prophylaxis with cotrimoxazole (or pentamidine or dapsone in those allergic to cotrimoxazol e) against Pneumocystis jiroveci (previously known as Pneumocystis carinii) pneumonia shoul d be provided while on cyclo- phosphamide; additionally, to prevent the adverse effects of corticos- teroids, a proton pump inhibitor, oral nystatin or \202 uco- nazole, and bone protection with calcium/ergocalciferol and b iphosphonates when appropriate should be provided. Renal transplantation In those patients who develop end-stage renal failure, transplantatio n is a safe option, with no risk of disease relapse unless circulating anti-GBM antibodies are present at the time of transplantation. A period of 6 months of disease remission with undetect- able anti-GBM antibodies is generally required prior to transplantation. Standard transplantation immunosuppressive protocols are appropriate. The optimal duration of immunosuppressant therapy is unknown; however, 3 months of cyclopho sphamide and prednisolone, followed by a further 6 months of prednisolone alone (reducing d ose) is a regimen that is widely adopted. It is not usually necessary to combine prednisolo ne with alternative, less toxic immunosuppressants once cyclo- phosphamide is stopped, alth ough azathioprine may be used if patients remain anti-GBM positive after 3 months of cyclop hosphamide treatment. Alport \200\231s syndrome and post-transplantation anti-GBM disease Patients with classical Alport \200\231s disease lack a normal 5 chain of type IV collagen, and cannot therefore synthesize a normal type IV collagen triple helix (consisting of 3, 4 and 5 chains) with in their GBM. Following transplantation with a kidney expressing normal GBM collagen cha ins, these are recognized as neoanti- gens and an immune response directed towards these an ti- gens is stimulated. As a result anti-GBM disease may develop that is indistinguishable on biopsy from classical anti-GBM disease, although the antibodies may be pre- dominantly d irected towards the 5 chain, and may thus be undetectable on standard anti-GBM ELISA. App roximately 5% of transplanted Alport \200\231s disease patients will develop anti-GBM disea se. Treatment is with immunosuppression and plasmapheresis as for classical anti-GBM diseas e, although graft outcome is universally poor. Alternative therapy Anecdotal case reports of successful treatment with other induction the rapies, such as mycophenolate mofetil and rituximab have been published, but direct compari son with standard therapy has not been made. Less aggressive treatment has been suggested f or dialysis- dependent patients without pulmonary hemorrhage, since most series report rena l recovery rates of only 0 \200\22318% if the presenting serum creatinine is >600 mol/L. However, a report on a large series of patients with serum creatinine >500 mol/L, some of whom required dialysis, suggests that some (with less severe biopsy changes) do recover re nal function. Therefore, use of immunosuppres- sion with the treatment regimens described a bove should be instituted regardless of renal function at presentation, unless patients are dialysis dependent with 100% crescents on renal biopsy. Further reading Browne G, Brown PA, Tomson CR, et al. Retransplantation in Alport post-tran splant anti-GBM disease. Kidney Int 2004; 65: 675 \200\223681. Who should be immunosuppressed? Patients with pulmonary hemorrhage. Patients with rapidly d eclining renal function. Patients recently started on dialysis, unless biopsy demon- strate s 100% glomerular crescents. Burns AP, Fisher M, Li P, et al. Molecular analysis of HLA class II genes in Goodpasture \200\231s disease. Q J Med 1995; 88: 93 \200\223100. Kalluri R, Danoff TM, Okada H, Neilson EG. Susceptibility to anti- glomerular basement memb rane disease and Goodpasture syn- drome is linked to MHC class II genes and the emergence o f T cell-mediated immunity in mice. J Clin Invest 1997; 100: 2263 \200\223 2275. Adjunctive therapeutic strategies Volume overload should be avoided in patients with alveo- lar hemorrhage since this can provoke further bleeding. Severe hemorrhage may require vent ilation in the prone position. Disease relapses are infrequent but are generally found in p atients who continue to smoke (therefore advice regard- ing smoking cessation is critically important) or in those with intercurrent infections (therefore infectious episodes should be treated promptly). Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membra ne antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001 ; 134: 1033 \200\2231042. Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patien ts with both ANCA and anti- GBM antibodies. Kidney Int 2004; 66: 1535 \200\2231540. Rees AJ, Lockwood CM, Peters DK. Enhanced allergic tissue injury in Goodpasture \200\231s s yndrome by intercurrent bacterial infection. Br Med J 1977; 2: 723 \200\223726. Disease outcome Survival of patients with anti-GBM disease treated with immunosuppression a nd plasmapheresis is dependent on Salama AD, Chaudhry AN, Ryan JJ, et al. In Goodpasture \200\231s disease, CD4(+) T cells es cape thymic deletion and are reactive with CHAPTER 3.10 Antiglomerular basement membrane (Goodpasture \200\231s) disease 127 See also Membranous nephropathy, p. 106 Crescentic glomerulonephritis, p. 120 Systemic vasc ulitis, p. 168 Alport \200\231s syndrome, p. 606 the autoantigen alpha3(IV)NC1. J Am Soc Nephrol 2001; 12: 1908 \200\2231915. Salama AD, Dougan T, Levy JB, et al. Goodpasture \200\231s disease in the absence of circul ating anti-glomerular basement membrane anti- bodies as detected by standard techniques. Am J Kidney Dis 2002; 39: 1162 \200\2231167. Salama AD, Chaudhry AN, Holthaus KA, et al. Regulation by CD25+ lymphocytes of autoantigen- specific T-cell responses in Goodpasture \200\231s (anti-GBM) disease. Kidney Int 2003; 64: 1685 \200\2231694. Turner N, Mason PJ, Brown R, et al. Molecular cloning of the human Good pasture antigen demonstrates it to be the alpha 3 chain of type IV collagen. J Clin Invest 1992; 89: 592 \200\223601. R. YAHYA 128 Infection-related glomerulonephritis Glomerulonephritis (GN) may occur in association with a variety of infections caused by bac terial, viral, fungal and other pathogens. sequelae are usually observed even when renal failure is severe enough to need dialysis. In adults, up to 25% have been reported to be left with some degree of CKD. Bacterial infections Post-streptococcal GN (PSGN) Epidemiology Globaly 0.5 million cases o f PSGN occur annually. The incidence is decreasing in developing countries. Sporadic cases occur worldwide. The peak incidence is between 2 and 14 years of age. Male: female 2:1. Endocarditis-associated GN Epidemiology GN may occur in 20% of cases of bacterial endocardi tis (acute and subacute). Etiology/pathogenesis The causative organisms are typically Streptococcus viridans (subacut e) or Staphylococcus aureus (acute). Deposition of immune complexes containing bacterial an tigen (similar to PSGN) has been identi \201 ed. Type III cryoglobulins can be found in up to 50% of patients. Etiology/pathogenesis PSGN is caused by nephritogenic strains of group A Streptococcus pyog enes (particularly strains 47, 49, 55 and 57 following skin infection and 1, 2, 4 and 12 fo llowing throat infection). GN is immune-mediated but the precise nature of the antigen \200 \223antibody interaction is unclear. Planting of strepto- coccal antigen in glomeruli is th ought to be an early event. Deposition of immune complexes in the glomerulus results in act ivation of the complement cascade (predominantly the alternative pathway). Clinical features Fever, arthralgia, anemia, leukocytosis, raised ESR and pur- pura are typ ical. Other characteristic findings of endocarditis such as Osler \200\231s nodes, Janeway lesions and splinter hemorrhages may occasionally be seen, but are often absent. Typical re nal manifestations are microscopic hematuria, and non-nephrotic proteinuria with or without renal fail- ure. Crescentic GN may occur and may result in acute kid- ney injury. Clinical features >90% of patients present with an acute nephritic syndrome (edema, hyperte nsion, hematuria, proteinuria and impaired renal function). Rapidly progressive glomerulone phritis (RPGN) is uncom- mon, but if present suggests extensive glomerular crescent formati on. Although most patients have a history of previous skin or throat infection, the infecti on may have resolved by the time the renal disease becomes apparent. Diagnosis Reduced C3 and C4 re \202 ect classical complement pathway activation. High tite rs of rheumatoid factor, circulating immune com- plexes and type III cryoglobulins are comm only found. cANCA (without myeloperoxidase (MPO) or proteinase-3 (PR3) speci \201 city) ma y occasionally be identi \201 ed. Renal biopsy \201 ndings include: \200 Diagnosis Reduced CH50 and C3, with normal C4 re \202 ect alternate complement pathway act ivation. A renal biopsy is not always required. If a biopsy is performed the pathological a ppearances are: \200 diffuse, proliferative, endocapillary GN, with the in \202 am- mato ry cell in \201 ltrate comprising mainly neutrophils. Crescents may be present. subacute disease \200\223 predominantly focal, segmental pro- liferative GN with more diff use immune complex depo- sition on immunohistochemistry; acute disease \200\223 acute, dif fuse, exudative, prolifera- tive GN. Crescents can be observed in 50% of such cases. Treatment Treatment should be focused on eradication of the endo- carditis with 4 \200\2236 weeks of appropriate antibiotics. In crescentic GN, pulse steroid therapy has been used in addition to antibiotic but carries risk of exacerbating the underlying infection. C3, IgG and IgM deposition in the mesangium and/or around capillary walls. subepithelial electron-dense deposits ( \200\230humps \200\231) are seen on electron microscopy. Treatment In the absence of renal failure, treatment is mainly support- ive with antihypert ensive agents and diuretics. Temporary dialysis may rarely be required. If the renal failur e is severe and prolonged (>2 weeks duration) and the renal biopsy shows extensive crescent formation, steroid therapy may be useful. Prognosis Mortality in patients with bacterial endocarditis is 20% and increases to 36% in patients who have renal failure. Shunt nephritis Epidemiology Approximately 30% of atrioventricular (AV) shunts become infec ted, and of those, 0.7 \200\2232% are associated with GN. Ventriculoperitoneal (VP) shunts are rarely complicated by GN. Prognosis In children, the prognosis is excellent with >95% of patients recovering renal fu nction within 3 \200\2234 weeks. No long-term CHAPTER 3.11 Infection-related glomerulonephritis 129 Table 3.11.1 Bacterial infection-related glomerular disease Etiology/pathogenesis Causative organisms include Staphylococcus epidemidis, S. aureus, Pro pionibacterium acne, diphteroids, Pseudomonas and Serratia spp. GN results from chronic low -level bacteremia, antibody production and immune complex formation. Deposition of bacteria l immune complexes in the glomeruli is associated with activation of both the classical and alternative com- plement pathways. Mycobacterium leprae Amyloidosis (AA) Glomerulonephritis Diffuse proliferative GN Focal pro liferative GN MCGN Mesangial proliferative GN Mycobacterium tuberculosis Amyloidosis (AA) MCGN type II Clinical features Common features are low-grade fever, arthralgia, weight loss, anemia, ski n rash, hepatosplenomegaly, hypertension and signs of raised intracranial pressure. Renal m anifestations are microscopic hematuria and pro- teinuria which may be heavy (25% of cases have nephrotic syndrome). Treponema pallidum Congenital syphilis Membranous nephropathy Acquired syphilis Membranous nephropathy Diffuse endocapillary GN MCGN Mesangial proliferative GN Amyloidosis (AA) Diagnosis Reduced C3, C4 and CH50. Rheumatoid factors and mixed cryoglobulins may be detect ed in some patients. Blood cultures are positive for the causative organism. Renal biopsy \201 ndings are most commonly mesangiocapil- lary GN (MCGN) type 1, although occasionally diffuse proliferative GN or mild mesangial proliferative GN can be seen. IgM, IgG and C3 de position is typical. Electron-dense deposits are observed in the subendothe- lial region. Salmonella typhi Mesangial proliferative GN IgA nephropathy Streptococcus pneumoniae Mesangial proliferative GN Diffuse proliferative GN Others reported in association with GN Brucella melitensis E. coli Klebsiella pneumoniae Ye rsinia enterocolitica Mycoplasma pneumoniae Legionella Bartonalla henselae Treatment Appropriate antibiotic therapy by itself is usually insuf \201 cient, and prompt removal of the infected AV shunt is necessary with subsequent placement of a VP shunt. If dialysis is required, hemodialysis is the modality of choice since peritonitis complicating peritoneal dialysis may lead to meningitis in patients with VP shunts. Prognosis The renal outcome is good if early diagnosis and prompt treatment is provided. Other bacterial infec tions causing GN are listed in Table 3.11.1. Polyarteritis nodosa (PAN) Epidemiology: The frequency of HBsAg in PAN is reported to be 17 \200\22352%. It is observed primarily in men and does not occur if HBV is acquired at birt h or during childhood. It is also more common if infection is acquired through blood transf usion or drug abuse. It tends to occur during recovery from an episode of mild hepatitis. C linical features: It typically presents with signs of serum sickness (fever, rash, and arth ralgia) during a mild or asymptomatic hepatitis. Arteritis of small and medium-sized arteri es can lead to myocardial/coronary ischemia, CNS alteration, peripheral neuropathy and mono neuritis multiplex. Renal vasculitis is manifested by microscopic hematuria, proteinuria (n ephrotic or non-nephrotic) and renal failure. Diagnosis: HBsAg positive, anti-HBc positive, anti-HBs negative. Mildly elevated transaminases. Biopsy of kidney, skeletal muscle, or pe ripheral nerves reveals transmural in \202 ammation of small or medium-sized arteries char acterized by \201 brinoid necrosis, leukocyte Viral infections Viral infections can result in various forms of renal disease (Table 3.11. 2). Hepatitis B virus (HBV) Renal disease associated with hepatitis B infection may manifest in several ways: Serum sickness This occurs during acute infection. It is characterized by fever, arthralgia s/arthritis, hepatitis, rash (urticaria/maculopapular) and renal involvement (microscopic h ematuria, sterile pyuria, and proteinuria). Renal biopsy, if performed, shows mesangial pro lifera- tive GN. The kidney involvement resolves when the hepatitis recovers. Approximately 10% of patients acutely infected with HBV become chronic carriers and are at risk for othe r renal manifestations of HBV. R. YAHYA 130 Oral lamivudine (100 mg daily for 52 weeks) is useful in inducing remission in nephrotic me mbranous nephropathy. However, resistance to lamivudine with long-term use is commonly repo rted. in \201 ltration, \201 brin deposition and occasional aneurysm formation. Angiography ma y show aneurysms of the celiac and renal arteries. Prognosis: Without treatment, almost all affected patients die within 2 \200\2235 years. Treatment: Combination therapy with cortic osteroids and a cytotoxic agent (usually cyclophosphamide) is associated with good short-te rm outcome. However, this treatment is associ- ated with accelerated progression of the liv er disease. Recent studies suggest an excellent survival and low relapse with combination t reatment with corticosteroids, plasma exchange, and antiviral treatment (vidarabine, inter- feron- , or lamivudine). Membranous nephropathy (MN) Epidemiology: This is more common in children (peak incidence 2 \200\223 12 years). There is a male preponderance (male:female 8:1). Pathogenesis: It is thought to be due to passive trapping or in situ forma- tion of i mmune complexes containing HBeAg, mainly in the subepithelial compartment of the glomerular capillary. HBeAg is found in 80% of cases. Spontaneous remission is associated with appear ance of anti-HBe antibodies. Clinical features: Nephrotic syndrome, microscopic hematuria, and renal failure (<10%). A history of clinically apparent hepatitis is often absent. Diagn osis: HBsAg positive, anti-HBc positive, HBeAg positive (80% cases). Reduced C3 and C4 leve ls are seen in 20 \200\22350% of cases. Renal biopsy: membranous nephropathy with granular deposits of IgG, IgM and C3 in the capillary wall. Electron- dense deposits may be seen in the mesangial and suben- dothelial areas in contrast to idiopathic MN. Prognosis: In childr en, a favorable outcome with a high spontaneous remission rate is observed. In adults, spon taneous remission is uncommon. 40% develop CKD and 10% develop ESRD within 5 years. Treatme nt: In children, treatment is not advocated due to the high spontaneous remission rate. How ever, data suggest that sustained resolution of proteinuria is significantly more frequent in treated children. Treatment is recommended for adults. Steroid and cytotoxic agents may enhance viral replication and precipitate hepatitic \202 ares. Antiviral therapy: \200 Interferon- (5 MU daily for 6 months) was shown to be beneficial in children but had vari able outcomes in adults. Combination treatment with lamivudine and interferon- is currently being evaluated. MCGN This is more common in adults than in children and is the most common glomerular lesio n in adults with HBV infection. It results in nephrotic syndrome, microscopic hematuria, hy pertension (80%) and renal insuf \201 ciency (50%). There is often no history of liver dis ease but patients have abnormal transaminases and also chronic persistent or chronic active hepatitis on liver biopsy. MCGN is induced by HBsAg and anti-HBs antibody- containing immu ne complexes. Histologically an MCGN type I pattern is observed. Antiviral treatment as des cribed above should be con sidered. Hepatitis C virus (HCV) HCV typically causes MCGN with or without cryoglob- ulinemia. Epidemiology HCV is present in 60% of patients with MCGN in Japan and in 10 \200\22320% in the USA. It predominantly affects adults in the \201 fth and sixth dec- ades of life. Pathogenesis HCV infects circulating B-lymphocytes and stimulates them to synthesize polycl onal IgM rheumatoid factor (RF) responsible for type III cryoglobulinemia or monoclonal RF causing type II cryoglobulinemia. Clinical features Renal involvement in HCV infection may be asymptomatic. The most common p resenting features are proteinuria, microscopic hematuria and renal insufficiency (50%). Ne phrotic syndrome occurs in 25% of cases. Renal disease occurs in 50% of patients with mixe d cry- oglobulinemia associated with HCV. They present with palpable purpura, arthralgia, n europathy and abdominal pain secondary to mesenteric vasculitis. RPGN may occur. Diagnosis Reduced C4, C1q, CH50, with normal/reduced C3. Cryoglobulin is present in 60 \200 \22370% of cases. Transaminases are elevated. Anti-HCV antibody positive and HCV RNA positi ve. Renal biopsy demonstrates MCGN type I, occasionally with cryoglobulin deposition. Prognosis The clinical course of renal disease is variable: \200 30% have partial or comp lete remission; \200 30% have an indolent course and do not progress to ESRF; 30% have intermittent \202 ares of acute nephritis or neph- rotic syndrome. Most patients die of heart disease, liver disease or infection. CHAPTER 3.11 Infection-related glomerulonephritis 131 Treatment There are several approaches available for the treatment of HCV-related GN: 1. Sy mptomatic treatment (BP control and RAS blockade). 2. Speci \201 c antiviral treatment: Dialysis survival is comparable to that of the general ESRD population. Renal transplantati on can be performed and the short- term outcome appears to be comparable to that of the gen eral transplant population. pegylated interferon- with ribavirin (ribavirin dose needs to be adjusted according to GF R and should not be used if GFR is <50 mL/min); others: standard interferon- therapy. Lupus-like syndrome This is found predominantly in African-Americans. It is an immune-compl ex-mediated disease associated with complement activation and cryoglobulin formation in 30 \200\22350% of patients. It presents with nephrotic syndrome or heavy proteinuria and micro scopic hematuria. Renal insuf \201 ciency and hyper- tension are common. The renal biopsy \201 ndings are similar to lupus nephritis with \200\230full house \200\231 deposition o f IgG, IgM, IgA, C3 and C1q, and with subendothelial immune deposits and wire loop changes. Typical SLE serology is not present. 70% of such patients progress to ESRD within 1 year o f diagnosis. The optimal treatment is unclear. It does not appear to be responsive to HAART or corticosteroids. HIV-associated thrombotic microangiopathy Most patients present with a cute kidney injury, microscopic hematuria, non-nephrotic proteinuria, evidence of micro- an giopathic hemolysis and neurological manifestations. Multiple organ involvement is frequent . The mortality rate is high and survival beyond 2 years is unusual. The incidence is falli ng with use of HAART. Other viral causes of glomerular disease are listed in Table 3.11.2. 3. Immunosuppressive therapy should be considered if vasculitis or RPGN develops: \200 \200 \200 \200 plasmapheresis to remove cryoglobulin; corticosteroid (pulse IV followed by oral); cyclopho sphamide; mycophenolate mofetil or rituximab (anti-CD20 monoclonal antibody) may also be he lpful. Human immunode \201 ciency virus (HIV) HIV can induce a number of renal manifestations. HIV-associated nephropathy Epidemiology: This affects 2 \200\22310% of untreated HIV-infect ed patients. It predominantly affects African-Americans (>95%). There is a male preponderan ce (male:female 10:1). Over 95% patients are in the advanced stages of infection (CD4 count <200/ L). Clinical features: It typically presents with severe nephrotic syndrome and ren al insuf \201 ciency. Hypertension and edema are uncommon. Pathogenesis: A direct effect o f HIV or viral protein on renal epithelial cells has been implicated. Diagnosis: USS demons trates highly echogenic normal-sized or large kidneys. Renal biopsy: \200 Focal segmental glomerulosclerosis (FSGS) with hyper- trophy and hyperplasia of visceral cell epithelium ( \200\230pseudo crescent \200\231), capillary wall collapse leading to shrunken glomerular tuft (collapsing variant of FSGS). \200 Tubules are focally enlarged with \200\230micro cystic \200\231 dilatation. \200 Tubuloreticular inclusion bodies in the endoplasmic reti culum of the endothelial cells can be seen on elec- tron microscopy. Table 3.11.2 Viral infection-related glomerular disease Acute GN Parvovirus B19 Hepatitis A virus MCGN and/or endocapillary GN Mesangial proliferative GN IgA dominant GN Acute renal failure Mesangial proliferative GN Dengue fever Measles Yellow fever Epstein \200\223Barr virus Chronic GN Hepatitis B virus Membranous GN \200\223 see text MCGN \200\223 see text Polyarteristis nodosa \200\223 se e text Mesangial proliferative Minimal change disease IgA nephropathy MCGN with or without cryoglobulinemia \200\223 see text Membranous GN Mesangial proliferative GN Focal glomerul osclerosis Fibrillary GN Immunotactoid glomerulopathy See text Collapsing glomerulopathy Fo cal segmental glomerulosclerosis Treatment: \200 HAART (highly active antiretroviral therapy) is effective in slowing disease progression. Proteinuria reduction with renin \200\223angiotensin system (RAS) blockade slows progressio n if the creatinine <176 mol/L (2 mg/dL). Hepatitis C virus Corticosteroids (reserved for patients at high risk of developing renal failure) may be hel pful but relapse is common when they are stopped. Prognosis: Without treatment ESRD usually develops within 3 \200\223 6 months. The use of H AART has reduced the proportion of HIV patients who develop ESRD. HIV Parvovirus B19 R. YAHYA 132 Parasitic infections Malaria Epidemiology Globaly, there are 300 \200\223500 million cases of malaria per year. 90% occur in Africa, India, South East Asia and Central America. Anti \201 larial treatment with diethylcarbamazine improves renal disease in those with su bnephrotic proteinuria. Nephrotic or nephritic patients tend not to improve with anti \201 larial treatment. Others Visceral Leishmaniasis (kala-azar) often presents with microscopic hematuria and pro teinuria with either diffuse proliferative GN, membranous nephropathy, or interstitial neph ritis on renal biopsy. Trichinosis may present with microscopic hematuria and proteinuria c aused by MCGN. Trypanosomiasis and toxoplasmosis may occasionally be associated with glomer ular disease. Clinical features Malaria is associated with a spectrum of renal involvement: Malarial acut e renal failure has a mortality of 15 \200\22345%. Acute GN: \200 This occurs with P. ova le, P. vivax and P. falciparum and is usually transient. Further reading Bandi L. Renal manifestations of hepatitis C infection. Postgraduate Renal manifestations are microscopic hematuria and mild proteinuria. C3 and C4 levels are reduced and circulating immune Med 2003; 113: 73 \200\22386. Guillevin L, et al. Hepatitis B virus associated polyarteritis nodosa. complexes may be identi \201 ed. Medicine 2005; 84: 313 \200\223322. Renal biopsy features are of a mesangioproliferative GN with \201 ne deposition of IgM an d C3 in mesangial and sub- endothelial regions. Haas M, et al. HIV-associated immune complex GN with lupus like features. Kidney Int 2005; 67: 1381 \200\2231390. Jones R, et al. Renal complications in HIV. Int J Clin Pract 2007; Chronic GN: This occurs with P. malariae. It predominantly occurs in children and young adu lts. It presents with the clinical features of quartan malaria, heavy proteinuria or overt nephrotic syndrome, and micro- scopic hematuria. Renal biopsy features are of MCGN without cellular pro liferation. Crescents are rare. Granular deposits of IgG, IgM and C3 are seen in the subendothelial region. Prognosis: Chronic renal insuf \201 ciency progresses inspit e of successful eradication of malaria, and steroids or immu- nosuppressive agents do not a lter the course of the disease. This topic is also covered in detail in Chapter 3.13. 61: 991 \200\223998. Kamar N, et al. Treatment of hepatitis C virus-related glomerulone- phritis. Kidney Int 2006; 636: 436 \200\223439. Khan S, et al. HIV-associated nephropathy. Adv Chronic Kidney Dis 2006;13:307 \200\223313. Lai ASH. Viral nephropathy. Nat Clin Pract 2006; 2: 254 \200\223262. Rodriguez-Iturbe B. Po st-infectious glomerulonephritis. Am J Kidney Dis 2000; 35: xlvi \200\223xlviii. Internet resources Review of nonstreptococcal infection-related GN: www.emedicine.com/med/topic888.htm Review of the pathology of infection-associated GN: www.kidneyatlas.org/book2/adk2_04.pdf Review about HIV-related renal disease: Schistosomiasis This topic is dealed with in detail in Chapter 7.4. www.emedicine.com/med/topic3203.htm Review of infection-related renal disease in the tropic s: Filaria Filarial infection can result in a variety of renal lesions. Nephropathy can presen t with variable proteinuria and microscopic hematuria. In some patients the nephrotic or ne phritic syndrome may develop. Onchocerca volvulus is found in South America and tropical su b-Saharan Africa and is associated with minimal change nephropathy and MCGN. Wuchereria ban crofti and Brugia malayi are found in Africa and South-East Asia and are associated with MC GN and diffuse proliferative GN. Loa loa infection is prevalent in West Central Africa and is associated with membranous GN, MCGN, and FSGS (collapsing variant). Pathologically, micr o \201 lariae can be identi \201 ed in the capil- lary loops and in most instances \201 larial antigens can be identi \201 ed in glomerular immune deposits. www.uninet.edu/cin2000/conferences/chugh/ chugh.html See also Glomerular disease in the tropics, p. 138 Membranous nephropathy, p. 106 Acute end ocapillary glomerulonephritis, p. 116 Systemic vasculitis, p. 168 Mixed cryoglobulinemia an d hepatitis C infection, p. 176 Schistosomiasis, p. 260 Renal tuberculosis and other mycoba cterial infections, p. 256 This page intentionally left blank H. EL SHAZLY 134 Malignancy-associated glomerular disease This study suggests a strong association based on a possi- ble common pathogenesis between glomerulonephritis and cancer. The etiology of renal failure in the setting of malignancy can be quite diverse (Table 3.12 .1). Table 3.12.1 Renal involvement in malignant disease Table 3.12.2 Glomerular disorders associated with malignant disease Direct effects Metastasis In \201 ltration Ischemia Obstruction Glomerular disease Associated malignancy Membranous nephropathy Colon, breast, stomach, and lung cancer Indirect effects Electrolyte disorders Hypokalemia, hyponatremia, hypercalcemia Acute renal failure Disseminated intravascular coagulation Thrombotic microangiopathy Renal vein throm bosis Amyloidosis Glomerular disease Nephrocalcinosis Minimal change disease Hodgkin \200\231s lymphoma, pancreatic cancer, mesothelioma, prostate cancer Focal segmental glomerulosclerosis Lymphoma, leukemia, lung cancer AA amyloidosis Carcinoma (especially renal) AL amyloidosis Myeloma Crescentic GN Lung carcinoma, renal cell carcinoma, stomach cancer, lymphoma, lung cancer Treatment-related Drug nephrotoxicity Tumor lysis syndrome Radiation nephritis Mesangiocapillary GN Chronic lymphocytic leukemia (CLL), lymphoma IgA nephropathy Lung carcinoma, lymphoma Light chain nephropathy Myeloma, lymphoma Fibrillary GN Lymphoma This chapter will focus on glomerular disorders asso- ciated with solid tumors and hematolo gical malignancies (Table 3.12.2). Renal disease resulting from plasma cell dyscrasias will be described in detail in Chapter 4.3. Thrombotic microangiopathy Stomach, prostate, pancreas and breast cancer Pathogenesis A number of mechanisms could potentially underlie the association between glom erulonephritis and malignancy. \200 Immune-complex-mediated glomerular injury is thought to be a common mechanism. This is supported by the observation that in contrast to idiopath ic membranous nephropathy (MN), mesangial and subendothelial elec- tron-dense deposits are often detected in secondary MN. This implicates circulating immune complexes in the pathoge nesis of disease. Epidemiology Urinary abnormalities such as proteinuria and microscopic hematuria are not uncommon in pat ients with cancer. The prevalence of malignancy-associated glomerulone- phritis is unknown. The incidence varies substantially with the type of cancer. In most series it is estimated to be <2% of the population with a particular cancer. Glomerulonephritis is a histological diagnosis that requires a renal biopsy. There is a paucity of renal biopsy data for a vari ety of reasons. This in turn has led researchers to depend on autopsy series. Many of the g lomerulone- phritides that occur with malignancy require immunolog- ical testing which may not be reliable on an autopsy tissue. Thus the accuracy of these series could be easily cha llenged. The Danish Kidney Biopsy Registry was examined for rates of cancer in patients wit h glomerular disease, and these rates were compared with those of the general Danish popula tion. \200 \200 Re-expression of fetal antigens may be important for dis- ease induction. In support of thi s concept, carcinoem- bryonic antigen (CEA) has been isolated from diseased glomeruli in pa tients with adenocarcinoma. Various cytokines that exhibit antitumor activity (e.g. IL-6) have also been implicated. Clinical features Glomerulonephritis is an intrinsic renal disease. The fol- lowing feature s are commonly encountered with glomeru- lar disorders. \200 Nephrotic range proteinuria and the classical features of nephrotic syndrome (NS) may be the primary manifesta- tion of the associated GN. However, non-nephrotic range proteinuria may also occur. 102 de novo cancers were found in 1958 patients. These cancer rates represent a two- to thr ee-fold excess of the expected number at <1 and 1 \200\2234 but not \211 5 years after a b iopsy. Non-Hodgkin \200\231s lymphomas were observed six to eight times more than expected. Microscopic hematuria (in the absence of bladder pathology) with erythrocyte casts and dysm orphic red cells indicates the presence of glomerulonephritis. Macroscopic nonglomerular hematuria is of particular significance because it is much more l ikely than CHAPTER 3.12 Malignancy-associated glomerular disease 135 microscopic hematuria to be associated with a urological malignancy. A bland urinary sediment (absent proteinuria, hematuria, erythrocyte casts) argues strongly against the diagno- sis of glomerulonephritis. In the context of renal func- tion impairme nt, alternative explanations such as obstructive uropathy and tubulointerstitial disease sh ould be considered. Acute renal failure is more likely to occur with crescen- tic and membranoproliferative glo merulonephritis. The former may present with extrarenal symptoms such as skin rash or hemop tysis. An elevated ESR is not uncommon in NS and by itself is not an indication to investigate for occult malignancy. Immunological testing for ANCA and anti-GBM antibodies is indicated whe n there is a reasonable suspicion of rapidly progressive glomerulonephritis with the releva nt features such as the characteristic vasculitic rash and active urinary sediment. Without such features, positive immunological testing carries little signi \201 cance. False-posi tive ANCA has been reported with several malignancies such as lympho- mas and lung cancer. Ultimately the con \201 rmation of the diagnosis and identi \201 ca- tion of the underlyi ng glomerulonephritis requires a renal biopsy. Renal biopsy is an invasive test, with poten tially serious complications. The decision to carry out such a test is affected by the prog nosis of the associated cancer. Although essential for diagnostic purposes, it may not alwa ys be technically possible due to concurrent coagu- lopathy and/or thrombocytopenia. Speci \201 c glomerular disorders Membranous nephropathy (MN) This is the commonest malign ancy-associated glomeru- lopathy. Up to 20% of patients, particularly those aged >60 years, who have MN are reported to have a malignancy. Age, smoking, and the presence of glomerula r leukocytic in \201 ltrates strongly increase the likelihood of malignancy in MN patients . Secondary MN will present with nephrotic syndrome with or without renal impairment. It is associated with solid tumors particularly cancers of the lung, breast stomach and colon. Fig. 3.12.1 Membranous nephropathy (MN). (Upper) Methana- mine-silver stain showing extensi ve \200\230spikes \200\231 in a case of advanced MN. The \200\230spikes \200\231 represen t basement membrane material laid down between the subepithelial immune complexes. The latt er are eventually incorporated into the basement membrane and are resorbed. (Lower) Global coarsely granular positivity for IgG highlighting the capillary walls in a case of \200 \230idiopathic \200\231 MN, which also showed a similar pattern of \202 uorescence with I gG and C3. IgG1 and IgG2 subtypes have been found to be more often associ- ated with malign ancy-associated MN, but these antibodies are not typically used in routine diagnostic pract ice. (Courtesy of Dr Nick Mayer, Consultant Histopathologist, University Hospitals of Leice ster, UK.) Histological \201 ndings in MN The renal biopsy appearances, particularly the immuno \202 u- orescence and electron micro scopy \201 ndings, will help dif- ferentiate idiopathic from secondary membranous nephrop athy. Diffuse thickening of the glomerular basement membrane without any hypercellularity i s typical on light microscopy (Fig. 3.12.1). In malignancy-associated MN, immuno \202 uore scence shows a diffuse granular pattern of IgG1 and IgG2 rather than IgG4 (which is charact eristic of idiopathic membranous nephropathy). Tubular basement membrane positivity on IF i s rare with idiopathic MN, but common in secondary forms of MN. Minimal change disease (MCD) This is the commonest glomerulonephritis encountered with Hodg kin \200\231s lymphoma. MCD has also been reported less frequently with leuke- mias, other lymphomas, and rarely with mesothelioma, and prostate and pancreatic cancer. In a review of 21 cases of MCD associated with Hodgkin \200\231s lymphomas: \200 nephrotic syndrome appeared before the diagnosis of lymphoma in 38% of patients; nephrotic syndrome was frequently steroid resistant (50%) or steroid dependent (12.5%); curative trea tment of the lymphoma resulted in remis- sion of the nephrotic syndrome. H. EL SHAZLY 136 It has been reported that nephrotic syndrome due to MCD may be diagnosed up to a median of 2 years prior to the diagnosis of malignancy. In the absence of features suggestive of an u nderlying neoplasm (e.g. fever, weight loss, lymphadenopathy), exhaustive investigation is not indicated. Light, immuno \202 uorescence and electron microscopy revealed \201 brin deposition in a ll cases and no evidence of anti-GBM or immune complex disease. Three patients experienced a rapidly progressive course while renal function improved in four patients following treat ment of the underlying malignancy. Treatment of crescentic GN requires immunosupression with steroids and other agents such as cyclophosphamide. In addition plasma exchange may be required to alleviate both the renal and nonrenal manifestations of the vasculi- tis. However, this may increase the neoplastic burden. Focal segmental glomerulosclerosis (FSGS) This has been observed primarily with hematologic al malignancies although with a lower frequency than the association of MCD and Hodgkin \200\231s lymphoma. It has also been reported with non small-cell lung cancer. In that case it presented with nephrotic syndrome and the proteinuria reduced dramatically during radio therapy for the lung cancer. Mesangiocapillary GN (MCGN) When nephrotic syndrome presents in association with lung cance r, MCGN tends to be the most common glomerulonephritis. Chronic hepatitis C virus infection has been linked to cryoglobulinemia, mesangiocapillary glomerulonephritis, and malignant B -cell lymphoproliferation. However, this proposed linkage has been challenged in a case rep ort where this clinical triad has occurred in the absence of hepatitis C infection. This fo rm of glomerulonephritis has a progressive nature and is usually associated with renal impa irment. Amyloidosis Both primary and secondary amyloidosis may be associ- ated with malignancies. P rimary amyloidosis (AL) occurs as a result of deposition of light chain fragments and may o ccur in association with multiple myeloma; these \201 brils are derived from light cha ins in the majority of cases. Secondary amyloidosis (AA) has been described in associ- atio n with a number of malignancies, particularly renal cell carcinoma, Hodgkin \200\231s lymph oma and CLL. \200 IgA nephropathy IgA nephropathy has been reported with small cell lung carcinoma, and lymph omas such as Hodgkin \200\231s disease.