A 63-year-old male was admitted to his regional hospital because of severe weakness, anorexia and weight loss (16 kg in the previous 4 months). Six months earlier, he had been admitted to the same hospital with fatigue, cervical lymphadenopathy, sialadenitis and peripheral facial palsy. He had then received oral steroids for 2 months with significant clinical improvement. Prior medical history included hypertension for 15 years, a self-limited vitiligo 2 years before and an episode of alithiasic cholecystitis, without pancreatic involvement 1 year before.
On admission, laboratory tests showed anemia (hemoglobin 8.2 g/dl), leukocytosis (WBCs 18.800/ml) with increased neutrophils (60-88%) and eosinophils (3-18%), increased C-reactive protein, rapid deterioration of renal function (peak urea 87 mg/dl, creatinine 2.8 mg/dl), positive antinuclear antibodies (ANA) 1:1,280, low serum complement, hypoalbuminemia (1.8 g/dl), proteinuria (1.8 g/daily), pyuria and mild hematuria in urinalysis. He was then referred to our hospital for renal biopsy with a presumptive diagnosis of lupus nephritis. On admission to our hospital, the patient had a low-grade fever, intense weakness affecting mobility, absence of arthralgias or arthritis. He was hemodynamically stable and normovolemic. The rest of the physical examination revealed only hepatomegaly and muscle wasting. Laboratory tests confirmed the inflammatory syndrome (elevated erythrocyte sedimentation rate and C-reactive protein) and immunological abnormalities with high IgG (2,020 mg/dl), low complement C3 and C4, positive ANA 1:640 and atypical pANCA 1:160. Antibodies against double-stranded DNA (anti-dsDNA) were found slightly positive only once, whereas the crithidia luciliae immunofluorescence (CLIF) test was negative. Serum and urine immunofixation, MPO/PR3 titers, hepatitis screening, serum cryoglobulins and angiotensin-converting enzyme were negative or normal. Both abdominal ultrasound and CT revealed large kidneys (13 and 14 cm) and marked hepatomegaly. Brain CT was normal and chest CT showed marginally enlarged mediastinal lymph nodes. Further analysis of IgG subclasses revealed extremely high IgG4 levels (1,210 mg/dl). A subsequent kidney biopsy showed irregular thickening of glomerular basement membranes (GBMs) with C4d deposition by immunohistochemistry, thickening of tubular basement membranes (TBMs) and diffuse interstitial inflammatory infiltrates disrupting normal kidney architecture. The infiltrates consisted mainly of polyclonal (kappa and lambda positive) plasma cells, the vast majority being IgG4+ (>50 per high power field, hpf) as well as CD3+ and CD20+ lymphocytes and eosinophils (fig. 1). Congo red stain was negative. Interstitial fibrosis was estimated at 30-35% of the substrate by Masson stain. Immunofluorescence showed moderate IgG and mild C3 depositions in GBMs. IgG was also found in interstitial infiltrates and IgM in the TBMs. Fluorescence for IgA, C4 and C1q was negative. Electron microscopy revealed the presence of several subepithelial dense deposits and scarce mesangial and TBM deposits. Based on biopsy findings, a final diagnosis of IgG4-RKD with TIN and secondary MN was made. Methylprednisolone therapy was started at a dose of 36 mg/day with gradual tapering to 4 mg/day for 1 year. This treatment resulted in a rapid improvement of symptoms and renal function (serum creatinine from 2.8 to 1.8 mg/dl within the first 10 days). At the 6 and 12 months follow-up, clinical, radiologic and laboratory findings have all returned to normal (serum creatinine at 1.1 mg/dl).