RPS Case of the Month
Dr. Shannon N. Wong
Dr. Susanna A. McRae
UBC Division of Nephrology
UBC Division of Pathology and Laboratory Medicine
Vancouver, BC, Canada
A 75-year-old male with a history of hypertension, impaired fasting glucose, and obstructive sleep apnea initially presented with a one-month history of shortness of breath and weakness. At the time, he was treated for a community-acquired pneumonia. His pattern of weakness was suspicious for polymyalgia rheumatica, and he was started on empiric prednisone therapy. At the time of his discharge, his creatinine was 197umol/L.
On outpatient nephrology follow up one month later, his renal function continued to deteriorate with a peak creatinine of 391umol/L. The patient also noted increasing peripheral edema and weight gain, with no associated hemoptysis or epistaxis. 24-hour urine protein returned at 3.36 grams daily. A full serologic workup was performed, and his anti-GBM level returned positive at 226 U/mL. He was sent to hospital for urgent plasmapheresis initiation and renal biopsy.
Kidney Biopsy Findings:
Figure 1: 54% of the sampled glomeruli were involved by cellular or fibrocellular crescents with or without necrosis. The first glomerulus (A) demonstrates a cellular crescent (red arrow). Segmental mesangial hypercellularity (black arrow) was noted in occasional glomeruli (B). Background tubulointerstitium shows acute tubular injury and focal inflammation. (PAS x200).
Figure 2: Cellular crescent with focal necrosis (black arrow) and break along the glomerular basement membrane (red arrow). No epimembranous spikes present. (Jones x200)
Figure 3: Diffuse linear and granular capillary wall IgG deposits. IgG subtypes were performed which showed IgG1 dominance (both linear and granular staining). PLA2R staining was negative. (Immunofluorescence microscopy).
Figure 4: Ultrastructurally, there were scattered electron-dense subepithelial deposits with little to no basement membrane reaction (Stage I/IV). Podocytes showed segmental foot process effacement. (Electron microscopy).
Anti-glomerular basement membrane (GBM) disease presents as a rapidly progressive glomerulonephritis. Early diagnosis and intervention are critical, as kidney and patient survival are closely correlated with the degree of renal impairment at presentation1. The underlying pathogenesis of the disease is due to antibodies directed against the non-collagenous domain 1 (NC1) of the alpha 3 chain of type IV collagen. This leads to a necrotizing and crescentic glomerulonephritis, characterized by linear deposits of immunoglobulin G (IgG) along the glomerular basement membrane. Patients may also develop diffuse alveolar hemorrhage, as the alpha 3 chain of type IV collagen is also highly expressed on alveolar basement membranes2-3.
Membranous nephropathy (MN) is characterized by granular capillary wall deposits of IgG on immunofluorescence and subepithelial immune deposits on electron microscopy (see Supplemental below for MN staging). This leads to podocyte injury and foot process effacement, and manifests clinically as marked proteinuria3-4. Primary MN accounts for 80% of MN cases, and is believed to be the product of circulating autoantibodies directed against an endogenous podocyte surface antigen. This target antigen has been identified as phospholipase A2 receptor (PLA2R) in 70-80%, and thrombospondin type 1 domain-containing 7A (THSD7A) in 2-5% of primary MN cases. On the other hand, 20% of MN cases are categorized as secondary, with immune complexes comprised of circulating antibodies directed against a foreign antigen or neo-epitope in the context of an active malignancy, systemic autoimmune condition, infection, or nephrotoxin exposure5. Attempts to differentiate primary from secondary MN are made with renal biopsy tissue, usually with the aid of IgG subtypes and PLA2R staining6, though a thorough workup for secondary causes should be standard of care when any case of MN is suspected5.
Anti-GBM disease infrequently coexists with membranous nephropathy (MN)3. The pathogenesis of concurrent anti-GBM and MN is unclear; currently, it is hypothesized that disruption of the glomerular architecture by one disease reveals hidden epitopes that allow the second disease process to occur2,7. Concurrent anti-GBM and MN has been described as early as 1976, when authors noted an acute and rapid decline in renal function in patients with previously longstanding proteinuria. Renal biopsies demonstrated a superimposed crescentic glomerulonephritis on a background of subepithelial immune deposits and positive serum anti-GBM levels8. Two case series have since described patients with concurrent disease, noting lower levels of serum creatinine at diagnosis, a lower proportion of oligoanuria and gross hematuria, and higher levels of urinary protein excretion as compared to isolated anti-GBM disease alone. Although limited by a small sample size, patients with concurrent disease also demonstrated improved renal recovery (with fewer patients on dialysis) at follow up2-3.In this case, our patient received a two-week course of plasmapheresis until his anti-GBM level was undetectable, but never required dialysis. He was treated with three months of oral cyclophosphamide and six months of oral prednisone. The patient also underwent extensive investigations to rule out a secondary cause of his membranous nephropathy, given the IgG1 dominant PLA2R negative staining on biopsy, which all returned negative. He did have a follow up renal biopsy performed four months later given persistent nephrotic range proteinuria; this demonstrated progression to Stage II/IV membranous nephropathy with more diffuse foot process effacement. By immunofluorescence, the staining along glomerular capillary walls appeared predominantly granular and remained IgG1 dominant and PLA2R negative. The anti-GBM disease no longer appeared active, with 10% of sampled glomeruli involved by fibrocellular crescents without necrosis and another 10% of glomeruli demonstrating segmental sclerosis with capsular adhesions. His renal function remains impaired and he is followed for proteinuric stage 4 chronic kidney disease (eGFR 18ml/min).
Histologic features (EM)
Sparse electron dense deposits without GBM changes
More extensive subepithelial deposits with formation of “spikes” between deposits and thickening of GBM
Stage II features + intramembranous deposits as GBM envelopes deposits
Irregular GBM thickening with incorporated deposits which appear electron lucent
Membranous nephropathy staging based on electron microscopy9-10. EM: electron microscopy, GBM: glomerular basement membrane
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Kuang-Yu Jen, MD, PhD