ent feature in lead neph- ropathy and may explain the confusion between lead neph- ropathy and gout nephropathy. The EDTA lead mobilization test (EDTA calcium disodium acetate, 2 g i ntramuscularly in divided doses 12 h apart, followed by the measurement of 24 h urinary lea d excre- tion over 3 consecutive days) facilitates the identi \201 cation of lead nephropa thy: persons without excessive lead expo- sure excrete <0.6 mg of lead over a 3 day period. Cadmium ( \200\230ouch-ouch \200\231 or \200\230ita -ita \200\231 disease) Chronic cadm ium intoxication leads to hypocellular inter- stitial renal \201 brosis. Endemic renal fa ilure (complicated by a severe painful osteomalacia), was described in Japanese villages af ter the contamination of rice \201 elds by cadmium-containing indus- trial discharge ( \200\230ouch-ouch \200\231 or \200\230ita -ita \200\231 disease). Injury of the renal p roximal tubular epithelium has been documented by an increase in urinary neutral endopepti- dase 24.11 (an enzyme of the proximal tubule brush bor- der), as well as by an increase in microproteinuria in workers chronically exposed to cadmium. Germanium nephropathy Germanium is contained in soil, plants, and animals as a trace metal. It is widely used in industry because of its semiconductive properties. Increased use of n atural remedies and trace elements has led to supplementation with germanium either through addition to food or by the means of elixirs and capsules. CHAPTER 6.6 Aristolochic acid nephropathy 241 Internet resources US Food and Drug Administration. Dietary supplements: Aristolochic acid: Chronic supplementation with germanium salts was asso- ciated with the development of chron ic interstitial nephri- tis (focal tubular atrophy and interstitial lymphocyte in \201 ltr ation) with renal tubular epithelial cells showing typi- cal small dark inclusions. http://www.cfsan.fda.gov/ dms/ds-bot.html. Drugs Chronic exposure to various drugs may lead to chronic interstitial nephritis. The dru gs most commonly associated with chronic inter- stitial nephritis are: analgesics, NSAIDs, lithium, calcineurin inhibitors and some antineoplastic agents. This subject is covered in more detail in Chapter 18.2. See also Balkan nephropathy, p. 238 Nephrotoxic metals, p. 236 Drug-induced nephropathies, p. 698 Further reading Debelle FD. Vanherweghem J-L, and Nortier JL. Aristocholic acid nephropathy : A worldwide problem. Kidney Inf. 2008; 74: 158 \200\223169. This page intentionally left blank 243 Chapter 7 Urinary tract infection Chapter contents Lower and upper urinary tract infection in adults 244 Urinary tract infection in children 2 52 Renal tuberculosis and other mycobacterial infections 256 Schistosomiasis 260 Fungal inf ections and the kidney 264 J. SCHOLLUM 244 Lower and upper urinary tract infection in adults Urinary tract infection (UTI) is a common condition result- ing in signi \201 cant morbidi ty and occasional mortality. UTI may be divided into several categories: \200 \200 \200 \200 \200 Table 7.1.1 Bacterial etiology of urinary tract infections Organism Urinary tract infection (%) asymptomatic bacteriuria; uncomplicated lower UTI; uncomplicated upper UTI; complicated UTI ; recurrent uncomplicated UTI. Uncomplicated Complicated Gram-negative organisms Escherichia coli 70 \200\22395 21 \200\22354 Proteus mirabilis 1 \200\2232 1 \200\22310 De \201 nitions Asymptomatic bacteriuria is the isolation of a speci \201 c quantitative count of bacteria, in an appropriately collected sample, in an asymptomatic patient. Uncomp licated lower UTI is a symptomatic bladder infec- tion (cystitis) in a woman with a normal genitourinary tract. Uncomplicated upper tract infection is a renal infection (acute pyelon ephritis) in a woman with a normal genitouri- nary tract. Complicated UTI is a symptomatic infection of any part of the urinary tract, in a patient with functional, metabolic or stru ctural genitourinary tract abnormalities. Reinfection is recurrent UTI with the same or a d ifferent organism following clearance of the organism from the genitourinary tract. Relapse is recurrent UTI with the same organism that has not been cleared from the genitourinary t ract. Klebsiella pneumoniae 1 \200\2232 2 \200\22317 Citrobacter spp. <1 5 Enterobacter spp. <1 2 \200\22310 Pseudomonas aeruginosa <1 2 \200\22319 Other <1 6 \200\22320 Gram-positive organisms 5 \200\22320 or more 1 \200\2234 Coagulase-negative staphylococci (S. saprophyticus) Enterococci 1 \200\2232 1 \200\22323 Group B streptococci <1 1 \200\2234 Staphylococcus aureus <1 1 \200\2232 Other <1 2 Adapted with permission from: Hooton (2003). Data for complicated infections from: Nicolle (1997). Epidemiology UTI is one of the most common medical conditions. 50 \200\22360% of women will have at least one UTI in their life- time. Young sexually active woman have an incidence o f UTI of 0.5 \200\2230.7 episodes per person-year. Approximately 10% of postmenopausal wome n have a UTI each year. Males have a far lower incidence of UTI (5 per 10 000 per year). Upper tract infections almost always occur as an ascending infection from the lower urinary tract. Multiple host factors predispose young, healthy women to UTIs. These include: \200 sexual intercourse; \200 use of a spermicidal agent; \200 previous recurrent UTI; \200 recent antimicrobial use; \200 nonsecretion of ABH blood group antigens; \200 P1 blood group phenotype (pyelonephritis). Microbiology Causative organisms are detailed in Table 7.1.1. Similar organisms cause uncom plicated upper and lower UTIs. Escherichia coli is by far the most common organism. Staphyl ococcus saprophyticus is a common cause of UTI in young women. Proteus, Klebsiella and Ente rococci spp. are less common pathogens. Complicated UTIs are caused by a broad range of pat ho- gens. E. coli remains the most common pathogen. Proteus, Klebsiella, Citrobacter, Pseud omonas aeruginosa, Enterococci, Group B streptococci and Staphylococci account for a higher proportion of cases. The lower incidence of UTI in males is likely due to a com- bination of: \200 a greater distance between the anus and the urethral ori \201 ce; a drier periurethral env ironment leading to less frequent colonization; increased urethral length; antibacterial su bstances in prostatic \202 uid. Bacterial factors also play an important role. \200 \200 \200 Bacteria and urothelial cells are both negatively charged. Bacteria are unable to overcome the negative \200\223 negative repulsion away from the urothelial cell, unless they have \201 mbriae or other adhesion systems. Uropathogenic E. coli have been demonstrated to be a ssociated with a small group of O-serotypes. These serotypes account for most cases of E. c oli acute pyelonephritis. Adhesins (lectins) on bacterial \201 mbriae or the bacterial su rface can recognize speci \201 c urothelial cell receptors. Pathogenesis In women UTIs occur when uropathogens from fecal \202 ora colonize the periu rethral area, enter the bladder via the urethra and stimulate a host response. CHAPTER 7.1 Lower and upper urinary tract infection in adults 245 Causes of sterile pyuria include: \200 leukocytes from other sources \200 interstitial nephritis \200 stone disease \200 uroepithelial tumor \200 Chlamydia trachomatis \200 Ureaplasma urealyticum infection \200 tuberculosis. This is demonstrated by the PAP adhesin which recog- nizes P blood group determinants on ur othelial cells. Nonsecretors of these blood group antigens have an increased incidence of r ecurrent UTIs. In addition, different adhesins induce different chemok- ine repertoires, le ading to different host responses. Multiple other bacterial virulence factors have been ide nti \201 ed. Complicated infections are associated with urinary obstruction, altered urinary \202 ow ( stasis), a nidus of infec- tion (renal calculi or foreign body) not readily treatable with antimicrobials, or mechanisms that alter host defenses (immunosuppression). Bacterial virul ence factors are prob- ably less important in these cases. Enterobacteriaceae convert urinary nitrate to nitrite which may be detected on dipsticks. O ther dipsticks detect leukocyte esterase which implies the presence of signi \201 cant pyu ria. These tests may be useful in con \201 rming a clinical diagnosis, but have high false -positive or false-negative rates depending on diagnostic criteria. Using a cut-off of 105 cfu/mL, dipstick testing for both leu- kocytes and nitrites has a positive predictive value of 66% and a negative predictive value of 90%. Urine microscopy and dipstick In most cases the identi \201 cation of bacteriuria is requi red to con \201 rm a diagnosis of a UTI. However, collected urine may be contaminated with bacte- ria from periurethral areas. Urine aspirated suprapubically is normally sterile and does not contain leukocytes. A positive culture from a suprapubic aspirate is the gold sta ndard for diagnosis of UTI. Clean-catch specimens are usually used in clinical practice. So me degree of contamination with urethral organisms must be accepted with specimens collecte d in this way. The technique for taking a clean-catch midstream urine is detailed in Table 7.1.2. Asymptomatic bacteriuria Asymptomatic bacteriuria is a common condition with a range of de \201 nitions dependent on patient gender and method of urine collection. By de \201 nitio n patients have no symptoms attributable to the urinary tract. Asymptomatic bacteriuria may be de \201 ned as: \200 in women, two consecutive voided urines, with isolation of the same bacterial strain, with quantitative counts of \211 105 cfu/mL; in men, a single clean-catch urine with isolation of a sin- gle bacterial strain, with a quantitative count of \211 105 cfu/ mL; a single ca theterized urine with isolation of a single bac- terial strain, with a quantitative count o f \211 102 cfu/mL in men or women. Table 7.1.2 Clean-catch urine technique Start with a full bladder Stand with legs either side of the toilet Women hold labia apart with one hand Epidemiology The prevalence of asymptomatic bacteriuria increases with age: \200 \200 Cleanse penis tip or vulva area with a sterile swab or soapy water (front to back) Pass urine into toilet until half \201 nished 1% in schoolgirls vs 20% in women aged >80 years; it is rare in young men vs 15% in men age d >75 years. Catch sample in a sterile pot (don \200\231t stop) Finish passing urine into the toilet It is strongly associated with: \200 \200 \200 \200 \200 sexual activity diabetes in women (but not men) impaired urinary voiding indwelling urinary devices residence in a long-term care facility. Noncommunicating collections in the kidney or perine- phric tissues, obstructed pyonephrosi s or bacterial prostatitis may not necessarily result in bacteriuria. Traditionally a bacte rial count of 105 cfu/mL of urine is con- sidered signi \201 cant bacteriuria. However, lo w count bacteriuria (102 \200\223105 cfu/mL) is com- mon particularly with Staphylococcus s aprophyticus or with increased urinary frequency. A bacterial count of \211 102 cfu/mL in association with pyuria, with suggestive symptoms, almost always repre- sents UTI. Contamin ation of carefully collected specimens is less common in men and a count of 103 cfu/mL is c onsidered signi \201 cant bacteriuria. White cell counting is now the preferred method for assessing pyuria. Most infections will have >104 leukocytes/ mL of urine. Bacteriuria in t he absence of pyuria is usually due to contamination. Natural history Pregnant women with asymptomatic bacteriuria have an: \200 \200 \200 increased risk of pyelonephritis; increased risk of premature delivery; increased risk of l ow birth weight infants. In patients with asymptomatic bacteriuria undergoing uro- logical intervention: \200 traumatic procedures associated with mucosal bleeding have a high rate of bacteremia and se psis. All others with asymptomatic bacteriuria have: \200 \200 an increased risk of symptomatic UTI; no increased risk of hypertension, chronic kidney dis - ease, proteinuria or genitourinary malignancy; no proven survival disadvantage. J. SCHOLLUM 246 Epidemiology As for UTIs as a whole, 50 \200\22360% of women will have at least one episode of cystitis in their lifetime. Young sexually active women have an incidence of cystitis o f 0.5 episodes/person/year. Microbiology E. coli remains the most common organism (generally strains with fewer virulen ce characteristics). Recommendations The Infectious Disease Society of America has recently reviewed asymptomati c bacteriuria and made a number of recommendations. These include: \200 Natural history Antimicrobial therapy hastens the resolution of symp- toms. Most women will improve without antibiotic therapy, but at a higher risk of upper tract or complicated inf ections. Cure rates of 85 \200\22395% are achieved with antimicrobial ther- apy. It is not associated with an increased risk of chronic kidney disease. Screening and treatment is not appropriate except for pregnant women and patients about to undergo trau- matic urological procedures. Pregnant women should be screened at least once in early pregnancy and if results are positive treated with a 3 \200\2237 day course of ant imicrobial therapy. Periodic screen- ing for recurrent bacteriuria should be undertaken fol - lowing therapy. Patients about to undergo traumatic urological proce- dures should be scr eened beforehand. If positive, appro- priate antimicrobial therapy should be given shortly before the procedure. Antimicrobial therapy should not be continued unless an indwelling ca theter remains in place. The role of screening and treatment is not established in patients with a renal allograft or in severely neutropenic patients. Clinical features Acute onset of dysuria, frequency and urgency of micturi- tion, and/or su prapubic pain. Usually there are no speci \201 c physical signs. Differential diagnosis Complicated infection is suggested by other conditions as detailed i n Table 7.1.3. Fever, \202 ank pain and systemic symptoms suggest infection of the upper tract. Acute urethritis due to Chlamydia trachomatis, Neisseria gonorrhoeae or herpes simpl ex. Vaginitis due to Candida or Trichomonas. Uncomplicated lower urinary tract infection Cystitis is very common. Urinary tract infectio ns are considered complicated if there are features which suggest a higher risk of treatmen t failure. Risk factors for treatment failure are detailed in Table 7.1.3. A pragmatic appr oach is to consider cystitis in healthy young nonpregnant women as uncomplicated and in all others as complicated. Diagnosis De \201 nitive diagnosis is made by demonstration of bacteriu- ria (traditionall y this is \211 105 cfu/mL). This may miss \200\230low count cystitis \200\231 which may a ccount for up to one-third of cases of cystitis. Counts of \211 103 cfu/mL in young women with typical symp- toms achieves reasonable sensitivity and speci \201 city. Urine dipstic k positivity for leukocytes and nitrites may be a useful diagnostic adjunct. Table 7.1.3 Complicated vs uncomplicated urinary tract infection Microbiology As detailed in Table 7.1.1, E. coli and Staphylococcus sapro- phyticus are the most common causative organisms. Uncomplicated Infections considered complicated Other conditions with an increased incidence of complicated infection (male gender, pregnan cy, elderly, recent urinary tract instrumentation, children, recent antimicrobials, diabete s mellitus, immunosuppression). Obstruction or other structural abnormalities of the urinar y tract (nephrolithiasis, malignancy, strictures, bladder diverticuli, cysts, \201 stulae , ileal conduits, and other urinary diversions). Functionally abnormal urinary tract (neuro genic bladder, vesicoureteric re \202 ux). Foreign bodies (urinary catheters, ureteric ste nts, nephrostomy tubes) Multiresistant organisms. Others (e.g. renal failure, renal transpl antation, nosocomial infection, prostatitis-related infection). Young healthy non-pregnant females Other investigations No other investigations are required in most women. Pharmacological therapy Three-day courses of trimethoprim, trimethoprim-sulfam- ethxazole ( TMP-SMX) and \202 uoroquinolones are as effec- tive as longer courses of these antimicrob ials (in most cases). Fluoroquinolones may not be as effective against Staphylo- coccal sap rophyticus when administered as a 3 day course. The optimal duration of nitrofurantoin ther apy is not well established. Beta-lactam antibiotics are less effective when given for 3 da ys and longer courses of these agents are probably required. The ef \201 cacy of single do se regimens remains controver- sial. Single dose regimens of TMP-SMX, \202 ouroquinolones and other agents, while highly effective, may not be as effective as three day regimens. Adapted with permission from: Hooton T. Urinary tract infections in adults. In: Johnson RJ, Feehally J (eds) Comprehensive clinical nephrology, 2nd edn. Baltimore: Mosby; 2003. Table 53.1, p. 695. CHAPTER 7.1 Lower and upper urinary tract infection in adults 247 Empiric therapy \200 \200 \200 Epidemiology It is much less common than cystitis. Incidence 20 \200\22380 per 10 000 peopl e per year. Narrow range of causative organisms. Relatively predictable antimicrobial sensitivities. Ba cterial culture and sensitivities are generally not avail- able until most patients are cur ed. Urine culture is usually unnecessary in cases with a typi- cal presentation. Presence o f leukocytes or nitrites on urine dipstick may aid clinical decision-making in this situati on (a recent study suggests, however, that treatment should be offered whatever the dipstic k result). Empiric therapy should re \202 ect local antimicrobial sensi- tivities. Antimic robial sensitivity data may overestimate resist- ance levels, due to the disproportionate q uantity of cul- tures obtained in treatment failures and more serious infections. An arbitr ary level of 20% resistance has been suggested as a cut-off for empiric antimicrobial choic e. Trimethoprim is as effective as TMP-SMX. Fluoroquinolone resistance is increasing. Natural history Acute uncomplicated pyelonephritis, when effectively treated, does not caus e chronic damage. Acute renal failure is an uncommon complication. It is usu- ally associat ed with complicated infection in an abnormal urinary tract. Clinical features Acute onset of \202 ank pain, nausea, vomiting, myalgia and fever with or without lower tract symptoms. Lower tract symptoms (when present) may occur before, afte r or at the same time as upper tract symptoms. The kidney(s) may be exquisitely tender. Differential diagnosis Complicated upper tract infection is suggested by the pres- ence of another condition as detailed in Table 7.1.3. Severe pain, insidious onset or severe sepsis suggests the presence of a complicated infection. Other causes of flank/back/abdominal pai n with fever include: \200 \200 \200 Alternative therapies \200 \200 There is no evidence supporting urinary alkalinization. There is no evidence for cranberry products in the treat- ment of cystitis (see \200\230Prevention \200\231). There is no evi dence for or against increasing \202 uid intake to increase urine volumes and micturition frequency. pneumonia/lung abscess/empyema; intra-abdominal sepsis (pancreatitis, appendicitis, chole- cystitis); pelvic in \202 ammatory disease; vertebral osteomyelitis/discitis; obstructive uropathy; other renal disease (acute glomerulonephritis, renal inf- arction, renal vein thr ombosis). \200 \200 \200 Follow-up Post-treatment urine cultures in patients whose symptoms have resolved are not in dicated. Prevention Avoid spermicidal agents. Cranberry products may prevent recurrence. Maintaining a high urine output with frequent micturition as well as voiding after intercourse are oft en recommended but are of unproven bene \201 t. Diagnosis Urine microscopy and culture is required in all suspected cases. Almost all patie nts have pyuria and a bacterial count of \211 104 cfu/mL. Blood cultures are not usually r equired (the demonstra- tion of bacteremia does not alter the management or out- come).