Anti-Glomerular Basement Membrane Disease

Stephen P. McAdoo and Charles D. Pusey

AbstractAnti–glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillarybeds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directlypathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes ofthese organs, although the inciting events that induce the autoimmune response are not fully understood. Therecent confirmation of spatial and temporal clustering of cases suggests that environmental factors, includinginfection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespreadglomerular crescent formation, presenting with features of rapidly progressive GN, and 40%–60% will haveconcurrent alveolar hemorrhage. Treatment aims to rapidly removepathogenic autoantibody, typicallywith the useof plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production andtissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early,themajority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion ofglomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrentdisease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantationfor Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCA-associated vasculitis andmembranous nephropathy seems to occur at a higher frequency thanwould be expectedbychancealone, and inadditionatypicalpresentationsofanti-GBMdiseaseare increasingly reported. Theseobservationshighlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, andhow to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors.

Clin J Am Soc Nephrol 12: 1162–1172, 2017. doi: https://doi.org/10.2215/CJN.01380217

Nomenclature and HistoryAnti–glomerular basement membrane (anti-GBM)disease is a rare small vessel vasculitis that affectsglomerular capillaries (where it may result in glo-merular necrosis and crescent formation), pulmonarycapillaries (where it may cause alveolar hemorrhage),or both. It is characterized by the presence of circu-lating and deposited antibodies directed againstbasement membrane antigens, and as such is classifiedan immune-complex small vessel vasculitis in theRevised International Chapel Hill Consensus Confer-ence Nomenclature of Vasculitides (1). The Consensusacknowledges the relative misnomer of anti-GBMdisease, given the frequent involvement of alveolarbasement membranes, although recognizes the widelyaccepted use of anti-GBM disease to describe thiscondition with or without lung involvement.

The eponymous term “Goodpasture disease” is alsoused to describe this condition, first being used byAustralians Stanton and Tange in 1958 (2), in theirreport describing nine cases of GN associated withlung hemorrhage. They credited Ernest Goodpasture,an American pathologist, with the first description ofthe syndrome in his 1919 paper describing a fatal caseof GN and lung hemorrhage that was, at the time,attributed to an atypic influenza infection (3). We donot know, however, if any of these patients had anti-GBM disease as we recognize it today, because it wasnot until the development of immunofluorescence

techniques in the 1960s that it became possible to de-tect anti-GBM antibodies in kidney tissue (4), and todemonstrate their pathogenic potential upon elutionand transfer to nonhuman primates (5). The detectionof circulating anti-GBM antibodies in patients quicklyfollowed (6), and the first comprehensive clinical de-scription of “anti-GBM antibody–induced GN” was byWilson and Dixon (7). It is of historical interest to notethat Goodpasture’s original description of lung andkidney disease in association with intestinal and splenicinflammation, after a subacute clinical presentation, wasperhaps more in keeping with a diagnosis of ANCA-associated vasculitis (AAV) than anti-GBM disease, andthat Goodpasture himself is said to have rejected theeponymous use of his name.The term “Goodpasture disease” has persisted, how-

ever, being generally reserved for patients with demon-strable anti-GBM antibodies, whereas “Goodpasturesyndrome” may be used to describe copresentationwith GN and pulmonary hemorrhage of any cause.We will use the term “anti-GBM GN” when referringspecifically to the kidney involvement seen in thiscondition, and “anti-GBM disease”when referring tothe broader spectrum of kidney and lung disease.

Epidemiology and Etiologic AssociationsGiven its rarity, definitive observations regarding

the incidence of anti-GBM disease are lacking. It is

Renal and VascularInflammation Section,Department ofMedicine, ImperialCollege London,London, UnitedKingdom

Correspondence: Dr.Stephen P. McAdoo,Renal and VascularInflammation Section,Department ofMedicine, ImperialCollege London,HammersmithHospital Campus, DuCane Road, LondonW12 0NN. Email:s.mcadoo@imperial.ac.uk

www.cjasn.org Vol 12 July, 20171162 Copyright © 2017 by the American Society of Nephrology

often said to have an incidence of,1 per million population/yrin European populations, largely on the basis of single-centerbiopsy- or serology-based series, although accurately definingpopulations at risk in such studies is difficult. A recent studyfrom Ireland is notable for being the first to define a nationwidedisease incidence, by identifying all cases over a decade viareference immunology laboratories and a nationwide pathol-ogy database (8). It reported a disease rate of 1.64 per millionpopulation/yr, higher than previous estimates. The disease iswell recognized in other white and in Asian populations (9–12),although is thought to be rarer in African populations (13).Anti-GBM GN accounts for 10%–15% of all cases of

crescentic GN in large biopsy series (14), although it ap-pears to be a rare cause of ESRD (15). A common observationfrom larger series of anti-GBM disease is that of a bimodalage distribution, with peak incidences in the third decade,where a slight male preponderance and presentation withboth kidney and lung disease is observed, and in the sixth toseventh decades, where presentation with isolated kidneydisease is more common (16–18).Some series have reported disease “outbreaks” and

seasonal variation in incidence (16,17), and the Irish studyidentified spatial and temporal clustering of disease, sug-gesting that environmental factors may be importanttriggers for disease onset, although they are yet to beaccurately defined (8,19). Infectious associations, particu-larly with influenza A, have been the subject of anecdotalreports (20,21), and may account for the aforementionedseasonal or geographic “clustering” of anti-GBM diseasecases, and a recent study described a high prevalence ofprodromal upper and lower respiratory tract infection in acohort of 140 Chinese patients (22). The causative natureof these associations, however, is not proven and remainsspeculative.Amore conclusive environmental association is that with

cigarette smoking and the development of lung hemor-rhage in anti-GBM disease (23). Similarly, inhalation ofhydrocarbons has also been implicated in disease onset(24). It is suggested that localized inflammation inducedby inhaled toxins may increase capillary permeability, orpotentially disrupt the quaternary structure of the alveolarbasement membrane, exposing usually sequestered anti-gens and allowing access to pathogenic autoantibodies.A more recently identified trigger for anti-GBM disease

is treatment with the anti-CD52 mAb, alemtuzumab, alymphocyte-depleting agent that is increasingly used in thetreatment of relapsing multiple sclerosis (25). It is thoughtthat loss of regulatory T cell subsets, or abnormal immunecell repopulation after depletion, may account for the in-creased incidence of many autoimmune diseases, includinganti-GBM disease, after exposure to this agent.It is likely that these environmental triggers act in genet-

ically susceptible individuals to induce disease onset. Anti-GBM disease has a strong HLA-gene association, withapproximately 80% of patients inheriting an HLA-DR2haplotype. A hierarchy of associations with particularDRB1alleles has been identified, some positively associated withdisease (DRB1*1501, DRB1*0401) and some conferring adominant-negative protective effect (DRB1*07), whichmight be attributed to the higher affinity of the latter allelesfor binding peptides from the target autoantigen (26). TheDRB1*1501 association has been replicated in Asian

populations (27,28). It should be noted, however, that thesesusceptibility alleles are common in most populations andthat they are also associated with other autoimmunediseases (including multiple sclerosis, perhaps contributingto the association with alemtuzumab treatment), highlight-ing that other factors are necessary to incite anti-GBMdisease, and thus HLA-gene testing is not routinely used inthe clinical work-up of these patients.Polymorphisms and copy number variation in non-HLA

genes have also been implicated in disease susceptibility,such as the genes encoding Fcg-receptors (29,30), consis-tent with the role of pathogenic autoantibodies in diseaseonset. On the basis of a small study, polymorphisms inCOL4A3, the gene encoding the Goodpasture autoantigen,are not thought to be involved in disease predisposition(31). To the best of our knowledge, there has not been anundirected genetic study in anti-GBM disease.

ImmunopathogenesisIn its native form, the GBM consists of a network of type

IV collagen molecules, each made up of triple-helicalprotomers of a3, a4, and a5 chains (Figure 1). The principaltarget of the autoimmune response in anti-GBM diseasehas been identified as the noncollagenous (NC1) domainof the a3 chain of type IV collagen (a3[IV]NC1; the“Goodpasture autoantigen”) (32,33). The clinical pattern ofreno-pulmonary disease reflects the restricted expression ofthis antigen to the basement membranes of glomerular andalveolar capillaries (and to a lesser extent, the retina, choroidplexus, and cochlea, where it is generally not associatedwith clinical disease [34]). Two principle autoantibody (B cell)epitopes within the autoantigen have been identified, desig-nated EA and EB (35), which in native GBM are usuallysequestered within the quaternary structure of the noncol-lagenous domains of the triple helix of a3, 4, and 5 chains.Sera from all patients with anti-GBM disease appear to

react to a3(IV)NC1, although a proportion will also haveantibodies directed against other collagen chains, includinga5 and a4, identified either in serum or upon elution fromkidney tissue, and thought to arise via a process of “epitopespreading” after a primary response to the a3 chain (36).The directly pathogenic potential of these antibodies wasclearly demonstrated by Lerner and colleagues in 1967,when they administered antibodies eluted from the kid-neys of patients with anti-GBM disease to nonhumanprimates, leading to the development of crescentic GN inthe recipients (5). The pathogenicity of these antibodies hassince been confirmed in a number of other species andanimal models.Clinical observations support a pathogenic role for these

antibodies; antibody titer, subclass, and avidity have eachbeen correlated with disease outcome (37–40). In addition,the rapid removal of circulating antibodies by plasmaexchange is associated with better outcome, and if kidneytransplantation is performed in the presence of circulatingantibodies, disease is likely to recur rapidly in the allograft(7,41).In addition to humoral responses, T cells also have a role

in disease pathogenesis. Data from animal models sug-gest that T cells may contribute directly to cell-mediatedglomerular injury, which can occur in the absence of

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significant humoral immunity (42,43), and glomerular Tlymphocytes may be observed in kidney biopsy samplestaken from patients with active disease (44,45). The strongHLA association and the presence of high-affinity, class-switched autoantibodies also indicate a necessity for T cellhelp in the development of the autoimmune response.Notably, mononuclear cells from patients proliferate inresponse to a3(IV)NC1 at much higher frequency than docells from healthy controls, and the frequency of auto-reactive T cells correlates with disease activity (46–48). Thepathogenic T cell epitopes in humans, however, have notbeen consistently defined.That these autoreactive T cells can be identified in

healthy individuals, along with low-level natural autoan-tibodies (49), suggests that tolerance to the a3(IV)NC1antigen is not fully achieved during immunologic develop-ment. In addition, a rising titer of anti-GBM antibodies hasbeen shown to predate the onset of clinical disease byseveral months (50), highlighting that several tolerancemechanisms must be disrupted before disease occurs. Onesuch breach of “peripheral” tolerance is disruption of thequaternary structure of the Goodpasture autoantigen, andin particular disruption of the sulfilimine crosslinks that

stabilize the association of opposing NC1 domains onindividual collagen chains (Figure 1). This may result inmodification or exposure of usually hidden epitopes, whichis suggested to be a key event in the pathogenesis of disease(36). This may account for the association with etiologicfactors that may disrupt alveolar (e.g., smoking, inhalationof hydrocarbons) or GBM (such as lithotripsy [51,52], andthe other kidney pathologies discussed below).The recovery phase of anti-GBM disease is associated

with a progressive fall in autoantibody titers (even in theabsence of immunosuppression) and a lower frequency ofT cells reactive to a3(IV)NC1. The emergence of a CD251suppressor T cell subset that may inhibit responses to a3(IV)NC1 has been described (53), suggesting that immu-nologic tolerance to a3(IV)NC1 can be re-established. Thismay explain the rarity of clinical relapses in anti-GBMdisease, and the association with lymphocyte-depletingtherapy with alemtuzumab.

Clinical Presentation and DiagnosisThe majority of patients (80%–90%) will present with

features of rapidly progressive GN. Forty percent to 60%

Figure 1. | Structure of the glomerular basementmembrane. In its native form, the collagen IV network in the glomerular basementmembraneconsists of triple-helical protomers of a3, a4, and a5 chains (shown individually in [A]). The carboxy-terminal domains of these a3 a4 a5protomers form a trimeric “cap” (B), end-to-end association of which results in the formation of the hexameric NC1 domain (C). The quaternarystructureof this hexamer is stabilizedbyhydrophobic andhydrophilic interactions across the planar surfaces of opposing trimers, and reinforcedbysulfiliminebondscrosslinkingopposingNC1domains.Twokeyautoantibodyepitopeswithina3(IV)NC1havebeendescribed,designatedEA(incorporating residues17–31 toward theamino terminus) andEB (residues127–141 toward thecarboxy terminus),which in thenative formaresequestered at the junctionwitha4 anda5 chainswithin the triple helical structure. Binding through 7s domains (shown in orange) completesthe lattice-like structure of the type IV collagen network (D). Reprinted from reference 102.

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will have concurrent lung hemorrhage, and a small mi-nority of patients may present with isolated pulmonarydisease. “Atypical” presentations are well recognized, anddiscussed in more detail below. Central to the diagnosis ofanti-GBM disease is the identification of anti-GBM anti-bodies, either in serum or deposited in tissue, along withpathologic features of crescentic GN, with or without evi-dence of alveolar hemorrhage.

Serologic TestingIn current practice, circulating anti-GBM antibodies are

usually detected using commercially available enzymeimmunoassays or bead-based fluorescence assays, whichtypically use purified or recombinant human or animalGBM preparations as antigenic substrate. Western blotting,using similar GBM preparations, may be a more sensitivemethod for antibody detection, although it is notwidely available outside research laboratories. Indirectimmunofluorescence using normal kidney tissue is analternative method, although this requires additionalinput from a kidney pathologist and is prone to givingfalse negative results. A proportion of patients whohave demonstrable deposition of IgG on the GBM byimmunofluorescence, but who are negative for circu-lating antibodies by these conventional techniques,may be positive when tested by highly sensitive bio-sensor assay (54). In anti-GBM disease, the pathogenicantibodies are usually of the IgG class, with IgG1 andIgG3 subclasses predominating (37,38), although rarecases of IgA- and IgG4-mediated disease have beendescribed (55,56). These antibodies may not be detectedon routine assays.Serologic testing for anti-GBM antibodies is, by defini-

tion, an urgent laboratory test, and we recommend thatresults should be available within 24 hours for patientspresenting with RPGN, particularly when there are contra-indications to kidney biopsy, because initiating treatmentbefore developing a need for RRT may have a significanteffect on outcome. It should be noted, however, thatapproximately 10% of patients do not have identifiablecirculating antibodies with conventional assays, and soserologic testing should not be the sole method of diagnosiswhen kidney biopsy is available.

Deposited AntibodyDirect immunofluorescence for Ig on frozen kidney

tissue has high sensitivity for detecting deposited anti-bodies, and is the gold-standard for diagnosis of anti-GBMdisease, typically showing a strong linear ribbon-likeappearance (Figure 2). An important caveat is that fluo-rescence may be negative or unclear in cases with severeglomerular inflammation, where the underlying architec-ture is so disrupted that the linear pattern may not berecognized. Other causes of linear fluorescence should beconsidered (including diabetes, paraproteinemias, lupusnephritis, and rarely fibrillary GN). Immunoperoxidasetechniques using paraffin-embedded tissue may also beused, but may be less sensitive. Lung biopsy samples arenot routinely used in the diagnosis of anti-GBM disease,and, in our experience, immunofluorescence on lung tissueis rarely informative.

Conventional direct immunofluorescence techniqueswill identify all IgG subclasses, although will not differ-entiate the antigenic target of the kidney-bound antibody.Noncollagen chain antigens, such as entactin, have beenidentified in historical case series, although their signifi-cance is not well characterized. In addition to detectingdeposited anti-GBM antibody, immunofluorescence maydemonstrate the presence of C components, in particularC3 and C1q, along the GBM (17). A proportion of patientsmay also demonstrate Igs or C deposition along tubularbasement membranes.

Renal Biopsy FindingsCrescent formation is the histopathologic hallmark of

anti-GBM disease (Figure 3). Large biopsy series suggestthat 95% of patients will have evidence of crescentformation on kidney biopsy, and that in 80% of patients.50% of glomeruli will be affected. The average proportionof affected glomeruli is approximately 75% (14,57). Theproportion of crescents observed in the biopsy samplecorrelates strongly with the degree of renal impairment atpresentation (17,18). These crescents will typically be ofuniform age (Figure 3F), in contrast to other causes ofRPGN, such as AAV, where a mixture of cellular, fibro-cellular, and fibrous crescents may be seen. Crescenticglomeruli are likely to have areas of fibrinoid necrosis in theunderlying glomerular tuft. Noncrescentic glomeruli maysimilarly have segmental fibrinoid change (Figure 3A),although often they may appear completely normal. Inearly or mild disease, segmental proliferative changemay be seen, with infiltrating neutrophils or mononu-clear lymphocytes. In severe disease, rupture of Bowman’scapsule, peri-glomerular inflammation (Figure 3E), pro-gressing to granuloma formation with multinucleate giantcells, may be observed in a proportion. Given the acuity ofdisease onset, interstitial fibrosis and tubular atrophy areuncommon in anti-GBM disease (unless there is preexistingkidney pathology) although interstitial inflammation maybe observed.

Figure 2. | Kidney biopsy sample immunofluorescence for IgG re-vealing linear deposits along the glomerular basement membrane,and weaker staining of Bowman’s capsule and tubular basementmembranes.

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Electron microscopy is of limited additional value in thediagnosis of anti-GBM disease, showing nonspecific fea-tures of crescentic GN including rupture of the GBM andextracapillary localization of fibrin and proliferating cells.Electron-dense deposits are not seen in isolated anti-GBMdisease, although electron microscopy is necessary to ex-clude concomitant glomerular pathologies, such as mem-branous GN, and may identify other diseases that maycause linear fluorescence (such as fibrillary GN and di-abetic GBM thickening).

Diagnosis of Alveolar HemorrhageDiffuse alveolar hemorrhage may be evident clinically,

or identified by radiologic examination. Broncho-alveolarlavage may identify hemosiderin-laden macrophages, acharacteristic feature of alveolar bleeding, and may also beuseful to exclude other pathologies, such as atypical in-fection. In addition, pulmonary function testing, in partic-ular the determination of the alveolar carbon monoxidetransfer factor (KCO) may assist with the differentiationof alveolar hemorrhage from other causes of pulmonaryinfiltration. The utility of both bronchoscopy and func-tional testing, however, may be limited by the clinicalcondition of the critically unwell patient.

TreatmentStandard treatment for anti-GBM disease includes plas-

mapheresis, to rapidly remove pathogenic autoantibody,along with cyclophosphamide and corticosteroids, to in-hibit further autoantibody production and to ameliorate

end-organ inflammation. The use of this combination oftherapies was first described in 1976 (58), and they remainthe core recommendation of the latest Kidney DiseaseImproving Global Outcomes guideline for treating anti-GBM GN (59). We have reproduced a recommendedtreatment schedule in Table 1 (13).The inclusion of plasmapheresis is supported by obser-

vational studies that suggest improved renal and patientsurvival compared with historical cohorts treated withimmunosuppression alone (18,60). In addition, a largecontemporaneous Chinese study of 221 patients suggestedbetter outcomes in patients who received plasmapheresisin addition to cytotoxic and corticosteroid therapy (61). Todate, there has only been one randomized trial in anti-GBMdisease, which compared the addition of plasma exchangeto cyclophosphamide and steroids. Although this studywas small (n517), the groups not ideally matched atrandomization, and its treatment regimens not represen-tative of current practice, its findings supported the use ofplasma exchange in anti-GBM disease (62). In particular, itdemonstrated a much more rapid fall in circulating anti-GBM antibodies and improved kidney function in patientsreceiving plasmapheresis.Immunoadsorption is an alternative form of extracor-

poreal therapy that may be more efficient than plasmaexchange for the removal of pathogenic autoantibody(although conversely it may not remove proinflammatoryor procoagulant factors). In small series, it appears to havecomparable outcomes to plasma exchange therapy (63,64),and we note that a prospective, open-label study is plannedto study the kinetics of anti-GBM antibody removal using

Figure 3. | Renal histopathology in anti–glomerular basement membrane (anti-GBM) GN. (A–C) Hematoxylin and eosin–stained sectionsdemonstrating (A) segmental fibrinoid necrotizing lesion in early anti-GBM GN; (B) small, circumscribed cellular crescent; and (C) large,circumferential cellular crescent. (D–E) Demonstrate the use of Jones methylamine silver stain to delineate glomerular and tubular basementmembranes, clearly identifying a segmental area of extracapillary proliferation (D). (E) Demonstrates obliteration of the glomerular architectureand rupture of Bowman’s capsule, with extravasation of red blood cells into the urinary space, and significant peri-glomerular inflammation.(F) Adjacent glomeruli with synchronous cellular crescent formation typical of anti-GBM disease.

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this technique (NCT02765789), which may be considered analternative depending on local availability.In AAV, the equivalence of daily oral and pulsed intra-

venous cyclophosphamide in induction therapy has beenestablished in a large randomized controlled trial (65).Nearly all published experience in anti-GBM GN, however,has used daily oral dosing, and so we recommend this asthe first-line approach in this disease. Because the risk ofrelapse is very low, and approximately only 3 months ofcytotoxic therapy is usually required, concerns about totalcumulative dose of cyclophosphamide are less relevantthan in AAV. In our experience, high-dose intravenous gluco-corticoids are not required in the treatment of anti-GBMdisease, provided the other components of therapy, inparticular plasma exchange, can be initiated promptly (18).The use of other immunosuppressive therapies in anti-

GBM disease is less well described. There are severalreports of rituximab use, as either “add-on” to standardtherapy or as a substitute for cyclophosphamide in patientswho are intolerant (66). Similarly, the use of mycophenolatemofetil and cyclosporine has been reported in individual

cases or small series (67–69). There is insufficient evidence,at present, to recommend their use in first-line therapy,although they may be considered in patients who havecontra-indication or intolerance to conventional treatment.In addition to targeted immunotherapy, patients may

require immediate organ support; in larger series, approx-imately half of patients require hemodialysis at the point ofinitial presentation (18). There are limited data on howfrequently artificial ventilation is required, although onesmall series estimated that this occurred in 11% of patientswith lung hemorrhage (70). There are case reports ofsuccessful use of extracorporeal membrane oxygenation inpatients with very severe lung disease (71–73).

Outcome and PrognosisLong-term follow-up of the largest cohort of patients

(n571) all treated with the combination of plasma ex-change, cyclophosphamide, and corticosteroids, from theHammersmith Hospital, London, United Kingdom, sug-gests that it is effective in treating lung hemorrhage in

Table 1. Initial Treatment of Anti-GBM Disease

Agent Details and Duration Cautions

Plasma exchange Daily 4 L exchange for 5% humanalbumin solution. Add fresh humanplasma (300–600 ml) within 3 d ofinvasive procedure (e.g., kidney biopsy)or in patients with alveolar hemorrhage.Continue for 14 d or until antibody levelsare fully suppressed. Monitor antibodylevels regularly after cessation oftreatment because plasma exchangemayrequire reinstatement if antibody levelsrebound.

Monitor and correct as required: plateletcount, aim .70 3 109/L; fibrinogen,aim .1 g/L (may requirecryoprecipitate supplementation tosupport PEX); hemoglobin, aim for.90 g/L; corrected calcium, aim tokeep in normal range

Cyclophosphamide 2–3 mg/kg per d given orally for 2–3 mo.Reduce dose to 2 mg/kg inpatients.55 yr.

Stop if leukocyte count falls to,43109/L and restart at reduced dose whenrecovered. Insufficient evidence torecommend use of IVcyclophosphamide.

Corticosteroids Prednisolone 1 mg/kg per d (maximum 60mg) given orally. Reduce dose weekly to20mg by 6wk, then gradually taper untilcomplete discontinuation at 6–9 mo.

There is no evidence to support the useof methylprednisolone, and it mayincrease the risk of infection

Prophylactic treatments Prophylaxis against oropharyngeal fungalinfection (e.g., nystatin, amphotericin, orfluconazole)while on high-dose steroids.Peptic ulcer prophylaxis (e.g., with PPI)while on high-dose steroid treatment.Prophylaxis against PCP (e.g.,cotrimoxazole) while receiving high-dose corticosteroids andcyclophosphamide. Consider acyclovirfor CMV prophylaxis. Considerprophylaxis against HBV reactivation(e.g., lamivudine) in patients who haveevidence of previous infection (HBV cAbpositive).

H2 receptor antagonists in thosewhoareintolerant of PPI. Cotrimoxazole maycontribute to leukopenia; monitorleukocyte count. Alternatives includenebulized pentamidine.

Modified from reference 13, with permission. GBM, glomerular basement membrane; PEX, plasma exchange; IV, intravenous; PPI,proton pump inhibitor; PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus; HBV, hepatitis B virus; cAb, core antibody.

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.90%, and in preserving independent kidney function inthe majority of patients, including those who presentwith severe kidney dysfunction (18). In patients presentingwith creatinine values ,500 mmol/L, renal survival was95% and 94% at 1 and 5 years, respectively. In patientspresenting with creatinine .500 mmol/L, but not requiringimmediate dialysis, renal survival was 82% and 50% atthe same respective time-points. In patients presentingwith an initial requirement for dialysis, however, renalrecovery occurred in only 8% at 1 year. Other reports havedescribed similarly low levels of renal recovery in patientspresenting with dialysis-dependent kidney failure, with thehighest rate of approximately 20% recovery in one series (66).Predictors of poor renal outcome include severity of

renal dysfunction at presentation, the proportion of glomer-uli affected by crescents, and oligoanuria at presenta-tion (17,18,74). In the Hammersmith series, no patient whorequired hemodialysis and had 100% crescents on kidneybiopsy recovered renal function, and so withholding treat-ment (and its incumbent toxicity) is often considered in thesecases. An isolated case of renal recovery despite thesefindings (75), however, highlights the need to consider allcases for treatment, with specific attention to other featuresthat might predict renal recovery on biopsy (such asconcomitant acute tubular injury) and the ability of patientsto tolerate each component of therapy. A short trial of earlytreatment may be considered, and rapidly tapered if there isno evidence of renal recovery within 2–4 weeks. In addition,the potential benefit of a period of immunosuppression toexpedite autoantibody clearance, thus allowing earlier kid-ney transplantation, should be considered in suitable pa-tients. We have used rituximab monotherapy, for example,in patients with ESRD who have an identified live-donorfor transplantation, but remain anti-GBM antibody–positive,although controlled evidence for this indication is lacking.A recent retrospective study (an Australia and New

Zealand Dialysis and Transplant Registry [ANZDATA]study) analyzed the long-term outcomes of 449 patientswith ESRD due to anti-GBM disease, and found that theirsurvival was comparable to patients with ESRD of othercauses, whether they remained on dialysis or underwentkidney transplantation (15). Chronic respiratory sequelaeafter alveolar hemorrhage are uncommon (70).Relapse is rare in anti-GBM disease, occurring in ,3% of

patients in the Hammersmith series (18). It is usually as-sociated with ongoing exposure to pulmonary irritantssuch as cigarette smoke and hydrocarbons (76,77), andavoidance of these precipitants is an essential part oflong-term management of these cases. We recommendrepeat kidney biopsy in cases of relapse with kidneyinvolvement, in order to secure an accurate diagnosis andto exclude concomitant pathologies such as AAV andmembranous nephropathy (discussed below). In confirmedcases, standard retreatment with cytotoxics and corticoste-roids is usually indicated. In a patient with multiplyrelapsing alveolar hemorrhage we have found treatmentwith rituximab beneficial.

Kidney Transplantation after Anti-GBM DiseaseKidney transplantation performed in the presence of

anti-GBM antibodies results in a high likelihood of disease

recurrence in the allograft, at frequencies of up to 50%in historical series (41). Most centers therefore recommenda period of at least 6 months’ sustained seronegativ-ity before undertaking transplantation in patients whohave reached ESRD due to anti-GBM disease (59). Underthese circumstances, and with current immunosuppres-sive regimens, recurrent disease is rare; the ANZDATAregistry study found that 6 of 449 (2.7%) patients de-veloped biopsy-proven recurrent anti-GBM disease,which led to graft failure in two cases (15). The frequencyof other causes of graft failure was similar to patientstransplanted for ESRD of other causes, and overall patientand renal survival in anti-GBM disease was similar toother groups in this study. These findings were somewhatin contrast to a previous European study that suggestedpatient survival was favorable in patients transplanted foranti-GBM disease compared with those transplanted forother primary kidney diseases (although significant dif-ferences in age at transplantation may account for thisapparent difference in patient survival) (78). The Euro-pean study also reported a higher frequency of recurrentdisease (14%), although this may reflect differences inimmunosuppressive use during an earlier era, and thestudy did not comment on anti-GBM titers and theirrelationship to timing of transplantation. In the currentera, isolated case reports of recurrent disease still exist(79).

Post-Transplant Anti-GBM Disease in AlportSyndromeMutations in any of the genes which encode the a3, a4, or

a5 chains may result in a failure to produce the normal typeIV collagen network present in GBM, and thus lead toprogressive kidney disease in Alport Syndrome. Mutationsin the COL4A5 gene located on the X chromosome are mostcommon, giving rise to typical X-linked Alport syndrome,although autosomal recessive and dominant disease arerecognized with COL4A3 and COL4A4 mutations. Afterkidney transplantation, these patients may develop anti-GBM antibodies as an alloimmune response to the neo-antigens contained in “normal” a3, a4, or a5 chains in thekidney allograft. In X-linked disease, these antibodies donot recognize the individual EA and EB epitopes of the a3chain recognized by sera from Goodpasture patients, butrather a distinct, composite epitope on the a5 chain, that isnot sequestered within the native hexamer of the Goopas-ture antigen (36). It should be noted that commerciallyavailable anti-GBM assays, which are optimized to detectreactivity to the a3(IV)NC1 antigen, may fail to detectcirculating antibodies in this setting. Anti-GBM anti-bodies may be detected in 5%–10% of Alport patientsafter transplantation, although the development of overtGN in the allograft is less frequent (perhaps owing to theeffects of maintenance immunosuppression). When GNdevelops, however, it usually occurs early and carries a highrisk of graft loss (80,81). Repeated transplantation in thissetting almost invariably leads to more aggressive diseaserecurrence and rapid graft loss, and is undertaken at veryhigh risk (82). Individuals with large COL4A5 gene dele-tions are at increased risk of post-transplant anti-GBMdisease, and recent guidelines encourage the use of genetic

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testing to inform discussions regarding the risk of de novoanti-GBM disease after transplantation (83).

Other Variant Forms of Anti-GBM DiseaseDouble-Positive Anti-GBM and ANCA-Associated GNThe concurrence of ANCA and anti-GBM antibodies is

recognized to occur at much higher frequency than ex-pected by chance alone. In some series, almost half ofpatients with anti-GBM disease have detectable ANCA(usually recognizing myeloperoxidase [MPO]), and up to10% of patients with ANCA also have circulating anti-GBMantibodies (84–86). The mechanism of this association isunclear, although it has been shown that ANCA may bedetected before the onset of anti-GBM disease, suggestingthat ANCA-induced glomerular inflammation may be atrigger for the development of an anti-GBM response,perhaps by modifying or exposing usually sequestereddisease epitopes in GBM (50). Conversely, a recent studyfound that up to 60% of anti-GBM cases also had anti-bodies directed against linear epitopes of MPO, versus 24%recognizing intact MPO. The authors hypothesize thatMPO-ANCA recognizing linear and conformational epi-topes may arise sequentially, via a process of inter- andintramolecular epitope spreading (87). We recently ana-lyzed the outcomes of a large cohort of these “double-positive” patients from four centers in Europe, and foundthat they experience the early morbidity and mortality ofanti-GBM disease, with severe kidney and lung disease atpresentation, requiring aggressive immunosuppres-sive therapy and plasma exchange (88). During long-termfollow-up, they relapsed at a frequency comparable to aparallel cohort of patients with AAV, suggesting theywarrant more careful long-term follow-up and maintenanceimmunosuppression, unlike patients with single-positiveanti-GBM disease.

Anti-GBM Disease Associated with MembranousNephropathyThere are several reports of anti-GBM disease associated

with membranous nephropathy, occurring as a preceding,simultaneous, or succeeding diagnosis (89,90). As withthe ANCA association, it is postulated that disruption ofglomerular architecture by one disease reveals hiddenepitopes that allow the second process to occur. A rapiddecline in kidney function in a patient with knownmembranous nephropathy should raise suspicion of thedevelopment of superimposed crescentic nephritis or anti-GBM disease, and rebiopsy is recommended. We suggestthat these cases are treated initially as for anti-GBM disease,although how they should be managed in the long-term isnot clear. The authors of a recent case report suggest thatrituximab may be a useful agent to treat both pathologiessimultaneously (91).

“Atypical” Anti-GBM DiseaseUnusual presentations of anti-GBM disease have been

recognized for as long as the disease itself. Wilson andDixon’s original 1973 report, for example, included thecase of a male 14-year-old who had the incidental findingof linear IgG deposition on a kidney biopsy sample taken

during splenectomy for hypersplenism and a diag-nostic workup for optic vasculitis, who was treated withsteroids only, and who had normal renal function after1 year follow-up (7). There have been a number of series of“atypical” cases published in recent years, often with lesssevere renal involvement than is seen in the classic pre-sentation of anti-GBM disease, although it not always clearwhether these represent distinct clinical subphenotypes orheterogenous cases on a spectrum of disease severity (92–95).The largest of these series, reported by Nasr and

colleagues, described 20 patients with mild and indolentlyprogressive renal impairment, who had linear Ig deposi-tion on kidney biopsy, but without predominant features ofcrescentic GN, and without overt lung hemorrhage (95).Circulating anti-GBM antibodies were not detected usingconventional assays, and both patient and renal prognosiswere good, with 90% and 85% survival at 1 year, re-spectively. They estimated that these atypical cases ac-counted for approximately 10% of anti-GBM cases at theircenter. Notably, half of the cases had light-chain restric-tion on immunofluorescence, although the authors suggestthat the pathologic features were not in keeping withproliferative GN with monoclonal Ig deposition. Theysuggest that differences in the antigen specificity, Ig sub-class, and/or the ability to fix C and recruit inflammatorycells, of these atyptical compared with “classic” anti-GBM an-tibodies, account for the less severe disease phenotype seen.Another small but well characterized series with a

distinct clinical phenotype was recently described inSweden; it included four young females, who had severelung disease and minimal kidney involvement, who werefound to have IgG4 subclass anti-GBM antibodies that werenot detectable with conventional anti-GBM assays (56). Thattwo of these patients demonstrated higher signal in the anti-GBM ELISA when using a nondenaturing buffer suggeststhat differences in epitope specificity might also account forthe negative testing seen with the routine assays, andsupports the hypothesis that differences in clinical pre-sentation might be related to differences in the subclass ortarget of the anti-GBM antibody.

Future DirectionsDespite being one of the better characterized autoim-

mune diseases, unanswered questions remain regardingthe pathogenesis of anti-GBM disease, which may haveimportant clinical implications. These include the need tofurther characterize the variant forms of disease, and howdifferences in antibody subclass or specificity might influ-ence presentation, the appropriate use of treatment, andoutcomes. Better understanding of T cell functions, and inparticular the role of regulatory cells that may suppressdisease, may have therapeutic significance, both in anti-GBM disease and other autoimmune conditions. Theinduction of immunologic tolerance using mucosal admin-istration of GBM antigen has been described in experimentalmodels (96), which may likewise have therapeutic potential.Finally, the inciting events that cause autoimmunity to GBMantigens remain unclear. Idiotype–anti-idiotype interactionshave been invoked in a recent study (97), and the role ofinfectious triggers that might operate via a similar mechanismin clinical disease induction could be explored further.

Clin J Am Soc Nephrol 12: 1162–1172, July, 2017 Anti-GBM disease, McAdoo et al. 1169

As a rare disorder requiring immediate treatment, co-ordinating large, prospective studies in anti-GBM disease ischallenging. In addition, the efficacy of current treatmentregimens, when started early enough, is widely accepted.Future therapeutic studies, therefore, should perhaps focus onidentifying “add-on” treatments that might improve outcomesin severe disease. We have recently shown that treatment withfostamatinib, a spleen tyrosine kinase (SYK) inhibitor, effec-tively reverses crescent formation in rodent models of anti-GBM disease (98,99) (and that intraglomerular SYK can bedetected in patient kidney biopsy samples [100]), so it wouldbe of interest to explore the use of this agent in advancedclinical disease. Another interesting agent that has shownefficacy in experimental models is IdeS (IgG-degrading en-zyme of Streptococcus pyogenes), an enzyme that is able tocleave both circulating and membrane-bound Ig (101). IdeSwas safe and tolerable in early-phase human studies, and aclinical study in severe anti-GBM disease, where it maypromote rapid clearance of pathogenic IgG, has been proposed(EudraCT number: 2016–004082–39). Finally, large multicenterstudies might aim to identify clinical and histopatho-logic indicators that reliably predict failure to respond totreatment, so that the toxicities associated with intensiveimmunosuppression may be avoided in futile cases.As an archetypal autoimmune disorder, such studies of

anti-GBM disease and its experimental correlates are likelyto provide fresh insights into the mechanisms of renalautoimmunity. However, it is the alarming clinical pre-sentation, and the need for emergency treatment, often incritically unwell patients, that underscores the need forclinicians to be mindful of this rare condition, the pitfallsassociated with its diagnosis, particularly in atypical andvariant presentations, and the early and appropriate use ofimmunosuppressive and extracorporeal therapies, in orderto prevent morbidity and to improve survival.

AcknowledgmentsWe acknowledge support from the National Institute for Health

Research Imperial Biomedical Research Centre.

DisclosuresNone.

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