Anti-GBM (Goodpasture) disease: Recurrence after transplantation

INTRODUCTION — Anti-glomerular basement membrane (GBM) disease is a rare small-vessel vasculitis that affects glomerular capillaries, pulmonary capillaries, or both. Most patients present with rapidly progressive (crescentic) glomerulonephritis, although some patients may present with relatively mild kidney impairment. In general, this disorder is typically associated with severe kidney injury that, if untreated, progresses quickly to end-stage kidney disease (ESKD).

Rare cases of recurrent anti-GBM disease following kidney transplantation have been reported.

This topic reviews recurrent anti-GBM disease after transplantation. The pathogenesis, diagnosis, and treatment of anti-GBM disease of the native kidneys are discussed separately:

●(See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis".)

●(See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

EPIDEMIOLOGY

●Incidence – In historical series, the incidence of recurrent linear immunoglobulin G (IgG) staining in the kidney transplant was as high as 50 percent among patients with positive anti-GBM antibodies at the time of transplantation; however, most patients remained asymptomatic [1].

Symptomatic recurrent anti-GBM disease is rare and has been described in limited case reports [2-12]. In one registry study of 224 patients with anti-GBM disease who underwent kidney transplantation, six patients (2.7 percent) experienced biopsy-confirmed recurrent disease in the allograft [13]. Other cohort studies have reported a similarly low rate of recurrence of approximately 2 to 4 percent [10,11].

The relatively low rate of clinical 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) [14-17]. 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 [18].

●Risk factors – Data on risk factors for recurrent disease are scarce. Proposed risk factors include the presence of anti-GBM antibodies before transplantation and the use of low-dose or no immunosuppressive therapy after transplantation [3,10]. Most transplant centers require at least six months of undetectable anti-GBM antibody levels before kidney transplantation.

PATHOGENESIS — Similar to anti-GBM disease in the native kidneys, recurrent anti-GBM disease after transplantation is caused by circulating antibodies directed against the noncollagenous 1 (NC1) domains of the alpha-3 and alpha-5 chains of type IV collagen (alpha-3[IV]NC1 and alpha-5[IV]NC1). Type IV collagen is a family of six alpha chains (alpha-1 through alpha-6); the alpha-3, -4, and -5 chains form a triple helical protomer, and oligomerization of alpha-3-4-5 protomers, by means of NC1-NC1 end-to-end associations, forms the hexameric NC1 domain. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)

The alpha-3-4-5 network is also the 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 binding of alloantibodies to the alpha-5(IV)NC1 domain in response to the "foreign" alpha-3-4-5 collagen network that is absent in the kidneys of patients with Alport syndrome but present in the kidney allograft. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)", section on 'Anti-GBM antibody disease'.)

The antibodies in patients with anti-GBM disease and those with Alport posttransplant anti-GBM nephritis appear to have different binding properties. In a study that examined the specificity of circulating and kidney-bound antibodies in patients with anti-GBM disease or Alport posttransplant anti-GBM nephritis, autoantibodies in patients with anti-GBM disease bound to distinct, hidden epitopes in the alpha-3(IV)NC1 and alpha-5(IV)NC1 monomers but did not bind to the native alpha-3-4-5(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 [19]. By contrast, in patients with Alport posttransplant anti-GBM nephritis, alloantibodies bound to the alpha-5(IV)NC1 epitope in the intact hexamer, and binding decreased with hexamer dissociation.

Although anti-GBM disease is usually mediated by IgG autoantibodies, in rare cases, anti-GBM antibodies of IgA or IgM class are involved [20-25]. There is one case report of a 62-year-old male with anti-GBM disease mediated by a monoclonal IgA-kappa antibody who progressed to end-stage kidney disease (ESKD) despite intensive immunosuppression [25]. 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 enzyme-linked immunosorbent assay (ELISA) and Western blot as the alpha-1/alpha-2 chains of type IV collagen. 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.

CLINICAL PRESENTATION — Patients with clinically evident recurrence of anti-GBM disease typically present with microscopic hematuria, proteinuria, and an elevated serum creatinine. Most patients have positive testing for circulating anti-GBM antibodies. In published case reports and series, the onset of recurrent anti-GBM disease has ranged from months to several years posttransplant, and the degree of allograft dysfunction at the time of diagnosis has varied from mild to severe [2-7,10]. Despite treatment, graft loss is common after the onset of recurrent anti-GBM disease [2].

Recurrence of atypical anti-GBM disease, a rare variant of anti-GBM disease, may present differently than recurrent typical anti-GBM disease. Circulating anti-GBM antibodies are usually not detected. (See 'Recurrent atypical anti-GBM disease' below and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Anti-GBM disease without detectable circulating anti-GBM antibodies'.)

SURVEILLANCE — For most kidney transplant recipients with anti-GBM disease as the cause of end-stage kidney disease (ESKD) in the native kidney, routine posttransplant monitoring is generally sufficient to monitor for signs of recurrent disease. Some centers may monitor serum anti-GBM antibody titers after transplantation at varying intervals, while others may perform protocol/surveillance biopsies to monitor for recurrent anti-GBM disease. (See "Overview of care of the adult kidney transplant recipient", section on 'Routine follow-up and laboratory monitoring'.)

DIAGNOSIS — The diagnosis of recurrent anti-GBM disease should be suspected in kidney transplant recipients with known anti-GBM disease in the native kidneys who present with hematuria, proteinuria, and/or an elevated serum creatinine level.

As recurrent anti-GBM disease is exceedingly rare, patients presenting with an elevated serum creatinine or new onset of proteinuria should be evaluated for other causes of acute kidney allograft dysfunction, as discussed separately. 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 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. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation and diagnosis'.)

TREATMENT

Approach to therapy — 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 [2-9]. As allograft outcomes in these case reports are poor, we treat all transplant patients with symptomatic recurrent anti-GBM disease and a kidney allograft biopsy showing a predominantly acute histologic pattern of injury (eg, proliferative glomerulonephritis), regardless of the severity of their disease. Patients with linear IgG staining without proliferative glomerulonephritis and who do not have symptoms do not require specific treatment for anti-GBM disease but should receive ongoing monitoring.

Our suggested approach to therapy is similar to that used for patients with 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'.)

Rituximab is an alternative therapy for patients who are unable to tolerate cyclophosphamide. However, we do not usually use rituximab as first-line therapy, because of insufficient evidence for its efficacy. If rituximab is used instead of cyclophosphamide, some clinicians would discontinue the antimetabolite (mycophenolate or azathioprine) used for maintenance immunosuppression for the duration of rituximab treatment and restart once rituximab therapy is completed; others would not discontinue the antimetabolite during rituximab therapy. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Alternatives to cyclophosphamide'.)

●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", section on 'Universal prophylaxis (high risk)'.)

Monitoring — As in patients being treated for anti-GBM disease in the native kidneys undergoing plasmapheresis, we monitor anti-GBM antibody levels weekly for the first six weeks until they are undetectable on two consecutive occasions. We subsequently monitor anti-GBM antibody levels every other week for four weeks, and if they remain persistently undetectable, we monitor levels once monthly for six months. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Monitoring the response to therapy'.)

Recurrent clinical signs, in the presence of positive anti-GBM antibody, should prompt a further course of plasmapheresis.

SPECIAL POPULATIONS

Recurrent atypical anti-GBM disease — Atypical anti-GBM disease is a rare variant of anti-GBM disease defined by linear IgG deposition along the GBM but without features of crescentic glomerulonephritis. Approximately half of cases show monotypic immunoglobulin staining, and circulating anti-GBM antibodies are usually not detected in these patients [26,27]. This disorder has a milder, more indolent course compared with typical anti-GBM disease. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Anti-GBM disease without detectable circulating anti-GBM antibodies'.)

The clinical and histologic features of recurrent atypical anti-GBM disease were described in a series of six kidney transplant recipients [12]. The mean time to recurrence was 3.8 months posttransplant (range 1 to 7 months). Three patients underwent kidney biopsy for an indication (hematuria or elevated serum creatinine) and three patients had protocol (surveillance) biopsies at four months posttransplant. Of the six biopsies, three showed no significant glomerular histologic changes, one showed focal mild glomerular microangiopathy, and two showed segmental endocapillary proliferative glomerulonephritis. All six allografts showed monotypic linear glomerular immunoglobulin staining by immunofluorescence (IgG kappa [two patients], IgG lambda, IgA kappa, IgA lambda, or IgM lambda). No patients had detectable serum anti-GBM antibodies or monoclonal proteins. Over a follow-up period that ranged from 36 to 62 months, none of the patients lost their allograft due to recurrent disease.

The optimal therapy of recurrent atypical anti-GBM disease is unknown. Some experts consider those patients with monotypic linear immunoglobulin staining of the GBM to have a monoclonal gammopathy of renal significance and would treat with anti-plasma cell– or anti-B cell–directed therapy [12]. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

Alport posttransplant anti-GBM nephritis — The development of de novo anti-GBM disease in patients with Alport syndrome who undergo kidney transplantation (also known as Alport posttransplant anti-GBM nephritis) is discussed separately. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)", section on 'Anti-GBM antibody disease'.)

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 AND RECOMMENDATIONS

●Epidemiology – In historical series, the incidence of recurrent linear immunoglobulin G (IgG) staining in the kidney transplant was as high as 50 percent among patients with positive anti-glomerular basement membrane (GBM) antibodies at the time of transplantation; however, most patients remained asymptomatic. Symptomatic recurrent anti-GBM disease is rare and has been described in limited case reports. (See 'Epidemiology' above.)

●Pathogenesis – Similar to anti-GBM disease in the native kidneys, recurrent anti-GBM disease after transplantation is caused by circulating antibodies directed against the noncollagenous 1 (NC1) domains of the alpha-3 and alpha-5 chains of type IV collagen (alpha-3[IV]NC1 and alpha-5[IV]NC1). (See 'Pathogenesis' above.)

●Clinical presentation – Patients with clinically evident recurrence of anti-GBM disease typically present with microscopic hematuria, proteinuria, and an elevated serum creatinine. Most patients have positive testing for circulating anti-GBM antibodies. The onset of recurrent anti-GBM disease has ranged from months to several years posttransplant, and the degree of allograft dysfunction at the time of diagnosis has varied from mild to severe. (See 'Clinical presentation' above.)

●Surveillance – For most patients, routine posttransplant monitoring is generally sufficient to monitor for signs of recurrent anti-GBM disease. Some centers may monitor serum anti-GBM antibody titers after transplantation at varying intervals, while others may perform protocol/surveillance biopsies to monitor for recurrent anti-GBM disease. (See 'Surveillance' above.)

●Diagnosis – Recurrent anti-GBM disease should be suspected in kidney transplant recipients with known anti-GBM disease in the native kidneys who present with hematuria, proteinuria, and/or an elevated serum creatinine level. 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. (See 'Diagnosis' above.)

●Treatment – Most transplant centers have very limited experience with this disorder. We treat all transplant patients with symptomatic recurrent anti-GBM disease and a kidney allograft biopsy showing a predominantly acute histologic pattern of injury (eg, proliferative glomerulonephritis), regardless of the severity of their disease. Patients with linear IgG staining without proliferative glomerulonephritis and who do not have symptoms do not require specific treatment for anti-GBM disease but should receive ongoing monitoring. Our approach to therapy is similar to that used for patients with anti-GBM disease of the native kidneys. (See 'Approach to therapy' above and "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Plasmapheresis plus immunosuppressive therapy'.)