INTRODUCTION — Anti-glomerular basement membrane (GBM) antibody disease may progress to end-stage kidney disease (ESKD), requiring either dialysis or kidney transplantation. The incidence of recurrent linear immunoglobulin G (IgG) staining in the transplant may be as high as 50 percent [1,2]. However, most patients remain asymptomatic [1].
There are only a limited number of reported cases of symptomatic recurrent anti-GBM disease in the literature [3-11]. A related phenomenon is the development of de novo anti-GBM disease in patients with Alport syndrome (also known as Alport posttransplant anti-GBM nephritis), which can lead to graft loss in up to 5 percent of recipients [12,13].
This topic reviews recurrent anti-GBM disease after transplantation. The pathogenesis, diagnosis, and treatment of anti-GBM disease are discussed elsewhere. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis" and "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)
De novo anti-GBM disease following transplantation in patients with Alport syndrome is also discussed elsewhere. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)", section on 'Anti-GBM antibody disease'.)
PATHOGENESIS — The target GBM antigens for recurrent anti-GBM disease are the noncollagenous-1 (NC1) domains of the alpha-3 and alpha-5 chains of collagen IV (alpha3[IV]NC1 and alpha5[IV]NC1) [14-17]. Collagen IV is a family of six alpha chains (alpha-1 through alpha-6) [18]. The alpha-3, alpha-4, and alpha-5 chains form a triple helical protomer, and oligomerization of alpha-345 protomers, by means of NC1-NC1 end-to-end associations, forms the hexameric NC1 domain.
The alpha-345 network is also a target for anti-GBM alloantibodies in anti-GBM disease following transplantation in patients with Alport syndrome (also known as Alport posttransplant anti-GBM nephritis). This anti-GBM syndrome is mediated by the deposition of alloantibodies to the alpha5(IV)NC1 domain in response to the "foreign" alpha-345 collagen network that is absent in the kidneys of patients with Alport syndrome but present in the kidney allograft [19,20].
In one study, an enzyme-linked immunosorbent assay (ELISA) was used to determine the specificity of circulating autoantibodies and kidney-bound antibodies in patients with anti-GBM disease or Alport posttransplant anti-GBM nephritis [17]. Among those with anti-GBM disease, autoantibodies to the alpha3(IV)NC1 monomer and alpha5(IV)NC1 monomer were detected in 100 and 79 percent of patients, respectively; fewer patients had autoantibodies to the alpha-4NC1 monomer. Autoantibodies in patients with anti-GBM disease bound to distinct, hidden epitopes in the alpha3(IV)NC1 and alpha5(IV)NC1 monomers but did not bind to the native alpha345(IV)NC1 hexamer until it was denatured, suggesting that dissociation or conformational change of the NC1 hexamer in vivo is required to expose the epitopes for antibody binding. By contrast, in patients with Alport posttransplant anti-GBM nephritis, alloantibodies bound to the alpha5(IV)NC1 epitope in the intact hexamer, and binding decreased with hexamer dissociation. Thus, the alpha345(IV)NC1 hexamer is targeted by antibodies that arise in both recurrent anti-GBM disease and in Alport posttransplant anti-GBM nephritis, but these antibodies have different binding properties.
Although anti-GBM disease usually is mediated by immunoglobulin G (IgG) autoantibodies, in rare cases, anti-GBM antibodies of immunoglobulin A (IgA) or immunoglobulin M (IgM) class are involved [21-25]. There is one case study of a 62-year-old man with anti-GBM disease mediated by a monoclonal IgA-kappa antibody, which progressed to end-stage kidney disease despite intensive immunosuppression [26]. He subsequently underwent living-related kidney transplantation and developed recurrent anti-GBM disease with lung hemorrhage and crescentic glomerulonephritis, resulting in allograft failure two years later. Indirect immunofluorescence demonstrated circulating IgA antibodies reactive against a basement membrane component, identified by ELISA and Western blot as the alpha1/alpha2(IV) collagen chains. Sensitivity to digestion with collagenase indicated that the IgA was bound to epitopes located in the collagenous domain rather than the more typical NC1 domain.
The relatively low rate of significant recurrence of anti-GBM disease is thought to be due to delaying kidney transplantation until circulating anti-GBM antibody levels have been undetectable for at least 12 months and there has been quiescent disease for at least six months posttreatment (without cytotoxic agents) [27-30]. The general lack of late recurrence reflects the usually self-limited nature of autoantibody formation in this disorder. In addition, the administration of maintenance immunosuppressive therapy may help suppress autoantibody production [31].
CLINICAL PRESENTATION AND DIAGNOSIS — Patients with clinically evident recurrence of anti-GBM disease typically present with microscopic hematuria, proteinuria, and an elevated serum creatinine. According to published case reports and series, the onset of recurrent anti-GBM disease can range from months to several years posttransplant, and the degree of allograft dysfunction at the time of diagnosis may vary from mild to severe [3-8,11]. The diagnosis is established by the presence of elevated circulating anti-GBM antibody titers and a kidney allograft biopsy demonstrating positive immunofluorescence staining for IgG in a linear pattern along the GBM, similar to what is observed in patients with anti-GBM disease in the native kidneys. Spontaneous resolution can occur, but graft loss is common after onset of recurrent anti-GBM antibody disease [3].
As recurrent anti-GBM disease is exceedingly rare, other causes of kidney allograft dysfunction should be considered before the diagnosis is made. Kidney transplant recipients with a history of native kidney anti-GBM disease who present with an elevated serum creatinine or new onset of proteinuria should be evaluated for kidney allograft dysfunction with the same approach used for kidney transplant recipients with other causes of native kidney failure. In addition, we perform anti-GBM antibody testing in such patients who have no clear cause of allograft dysfunction (eg, hypovolemia, calcineurin inhibitor toxicity) or who have evidence of microscopic hematuria. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)
The diagnosis of Alport posttransplant anti-GBM nephritis is discussed elsewhere. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)", section on 'Anti-GBM antibody disease'.)
TREATMENT — Given the rarity of recurrent anti-GBM disease after transplantation, most transplant centers have very limited experience with this disorder. There are no high-quality studies to guide optimal therapy, and the only available data come from a limited number of case reports [3-10]. As allograft outcomes in these case reports are poor, we treat all transplant patients with recurrent anti-GBM disease, regardless of the severity of their disease, assuming that the kidney allograft biopsy reveals a predominantly acute histologic pattern of injury. Our suggested approach to the initial therapy of recurrent anti-GBM disease in the transplant patient is primarily based upon clinical trials of patients treated for anti-GBM disease in the native kidneys. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)
●We perform plasmapheresis as soon as possible to remove the circulating anti-GBM antibody. The plasmapheresis prescription and duration of treatment are similar to those used in the treatment of disease in the native kidneys. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Plasmapheresis regimen'.)
●We start oral cyclophosphamide and discontinue the antimetabolite used for maintenance immunosuppression (mycophenolate or azathioprine). The dose of cyclophosphamide and duration of treatment are similar to those used in the treatment of disease in the native kidneys. The antimetabolite should be discontinued for the duration of cyclophosphamide treatment and restarted once cyclophosphamide therapy is completed. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Immunosuppressive therapy'.)
●We administer high-dose oral prednisone (1 mg/kg per day to a maximum of 60 to 80 mg/day), followed by a taper to the original maintenance dose once remission is induced. In patients who present with concomitant pulmonary hemorrhage, we give pulse methylprednisolone (15 to 30 mg/kg to a maximum dose of 1000 mg) daily for three doses prior to starting daily oral prednisone. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Immunosuppressive therapy'.)
●We augment maintenance immunosuppression by targeting higher trough levels of the calcineurin inhibitor (ie, tacrolimus levels of 7 to 10 ng/mL or cyclosporine levels of 100 to 150 ng/mL). These higher trough levels should be maintained indefinitely as tolerated to help prevent disease recurrence.
●We administer antimicrobial and antiviral prophylaxis for as long as the patient receives cyclophosphamide, with a regimen that is identical to that administered in the immediate posttransplant period. This includes prophylaxis against Pneumocystis pneumonia (PCP), cytomegalovirus (CMV) infection and disease, and herpes simplex infection (in patients who are at low CMV risk). In addition, we also administer antifungal prophylaxis, although this practice may vary by transplant center. A detailed discussion of the different prophylactic regimens is presented separately. (See "Prophylaxis of infections in solid organ transplantation", section on 'Pneumocystis pneumonia' and "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis' and "Prevention of cytomegalovirus disease in kidney transplant recipients".)
As in patients being treated for anti-GBM disease in the native kidneys, anti-GBM antibody levels should be monitored every one to two weeks until they are negative on two occasions. We periodically monitor anti-GBM levels for up to six months to confirm that remission is maintained or at any time if there are clinical signs suggestive of recurrence. Recurrent clinical signs, in the presence of positive anti-GBM antibody, should prompt a further course of plasmapheresis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY
●Although anti-glomerular basement membrane (GBM) antibody disease may progress to end-stage kidney disease, the rate of clinically significant recurrence is low. The low rate of significant recurrence may be due to the practice of delaying transplantation until disease is quiescent. Maintenance immunosuppressive therapy may also prevent recurrence. (See 'Introduction' above.)
●The target glomerular basement membrane antigens for recurrent anti-GBM disease are the noncollagenous-1 (NC1) domains of the alpha-3 and alpha-5 chains of collagen IV (alpha3[IV]NC1 and alpha5[IV]NC1). Collagen IV is a family of six alpha chains (alpha-1 through alpha-6). The alpha-3, alpha-4, and alpha-5 chains form a triple helical protomer, and oligomerization of alpha-345 protomers, by means of NC1-NC1 end-to-end associations, forms the hexameric NC1 domain. (See 'Pathogenesis' above.)
●Patients with clinically evident recurrence present with microscopic hematuria, proteinuria, and an elevated serum creatinine. Graft loss due to recurrent anti-GBM antibody disease is common. (See 'Clinical presentation and diagnosis' above.)
●We treat all transplant patients with recurrent anti-GBM disease, regardless of the severity of their disease, assuming that the kidney allograft biopsy reveals a predominantly acute histologic pattern of injury. Our suggested approach to the initial therapy of recurrent anti-GBM disease in the transplant patient is primarily based upon clinical trials of patients treated for anti-GBM disease in the native kidneys. (See 'Treatment' above.)
●De novo anti-GBM antibody disease may occur in some patients who have Alport syndrome (also known as Alport posttransplant anti-GBM nephritis) as the cause of end-stage kidney disease. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)
