Infection screen of blood, urine, stool, sputum as appro- priate. Echocardiography and CXR as appropriate. Antistreptolysin antibody titers. \200 CHAPTER 3.8 Acute endocapillary glomerulonephritis 117 Other serology may be required to identify other causa- tive organisms. (a) Investigations directed at excluding the differential diag- noses would include: \200 \200 \200 \200 \200 \200 Antinuclear and anti-dsDNA antibodies. Complement levels. ANCA. Anti-GBM antibodies. Cryogl obulins. Blood \201 lm. Renal biopsy \201 ndings The principal abnormality is glomerular hypercellularity. Light microscopy Two aspects contribute to the hypercellularity of the glomeruli: \200 (b) Resident glomerular cell (endothelial and mesangial) proliferation. In \202 ammatory cell in \201 ltration (neutrophils initially, mono- cytes and lymphocytes later. A lymphocytic interstitial in \201 ltrate is also typical). The glomerular basement membrane is normal. Crescent formation is described but is rare. Immuno \202 uorescence Immune deposits are found in the GBM and mesangium. The deposits us ually contain C3, C5b \200\223C9 and immu- noglobulins (typically IgG and IgM). The pattern and distribution of immuno \202 uorescence stain- ing is said to vary according to the ti me after onset of dis- ease and with the degree of proteinuria. Electron microscopy Subepithelial deposits ( \200\230humps \200\231) are typical in post-st repto- coccal glomerular lesions. Subendothelial and intramembranous electron-dense deposit s also occur in post-streptococcal and nonstrepto- coccal AEGN. Fig. 3.8.1. (a) Methanamine-silver-stained glomerulus showing diffuse proliferative changes with endocapillary proliferation. (b) Electron micrograph demonstrating a well-demarcated subepithe- lial electron-dense deposit. (Courtesy of Dr Nick Mayer, Consultant Histopatholo gist, University Hospitals of Leicester, UK.) Risk strati \201 cation Older age, male gender, persistent proteinuria (beyond 4 years) an d long-term impaired renal function are poor prognostic markers. The presence of acute rena l failure at presentation is not necessarily associated with a poor outcome. Blood pressure: treat to levels suggested by National Guidelines. \200 \200 \200 \200 Dietary sodium restriction. Diuretics. Renin \200\223angiotensin system blockade. Additiona l antihypertensive agents where necessary. Patient advice General Those in whom renal function returns to normal can be reassured, and long-term follow-up is not required. However, in individuals in whom AEGN leads to CKD, in line with the management of other glomerular lesions that may lead to progressive renal im pairment, attention should be paid to cardiovascular risk: \200 \200 \200 Secondary hyperlipidemia: \200 \200 Dietary measures. HMG CoA reductase inhibitors (aim for LDL-choles- terol <3 mmol/L, total cholesterol <5 mmol/L, or a 30% reduction from baseline for either parameter; extrapo- late d from current national targets). stop smoking; eat a healthy and balanced diet; exercise regularly. Decrease urinary protein excretion: Renin \200\223angiotensin system blockade with ACEI or A2R blockers, titrated to a maximal dose (alone or in combina- tion) as long as adverse eff ects on systemic blood pressure, GFR or serum potassium concentration (a greater risk if ol iguric) are avoided. Pharmacological treatment Nonspeci \201 c measures For the minority in whom long-term rena l impairment develops, the general management should be as in any other GN lesion. A. SALMON AND S. HARPER 118 Anticoagulation: This is usually considered if the presentation is primarily with nephrotic syndrome and in those in whom there is signi \201 - cant hypoalbuminemia (<20 g/L) and lo w bleeding risk. considered although usually after de \201 nitive treatment for the primary infection is we ll underway. References Levy M. Infection-related proteinuric syndromes. In: Cameron JS, Glassock RG (ed s), The nephrotic syndrome. New York: Dekker; 1988. pp. 745 \200\223804. Supportive measures Acute kidney injury: supportive renal replacement therapy as required. Hypertensive encephalopathy is rare but requires aggres- sive therapy. Primary infection sh ould be appropriately treated avoiding nephrotoxic antimicrobials whenever possible. Moroni G, Pozzi C, Quaglini S, et al. Long-term prognosis of diffuse proliferative glomerul onephritis associated with infection in adults. Nephrol Dial Transplant 2002; 17: 1204 \200 \2231211. Naicker S, Fabian J, Naidoo S, Wadee S, Paget G, Goetsch S. Infection and glomerulonephriti s. Semin Immunopathol 2007; 29: 397 \200\223414. Simon P, Ram e MP, Autuly V, et al. Epidemiology of primary glomerular diseases in a Frenc h region. Variations according to period and age. Kidney Int 1994; 46: 1192 \200\2231198. Disease-speci \201 c measures The primary aim is to treat the underlying infective lesion with the notional aim of removing the offending putative antigen. There is no controlled tr ial data to suggest that the use of corticosteroids or other anti-in \202 ammatory/ immuno sup- pressant agents are of any bene \201 t and these are often rela- tively contraindicat ed by the underlying infective process. However, in severe disease in which there is widesp read crescent formation on biopsy, corticosteroids are sometimes Sotsiou F. Postinfectious glomerulonephritis. Nephrol Dial Transplant 2001; 16(Suppl 6) :68 \200\22370. Yoshizawa N. Acute glomerulonephritis. Intern Med 2000; 39: 687 \200\223694. See also Infection-related glomerulonephritis, p. 128 Glomerular disease in the tropics, p. 138 This page intentionally left blank A. D. SALAMA 120 Crescentic glomerulonephritis De \201 nitions A crescent is an area of extracapillary cell accumulation within Bowman \200\231s space, associated with severely damaged glomerular tufts (Fig. 3.9.1). It is so-n amed because of its appearance on renal biopsy. Crescents consist of: \200 proliferating parietal and visceral epithelial cells (podo- cytes); leukocytes: predominant ly monocytes, macrophages and lymphocytes; \201 broblasts; \201 brin; other serum compo nents leaking from the ruptured glomerular tuft. \200 \200 Crescents may enlarge rapidly and compress the glomeru- lar tuft, preventing effective glom erular blood \202 ow and \201 ltration. Crescentic glomerulonephritis (CGN) is a pathol ogical de \201 nition, which may result from a number of different etiological processes. Diffuse CGN (DCGN) is de \201 ned as crescent formation in >50% of glomeruli in a kidney b iopsy. DCGN is clinically associated with a rapid decline in renal function over weeks to m onths. This is known as rapidly progressive glomerulonephritis. The diagnosis of CGN requir es a renal biopsy to be performed. Further assessment by immunohistochemistry, electron mic roscopy and serological analysis is required to identify the particular underlying conditio n. A rapid assessment of the particular form of crescentic GN is essential for appropriate therapy to be instituted in order to avoid permanent renal failure. CGN may heal by scarrin g and lead to glomerular sclerosis with permanent glomerular damage and some degree of chro nic kidney disease. Treatment may lead to complete resolution of the crescen- tic change or healing with scarring. Based on the histological similarities in all forms of CGN, similar treatment protocols have initially been tried for the different underlying conditions. Mor e recently these have been refined based on our current understanding of the pathogenesis o f individual diagnoses. Fig. 3.9.1 The glomerular crescent is outlined by the dotted line and black arrow. The comp ressed glomerular tuft is shown by the solid white arrow. Pathogenesis Crescents form following severe damage to the glomerular tuft by activated leu kocytes, resulting in rupture of the GBM or, when periglomerular in \202 ammation occurs, of Bowman \200\231s capsule. This releases cells and soluble mediators into Bowman \200\231 s space where they stimulate proliferation of epithelial cells, as well as recruitment of f urther leukocytes from the circu- lation along chemotactic gradients. Fibrin may be deposit ed and \201 broblasts may be recruited and activated leading to the production of \201 brocellular or \201 brous crescents. Differential diagnosis Other conditions may present with a rapidly progressive decline in r enal function that is not caused by a diffuse cres- centic glomerulonephritis. Examples of these are: \200 thrombotic microangiopathy (occasional crescents may be seen in association with intraglome rular thrombosis); acute tubulointerstitial nephritis; myeloma. \200 These have particular clinical features that may give clues to the cause of the rapid renal failure, but ultimately renal biopsy is required to con \201 rm or exclude DCGN. Etiology and epidemiology The particular conditions giving rise to CGN, classi \201 ed acc ording to the pattern of IgG and complement staining, have been reported from large kidney biopsy series (Figure 3.9.2). In the UK and USA, the largest proportion were pauci- immune CGN, now known to be mostly associated with ANCA, followed by immune complex-mediated CGN, and anti-GBM disease. Causes of CGN: \200 \200 Classi \201 cation Pathologically, crescentic glomerulonephritis has been clas- si \201 e d according to the pattern of IgG and complement deposition in the glomerulus, determined b y immuno \202 uo- rescence or immunoperoxidase staining. Three patterns have been describe d: \200 linear capillary loop deposition (anti-GBM disease); \200 granular capillary an d/or mesangial deposition, (associated with immune complex deposition (e.g. SLE or postinfe c- tious GN)); pauci-immune CGN. immune complex CGN including: \200 \200 \200 SLE; cryoglobulinemia; IgA disease; little or no deposition (pauci-immune) (mostly due to antineutrophil cytoplasm antibody (AN CA)-associated disease); CHAPTER 3.9 Crescentic glomerulonephritis 121 sections to con \201 rm the presence of CGN, to assess the degree of glomerular involvemen t, and determine the degree of renal scarring. Anti-GBM CGN Immunohistochemistry for IgG, IgA, IgM, C3 and C4, and C1q. Pauci-immune CGN Serological investigations \200 Anti-GBM antibodies. \200 ANCA, antimyeloperoxidase (MP O) antibodies, antipro- Immune complex CGN teinase 3 (PR-3) antibodies. Other CGN Antinuclear antibodies (ANA), Anti-dsDNA antibodies, Fig. 3.9.2 Percentage of underlying disease causing CGN from >600 renal biopsies. Adapted f rom Jennette and Nickeleit (2006). ENA. Complement components C3, C4, CH50. \200 Antistreptolysin-O titre (ASOT). \200 IgG, IgA and IgM. \200 Serum protein electrophoresis or free light chain assay. \200 Urine prot ein electrophoresis for Bence \200\223Jones protein. \200 Cryoglobulins. \200 C-reactiv e protein (CRP). Other investigations \200 Blood cultures: for evidence of infection-rela ted immune Henoch \200\223Sch nlein purpura; postinfectious glomerulonephritis; mesangiocapillary glo merulonephritis; nonlupus membranous glomerulopathy; \201 brillary glomerulonephritis. an ti-GBM disease-associated CGN. \200 \200 \200 \200 \200 These proportions vary according to the geographical location and the age of the patients s tudied (Fig. 3.9.3): In China, immune complex-mediated CGN predominates (half of these case s are due to SLE), whereas in Eastern Europe postinfectious CGN is most common, possibly du e to the presence of certain common local infectious agents. In children Henoch \200\223Sch nlein purpura and mesangiocapil- lary CGN were most common. Since ANCA-associated vasculi tis is more common in older patients, it is not surprising that pauci-immune CGN is the mos t frequent cause of CGN in adult patients. complex disease. FBC and blood \201 lm for evidence of thrombotic microan- giopathy. Biochemistry pro \201 le. \200 CXR, pulmonary function tests (with KCO), and/or bronchos copy for evidence of pulmonary involvement (hemorrhage). General management principles Treat the underlying condition. Not all forms of CGN require immunosuppression. The degree of crescentic change and the rate of decline in renal functio n will in \202 uence the choice of therapeutic options. In certain severe aggressive forms of CGN early immuno- suppressive therapy prevents further renal function decline. The outc ome is mostly dependent on the renal function at presentation, although certain conditions fair better than others with similar degrees of renal dysfunction. Generally, CGN associate d with ANCA or anti-GBM anti- bodies requires treatment as it is likely to progress, while CGN associated with postinfectious GN is less severe and should resolve spontaneously (or f ollowing treatment of the causative infection). CGN associated with IgA nephropathy has a p oor progno- sis even with treatment, while CGN associated with SLE responds to treatment of class IV lupus nephritis. Anti-GBM Pauci-immune All Immune Complex Post Infectious Macedonia China USA UK 0 10 20 30 40 50 60 70 80 90 Percentage of cases of CGN Fig. 3.9.3 Differences in reported percentages of each type of CGN (and the percentage of p ostinfectious CGN) in adults from various series. Clinical presentation Patients may present with loin pain due to nephromegaly and capsule d istension, systemic malaise and symptoms relating to their underlying disorder. They will h ave deteriorating renal function, an active uri- nary sediment, with microscopic hematuria, proteinuria, and red cell casts. With more advanced renal impairment, patients may have ur emic symptoms and, in some, symptoms relating to pul- monary hemorrhage may be present. How ever, pulmonary hemorrhage may be subclinical, and radiological assessment, pulmonary funct ion tests or bron- choscopy may be required in order to make the diagnosis. Individual management principles Pauci-immune CGN This is generally associated with ANCA. T he autoantigens are PR-3 and MPO, which are constitu- ents of neutrophil granules and monoc yte lysosomes. Three clinical syndromes are recognized: \200 \200 \200 Wegener \200\231s granulomatosis; Microscopic polyangiitis; Churg \200\223Strauss syndrome. Investigations in CGN Renal biopsy \200 Light microscopy of hematoxylin and eosin-, Perio dic acid \200\223Schiff (PAS)-, and methanamine-silver-stained tissue (ANCA-associated renal-limited vasculitis causing CGN is considered a form of limited micro scopic polyangiitis.) A. D. SALAMA 122 These three conditions cannot be distinguished histologically, therefore classi \201 catio n is dependent on the associated clinical features. Treatment protocols are dependent on di sease severity. Patients with mild \200\223moderate renal impairment (<500 mol/L) require induction treatment with steroids and cyclophosphamide, and maintenance therapy with stero ids and azathioprine. At least 18 months of therapy are required. Longer treat- ment is req uired for anti-PR3-associated disease which has a greater tendency for relapse. More severe renal failure (serum creatinine >500 mol/L or if dialysis dependent) or the presence of pulmonary hemorrhage requires the above treatment with additional plasmapheresis (shown to be more effective than methyl- prednisolone pulses). Plasmapheresis regimen is 60 mL/kg exc hange, maximum 4 L, using human albumin solution as replacement (with additional FFP if the re is active bleeding or if a renal biopsy has been performed recently). Prophylaxis agains t Pneumocystis jiroveci (previously known as Pneumocystis carinii) pneumonia with cotrimoxa zole (or pentamidine or dapsone in those allergic to cotrimoxa- zole) should be provided wh ile taking cyclophosphamide. In addition, to prevent the adverse effects of corticoster- oi ds, a proton pump inhibitor, oral nystatin, \202 uconazole, or amphotericin, and bone pro tection with calcium/ergocal- ciferol and bisphosphonates when appropriate should be provid ed. Novel treatment strategies with alternative induction agents are currently being triale d. The outcome is dependent on the severity of renal failure and the presence of alveolar h emorrhage at presentation. Approximately 50% of patients presenting with dialysis- dependen t renal failure will regain independent renal func- tion if treated aggressively. Relapses are common with a 30 \200\22340% relapse rate overall. Severe immune complex-mediated crescentic glomeru- lonephritis has been treated with immuno suppression using steroids, cyclophosphamide and in some cases plas- mapheresis or pulsed s teroid therapy, in a way that is anala- gous to the treatment of anti-GBM disease. The outc ome of crescentic immune complex disease appears to be dependent on the underlying conditio n. In crescentic IgA disease, cyclophosphamide and steroids with plasmapheresis have been u sed, but many series show continued decline to ESRF despite immunotherapy (over 12 months). Lupus class III/IV nephritis has been successfully treated with steroids and cyclophospham ide (low or high dose) or mycophenolate mofetil (MMF) with equal success, and such regimens would be used in CGN, possibly with the addition of plasmapheresis. Postinfectious crescen tic GN requires immunosuppression only in the face of rapidly declining renal function and DCGN. Pulsed steroids, and combined steroids and cyclo- phosphamide have been used. Treatme nt of the underlying infection is a prerequisite. CGN with membranous GN has been successfu lly treated with steroids and cyclophosphamide (or chlorambucil) ( \200\230Ponticelli regim en \200\231). Small series suggest that MMF or tacrolimus may be as effective although thes e have not specifically addressed membranous with CGN changes. In cryoglobulinemic CGN, ste roids, cyclophosphamide, plasmapheresis and more recently rituximab have been used. Care ne eds to be taken with immunosuppression in hepatitis B or C virus-related disease because of the risk of enhancing viral replication. Further reading Angangco R, Thiru S, Esnault VL, et al. Does truly \200\230idiopathic \200 \231 cres- centic glomerulonephritis exist? Nephrol Dial Transplant 1994; 9: 630 \200\22363 6. Booth AD, Almond MK, Burns A, et al. Outcome of ANCA-associ- ated renal vasculitis: a 5-yea r retrospective study. Am J Kidney Dis 2003; 41: 776 \200\223784. Anti-GBM disease The autoantigen is the noncollagenous domain of the 3 chain of type IV c ollagen, which is located in glomerular and alveolar basement membranes. Approximately 60% of patients present with associated pulmonary hemorrhage. Treatment is with plasmapheresis, and oral cyclophospha- mide and steroids for up to 3 and 6 months respectively. Relapses a re rare, unlike ANCA-associated disease. Treatment should be offered for all patients with renal fail- ure unless they are dialysis dependent with 100% crescents on renal biopsy, whe n they are unlikely to regain independ- ent renal function. Dewan D, Gulati S, Sharma RK, et al. Clinical spectrum and out- come of crescentic glomerul onephritis in children in developing countries. Pediatr Nephrol 2008; 23: 389 \200\223394. Grcevska L, Polenakovic M. Crescentic glomerulonephritis as renal cause of acute renal failure. Renal Fail 1995; 17: 595 \200\223604. Jardim HM, Leake J, Risdon RA, et al. Crescentic glomerulonephritis in children. Pediatr Nephrol 1992; 6: 231 \200\223235. Jayne D, Rasmussen N, Andrassy, et al. A randomized trial of maintenance therapy for vascul itis associated with antineu- trophil cytoplasmic autoantibodies. N Engl J Med 2003; 349: 3 6 \200\22344. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive ther- apy for severe renal vasculitis. J Am Soc Nephrol 20 07; 18: 2180 \200\223 2188. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Immune complex disease This group encompasses a diverse number of disease processes. Genera lly immune complex disease involves less severe crescentic GN than is seen in either anti-G BM antibody or ANCA-associated disease. Treatment is variable and dependent on the underlyi ng disease. Kidney Int 2003; 63: 1164 \200\2231177. Jennette JC, Nickeleit V. Antiglomerular basement membrane glomerulonephritis and Goodpastu re \200\231s syndrome. In: Jennette JC, Olso, JL, Schwartz MM, Silva FG (eds), Pathology of the kidney. Philadelphia: Lippincott Williams & Wilkins 2006; 613 \200\223643. Tang Z, Wu Y, Wang Q, et al. Clinical spectrum of diffuse crescentic glomerulonephritis in Chinese patients. Chin Med J (Engl) 2003; 116: 1737 \200\2231740. CHAPTER 3.9 Crescentic glomerulonephritis 123 Internet resources The EUVAS group website with all the details of current and previous tri als, classi \201 cations, disease assessment tools and other ANCA-related resources: www.v asculitis.org Antiglomerular basement membrane disease, p. 124 Infection-related glomerulonephritis, p. 1 28 Systemic vasculitis, p. 168 Mixed cryoglobulinemia and hepatitis C infection, p. 176 Sys temic lupus erythematosus, p. 180 See also Urinalysis and microscopy, p. 8 Immunological investigation of renal disease, p. 3 6 A. D. SALAMA 124 Antiglomerular basement membrane (Goodpasture \200\231s) disease Antiglomerular basement membrane (anti-GBM) disease, or Goodpasture \200\231s disease, is a rare pulmonary \200\223renal syn- drome characterized by crescentic glomerulonephritis whi ch generally manifests as rapidly progressive renal fail- ure and, in more than half of pat ients, concurrent pulmo- nary hemorrhage. Subsequent clinical data demonstrated that anti-GBM anti- body levels broadly correlate wit h disease activity, while rapid resolution of disease occurs following antibody depletion. Cell-mediated immunity Data from both animal models and patients demonstrate that disease i s also critically dependent on autoreactive T-cells. Crescentic glomerulonephritis, identic al to that found in anti-GBM disease, can be induced by immunization of animals with the 3 chain of type IV collagen, even when animals are incapable of producing antibodies. By co ntrast, anti-GBM antibody transfer into T-cell- de \201 cient mice does not result in dise ase, demonstrating that 3(IV)collagen-reactive cellular immune effectors are also require d. In patients, T-cells reactive against the Goodpasture antigen can be found at high frequ encies in patients with acute disease, and at much lower frequencies following treat- ment and disease resolution. Additional evidence for T-cell involvement includes the observation s that: \200 Epidemiology Anti-GBM disease has an incidence of 0.5 \200\2231 pmp per year with two age peaks in 20 \200\22330- and 60 \200\22370-year-olds. It is marginally more common in men, a nd occurs almost uniquely in Caucasians. Men tend to present at a younger age than women (m edian age 35 years compared with 45 years respectively). Pulmonary hemorrhage occurs in 60 % of cases and is more common in younger patients. Etiology Anti-GBM disease is associated with: \200 Exposure to hydrocarbons. \200 Smoki ng (pulmonary hemorrhage). \200 Direct renal insults, e.g. lithotripsy. \200 Other form s of glomerulonephritis, e.g. membranous disease is strongly HLA-associated, with nearly all patients carrying the HLA-DRB1 1501 or 0401 alleles; T-cells are found in the affected glomeruli of patients with anti-GBM disease ; anti-GBM autoantibody is a class-switched IgG implicat- ing the involvement of T-cell hel p. nephropathy. One explanation linking these provoking factors with anti- GBM disease is that they all res ult in damage to the GBM (or alveolar basement membrane in the case of smoking and other in haled agents), which exposes cryptic immuno- logical epitopes, which in turn stimulates a n ovel autoim- mune response. Although originally described during the in \202 uenza pan- de mic, and despite clinical associations between disease activity and infectious episodes, th ere have been no \201 rm associations with any particular infectious agents. Following acute disease, regulatory T-cells (expressing CD4 and CD25), inhibiting 3(IV)co llagen-reactive effec- tor T-cells are generated which persist long term; this may explain the rarity of disease relapse. Disease associations A proportion of patients are positive for both anti-GBM antibodies and antineutrophil cytoplasm antibodies (ANCA) (generally pANCA with antimyeloperoxidase (MPO) speci \201 city). These double-positive patients behave more like patients with anti-GBM disease rather than patients with ANCA- associated vasculitis, in that they have a low like lihood of recovering renal function once they are established on dialysis. Anti-GBM disease is also associated with membranous nephropathy (MN), which may precede or follow the epi- sode of anti-GBM disease. The diagnosis of MN may be suspected if heavy proteinu- ria devel ops in a patient with known anti-GBM disease. Alternatively, if a patient with MN develops a rapid decline in renal function, anti-GBM disease should be suspected. The diagnosis is c on \201 rmed on renal biopsy with electron microscopy demonstrating the characteristic sub epithelial deposits of membranous GN. Pathogenesis Anti-GBM disease remains one of the few human autoim- mune diseases in which t he autoantigen has been fully characterized, and this has led to considerable under- standi ng of the immune perturbations that underlie the condition. Both humoral and cellular arms of the immune response contribute to kidney injury. Humoral immunity The deposited and circulating anti-GBM antibodies react with the noncollag enous domain of the 3 chain of type IV collagen, termed the Goodpasture antigen. This col lagen chain is found only in specialized basement membranes in the kidney, lung, choroid pl exus, retina and cochlea. The similar collagen composition of alveolar and glomerular basem ent membranes explains the clinical fea- tures of the pulmonary \200\223renal syndrome. The pathogenicity of the autoantibodies was established following transfer experiments using e luted human autoan- tibodies transferred into primates, and from the observa- tion of rapid disease recurrence in transplanted kidneys if circulating anti-GBM antibodies were present in the recipi- ent at the time of transplantation. With the recognition of the pathogenici ty of the antibody, plasmapheresis was introduced as a mainstay of treatment. Clinical features Patients may present early with macroscopic hematuria, loin pain, or pulm onary hemorrhage, which may be acute or subclinical, or late with rapidly progressive renal impair- ment and oligoanuria. CHAPTER 3.10 Antiglomerular basement membrane (Goodpasture \200\231s) disease 125 Other major systemic symptoms are often lacking, differ- entiating it to some extent from s ystemic vasculitis. Lung hemorrhage occurs in over half the patients and is generally found in smokers. It may result in breathlessness, cough and hemoptysis. In some cases it may be subclinical and only found following investigation, with evidence of iron de \201 ciency anemia, shadowing on chest radiography or an elevated carbon monoxide gas transfer coef \201 cient (KCO). Bronchoalveolar lavage may demonstrate frank blood or hemosiderin-laden m acrophages. Rarely, anti-GBM-mediated pulmonary hemorrhage may occur in the absence of glom erulonephritis. (a) Investigations The diagnosis is suggested by the clinical features but is established on se rology and renal biopsy. Appropriate investigations for a patient presenting with the featu res of anti-GBM disease include: \200 serum urea and electrolytes, creatinine. \200 FBC and MCV. \200 C-reactive protein. \200 anti-GBM antibody. \200 ANCA. \200 anti-MPO , anti-PR3 antibodies. \200 complement C3, C4. \200 immunoglobulins, serum protein elec trophoresis. \200 hepatitis B sAg and HCV Ab, HIV Ab test. \200 urinalysis. \200 urin e microscopy. \200 urine protein/creatinine ratio. \200 CXR. \200 pulmonary function tests with KCO. \200 renal biopsy. Urinalysis demonstrates hematuria and proteinuria, tho ugh generally not in the nephrotic range (unless associated with membranous GN \200\223 se e above). Urine microscopy may demonstrate red cell casts. Anti-GBM antibodies are found al most exclusively in patients with disease, and very rarely in healthy individuals, thus the y have high speci \201 city and sensitivity for Goodpasture \200\231s disease. False-posit ive tests may occur in the context of viral infec- tions such as hepatitis C virus or HIV. In such cases, renal biopsy should effectively exclude anti-GBM disease. Rarely anti-GBM di sease may occur in the absence of circu- lating anti-GBM antibodies (on conventional ELISA) and again these cases require biopsy to con \201 rm the diagnosis. Renal biopsy Although positive anti-GBM antibody serology may be suf- \201 cient evidence to make the diagnosis and begin treatment, renal biopsy should be performed to con \201 rm the diagnosis, provi de an assessment of the extent and severity of glomerular involvement, and assess the sever ity of any accompanying acute tubular necrosis (ATN). Anti-GBM disease is characterized by crescentic glomeru- lonephritis and segmental glomerular \201 brinoid necrosis, with the glomeruli containing crescents of similar age (in contrast to ANCA-associated vasculitis in which cres- cents of different stages of evolution are typically seen ( ) (Figure 3.10.1). (b) Fig. 3.10.1 (a) Renal biopsy showing crescentic glomerulonephritis with all glomeruli affec ted with crescents of a similar age. (b) Immuno \202 uorescence microscopy demonstrating l inear IgG staining around the capillary loops. There is often associated ATN. Immunohistochemistry demonstrates linear deposition of IgG a nd C3 (Figure 3.10.1), with IgA, IgM and other com- plement components being deposited less frequently. Linear basement membrane IgG deposition may occur in other conditions, particu larly diabetes, and in older patients with atherosclerosis. However, the associated glomeru lar pathology and additional immunohistochemical tests should easily permit exclusion of th ese conditions. Treatment Due to the relative rarity of anti-GBM disease, no ran- domised controlled clinic al trials have been performed with regards to immunosuppressive regimens. Standard therapy This consists of: \200 oral cyclophosphamide (starting at 2 \200\2233 mg /kg/day and adjusted for age); prednisolone (starting at 1 mg/kg/day with a maximum starting dose of 60 mg/day); A. D. SALAMA 126 plasmapheresis (60 mL/kg exchange, maximum 4 L, using human albumin solution as replacement with additional FFP if either there is active bleeding or a renal biopsy has been performe d recently). This is continued for at least 14 treatments or until anti-GBM antibodies beco me undetectable. Anti-GBM antibody levels, platelets and \201 brinogen levels need to be closely monitored; their presenting renal function, dialysis requirements and the presence of pulmonary hemorr hage. Outcome is best in those with less severe renal failure or in those in whom dialysis is not immediately required. Therefore, at 1 year, independent renal function was achieved in 95% of patients presenting with a creatinine <500 mol/L, in 82% of those with a creati nine >500 mol/ L but not requiring immediate dialysis, but in only 8% of patients who pre sented dialysis dependent. Pulmonary hemorrhage is associated with an increased early morta lity. 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).