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 Macrophages Ova late IL-4, Somatostatin early Soluble egg antigens IL-1, TNF-a, GM-CSF Gut antigens Th1 B-lymphocytes CD8, Eosinophils Lower UT Granulomas Class I SG Class II SG IgG, C3, Salmonella Ag Salmonella Bacterial infection IgM, C3 Gut Ag Chronic cystitis Papilloma infection Bladder cancer Hepatic fibrosis Th2 IL-10 IL-13 HCV infection Class III SG Class VI SG IgM, C3 Bladder fibrosis IgA Genetic factors Ethnic factors Ureteric obstruction Vesicourteric reflux Class IV SG Class V SG IgA Bacterial infection Chronic interstitial nephritis Tubular functional defects Chronic renal failure Fig. 7.4.1 The main immunological pathways involved in the pathogenesis of morbidity from s chistosomiasis. SG, schistosomal glomerulopathy. CHAPTER 7.4 Schistosomiasis 261 (b) (c) (a) (d) (e) (f) (g) (h) Fig. 7.4.2 Pro \201 le of schistosomiasis of the urinary tract, usually caused by S. haema tobium. (a) Schistosomal granuloma (left panel) with sheets of S. haematobium eggs in the b ladder mucosa (right panel). (b \200\223e) Cystoscopic appearances in phase II: pseudotuber cles (b), sessile mass (c) and phase IV: sandy patches (d), cystitis cystica (e). (f \200 \223h) Radiological appearances: linear calci \201 cations (f), bladder cancer (g) and gra de V vesicoureteric re \202 ux (h). radiological examination of the lower urinary tract which may show typical bladder calcific ations (Fig. 7.4.2); liver ultrasonography which may show evidence of peri- portal \201 b rosis. in \202 ammatory bowel disease, or malignancy. Diagnosis is con \201 rmed by \201 nding ova in the stools, or by endoscopic examination and biopsy of suspicious lesions. Phase III This is a quiescent period that extends for many years, often to the end of the p atient \200\231s life, without any symptoms. In contrast to cure, which may follow effectiv e therapy in phase II, the disease in phase III is active but clinically dormant, as a resu lt of balanced host \200\223parasite concomitant immunity. Evidence of asymptomatic disease may be obtained by: \200 Phase IV This is the cause of chronic morbidity from schistosomiasis. Its incidence varies from <10% to >40% of infected indi- viduals, depending on parasite, host and environmental fac- tors. Any organ can be simultaneously or sequentially involved, particularly the urina ry, gastrointestinal, cardiop- ulmonary and central nervous systems. There are three domain s of late schistosomal involvement of the urinary system: Lower urinary tract Chronic cysti tis, with dysuria, scalding, frequency and hematuria may result from the advanced schistoso mal examination of the urine or stools for evidence of ovishedding; examination of the urine fo r microalbuminuria or microhe- maturia which indicates early glomerular pathology; serologi cal tests, including hemagglutinin inhbition, circu- moral precipitin, ELISA, or others, wh ich may provide evidence of recent (<3 months) release of schistosomal antigens; R. BARSOUM 262 lesions of chronic ulcers, cystitis cystica or sandy patches (Fig. 7.4.2). \200 species, and class V lesions have been more often associ- ated with mixed infections. It is noteworthy that the lesions are nonspeci \201 c, which may lead to confusion with primary or other secondary glomer- ulopathies with similar pictures. With the exception of a few p atients (usually class I), in whom schistosomal antigens are demonstrated by immun- o \202 uorescence, the diagnosis of schistosomal glomerulopa- thy (SG) is usually made on circums tantial evidence, such as having lived in an endemic area, with historic or current evidenc e of schistosomal infection, the presence of schis- tosomal hepatosplenomegaly, and compati ble renal his- topathology. The bladder capacity may be either reduced due to detrusor fibrosis or increased due to bla dder neck obstruction. Secondary bacterial infection very often confounds the pathology, sy mptomatology and response to therapy. Bladder malignancy may further complicate this situa- tion. It should be suspected when there is worsening or change in the pattern of symptoms, passage of necrotic tissue in the urine (necroturia), or when a bladder mass is palpated o n rectal examination. Upper urinary tract Distal ureteric obstruction and vesicoureteric re \202 ux are the two major consequences of late bladder pathology. (Both can also be transiently seen in phase I I, but at that time are reversible with antiparasitic treatment). \200 Management Active schistosomal infection must be eradicated by spe- ci \201 c treatment. T he drug of choice is Praziquantel in a dose of 40 mg/kg body weight as a single dose for S. haemato- bium and S. mansoni and 60 mg/kg body weight in two divided doses for S. japonicu m. Associated Salmonella infection in class II SG should be simultaneously treated with amp icillin and cotrimoxa- zole. Concomitant hepatitis C virus infection may be treated with in terferon and ribavirin in accordance with the gen- eral indications for such therapy. Assoc iated bacterial infection in urinary schistosomiasis should be treated; long term, low dose chemotherapy may be needed in chronic or relapsing infections. Complicated upper urinary t ract schistosomiasis may need surgical treatment. Little can be done for SG beyond class II . Class I may respond to antiparasitic treatment and there are con \202 ict- ing reports o n the bene \201 t of corticosteroids and immuno- suppression. Chronic obstruction results from \201 brosis at the ureter- ovesical junction. The ureter usually compensates for distal obstruction by dilatation hypertrophy of its spin- dle, wit hout further upstream consequences. Failing this, back pressure eventually leads to hydrone phrosis. Vesicoureteric re \202 ux may result from schistosomal blad- der \201 brosis pe r se, but more often results from attempted instrumental dilation for obstruction. Secondar y bacterial infection may complicate the pic- ture of obstruction or re \202 ux and is oft en the underlying cause of secondary stone formation. Interstitial \201 brosis eventually develops, leading to impair- ment of tubular function, particularly with regards to salt c onservation and urine acidi \201 cation. Finally end-stage renal failure supervenes. Glomerular disease Glomerular pathology (Table 7.4.1, Fig. 7.4.3) is mostly seen with S. ma nsoni, although class I lesions may occur with any (a) (b) (c) (d) (e) (f) Fig. 7.4.3 Pro \201 le of glomerular disease in schistosomiasis, usually caused by S. mans oni. (a) Class I, mesangial proliferative; (b) class II, exudative; (c) class III, type I m esangiocapillary (membranoproliferative); (d) class IV, focal segmental sclerosis; (e) clas s V, amyloidosis (apple-green birefringence under polarized light); (f ) class VI, cryoglob ulinemic. CHAPTER 7.4 Schistosomiasis 263 Table 7.4.1 Classi \201 cation of schistosomal glomerulopathies Class Histology IF Etiologic agent Prevalence Clinical \201 ndings Treatment of renal disease S. haematobium S. mansoni S. Japonicum 27 \200\22360% of asymptomatic patients, 10 \200\223 40% of patients with renal disease Sal monella infections. Reduced serum C3 7 \200\22320% of asymptomatic patients and in 80% of p atients with overt renal disease 11 \200\22338% Microhematuria Proteinuria Anti-parasitic treatment Mesangiopro- liferative IgM, C3. Schistosomal gut antigens I S. haematobium S. mansoni + Salmonella spp. Acute nephritic syndrome Toxemia Combined treatment of schistosomal and salmonella infection Diffuse proliferative exudative C3. Salmonella antigens II S. mansoni (S. haematobium?) No Mesangiocapillary IgG, IgA, C3. Schistosomal antigens Hepatosplenomegaly nephrotic syndrome hypertension, renal failure III S. mansoni No Focal segmental glomerulosclerosis IgM, IgG (occasionally IgA) Hepatosplenomegaly, nephrotic syndrome, hypertension, renal failure Hepatosplenomegaly, nep hrotic syndrome, hypertension, renal failure Hepatosplenomegaly nephrotic syndrome, purpura , vasculitis, arthritis, hypertension, renal failure IV S. mansoni S. hematobium No 16 \200\22339% Amyloid AA protein V ? Interferon + ribavirin Corticosteroids. Immunosuppression Plasmapheresis Cryoglobulinemic IgM, C3 S. mansoni + HCV Unknown VI Patients with end-stage kidney disease may pose certain problems with renal replacement the rapy. \200 Barsoum R. The kidney in schistosomiasis. In: Feehally J, Floege J, Johnson R (eds), Compre hensive clinical nephrology, 3rd edn. St Louis, MO: Mosby/Elsevier; 2007. pp. 631 \200\2236 39. Hemodialysis may constitute a risk for bleeding from esophageal or gastric varices associat ed with advanced liver disease. Peritoneal dialysis may not be possible in the presence of ascites. Transplantation may be technically dif \201 cult in the pres- ence of signi \201 cant lower urinary tract pathology, and the metabolism of immunosuppressive drugs may be a ltered in those with significant hepatocellular dysfunction. However, the overall outcome o f renal transplantation in patients without these limitations is satisfactory. Recurrence m ay occur in transplanted kidneys if the dis- ease is still active in the recipient. Mostafa MH, Sheweita SA, O \200\231Connor PJ. Relationship between schistosomiasis and blad der cancer. Clin Microbiol Rev 1999; 12: 97 \200\223111. Internet resources World Health Organization: http://www.who.int/topics/schistosomiasis/en/ CDC Division of Parasitic Diseases: http://www.cdc.gov/ncidod/dpd/parasites/schis- tosomiasis/ Schistosomiasis Control Initiati ve: http://www.schisto.org/ Further reading Abdel-Wahab, MF Schistosomiasis in Egypt. Boca Raton: CRC Press; See also Infection-related glomerulonephritis, p. 128 Glomerular disease in the tropics, p. 138 1982. Barsoum, RS. Schistosomal glomerulopathy: selection factors. Nephrol Dialysis Transplant 1987; 2: 488 \200\223497. Barsoum RS: Schistosomiasis. In: Davison AM, Cameron JS, Grunfeld JP, Ponticelli C, Ritz E, Winearls CG, Van Ypersele (eds): Oxford textbook of clinical nephrology, 3rd edn. Oxford: Oxford University Press; 2005. Vol. II, Chap. 7-4, pp. 1173 \200\2231184. K.L. GUPTA 264 Fungal infections and the kidney Clinical features Candidal urinary tract infections can cause a variety of clinical symptom s and signs. Patients may be asymptomatic or have features of bladder irritability (pyuria, hematuria or pneumaturia) suggesting candida cystitis. Cystoscopy reveals gray-white patch es on the bladder wall, mucosal edema and erythema, and also on occasion a \200\230snow st orm effect \200\231 that obscures visualization. Urinary colony counts of >10 000 \200\2231 5 000/mL, and urinary casts containing fungal material (Papanicolaou stain) sug- gest bladd er infection rather than colonization. Classical pyelonephritis with \202 ank pain, renal tenderness and fever may also develop. Pathological \201 ndings may include evidence of multiple abscesses in the interstitium and glomeruli, with budding yeast and pseudomycelia in peritubular vessels and collect- ing tubules. Emphysematous pyelonephritis, pyelitis and renal papillary necrosis have also been described. Flank pain and symptoms of renal colic may also be caused by the passage of fungal balls that obstruct the collecting system. Fung al accretions may develop in the collecting system without overt clinical \201 ndings. Ol iguria and anuria have also been known to occur. The incidence of invasive fungal infections (IFIs) has risen dramatically in the last 20 ye ars with the increased survival of patients with immunocompromised states. These infections are often insidious and their diagnosis is usually delayed because of coexisting illnesses . There are many fungi which may involve deeper tissues including the kidneys (Table 7.5.1) . Candida and Aspergillus species are common causes but Zygomycetes, Cryptococcus and Dimor phic fungi (e.g. Histoplasma, Coccidioides, Blastomyces and Penicillium) spe- cies may also rarely involve the kidneys. Table 7.5.1 Pathogenic fungi affecting the genitourinary system Common Rare and unusual Geotrichum candidum Paracoccidioides brasilensis Penicillium glaucum Penicillium ciftrinum Trichosporon Fusarium Pseudallescheria boydii Cunninghamella Rhinosporidium seeberi Sporoth rix schenckii Primary pathogens Histoplasma capsulatum Coccidioides immitis Blastomyces dermatidis Opportunistic pathogens Candida albicans Aspergillus species Cryptococcus neoformans Zygomy cetes fungi Zygomycosis Zygomycosis (previously known as phycomycosis and mucormycosis) is a rare mycot ic infection caused by angio- invasive fungi belonging to the class Zygomycetes. The most c ommon pathogenic species include Rhizopus oryzae, Rhizomucor pusillus, and Absidia corymbif era. They usually cause serious disease in immunocompromised patients. Rarely apparently he althy subjects may also be affected. The list of predisposing conditions continues to grow, the latest additions being desferrioxamine therapy for iron/alu- minium overload in dialys is patients. The organisms invade blood vessels leading to ischemia and necrosis associated with acute in \202 ammation in the affected organ. The four main presentations of zygomyc osis in man are the rhinocerebral, pulmonary, gastrointestinal and dissemi- nated forms. Ra rely infection of isolated organs such as bones, kidney or heart may occur. Renal involveme nt occurs both as part of disseminated infection, or in apparent isolation probably due to hema- togenous dissemination from subclinical pulmonary infec- tion (similar to renal tuber culosis). Pathogenesis Most IFIs are caused by hematogenous spread. Animal experiments have shown tha t fungi injected intra- venously are usually cleared from the bloodstream. In the immunocom promised host, however, bloodborne fungi infect the kidneys by attachment to endothelial su rfaces followed by penetration into the interstitium, and multipli- cation. Ascending infec tion of the kidneys may also be important in a minority of individuals. Risk factors for th e multiplication of the organisms in renal tissue include: AIDS, diabetes, lymphoma, leukem ia, burns, renal failure, organ transplantation, and immunosuppres- sive drugs. Opportunistic infections Candidiasis Candidiasis refers to the range of infections caused b y spe- cies of the genus Candida which includes >160 species. The \201 ve most frequent h uman pathogens are C. albicans, C. krusei, C. parapsilosis, C. tropicalis, and C. glabrata (also called Torulopsis glabrata). Candida can exist in two morphological states: yeast (ce l- lular form) and \201 laments (hyphal or mycelial form). Torulopsis (Candida) glabrata, which does not develop pseudohyphae or produce germ tubes, represents 5 \200\22321% of the isolates from positive fungal cultures and is the sec- ond most common genitourinary funga l pathogen. It has a worse prognosis than other Candida species. Clinical features Renal zygomycosis causes fever, \202 ank pain and oligoanuria. Renal fa ilure (occurs in up to 95% of patients with bilateral involvement) results from the near to tal occlusion of the renal arteries and/or their branches. Pathologically the kidneys may b e enlarged with extensive cortical and medullary involvement, evidence of vasculitis with i nfarction, and parenchymal neutrophil in \201 ltration. CHAPTER 7.5 Fungal infections and the kidney 265 Fungal hyphae can often be seen in the in \201 ltrate with gran- ulomata and Langhans-type multinucleated giant cells. Hyphae may be seen invading both glomeruli and tubules. Dissemination may occur with involvement of the CNS, bone, spleen, gastrointestinal system, and kidneys (in 50% of cases). Cystitis, pyuria, hematuria, moderate proteinuria and mild renal insuf \201 ciency may develop. Cryptococcal infection has never been reported to cau se renal failure. The pathological changes can range from sparse lym- phocytic in \201 ltr ation to an intense granulomatous reaction in the renal parenchyma with caseation and micro abscess formation. In the medulla, abscesses may be accompanied by intersti- tial in \202 ammation, \201 brosis and papillary necrosis. Tubular obstruction, dilatation and atrophy may result, associated with intense interstitial and glomerular \201 brosis. Imaging studies Radiographic studies demonstrate poor excretory renal function and obstruct ive uropathy caused by fungal hyphae occluding the vascular and collecting systems respecti vely. Characteristic \201 ndings on CT scanning include diffuse enlargement of the kidney s, the absence of contrast excre- tion, and the presence of multiple low density areas in t he renal parenchyma (fungal abscesses). Abscess rupture may result in perinephric collectio ns. MRI scanning may be preferred in diabetic patients in order to avoid the use of nephrot oxic contrast agents. Endemic infections Histoplasmosis Histoplasma capsulatum, a dimorphic fungus, is found worl dwide in soil contaminated by bird excreta. Infection often develops in city dwellers expos ed to con- struction excavations. Approximately 90% of these infections result in mild and clinically insigni \201 cant respiratory infection. Approximately 1:2000 individuals expos ed to H. capsula- tum develops disseminated disease involving the lungs, the reticuloendoth elial system (liver, spleen and bone mar- row), and the genitourinary system. The kidneys a re involved in 20% of cases of disseminated disease. The renal lesions include noncaseatin g granulo- mata, microabcesses, and rarely cutaneous \201 stulae. These are usually not a ssociated with signi \201 cant renal symptoms. Histoplasmosis in transplant recipients may lead to graft loss, and sometimes obstructive uropathy secondary to sloughed papillae. Aspergillosis Invasive aspergillosis is caused by fungi of the genus Aspergillus. Twenty as pergillus species are said to be pathogenic to human beings including A. fumigatus, A. \202 avus, A. terreus, A. nidulans and A. niger species. They have characteristic septate h yphae with dichotomous branching which readily distinguishes them from the hyphae of Mucor. Aspergillosis is primarily a pulmonary infection, which can present with allergic alveolit is and bronchopulmonary aspergillosis. Disseminated infection can occur following hematogen ous spread in patients with debilitating diseases. Renal involvement has been reported in 8 \200\22313% of patients with disseminated disease. Most (80%) have unilateral involvement. Clinical features Clinically proteinuria, pyuria, hematuria and sometimes oliguric renal fa ilure is present. Most have fungal bezoars producing hydronephrosis and less frequently the y may have single or multiple parenchy- mal abscesses. The fungi are angioinvasive, therefo re vascular thrombosis and patchy infarction in the kidney may develop (less severe than wi th zygomycosis). Renal papillary necrosis may also occur. Renal aspergillosis may present i n the following ways: 1. Disseminated aspergillosis with renal involvement. It results from hematogenous spread of fungi to the kidneys leading to formation of multiple focal abscess es. Blastomycosis Blastomycosis is a systemic pyogranulomatous infection, caused by the fungus, Blastomyces dermatidis. It primarily involves the lungs and frequently disseminates to oth er organs. It exhibits thermal dimorphism, with a mycelial phase at 25 C and a yeast phase at 37 C. Humidity is important in promoting growth of the organism. Pulmonary infection m ay be followed by hematogenous dissemination in adult males, pregnant women and their unbor n children, and immunocompromised patients with end-stage AIDS and organ transplants. Skin, bone, and the CNS are common sites of extrapulmo- nary blastomycosis. Genitourinary diseas e has also been reported in as many as 20 \200\22330% of patients with disseminated disease . Involvement of the prostate, epididymis and testes is com- mon whereas kidney and ureteri c involvement is less fre- quent. Patients may present with symptoms of prostatitis. Pyuria and hematuria are found in the majority. Infections of the female genital tract are uncomm on. 2. Aspergillus cast of the renal pelvis. It results in obstruc- tive uropathy which may pre sent with urinary retention or anuria. 3. Ascending panurothelial aspergillosis. This refers to ascending infection involving the urethra, bladder, ure- ters and the kidney. Cryptococcosis Cryptococcosis, also known as torulopsis, is caused by the basidiomycetous e ncapsulated yeast, Cryptococcus neofor- mans, which is found in bird excreta, decaying orga nic mat- ter and soil. The initial focus of infection is usually the respiratory tract whic h occurs following inhalation of the fungal spores. Coccidiomycosis Coccidioidomycosis is the infection caused by the dimor- phic fungus, Cocci dioides immitis, which is endemic to the semi-arid sub-Sonoran regions of the western USA. K.L. GUPTA 266 Treatment of fungal infections The treatment of invasive deep-seated fungal infections can be dif \201 cult due to the limited number of drugs available and the undesirable toxicity of some of them. Amphotericin B, \202 uconozole and itraconozole have been the mainstay of therapy for IFI, but recent advances in ther- apy are described below. The saprophytic mycelial phase of this fungus exists in the soil and under proper environme ntal conditions is highly infectious. Following inhalation, an asymptomatic and transient p ulmonary infection ensues. 60% of infected individuals have subclinical disease while the r emainder will have a mild \200\223severe respiratory illness with complete resolution. Appr oximately 5% will have residual pulmonary infection and <1% develop extrapulmonary multiple organ dissemi- nation (to the meninges, bone, joints, skin, and soft tis- sues). Renal inv olvement occurs in 46 \200\22360% of cases of dissemi- nated disease. Microabcess or granul omata formation typically develops. Bladder infection may present with hematuria, pneumatu- ria (caused by a vesicocolic \201 stula) and concomitant bacil- luria. Prostate infectio n may present with symptoms suggestive of a bladder out \202 ow tract obstruction. Lipid formulations of amphotericin B Whereas the continuous 24 h infusion of amphotericin B has been found to have less overall infusional toxicity and nephrotoxicity than convention al 4 h infusion, there is a clear bene \201 t with the use of lipid formulations. These al low higher doses of amphotericin B to be administered before toxicity develops. The three a vailable lipid formulations are liposomal amphotericin B (AmBi-some), amphotericin B lipid complex (Abelcet), and amphotericin B colloidal dis- persion (Amphocil). Triazoles Voriconazole, a new triazole, has activity against yeasts, including those intrin sically resistant to \202 uconazole, as well as molds such as Aspergillus spp., some Fusa rium spp. and, importantly, Scedosporium spp., which are often resistant to amphotericin B. However, voriconazole speci \201 cally causes transient visual disturbance and interacts with various drugs including rifampicin, erythromycin, ciclosporin, and cyclophospha- mide through inhibition of the hepatic enzymes CYP2C9 and CYP2C19, The newer triazoles, posacona zole and ravuconazole, also have broad spectrum in vitro activity against \201 lamentous fungi. Posaconazole, in particular, has found clinical utility as salvage therapy in zygomy cosis. Laboratory diagnosis of renal mycosis Conventional microbiologic methods Direct microscopy (Gram, Giemsa, and KOH/calco \202 uor stains), culture, identi \201 cation and susceptibi lity testing. Histopathologic methods Conventional microscopy, direct immuno \202 uorescence and in situ hybridization. Immunologic and biochemical methods Histoplasma antigen test, cryptococcal antigen test, ga lac- tomannan test (for Aspergillosis with 67 \200\223100% sensitivity and 81 \200\22398% s pecificity), and (1,3) -D-glucan test (for Candida and Aspergillus spp.). Echinocandins Echinocandins inhibit the synthesis of -1,3-D-glucan in the fungal cell wal l. They have most activity in the growing ends of fungal hyphae and rapidly cease hyphal gr owth and replication. Although caspofungin has activity against Aspergillus and Candida, it is not active against Cryptococcus, Fusarium or Zygomycetes. Micafungin and anidulafungin are the two other Echinocandins approved by the US Food and Drug Administration. Molecular methods Direct detection and identi \201 cation, e.g. peptide nucleic acid \202 uorescence in situ hybridization (PNA FISH) for Candida spp. Polymerase chain reaction , although promis- ing for the diagnosis of IFI, has not been widely used. Fungal infections following renal transplantation Fungal infections remain a signi \201 ca nt challenge after trans- plantation. Their incidence varies according to the organ transpl anted. In renal transplant recipients an incidence of 1 \200\22314% has been reported and t hese infections are associated with a very high mortality. This is related to environmental expo- sure and the degree of immunosuppression. In an analysis of 850 renal transplant rec ipients from a terti- ary care center in North India, Gupta (2001) described fungal infecti ons in 83 patients (9.8%). These were candidia- sis in 25 (2.8%), cryptococcosis in 16 (1.9 %), aspergillosis in 20 (2.3%), zygomycosis in 17 (2.0%) and rare fungal infec- tions in \201 ve others including pheohyphomycosis in three and disseminated histoplasmosis in two p atients. The role of prophylaxis or pre-emptive therapy in subsets of solid organ transplan t patients is still being de \201 ned, but evidence supports the use of \202 uconazole p rophylaxis in liver transplant recipients. Emerging fungal pathogens may be resistant to co nven- tional antifungal agents, and speci \201 c microbiological diag- nosis is important. Combination therapy With the availability of antifungal agents acting on different targets in the fungal cell, the possibility of combination therapy exists. In vitro testing suggest s combination therapy (e.g. caspofun- gin + \202 uconazole or \202 ucytosine + amphoter icin) produces synergy which is particularly useful in dif \201 cult-to-treat infections s uch as scedosporiosis and aspergillosis as well as candidiasis and cryptococcosis. The drug management of various renal mycoses is described in Table 7.5.2. Surgery Surgical measures may also be necessary to treat the fungal balls as well as to rem ove infected tissue. Debulking of bezoars in patients with candidiasis and aspergillosis ma y be carried out by percutaneous nephros- tomy, endoscopic removal, or open pyelotomy. In a ddition, it may be combined with local irrigation with amphotericin B. CHAPTER 7.5 Fungal infections and the kidney 267 Immune therapy Adjunctive immune therapy with interferon- , granulocyte- macrophage colony -stimulating factor and granulocyte colony-stimulating factor can be considered for severe IFI refractory to conventional antifungal treatment. Table 7.5.2 Treatment of invasive fungal infections Infection Drugs and dosage Candiduriaa Fluconazole 200 mg/day (loading 400 mg) for 14 days Amphotericin B 0.3 \200\2230.7 mg/kg/day for 1 \200\2237 days Further reading Almyroudis NG, Sutton DA, Linden P, et al. Zygomycosis in solid organ trans plant recipients in a tertiary transplant center and review of the literature. Am J Transpl ant 2006; 6: 2365 \200\2232374. Candidemiaa/ invasive candidiasis Fluconazole 200 \200\223400 mg/day or Chayakulkeeree M, Ghannoum M, Perfect J. Zygomycosis: the re- emerging fungal infection. Eu r J Clin Microbiol Infect Dis 2006; 25: 215 \200\223229. Caspofungin 70 mg on day 1, 50 mg/day thereafter or Amphotericin B 0.5 \200\2231 mg/kg/day or Lipid- AmB 5 mg/kg/day Comments C. krusei, C. glabrata are \202 uconazole resistant; t reat with an echinocandin, voriconazole or posaconazole Chugh KS, Sakhuja V, Gupta KL, et al. Renal mucormycosis: compu- terized tomographic \201 ndings and their diagnostic signi \201 cance. Am J Kidney Dis 1993; 22: 393 \200\223397. Gabardi S, Kubiak DW, Chandraker AK, et al. Invasive fungal infec- tions and antifungal the rapies in solid organ transplant recipients. Transpl Int 2007; 20: 993 \200\2231015. Gupta KL. Fungal infectons and the kidney. Ind J Nephrol 2001; 11: Invasive aspergillosis Voriconazole 6 mg/kg IV \2272 doses, then 147 \200\223154. 4 mg/kg/day twice daily IV, can convert to 200 mg twice daily orally. Caspofungin 70 mg on day 1, 50 mg/day thereafter Amphotericin B 1 \200\2231.5 mg/kg/day or Lipid- AmB 5 mg/kg/da y Itraconazole 400 mg/day Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit. Clin Infect Dis 2007; 45: 205 \200\223216. Pappas PG, Rex JH, Sobel JD, et al. Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis 2004; 38: 161 \200\223189 [Revised in 2008: see j ournal website.] Pappu LD, Purohit DM, Bradford BF, et al. Primary renal candidiasis in two preterm neonates . Report of cases and review of literature on renal candidiasis in infancy. Am J Dis Child1 984; 138: 923 \200\223-926. Scheinfeld NA. Review of the new antifungals: posaconazole, mic afun- Fluconazole 200 \200\223400 mg/day or itraconazole 200 \200\223400 mg/day; or Lipid-AmB 5 m g/kg/day with \202 ucytosine 100 mg/kg/day for 2 weeks followed by \202 uconazole 400 m g/day Cryptococcosis gin, and anidulafungin. J Drugs Dermatol 2007; 6: 1249 \200\2231251. Internet resources Infectious Diseases Society of America. Guidelines for treatment of cand idiasis. 2008 update: Posaconazole 800 mg/day Lipid-AmB 5 \200\22315 mg/kg/day Zygomycosis www.idsociety.org/WorkArea/downloadasset. aspx?id=7818 Information about aspergillus and ap ergillo-sis: a Infectious Diseases Society of America (IDSA) published guidelines for the treatment of c andidiasis (2004). http://www.aspergillus.org.uk/ Information about human mycoses: For extensively damaged tissues in patients with angioinva- sive infections such as mucormy cosis, debridement and excision of the tissue (which may include nephrectomy) may be necess ary. http://www.doctorfungus.org/ See also Infection-related glomerulonephritis, p. 128 This page intentionally left blank 269 Chapter 8 Renal stone disease Chapter contents Medical management of stone disease 270 Surgical management of stone disease 274 Nephrocalc inosis 278 Renal stone disease in children 282 R. AL JAYYOUSI 270 Medical management of stone disease De \201 nition Nephrolithiasis is the formation of stones in the renal tubules or collecti ng system. Epidemiology and incidence The incidence of nephrolithiasis varies geographicall y. In industrialized nations the incidence is 1 in 1000. The peak age is the third decade and the prevalence is higher in men. A prevalence of 10% occurs in industrialized nations b ut is higher in areas such as the Middle East. The recurrence rate for nephrolithiasis rang es from 50 to 80%. Environmental factors \200 \200 \200 \200 \200 Occupation. Fluid intake. Diet. Exercise intensity. Urine volume. Drug history Drugs that may precipitate into stones \200 \200 \200 Triamterene. Aciclovir. Indinavir. Drugs that increase the risk of stone formation \200 \200 \200 \200 \200 \200 \200 \200 \200 Loop diuretics. Calcium and vitamin D supplements. Glucocorticoids. Antacids. Theophylline. Acetozalamide. Salicylates. Probenecid. Vitamin C. Etiology Stones form when the urinary concentration of the stone constituents rises above t he supersaturation level. The super- saturation level re \202 ects the product of free ion activities. It is not solely dependent on the concentration of consti- tuents but also on the presence of promoters and inhibitors of stone formation such as urine pH and citrate co ncentration. The common types of renal stones are listed in Table 8.1.1. Examination Physical examination should be undertaken to identify other possible causes for pain and hematuria. Table 8.1.1 Types of renal stones (listed in order of decreasing prevalence) Combination of calcium oxalate and calcium phosphate Calcium oxalate Struvite Calcium phosp hate Uric acid Cystine