A Diverse Spectrum of Immune Complex- and Complement-Mediated Kidney Diseases Is Associated With Mantle Cell Lymphoma.

Introduction: There are limited reports on kidney biopsy findings in patients with mantle cell lymphoma (MCL). Methods: We initiated a multi-institutional, retrospective review of kidney biopsy findings in patients with active and treated MCL. Results: A total of 30 patients with MCL and kidney biopsies were identified, with a median age of 67 (range 48-87) years, 73% of whom were men. A total of 20 patients had active MCL at the time of biopsy, of whom 14 (70%) presented with acute kidney injury (AKI), proteinuria and/or hematuria, and biopsy findings potentially attributable to lymphoma. Of the 14, 11 had immune complex (IC) or complement-mediated (C3) disease including proliferative glomerulonephritis (GN) with monotypic Ig deposits (PGNMID [2]), C3GN, (2), secondary membranous nephropathy (MN [3]), tubular basement membrane (TBM) deposits (2), and modest lupus-like GN (2). Lymphomatous infiltration was present in 8 of the 20 patients, 5 with coincident IC or C3 lesions. A total of 6 patients with available follow-up were treated for MCL, all with clinical remission of GN (2 PGNMID, 2 C3GN, and 2 MN). Conclusion: MCL is associated with diverse monoclonal and polyclonal glomerular and extra-glomerular IC and C3 disease. For patients with active MCL and kidney dysfunction requiring biopsy, 70% had findings due or potentially due to lymphoma, including 55% with IC or C3 disease and 40% had lymphomatous kidney infiltration. IC and C3GN in the setting of active MCL was responsive to lymphoma-directed therapy.

Anti-LRP2 nephropathy with concurrent kidney infiltration by lymphoma.

Anti-low-density lipoprotein receptor-related lipoprotein 2 (LRP2) nephropathy/anti-brush border antibody disease is rare and characterized by tubular basement membrane, Bowman's capsule and glomerular subepithelial immune deposits on kidney biopsy. No reported cases have occurred in patients with lymphoproliferative disorders or monoclonal gammopathies. We present two cases of anti-LRP2 nephropathy that occurred in patients with progressive low-grade B-cell lymphoma and had concurrent kidney infiltration by lymphoma on biopsy. We speculate that underlying immune dysregulation related to lymphoma may contribute to the development of this rare autoimmune kidney disease in some patients.

Smoking-related glomerulopathy: expanding the morphologic spectrum.

BACKGROUND: Chronic smoking and hypertension may lead to smoking-related nodular glomerulopathy (SRNG), a well-recognized entity that clinically and pathologically mimics nodular diabetic nephropathy (DN). However, like DN, diffuse mesangial sclerosis may occur in this setting without nodules. METHODS: The clinicopathologic features of 10 non-diabetic patients with a long smoking history diagnosed from 2003-2012 showing diffuse mesangial glomerulosclerosis (6) or SRNG (4) were analyzed. RESULTS: Nine of 10 patients were men, aged 58-80 with a 20-58 pack-year smoking history. None of the patients manifested diabetes, but all of them had hypertension. Numerous other cardiovascular comorbidities were present. At biopsy, the mean creatinine was 1.9 mg/dl (range 1.4-3) and the mean proteinuria was 3.9 g/24 h. The renal pathologic findings were similar in all patients except mesangial nodules in SRNG. Global glomerulosclerosis was seen in 6-72% of glomeruli (mean 31%), glomerulomegaly in all cases, and a range of interstitial fibrosis in 10-70% (mean 43%). Moderate (40%) and severe (50%) arteriosclerosis and arteriolar hyalinosis (80%) were also observed. Glomerular hilar or mesangial neovascularization was prominent. Endothelial swelling, subendothelial widening, and new basement membrane formation suggesting chronic healing thrombotic microangiopathy (TMA) was noted in 80%. No immune complexes were localized. CONCLUSIONS: Kidney biopsies from patients with proteinuria and chronic renal insufficiency in the setting of prolonged smoking and hypertension show either diffuse or nodular mesangial glomerulosclerosis. Chronic glomerular mesangial and endothelial injury associated with smoking leads to a chronic TMA appearance in the appropriate setting, even in the absence of mesangial nodule formation.

Central tolerance regulates B cells reactive with Goodpasture antigen alpha3(IV)NC1 collagen.

Patients and rodents with Goodpasture's syndrome (GPS) develop severe autoimmune crescentic glomerulonephritis, kidney failure, and lung hemorrhage due to binding of pathogenic autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen. Target epitopes are cryptic, normally hidden from circulating Abs by protein-protein interactions and the highly tissue-restricted expression of the alpha3(IV) collagen chain. Based on this limited Ag exposure, it has been suggested that target epitopes are not available as B cell tolerogens. To determine how pathogenic anti-GPS autoantibody responses are regulated, we generated an Ig transgenic (Tg) mouse model that expresses an Ig that binds alpha3(IV)NC1 collagen epitopes recognized by serum IgG of patients with GPS. Phenotypic analysis reveals B cell depletion and L chain editing in Tg mice. To determine the default tolerance phenotype in the absence of receptor editing and endogenous lymphocyte populations, we crossed Tg mice two generations with mice deficient in Rag. Resulting Tg Rag-deficient mice have central B cell deletion. Thus, development of Tg anti-alpha3(IV)NC1 collagen B cells is halted in the bone marrow, at which point the cells are deleted unless rescued by a Rag enzyme-dependent process, such as editing. The central tolerance phenotype implies that tolerizing self-Ag is expressed in bone marrow.