Anti-glomerular basement membrane (anti-GBM) is a rare autoimmune but life-threatening disease cause by pathogenic autoantibodies targeting a well characterized autoantigen (a-3 chain of type IV collagen) expressed in the basement membranes of the kidney and lung.
Standard treatment normally includes the combination of plasma ex- change, oral cyclophosphamide and corticosteroids. Despite all therapeutic efforts, renal prognosis remains very poor in many cases.
Recent studies demonstrated the pathogenic role of complement activation in renal damage of this disease. Eculizumab is a terminal complement inhibitor that binds to the human C5 complement protein, thus blocking the generation of proinflammatory C5a and C5b-9. This provides an immediate inhibition of the proinflammatory and cytotoxic sequelae of the complement system.
Here, we report the successfully use of eculizumab in 2 patients with progressive anti-GBM disease.
La enfermedad anti-membrana basal glomerular (anti-MBG) es una enfermedad autoinmune poco frecuente pero potencialmente mortal que se caracteriza por la presencia de una glomerulonefritis rápidamente progresiva y/o hemorragia alveolar. Esta originada por autoanticuerpos dirigidos contra la cadena α-3 del colágeno tipo IV expresado en las membranas basales del riñón y el pulmón.
El tratamiento estándar incluye normalmente el intercambio plasmático, ciclofosfamida y corticosteroides. A pesar de todos los esfuerzos terapéuticos, el pronóstico renal sigue siendo muy pobre en muchos casos.
Estudios recientes han sugerido el papel patogénico de la activación del complemento en el daño renal de esta enfermedad. Eculizumab es un inhibidor terminal del complemento que se une a la proteína C5, bloqueando así la generación de los componentes proinflamatorios C5a y C5b-9. Esto proporciona una inhibición inmediata de las secuelas proinflamatorias y citotóxicas del sistema del complemento.
Aquí reportamos el uso exitoso de eculizumab en 2 pacientes con enfermedad anti-MBG.
A 26-year-old woman was admitted to the internal medicine ward for dyspnea, cough, and hemoptysis of one month’s duration. On arrival, she presented with: blood pressure (BP) 106/65 mmHg, serum creatinine (sCr) 0.73 mg/dl and hemoglobin (Hb) 8.5 g/dl. Urinalysis showed blood (+2) and protein (+2). Chest X-ray and CT scan revealed diffuse alveolar infiltrates consistent with alveolar hemorrhage. With suspicion of small-vessel vasculitis, methylprednisolone (500 mg intravenously for 3 days) was administered and cyclophosphamide was initiated at a dose of 2.5 mg/kg intravenously every two weeks. On day five, anti-GBM antibodies returned positive (titer 28; negative < 10). At that point, consultation with our nephrology department was requested. That same day, daily plasma exchange and kidney biopsy were scheduled; however, the patient deteriorated from a respiratory standpoint, developing global respiratory failure requiring admission to the intensive care unit (ICU).
In the ICU, orotracheal intubation was required. Plasma exchange sessions were initiated and a new methylprednisolone pulse was administered (500 mg for 3 days). Additionally, intravenous cyclophosphamide was continued (2.5 mg/kg every 2 weeks, adjusted for kidney function) and, given the severity of the situation, rituximab was added 15 days after ICU admission (2 doses of 1 g, 15 days apart).
Despite the measures implemented, the patient worsened, with no cessation of alveolar hemorrhage and progressive deterioration of kidney function, with sCr reaching 4 mg/dl and oligoanuria necessitating the initiation of hemodiafiltration. Given treatment refractoriness, C5b-9 was requested, which was elevated, with normal C3. In this setting, with no improvement despite 20 plasma exchange sessions, one month after diagnosis, eculizumab was administered (900 mg weekly). After its initiation, the hemorrhage ceased, allowing extubation, and sCr and urine output improved, enabling withdrawal of hemodiafiltration. After one and a half months in the ICU, the patient was transferred to the general ward, where kidney function progressively improved to near normalization. A total of 3 weekly doses of 900 mg eculizumab were administered (Fig. 1).
The image shows the clinical course of the patient in case 1 during hospitalization, the treatment received, and the changes in serum creatinine. Throughout hospitalization, the patient received several cycles of steroid pulses, cyclophosphamide, rituximab, and finally eculizumab. A clear decrease in serum creatinine can be observed following eculizumab administration.
Regarding the kidney biopsy, once on the general ward and after stabilization, the procedure was performed; however, insufficient tissue was obtained to establish a diagnosis and/or assess chronicity by light microscopy. Direct immunofluorescence did show linear positivity for IgG along the basement membrane and was negative for C3, IgA, IgM, fibrinogen, kappa, and lambda. Immunohistochemistry for C4d was performed, which was positive.
As complications, the patient developed asymptomatic neutropenia due to rituximab and cyclophosphamide, which resolved with granulocyte colony-stimulating factors. Prophylaxis with valganciclovir and amoxicillin was administered while awaiting vaccination.
Case 2A 29-year-old male smoker presented with dyspnea and hemoptysis of 2 weeks’ duration. On arrival, oxygen saturation was 70%, which improved to 93–97% with a Venturi mask at 50%. Laboratory findings were notable for sCr 1.5 mg/dl and Hb 6.5 g/dl. Urinalysis revealed blood (+3), protein (+4), and numerous red blood cell casts. Chest X-ray and CT scan showed diffuse alveolar infiltrates. With suspicion of small-vessel vasculitis, methylprednisolone (1000 mg intravenously for 3 days) and cyclophosphamide (2.5 mg/kg intravenously, adjusted for kidney function) were administered. On day 2, anti-GBM antibodies returned positive (13; negative < 10), with negative ANCA. The remaining laboratory workup was notable for low C3 with normal C4. Daily plasma exchange was initiated, with a total of 11 sessions administered until anti-GBM antibodies became negative and there were no signs of bleeding. On day 12, in the absence of bleeding, a kidney biopsy was performed, which showed necrotizing glomerulonephritis with crescents in 12 viable glomeruli, without evidence of chronicity. Immunofluorescence revealed linear deposition of IgG and C3, as well as kappa and lambda. C4d staining was also requested, which was likewise positive (Fig. 2).
The image shows the clinical course of the patient in case 2 during hospitalization, the treatment received, and the changes in serum creatinine. Throughout hospitalization, the patient received a cycle of corticosteroids, cyclophosphamide, and finally eculizumab. A clear decrease in serum creatinine can be observed following eculizumab administration.
The initial course was favorable, without the need for hemodialysis and with discontinuation of supplemental oxygen. Given the absence of symptoms, induction treatment with intravenous cyclophosphamide was completed at a dose of 2.5 mg/kg, adjusted for kidney function, administered biweekly on an outpatient basis. Subsequently, one month after initiating cyclophosphamide treatment, the patient developed progressive deterioration of kidney function with sCr reaching 3.5 mg/dl, increased hematuria and proteinuria, as well as further decrease in C3. Due to the analytical worsening and based on complement consumption, the decision was made to add eculizumab. Four weekly doses of 900 mg were administered, along with antibiotic prophylaxis until appropriate vaccination was obtained. The patient ultimately showed biochemical improvement with normalization of sCr and resolution of hematuria and proteinuria (Fig. 2).
DiscussionAnti-GBM disease is a rare but potentially fatal autoimmune condition whose standard treatment includes plasma exchange, corticosteroids, and oral cyclophosphamide. In refractory cases, rituximab has been used.1 In alveolar hemorrhage, oral administration may not be feasible; therefore, intravenous cyclophosphamide can be used, following the ANCA vasculitis protocol.2
In anti-GBM disease, the linear deposition of IgG and C3 is well recognized, which has traditionally suggested that the complement system should have an involvement in its pathogenesis.3 In animal models, Groggel et al. observed that genetically modified mice with C6 deficiency exhibited less proteinuria and sCr elevation, suggesting an involvement of the membrane attack complex in renal damage.4 Sheerin et al. demonstrated that mice in which C3 or C4 deficiency was induced not only exhibited less proteinuria but also showed reduced neutrophil infiltration and thrombosis at the renal level.5 In humans, Rui Ma et al. observed an association between serum C5b-9 levels and sCr elevation. Furthermore, they demonstrated the deposition of C1q, factor B, properdin, C3d, C4d, and C5b-9 along the glomerular basement membrane of 10 patients with anti-GBM disease.6 Thus, not only has classical complement pathway activation been postulated, but recent studies have also raised the involvement of the alternative and lectin pathways in renal damage.
To the best of our knowledge, there are few published cases in which eculizumab has been used as treatment for anti-GBM disease.7,8 Recently, Nithagon et al. reported 2 cases treated with eculizumab, one with recovery and the other without response. Additionally, they described increased C5b-9, C3d, and C4d in glomeruli and tubules, reinforcing the involvement of complement in this disease.8
In our case 1, the use of eculizumab was considered given the lack of response to standard therapy combined with rituximab, and following the suspicion of complement activation based on elevated C5b-9. In case 2, although C5b-9 could not be measured, the presence of C3 deposition on biopsy, decreased serum C3, along with progressive sCr deterioration and hematuria, led to the decision to prioritize eculizumab over rituximab to attempt a rapid response and prevent progressive loss of kidney function. Moreover, in both cases, C4d staining was requested on the kidney biopsy specimens, both of which were positive, pointing toward possible activation of the classical or lectin pathway, which would ultimately trigger activation of the membrane attack complex contributing to renal damage, as has been suggested in the aforementioned studies.
Regarding the eculizumab treatment regimen, a rapid and short course was planned, assuming secondary complement pathway activation, as has been postulated in other autoimmune diseases.9,10 Thus, 4 weekly induction doses of 900 mg were planned, although the fourth dose was ultimately not administered in the first case due to clear analytical improvement.9
In both cases, eculizumab appears to have been capable of halting the complement cascade and the inflammation that was accelerating the decline in kidney function. It is possible that, in a disease with so few therapeutic options, this complement blocker may be useful in refractory cases that are not responding to standard therapy. In any case, more data and studies are needed to establish definitive conclusions.
The authors declare that they have no conflicts of interest.
