Double Whammy: Anti-Glomerular Basement Membrane and Anti-Neutrophil Cytoplasmic Antibody Positive Rapidly Progressive Glomerulonephritis

Dear Editor,

Anti-glomerular basement (anti-GBM) disease is characterized by circulating anti-GBM antibodies (AGBMA), and causes clinically aggressive disease which can rapidly damage the glomeruli, much like antinuclear cytoplasmic antibodies (ANCA). The condition of having both in the circulation is described as “double positivity” or “double antibody positive” (DAP) glomerulonephritis. This condition has been known but is sparingly described in medical literature.^1,2

We report six female patients with history of cough, shortness of breath, and reduced urine volume; two had hemoptysis. On examination, they had high blood pressure, pallor, and swelling of the body. They also had hematuria, variable degrees of proteinuria, raised serum creatinine, and normally sized kidneys on ultrasound. The summary of clinical information has been presented in Table 1. All patients received intravenous methylprednisolone (IVMP) 1 g/day for 3 days, followed by oral steroids. All got at least one dose of intravenous cyclophosphamide (IVC) 500mg [Table 1]. Three got membrane filtration plasma exchange alternate-day (PLEX) sessions, 1.5 plasma volumes in each session. All needed renal replacement therapy and remained dialysis-dependent. Three expired within a month of diagnosis, one due to intracranial bleed and two due to pulmonary hemorrhage [Table 1].

The reported DAP incidence is ∼0.6 per million population.³ While many (∼30%) AGBMA-positive patients can show coexistent ANCA, a relatively smaller number (5-7%) of ANCA-positive patients are AGBMA-positive.^1,4 Likewise, 83.33% of our cases were AGBMA positive, and 100% were ANCA positive. Similarly, when >80% of ANCA are expected to be anti-myeloperoxidase (MPO) antibodies, all of our patients demonstrated these antibodies.⁴ A larger patient cohort could have shown matching data. The small size of our cohort also presumably affected the sex distribution. We had all female patients but the literature reports equal sex distribution.^3,5 This study had younger patients in contrast to the reported average age at diagnosis (>60 years).^3,5

All patients had rapidly progressive renal failure and chest symptoms, with only two having hemoptysis. These features agree with the reported data, where most of these patients present with acute kidney failure due to rapidly progressive glomerulonephritis (RPGN), and ∼50% have lung hemorrhage.^4,5 Apart from these, the entire cohort had hypertension, anemia, and respiratory symptoms. All had proteinuria and hematuria. None of them had any features of vasculitic skin lesions.

Double-positive patients (DPPs) share AAV and anti-GBM disease characteristics.⁶ All patients had high ANCA titers, but kidney biopsy reports, in those who could be biopsied, were suggestive of anti-GBM disease. We had a patient with qualitative positive AGBMA but no demonstrable antibody titer in circulation. The patient’s renal biopsy findings were still suggestive of anti-GBM disease. Such a pattern has also been reported elsewhere.⁵

We treated our patients with IVMP (1 g daily for 3 days), followed by oral prednisolone; IVC (500 mg every 2 weeks); and PLEX as treatment modalities depending upon patient characteristics. Our treatment strategies were comparable to those reported in the literature and recommended in guidelines.^5,6 Financial conditions limited the use of plasmapharesis in other patients. No patient was administered rituximab.

All patients needed hemodialysis, and all survivors remained dialysis-dependent. This result was consistent with those from other reports, suggesting that patients needing hemodialysis had low renal recovery rates.^4,6 Available evidence suggests that having double positivity at diagnosis is related to lower renal recovery and higher end stage kidney disease (ESKD) rates.^5,S1 Reported renal survival rates at 1 year are close to 30%.⁴

Comparison of outcomes reported in various available studies has been presented in Table 2.^3-6,S1-S3 In our cohort, one patient expired due to an intracranial hemorrhage, and two others were out-of-hospital deaths. From information obtained from the relatives, the deaths appeared to be related to lung hemorrhage. Patients with pulmonary hemorrhage are reported to have higher mortality than others.⁴ Reported one-year patient survival rates are ∼50%.⁴

We show that it is difficult to control DAP RPGN despite aggressive treatment. The outcomes of the current treatment are often grave.