A 37-year-old woman comes to the office due to worsening leg swelling for the past 2 months. She has also felt excessively tired and has had achy pain in her hands. Temperature is 37.3 C (99.1 F), blood pressure is 156/92 mm Hg, and pulse is 86/min. BMI is 32 kg/m2. Physical examination shows 2+ pitting bilateral edema in the lower extremities. Bilateral finger joints and wrists are mildly swollen and tender to palpation. Serum creatinine level is 1.8 mg/dL. Urinalysis is positive for proteinuria and hematuria. Light microscopy of samples from a kidney biopsy shows diffuse, global endocapillary hypercellularity. Direct immunofluorescence demonstrates "full-house" staining with diffuse, global, granular staining of glomerular capillary walls by IgG, IgM, IgA, C1q, and C3. Electron microscopy shows abundant subendothelial electron-dense deposits. Which of the following is the most likely underlying cause of this patient's renal disease?
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This patient's hematuria with proteinuria, renal insufficiency (elevated creatinine), and sodium/fluid retention (hypertension and edema) are indicative of glomerulonephritis (GN). Although GN has many etiologies, the patient's tender and swollen hand joints (inflammatory arthritis) and renal biopsy findings are strongly suggestive of underlying systemic lupus erythematosus.
An immunofluorescence pattern containing IgG, IgM, IgA and C3, C1q is highly characteristic of lupus nephritis and is referred to as a full-house (ie, a poker hand with three of a kind [3 immunoglobulin classes] and two of a kind [2 complement components]). The full-house pattern reflects the pathogenesis of lupus: loss of immune tolerance to self-antigens (eg, double-stranded DNA) leads to generation of polyclonal autoantibodies that form circulating immune complexes; these deposit in the glomeruli, where they cause local injury by activating the classical complement cascade.
Immune complex deposition in the subendothelial space (visible on electron microscopy) allows for direct contact with inflammatory cells (eg, neutrophils), causing glomerular inflammation. The resulting leukocyte infiltration is seen on light microscopy as endocapillary hypercellularity.
(Choice A) Granulomatosis with polyangiitis is an antineutrophil cytoplasmic antibody–associated vasculitis that can cause GN and arthritis. However, there is characteristically a lack of immunoglobulin or complement (ie, pauci-immune) on immunofluorescence.
(Choice B) Group A Streptococcus infection can result in poststreptococcal GN (PSGN). Although LM reveals endocapillary hypercellularity, immunofluorescence contains mostly IgG and C3 deposits (vs a full house). Moreover, PSGN is usually preceded by throat or skin infections, and arthritis is atypical.
(Choice C) Renal disease in multiple myeloma most commonly results from excessive secretion of immunoglobulin light chains (eg, kappa) that form obstructing casts within the renal tubules. Glomerular deposition of multiple immunoglobulin classes and complement components would be unexpected.
(Choice D) Although rheumatoid arthritis is characterized by small joint inflammatory arthritis, GN is rare, and immunofluorescence would not be expected to show a full-house pattern.
Educational objective:
Lupus nephritis from systemic lupus erythematosus can manifest as glomerulonephritis. Immunofluorescence microscopy showing a full house with 3 immunoglobulin classes (IgG, IgM, IgA) and 2 complement components (C3, C1q) is highly characteristic.