A 42-year-old man comes to the office due to a 2-week history of reddish-brown urine, fatigue, joint pain, and a lower extremity rash. The patient has no medical history, and family history is unremarkable. He has had multiple sexual partners and only uses protection intermittently. Temperature is 37.7 C (99.9 F), blood pressure is 146/94 mm Hg, and pulse is 75/min. Palpable purpura and pitting edema are present in bilateral lower extremities. Laboratory results are as follows:
| Serum chemistry | |
| Creatinine | 3.2 mg/dL |
| Liver function studies | |
| Aspartate aminotransferase (SGOT) | 78 U/L |
| Alanine aminotransferase (SGPT) | 96 U/L |
| Immunologic studies | |
| C3 | low |
| C4 | low |
| Urinalysis | |
| Protein | 3+ |
| White blood cells | 2-3/hpf |
| Red blood cells | many/hpf |
| Casts | several RBC casts |
Which of the following immunologic mechanisms is most likely responsible for this patient's renal injury?
Immune mechanisms of glomerular injury* | |
Immune complex formation |
|
Preformed immune complex deposition from the circulation |
|
Neutrophil activation: minimal (pauci-) immune complex deposition |
|
*Clinical picture determined by site of glomerular immune injury:
ANCA = antineutrophil cytoplasmic antibody; GBM = glomerular basement membrane; GN = glomerulonephritis; | |
This patient's acute kidney injury (eg, elevated creatinine), proteinuria, hypertension, and glomerular hematuria (eg, red cell casts) are indicative of glomerulonephritis (GN). GN is commonly a manifestation of small vessel vasculitis (SVV), which usually has associated systemic symptoms (eg, fever, fatigue). GN due to SVV is immune mediated by 3 possible mechanisms:
Antibodies targeting antigens in the glomerulus (intrinsic or deposited) with immune complex (IC) formation in the kidney
Preformed circulating ICs targeting endogenous or exogenous antigens with subsequent kidney deposition
Antibodies targeting neutrophil antigens causing neutrophil activation without significant IC deposition
Several features of this patient's presentation suggest GN/SVV due to hepatitis C virus (HCV). Evidence for HCV infection includes multiple sexual partners and elevated aminotransferases. HCV-infected patients often produce cryoglobulins against exogenous HCV antigens that form circulating ICs, which activate complement, causing hypocomplementemia. These circulating ICs can deposit in small vessels ("cryoglobulinemic vasculitis") affecting the kidney (eg, membranoproliferative GN), skin (eg, palpable purpura), and joints (eg, arthralgias).
(Choices A and B) Antibodies targeting glomerular antigens, whether intrinsic (eg, membranous nephropathy) or deposited (eg, poststreptococcal GN), form ICs within the kidney; this typically results in renal-limited disease. Anti-GBM disease is an exception because the antibodies are directed against type IV collagen, which is also present in alveoli resulting in alveolar hemorrhage. This patient's fever, arthralgias, and rash indicate a systemic process characteristic of circulating immune complex deposition.
(Choice C) Antibodies targeting neutrophil antigens (myeloperoxidase, proteinase 3) can activate neutrophils, causing ANCA-associated GN and SVV (without significant IC deposition). Although the skin and joints can be affected, the respiratory tract and nerves are typically involved, and hypocomplementemia is unusual.
(Choice D) Preformed circulating ICs against endogenous antigens are the cause of IgA nephropathy and lupus nephritis. IgA nephropathy is more common in children following upper respiratory infections; serum complement is usually normal because IgA fixes complement poorly. Lupus nephritis is associated with arthralgia, vasculitis, and hypocomplementemia; however, this patient's presentation (eg, male sex, sexual risk factors) is more suggestive of underlying hepatitis C infection.
Educational objective:
Immune glomerular injury results from immune complexes (ICs) or neutrophil activation. IC formation in the kidney typically produces renal-limited disease (except anti–glomerular basement membrane disease). Preformed circulating IC deposition is usually associated with small vessel vasculitis and hypocomplementemia.