Antibiotic Treatment (mg/kg/day) Prophylaxis (mg/kg/ day) Not recommended Coamoxiclav Check BNF as depends upon age and drug concentration Trimethoprim 4 mg/kg orally 12- hourly 2 mg/kg 24-hourly (at night) Cefuroxime 20 mg IV (max 750 mg) 8-hourly NR Cefradine 12.5 \200\22325 mg/kg orally 12-hourly 3 mg/kg 24-hourly (at night) Nitrofurantoin 0.75 mg/kg orally 6-hourly 1 mg/kg 24-hourly (at night) Management Acute infection If the child is not unwell enough to require hospitalization, or al therapy with an antibacterial drug chosen from Table 7.2.1 can be used. The best choice of empiric antibiotic should be based upon information available from the local microbiolog y labora- tory. Antibiotic resistance is high for ampicillin alone and increasing for trime thoprim. A cephalosporin is probably best \201 rst choice at present. Parenteral antibiot ic therapy is recommended in the unwell child with vomiting but oral therapy has recently b een shown to be as effective. Therapy in neonates is usually IV ampicillin and gentamicin b ut in the older child cepha- losporins such as cefotaxime are used. There is no \201 rm e vidence for the optimal duration of treat- ment but usually 10 days of oral or IV/oral anti biotics in those with vomiting appears equally effective in children with suspected pyelone phritis. A 2 \200\2234 day course of oral antibiotics for the child with lower tract sympto ms who is systemically well is adequate and supported by meta-analysis data. For children w ho have had an abnormal early ultrasound, prophylactic therapy should be continued until in vestiga- tions are completed. In all groups, a urine culture should be taken to ensure reso lution of infection. Treatment and investigation of UTI in children go hand-in- hand. Child ren who are hospitalized with severe illness and recurrent or atypical UTI should have an u ltrasound per- formed during the acute admission to rule out underlying obstructive uropath y such as posterior urethral valves or other congenital abnormalities. Such patients should be managed in centers where there is both urology and neph- rology expertise. Cipro \202 oxacin Not licensed but refer to BNF Not recommended demonstrated to have Grades 3 \200\2235 VUR (re \202 ux distending the pelvis and calyces) . Prophylaxis is usually maintained for \211 2 years in this situation. There are no forma l trials comparing prophylactic antibiot- ics vs urine culture when symptoms develop (a poi nt which needs to be stressed to parents/carers even if the child is on antibiotics). Howev er, some recent evidence indicates that prophylaxis may not signi \201 cantly decrease the risk of recurrent UTI and may increase the risk of antibiotic resist- ance. Shorter course s of prophylactic antibiotics (6 months) may be employed in children (usually girls) with r ecurrent UTIs and normal urinary tracts along with continued emphasis on general preventati ve measures. Dysfunctional voiding can be assessed by monitoring bladder emptying on ultra- sound or occasionally urodynamics if symptoms are severe. Investigation This is a surprisingly controversial area previously with a lot of focus on d etecting VUR because of its known asso- ciation with scarring (reflux nephropathy), CKD, an d hypertension. There is increasing recognition from antenatal studies that VUR without inf ection may be associated with abnormal renal development giving rise to \200\230global sca rring \200\231 without UTI (dysplasia). A signi \201 cant dissociation between the presenc e of scars on DMSA and the presence of VUR has been recognized. In younger children VUR can only be de \201 ned by micturat- ing cystourethrography (MCUG) which is a potentially tra umatic examination in children. For continent children aged >4 years, one can assess re \202 ux by using MAG3 scans with indirect micturating cystograms (see below). Algorithms fo r the investigation of UTI have not distin- guished between those who have upper tract symp toms from those with lower tract (dysuria and frequency) symptoms. Until recently, the cons ensus was that all chil- dren (both boys and girls) should undergo appropriate investigatio n after the \201 rst proven UTI. However, there is often dif \201 culty interpreting uri ne cultures, particularly in young children where the risk of renal damage is probably grea test. Prevention of UTI recurrences Recurrence of UTI is common with 30% of girls having another UTI within 1 year (mainly lower urinary tract in nature). A good \202 uid intake needs t o be encouraged with regular voiding (school toilets are often a problem!). Enquire about c onstipation which has a strong association with voiding dysfunction and recurrent UTI. Ensu re that personal hygiene is stressed with proper wiping, and avoidance of bubble bath and t ight- \201 tting underwear. Antibiotic prophylaxis with trimethoprim or nitrofu- rantoin ( Table 7.2.1) is usually only employed in patients A. WATSON 254 Ultrasound scan (USS) is the primary investigation and will reveal anatomical information e ven in nonfunctioning kid- neys. Kidney size should be recorded and interpreted with refere nce to centile charts based on the child \200\231s height. USS will also reveal problems wi th bladder obstruction and other abnormalities such as stones (plain AXR is no longer routi nely performed). USS is operator dependent and can demonstrate scarring of kidneys in exper ienced hands. One important caveat is that significant VUR may be present with a normal USS , particularly in the newborn period. Recent NICE guidance suggests restricting MCUG to tho se aged <6 months who have severe, atypical, or recurrent UTI (Table 7.2.2(a)). MCUG is onl y required in older children if operative inter- vention is being considered. MCUG is the m ost traumatic of the imaging investiga- tions for a UTI and children require prophylactic a ntibiot- ics for 48 h to cover the procedure. In addition infor- mation for the family and play preparation for the child is required. A DMSA scan is the best technique for detection of scars and determination of differential renal function. This should be delayed for 6 mo nths after the UTI if permanent renal damage following an episode of pyelonephritis is bein g sought. Isotope renography (MAG3) is used to determine the presence of obstruction as wel l as for calculating differen- tial kidney function. In the co-operative child aged >4 year s the scanning can be continued until the child empties his or her bladder (indirect mictur ating cystography). Direct nuclear cystography has less radiation burden but still requires catheterization. IVU, CT or MRI should be used after consultation at the nephrouroradiolog y meeting. The majority of children with UTI have lower tract cystitis-like symptoms and no demonstrable abnormality on imaging. However, it can be difficult to distinguish between u pper and lower tract symptoms and there is always the concern regarding the presence of rare abnormalities of the urinary tract. NICE guidelines (2007) suggest that in children with UTI who are systemi- cally well it is only those who are aged <6 months who need a routine ultrasound. In older children it should onl y be done in those with atypical or recurrent UTI (Table 7.2.2(b,c)). Vesicoureteric re \202 ux This is classi \201 ed grades 1 \200\2235; grade 1 into ureter only and grade 5 gross dilatation of pelvis and calyces involving tor- tuosity of the urete r. Although 30% of children investigated for symptomatic UTI have VUR, in most it is of mi nor grade. Table 7.2.2(b) Atypical UTI Recurrent UTI Responds well to treatment within 48 h without any features for atypical and/or recurrent U TI Children aged \211 6 months but <3 years Yesa USS during the acute infection No No USS within 6 weeks No No Yes Yesb Yesb No DMSA 4 \200\2236 weeks follow- ing the acute infection Noc Noc MCUG No a In a child with a non-E.coli UTI, responding well to antibiotics and with no other featur es of atypical infection, the USS can be requested on a nonurgent basis to take place withi n 6 weeks. b A detailed USS by an experienced operator can detect renal scarring. c While M CUG should not be performed routinely it should be considered if the following features are present: dilatation on USS; poor urine \202 ow; non- E.coli infections; family history o f VUR. Table 7.2.2(c) Atypical UTI Recurrent UTI Children aged \211 3 years Responds well to treatment within 48 h without any features for atypical and/or recurrent U TI Table 7.2.2(a) Scheme for investigation of children following UTI based on recent NICE guid ance Atypical UTI Recurrent UTI Children aged <6 months Responds well to treatment within 48 h without any features for atypical and/or recurrent U TI Yesa,b USS during the acute infection No No Yesa USS within 6 weeks No No Yesa Yesa USS during the acute infection No Yesc No No DMSA 4 \200\2236 weeks following the acute infection Yesb USS within 6 weeks No No Yesc Yesc No DMSA 4 \200\2236 weeks following the acute infection Noa Nod MCUG No a USS in toilet-trained children should include repeat scan after bladder empyting if bladd er very full. b In a child with a non-E.coli UTI, responding well to antibiotics and with n o other features of atypical infection, the USS can be requested on a nonurgent basis to ta ke place within 6 weeks. c A detailed USS by an experienced operator can detect renal scarr ing. d MAG3 scan with indirect cystogram may be considered in continent child aged >4 years if USS is abnormal. MCUG No Yes Yes a In a child with a non-E. coli UTI, responding well to antibiotics and with no other featu res of atypical infection, the USS can be requested on a nonurgent basis to take place with in 6 weeks. b If abnormal consider MCUG. c A detailed USS by an experienced operator can de tect renal scarring. CHAPTER 7.2 Urinary tract infection in children 255 Hence there is reluctance to perform routine MCUG except in young, febrile children with pr oven UTI since it is potentially traumatic and involves a high radiation dose. Evidence ind icates that clinical management for VUR (anti- biotic prophylaxis) and reimplantation surge ry have similar outcomes in terms of incidence of renal scarring, renal function and recurr ent UTI. Controlled trials of prophylactic antibiotics versus urine culture and treatment o f UTIs on an expectant basis in children with VUR have not yet reported. Children who suffe r recurrent febrile UTIs despite prophy- laxis (also consider compliance issues) require di scussion with urologists for consideration of reimplantation surgery or more likely endosco pic correction (injection of a bulk- ing substance around the entry of the ureter into the blad- der: STING procedure). When adult, depending on the GFR, the patient should either be transferred to an adult cent er or followed up in primary care with provision of clear guidance on the crite- ria for su bsequent referral. References Barry BP, Hall N, Cornford E, et al. Improved ultrasound detection of renal scar ring in children following urinary tract infection. Clin Radiol 1998; 53: 747 \200\223751. Bloom \201 eld P, Hodson EM, Craig JC. Antibiotics for acute pyelone- phritis in children. Cochrane Database Syst Rev 2005; (1): CD003772. Conway PH, Cnaan A, Zaoutis T, et al. Recurrent urinary tract infec- tions in children: ris k factors and association with prophylactic antimicrobials. J Am Med Assoc 2007; 298: 179 \200\223186. Gordon I, Barkovics M, Pindoria S, et al. Primary vesicoureteric re \202 ux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and meta-analysis. J Am Soc Nephrol 2003; 14: 739 \200\223744. Long-term follow-up of children with VUR If antibiotic prophylaxis is used it is usually gi ven for a 2 year period and discontinued if the child has been infec- tion-free. After 2 ye ars the kidneys can be checked with ultrasound for growth and scarring. If the quality of u ltrasound is inad- equate, a DMSA scan may be required. Discharge to primary care is approp riate if there is no evi- dence of scarring with referral back if recurrent infections deve lop. If scarring is identi \201 ed in one kidney an annual review for 5 years is required to check for recurrence of infections and measurement of the blood pressure, since there is a small risk (<2%) of developing hypertension as a result of renal scarring. The child can then be referred back to pri- mary care for annual blood pressure measurements and urinaly sis until growth is completed. Bilateral renal scarring puts children at high risk for deve l- oping CKD and/or hypertension. Review in a pediatric nephrology or shared renal clinic f or monitoring of blood pressure, urinalysis (for proteinuria), and estimated GFR at interva ls may be appropriate depending upon the stage of CKD. If the child develops recurrent UTI, discuss with urologist about operative intervention. In older children this is likely to b e an endoscopic STING procedure. Hodson EM, Wheeler DM, Vimalchandra D, et al. Interventions for primary vesicoureteric re \202 ux. 2007. Cochrane Database Syst Rev 2007; (3): CD001532. Jodal U, Smellie JM, Lax H, Hoyer PF. Ten-year results of randomized treatment of children with severe vesicoureteral re \202 ux. Final report of the International Re \202 ux Study in Children. Pediatr Nephrol 2006; 21: 782 \200\223792. Michael M, Hodson EM, Craig JC, et al. Short versus standard dura- tion oral antibiotic the rapy for acute urinary tract infection in children. 2003. Cochrane Database of Systematic R eviews 2003; (1): CD003966. Montini G, Toffolo A, Zucchetta P, et al. The IRIS 1 study of antibiotic treatment of pyelo nephritis in children: a multicentre randomized controlled non inferiority trial. Br Med J 2007; 335(7616): 386. Internet resources National Kidney Federation: http://www.kidney.org.uk/ NICE Clinical Guideline CG54. Urinary tract infection in children : diagnosis, treatment and long-term management. Aug 2007: http://guidance.nice.org.uk/CG34 See also Renal and urinary tract stone disease in children, p. 282 Lower and upper urinary tract infection in adults, p. 244 Imaging in renal disease, p. 20 K.L. GUPTA 256 Renal tuberculosis and other mycobacterial infections The members of genus Mycobacterium have characteristic acid-fastness due to their elaborate lipid-rich cell walls. They are comprised of two major pathogens: the Mycobacterium tuberc ulosis complex (M. tuberculosis, M. bovis, M. africanum M. microti and M. canetti); and Myc obacterium leprae. In addition there are many mycobacterial species which live freely in th e environment as saprophytes and cause opportunistic human disease (environmental mycobacte ria (EM)). These are divided into two main groups: rapid and slow growers. Slow growers are mainly responsible for human disease. Major pathogenic EM are M. avium-intracel- lulare, M . kansasii, M. xenopi, M. malmoense, M. fortuitum, M. chelonei, M. ulcerans and M. marinum. Renal involvement is mainly seen with M. tuberculosis, M. leprae and a small number of EM as discussed below. Clinical features Classical renal tuberculosis Early features: \200 \200 \200 \200 symptoms of cystitis; microscopic or macroscopic hematuria; pyuria with negative bacterial culture ( \200\230sterile pyuria \200\231); constitutional symptoms. Late features: \200 \200 \200 \200 nephrolithiasis and ureteral colic; intractable frequency and urgency; refractory hypertens ion; renal insuf \201 ciency due to obstructive nephropathy. Tuberculous interstitial nephritis Tuberculosis can affect the kidney more insidiously. For example in three patients with advanced renal failure and normal-sized kidneys, a renal bi opsy demonstrated chronic tubulointerstitial nephritis with granuloma formation and caseati on. Evidence of pulmonary tuberculosis was seen in two patients and one had tuberculous per itonitis. Renal tuberculosis Epidemiology Globaly, tuberculosis is a common disease, with 8 \200\2231 0 mil- lion new cases annually with 95% of these occurring in developing countries. The gen itourinary system is involved in 15 \200\22320% of cases of extrapulmonary tuberculosis. Ap proximately 4 \200\2238% of patients with pulmonary tuberculo- sis will develop clinically signi \201 cant genitourinary infection. Approximately 25% of patients who present with ge ni- tourinary tuberculosis (GUTB) have a background of pul- monary tuberculosis and an addi tional 25 \200\22350% of patients will have radiographic evidence of previous subclinical p ul- monary infection. GUTB occurs later than other forms of TB (age 20 \200\22340 years), a nd is more common in males (other UTIs are more common in females) and in the right kidney. Predisposition to genitourinary TB is increased by medical conditions such as: HIV, diabet es mellitus, analgesic abuse, and a number of urinary tract abnormalities such as vesi- cou reteral re \202 ux, neurogenic bladder, urinary obstruction, and congenital anomalies. Tuberculosis and glomerular disease Chronic tuberculosis may be complicated by amyloidosis and in areas where tuberculosis is endemic it can be a com- mon cause of amyloidosis. Mesan giocapillary glomerulone- phritis type II and focal proliferative glomerulonephritis have a lso been reported in patients with tuberculosis; however, a causal link has not been establ ished Hyponatremia Mild hyponatremia (plasma sodium concentration usually between 125 and 135 mmo l/L) may develop in patients with active pulmonary or miliary tuberculosis. Most patients a ppear to have the syndrome of inappropriate ADH secretion, with approximately one-third hav ing a reset osmostat. Hyponatremia resolves after effective therapy of the infection. Tuberculosis causing end-stage renal disease (ESRD) Progressive renal failure due to tuberc ulosis, although uncommon, is potentially preventable and treatable. Since most of the tube rculosis patients are in developing coun- tries with inadequate registries and diagnostic f acilities, there is little information on the contribution of tuberculo- sis to the burden of renal disease. In 1991, European Dialysis and Transplant Association reg- istry data rev ealed that 195 of 30 064 new patients (0.65%) had renal failure caused by renal tuberculosi s, an incidence similar to that of previous years. Pathogenesis M. tuberculosis reaches the kidney by hematogenous spread. Granulomata (tuberc les) develop in the glandular and cor- tical arterioles near glomeruli. Tubercles may remai n dormant for several years after infection (up to 15 \200\22320 years) before rupturing an d releas- ing live bacilli into the proximal tubule. These then reach the loop of Henle and lead to the formation of medullary granulomata and eventually papillary necrosis. Granulom ata may coalesce into large, necrotic, irregular cavities which usually communicate with th e renal collect- ing system. This may progress to a pyonephrosis-like lesion (cement or put ty kidney). Renal calci \201 cation occurs in 24% of cases and is associated with renal or ureteric stones in up to 19% of cases. Ureteric involvement with strictures and segmental dilata- tion can lead to obstruction and/or vesicoureteric re \202 ux. Urinary bladder inv olvement starts with interstitial cystitis and mucosal ulceration. Later, thickening of the bladder wall with a diminished capacity ( \200\230thimble \200\231 bladder) may result. Tuberculosis in patients with chronic renal insuf \201 ciency and ESRD Tuberculosis is mor e common in patients with renal dys- function than in the general population. There is evid ence for a state of relative immunological anergy in uremia as indicated by skin testing. C ommonly, the patient presents with fever, anorexia, and weight loss, and usually is either known to have had pulmonary or other forms of tuberculosis or is a member of a high risk et hnic or social group. The recrudescence is extrapulmonary in most cases and hence it is lik ely that the disease is due to reactivation of past disease rather than a primary infection . CHAPTER 7.3 Renal tuberculosis and other mycobacterial infections 257 with organisms ( \200\230multibacillary histiocytosis \200\231). Caseous necrosis is not a feature. In some patients with pulmonary or disseminated tuber- culosis, there is evidence of renal failure without typical miliary involvement or localized genitourinary lesions. In such cases, biopsy demonstrates interstitial nephritis, usually with granuloma formation. Healing produces scarring and usually calci \201 cation. Tuberculosis in transplant recipients Tuberculosis is a serious complication in solid organ transplantation, with an incidence, depending on geo- graphic region, from 0.3% in the US A to as high as 15% in the Indian subcontinent. In most cases, the disease involves the lun g, but it is dissem- inated in one-third of cases. Patients who had tuberculosis while on d ialysis are at increased risk. Immunosuppression can obscure the diagnosis (false-nega- tiv e tuberculin tests) and mask the common symptoms of the disease. The diagnosis is therefore often delayed and the mortality is high ( 30%). The differential diagnosis of necrotizing granulomata in the renal tract includes fungal in fections and Wegener \200\231s granu- lomatosis. Noncaseating granulomata may be seen in sa r- coidosis, leprosy, and brucellosis. Imaging Plain radiology Signs of extrarenal tuberculosis may be apparent, for exam- ple oss eous or paraspinal changes, and old healed calci \201 ed splenic, hepatic, lymph node, and adrenal granulomata. Chest radiographs may show evidence of active or healed tuberculosis in 50% of patients. A plain KUB radiograph may show a variety of patterns of calci \201 ca tion: punctate, speckled, or hazy. Intravenous urography A variety of radiologic abnormalit ies may be demonstrated: \200 Smudged papillae with surface irregularity and a moth- eate n calyx (early sign). Papillary necrosis (Fig. 7.3.2). Hydrocalycosis without pelvic dilata tion, an atrophic pel- vis, and cephalic retraction of the inferior medial margin of the re nal pelvis ( \200\230the hiked-up renal pelvis \200\231) are highly suggestive of tuberculo sis. There may be no calyceal \201 lling and the infundibulum shows a typical \200\230pi nched-off \200\231 appearance. The whole pel- vicalyceal system and ureter may be outlined by calci \201 - cation ( \200\230tuberculous autonephrectomy \200\231). Ureters may show a symmetrical involvement (mainly upper and lower thirds): Intraluminal \201 lling defects due to mucosal granulomata; and irregularity in outline of contrast- \201 lled ureter resu lting in a beaded or corkscrew con \201 guration. Laboratory diagnosis \200 Three early morning urine samples: acid-fast bacilli (AFB) may be demonstrated by Ziehl \200\223Neelsen (ZN) staining of the sediment after centrifugation. De \201 nitive proof b y urine culture on L wenstein \200\223Jensen medium (may take 2 \200\2238 weeks). More rap id radiometric culture system (BACTEC)- mycobacterial growth within 2 \200\22310 days. Nucl eic acid ampli \201 cation techniques, e.g. polymerase chain reaction. Histopathology Tuberculosis may involve the kidney as part of genera- lized disseminated in fection or as localized genitourinary disease. The morphology of the lesions depends on the type of infection, the virulence of the organism, and the immune status of the patient. Hi stological \201 ndings include: \200 \200 Miliary tubercles (up to 3 mm in diameter) seen through- out the renal cortex. Histological ly, they consist of epi- thelioid granulomata, with or without caseation, and often contain Langhans-type giant cells (Fig. 7.3.1). Organisms may be demonstrated microscopically with in these lesions. In immunosuppressed patients more diffuse and poorly formed granulomas ar e seen. These contain histiocytic cells with abundant pale cytoplasm packed (a) (b) Fig. 7.3.2 (a) Intravenous urogram image showing papillary necrosis and contrast- \201 lle d cavities communicating with pelvicalyceal system. (b) Multiple calci \201 ed lymph nodes in the mesentery and markedly reduced capacity of urinary bladder ( \200\230thimble bladde r \200\231). (Courtesy of Dr Anupam Lal, Postgraduate Institute of Medical Education and Re search, Chandigarh, India.) Fig. 7.3.1 Photomicrograph of H&E-stained renal biopsy showing multiple epithelioid cell gr anulomata in the tubulointerstitium (magni \201 cation: \227200). Inset: Granuloma with L anghans-type giant cell (arrow). (Courtesy of Dr Ritambra Nada, Postgraduate Institute of M edical Education and Research, Chandigarh, India.) K.L. GUPTA 258 day). Pyridoxine-resistant isoniazid-induced encephalopathy has rarely been reported in hem odialysis patients. Recovery occurs with isoniazid withdrawal. Rifampicin can cause interst itial nephritis and rarely cres- centic glomerulonephritis. Rifampicin increases the rate o f metabolism of a wide range of drugs, including corticosteroids, cyclosporin, and tac- rol imus, therefore close drug level monitoring is required. In HIV-positive patients, rifampic in interacts with HAART, therefore rifabutin may be used in preference. The dura- tion of t herapy can be extended to 9 months. Thickened bladder wall with reduced bladder volume ( \200\230thimble bladder \200\231) (Fig . 7.3.2), trabeculations, incompe- tence of the vesicoureteric junction (VUJ) ori \201 ce, or VUJ narrowing with hydroureter and hydronephrosis. Bladder wall calci \201 cation is r arely seen. CT scan CT scans clearly reveal changes of renal tuberculosis (calci \201 - cation, calyce al dilatation without hydropelvis, parenchymal loss, and extrarenal spread) particularly in advanced disease. MRI MRI with contrast enhancement is good at demonstrating tuberculous cavities, sinus trac ts, \201 stulous communications, and extrarenal and extraprostatic spread. Multiplanar MR I allows evaluation of the disease extent in the prostatic bed and the presence of sinuses and \201 stulae. MRI is also useful in the evaluation of peritoniteal involvement and adn exal masses. Surgical intervention This is undertaken in the following circumstances: \200 \200 to correct obstruction caused by \201 brosis; to remove large foci of infection that can be dif \201 cult to treat medically. Surgery should be performed after 8 \200\22312 weeks of antituberculous treatment; partial/total nephroureterectomy and/or cystectomy may be req uired in extensive disease. Ultrasound Ultrasonography is not as sensitive as intravenous urogram or CT scanning becaus e of problems with identifying calyc- eal, pelvic, or ureteric abnormalities. TB prophylaxis in transplant patients Many renal transplant units give isoniazid prophylaxi s for 1 year to patients at high risk of developing active tubercu- losis. The European Bes t Practice Guidelines for Renal Trans- plantation (2002) recommend that all renal transplan t candi- dates and recipients considered as having latent tuberculosis be treated with ison iazid 300 mg daily for 9 months. Such patients are de \201 ned as those with one or more o f the following: \200 Nuclear medicine Radionuclide imaging is con \201 ned to assessment of relative renal func tion when surgery or nephrectomy is contem- plated. Treatment of tuberculosis Most modern regimens are based on an intensive phase, usually las ting 2 months, during which time virtually all the tubercle bacilli in the lesions are kill ed, followed by a 4 month less-intensive phase designed to kill any remaining organisms. Th e drugs used in the intensive phase are rifampicin, isoni- azid, pyrazinamide, and ethambut ol. Rifampicin is the principal drug used in the continuation phase (unique ability to kill near-dormant organisms), in combination with isoniazid (kills rifampicin-resistant mutants that may arise). Multidrug-resistant tuberculosis, (disease caused by bacilli resistant to rifampicin and isoniazid, with or without resist- ance to other drugs) is becoming increas ingly common. Therapy requires the use of at least four drugs that are selected on the basi s of drug susceptibility tests. Options include: ethionamide, prothionamide, quinolones (e. g. o \202 oxacin), newer macrolides (e.g. clarithromycin), cycloser- ine, kanamycin, viomy cin, capreomycin, thiacetazone, and para-aminosalicylic acid. These are less effective, oft en more toxic, and often more expensive than the \201 rst-line drugs. Therapy may need to be prolonged (18 months or longer). induration after Mantoux testing of 5 mm (transplant recipients) or 10 mm (transplant candi dates on dialysis); a history of inadequately treated tuberculosis; a CXR suggestive of old tuberculosis; and close contact with a person with tuberculosis. \200 \200 Preventive therapy should also be given to tuberculin-neg- ative patients who receive a kid ney from a tuberculin-posi- tive donor. Leprosy and renal disease Direct involvement of the kidney by M. leprae is unusual but lepr osy patients may have a large spectrum of renal manifestations. These include interstitial nephritis, amy- loidosis, and most forms of glomerulonephritis. Between 11 and 38% of lepro sy patients die because of renal failure due to glomerulonephritis or amyloidosis and there fore renal disease may be the main cause of death in such patients. Organ dysfunction seems to correlate with the quantity of bacilli and/or the presence of coexistent disease, amylo id in \201 ltration, concomitant infections, leprosy reactions and side-effects of drugs. The incidence of the various forms of renal disease varies geographically. In an autopsy st udy in Brazil of 199 leprosy patients dying between 1970 and 1986, renal lesions were found in 144 (72%). The renal lesions were: amyloidosis 43%, glomerulonephritis 20%, nephroscler osis 15%, tubu- lointerstitial nephritis 12%, granulomata in 1%, and other lesions in 6%. I n the Indian subcontinent and Japan renal amyloidosis is less frequent. Glomerulonephritis and amyloidosis are associated with multibacillary (lepromatous and borderline lepromatous) leprosy. Treatment of tuberculosis in patients with impaired renal function Rifampicin, isoniazid, p yrazinamide, ethionamide, and pro- thionamide may be given in normal doses. Streptomycin an d other aminoglycosides should be avoided if possible in patients with impaired renal funct ion, espe- cially those on ciclosporin, because of the high risk of nephrotoxicity. Ethambu tol is renally excreted and a reduced dose is therefore used (according to the GFR) to mini mize the risk of optic neuritis. Isoniazid-induced encephalopathy is an uncommon compli- ca tion and is usually prevented by pyridoxine (25 \200\22350 mg/ CHAPTER 7.3 Renal tuberculosis and other mycobacterial infections 259 Glomerulonephritis appears to be related to immune complex deposition (containing IgG, IgM and C3) although mycobacterial antigen has not been identified in the immune complexes or r enal lesions. Episodes of erythema nodosum leprosum (ENL) may be associated with reversible acute kidney injury. It is unclear whether ENL is associated with glomerulonephritis. Amyl oidosis occurs more frequently in patients with recur- rent \202 ares of ENL and trophic ulcers. More severe proteinuria (may be nephrotic range), hematu- ria, and renal dysfunctio n are found in multibacillary patients. Distal tubular dysfunction (urinary acidi \201 cat ion and con- centration defects) have also been documented in leprosy patients. EM disease in transplant patients may be disseminated, localized to the lungs, or most comm only con \201 ned to the skin. Typical causative organisms include: M. haemophilum, M. mar inum, M. chelonae, and M. fortuitum. Treatment of EM disease Owing to their rarity, there a re no good data on the opti- mal therapy of genitourinary disease caused by EM. The therape utic choices depend on the causative species and specialist reference centers should be con sulted. Broadly, treatment regimens are based on those that have been evaluated for pulmona ry and disseminated disease. These include (azithromycin, 600 mg daily or clarithromy- cin, 500 mg twice daily), in combination with ethambutol for disease due to MAC-complex infecti ons. Further reading Ahsan N, Wheeler DE, Palmer BF. Leprosy-associated renal disease: case repo rt and review of the literature. J Am Soc Nephrol 1995; 5: 1546 \200\2231552. Treatment of leprosy Treatment is with standard antileprosy drugs (rifampicin, dapsone and clofazimine (for multibacillary leprosy)), mak- ing allowance for the degree of renal dysfu nction. Altintepe L, Tonbul HZ, Ozbey I, Guney I, et al. Urinary tuberculosis: Environmental mycobacterial (EM) disease Disease of the genitourinary system due to EM is e xceed- ingly rare. Because EM are commonly found in the urine as harmless contaminants, mak ing a diagnosis of EM-mediated disease can be dif \201 cult. Six diagnostic criteria have therefore been proposed: 1. Symptoms of chronic or recurrent genitourinary infection. 2. Ra diological or endoscopic evidence of genitourinary ten years \200\231 experience. Ren Fail 2005;27:657 \200\223661. Corbishley, CC, Grange, JM. Tuberculosis and the kidney. J Am Soc Nephrol 2001; 12: 1307 \200\2231314. da Silva J nior GB, Daher Ede F. Renal involvement in leprosy: ret- rospective analysis of 461 cases in Brazil. Braz J Infect Dis 2006; 10: 107 \200\223112. Eastwood JB, Abdelrahman M, Sinha AK, Karkar A. Tuberculosis in end-stage renal disease pat ients on hemodialysis. Hemodial Int 2006; 10: 360 \200\223364. Glassroth J. Pulmonary disease due to nontuberculous mycobacte- ria. Chest 2008; 133: 243 \200\223251. disease. John GT, Shankar V, Abraham AM, Mukundan U, et al. Risk factors for post-transplant tubercu losis. Kidney Int 2001; 60: 1148 \200\2231153. Mallinson WJW, Fuller RW, Levison DA, et al. Diffuse interstitial renal tuberculosis \200\223 an unusual cause of renal failure. Q J M ed 1981; 50: 137 \200\223148. 3. Abnormalities on urinalysis. 4. Failure to isolate other urinary tract pathogens. 5. Rep eated isolation of the same mycobacterial species. 6. Histological demonstration of granulo mata and, prefer- Mapukata A, Andronikou S, Fasulakis S, et al. Modern imaging of renal tuberculosis in child ren. Australas Radiol 2007; 51: 538 \200\223542. Muttarak M, ChiangMai WN, Lojanapiwat B. T uberculosis of the genitourinary tract: imaging features with pathological correla- tion. S ingapore Med J 2005; 46: 568 \200\223574. ably, AFB. The \201 rst four criteria should alert the clinician to the pos- sibility of a mycobacte rial etiology, the \201 fth strongly sug- gests the diagnosis, but only the sixth is con \201 rmatory. A retrospective application of these criteria showed a high false-negative r ate for diagnosis. Only few cases of renal tract disease caused by EM have been documented in immunocompetent hosts. These include renal disease caused by M. avium \200\223intracellu lare (MAC), epididymitis due to M. xenopi and M. kansasii, and prostatitis caused by M. xen opi and M. fortuitum. Nakayama EE, Ura S, Fleury RN, Soares V. Renal lesions in leprosy: a retrospective study of 199 autopsies. Am J Kidney Dis 2001; 38: 26 \200\22330. Youmbissi JT, Malik QT, Ajit SK, e t al. Non tuberculous mycobacte- rium peritonitis in continuous ambulatory peritoneal dialy sis. J Nephrol 2001; 14: 13213 \200\22313215. Internet resources Centers for Disease Control and Prevention document on the treatment of tuberculosis: EM disease in end-stage renal disease There have been number of reports of EM causing disea se in dialysis and transplant patients. http://www.cdc.gov/mmwR/preview/mmwrhtml/ rr5211a1.htm World Health Organization Tuberculos is information: Hemodialysis Small clusters and isolated cases of disseminated disease due to M. chelonae h ave occurred in patients on hemodi- alysis (probably due to contamination of the dialysis m achine by EM). http://www.who.int/topics/tuberculosis/en/ World Health Organization Leprosy information: http://www.who.int/lep/en/ See also Infection-related glomerulonephritis, p. 128 Glomerular disease in the tropics, p. 138 Nephrocalcinosis, p. 278 Peritoneal dialysis (PD) A number of EM have been implicated as rare causes of PD peritonit is. These include: M. chelonae, M. fortuitum, M. kansasii and M. gordonae. Renal transplantation The incidence of mycobacterial disease following renal transplantatio n is much higher than in the general popula- tion and in 25 \200\22340% of cases an EM is t he cause. R. BARSOUM 260 Schistosomiasis Schistosomiasis is a parasitic disease, acquired by contact with contaminated fresh water, that causes significant morbidity and mortality in >20 million inhabitants of 76 countries. While its prevalence is decreasing in a few endemic foci owing to effective eradication pr ograms (e.g. China), it is still increasing in most other areas (e.g. Africa), as well as i n nonendemic regions owing to the exchange of immigrants and expatriates. The disease is ca used by a blood \202 uke that belongs to the family Schistosomidae, of which three specie s are responsi- ble for the bulk of human infection: \200 glomerular lesions (Fig. 7.4.3) mostly seen with hepat- osplenic schistosomiasis. Clinical features The clinical pro \201 le of schistosomal infection passes through four p hases: Phase I This occurs at the time of \201 rst acquisition of infection, and is attri butable to the immune response to the infective cer- cariae. The site of entry may form a s mall itchy skin papule or blister, which resolves spontaneously in <48 h. A couple of weeks later, a serum-sickness-like syndrome (Takayama disease) may occur, particularly in expatr iates, which resolves in a few days. Phase II This occurs several weeks later after the par asite has matured and the females have started laying eggs. While the majority of ova are p assed with respective excreta, some are deposited in the lower urinary tract, sigmoid or re ctum. The local in \202 ammatory response caused by tissue oviposition is responsible for the symptoms which hall- mark this phase. These are: \200 S. hematobium which causes lower urinary tract morbid- ity and upstream consequences, in Af rica; S. japonicum which causes hepatosplenic disease often complicated by neurological seq uelae, in the Far East; S. mansoni which causes hepatosplenic disease occasion- ally compli cated by glomerular pathology, in Africa, South and Central America, and certain parts of A sia. Pathology All pathological lesions in established schistosomiasis (Fig. 7.4.1) are attribut ed to two types of host immune response. \200 Terminal hematuria and dysuria in S. hemato- bium infection, which can mimic calculus disea se, tuber- culosis, or severe bacterial cystitis. The diagnosis is con \201 rmed by \201 nding live ova in the urinary sediment. Failing this, a cystoscopic examination can con \201 rm the diagnosis, by showing the typical lesions (Fig. 7.4.2). Tenesmus, diarrhea and the passage of red blood in stools with S. mansoni or S. japonicum infection. This presenta - tion may be confused with amebic or bacillary dysentery, Type IV delayed hypersensitivity to soluble egg antigens is the prototype of the supervenin g granulomatous response (Fig. 7.4.2) at the sites of oviposition in the lower urinary and intestinal tracts, as well as in distant metastatic sites in most organs. Type-III immune-c omplex-mediated response to adult worm gut antigens is responsible for the less common Adult worms Ova S. mansoni S. haematobium