Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.

Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults.

Nephropathic cystinosis is a multisystem autosomal recessive disease caused by cystine accumulation, which is usually treated by oral cysteamine. In order to determine long-term effects of this therapy, we enrolled 86 adult patients (mean age 26.7 years) diagnosed with nephropathic cystinosis, 75 of whom received cysteamine. Therapy was initiated at a mean age of 9.9 years with a mean duration of 17.4 years. By last follow-up, 78 patients had end-stage renal disease (mean age 11.1 years), 62 had hypothyroidism (mean age 13.4), 48 developed diabetes (mean age 17.1 years), and 32 had neuromuscular disorders (mean age 23.3 years). Initiating cysteamine therapy before 5 years of age significantly decreased the incidence and delayed the onset of end-stage renal disease, and significantly delayed the onset of hypothyroidism, diabetes, and neuromuscular disorders. The development of diabetes and hypothyroidism was still significantly delayed, however, in patients in whom therapy was initiated after 5 years of age, compared with untreated patients. The life expectancy was significantly improved in cysteamine-treated versus untreated patients. Thus, cysteamine decreases and delays the onset of complications and improves life expectancy in cystinosis. Hence, cysteamine therapy should be introduced as early as possible during childhood and maintained lifelong.

Complement alternative pathway acts as a positive feedback amplification of neutrophil activation.

Complement alternative pathway plays an important, but not clearly understood, role in neutrophil-mediated diseases. We here show that neutrophils themselves activate complement when stimulated by cytokines or coagulation-derived factors. In whole blood, tumor necrosis factor/formyl-methionyl-leucyl-phenylalanine or phorbol myristate acetate resulted in C3 fragments binding on neutrophils and monocytes, but not on T cells. Neutrophils, stimulated by tumor necrosis factor, triggered the alternative pathway on their surface in normal and C2-depleted, but not in factor B-depleted serum and on incubation with purified C3, factors B and D. This occurred independently of neutrophil proteases, oxidants, or apoptosis. Neutrophil-secreted properdin was detected on the cell surface and could focus "in situ" the alternative pathway activation. Importantly, complement, in turn, led to further activation of neutrophils, with enhanced CD11b expression and oxidative burst. Complement-induced neutrophil activation involved mostly C5a and possibly C5b-9 complexes, detected on tumor necrosis factor- and serum-activated neutrophils. In conclusion, neutrophil stimulation by cytokines results in an unusual activation of autologous complement by healthy cells. This triggers a new amplification loop in physiologic innate immunity: Neutrophils activate the alternative complement pathway and release C5 fragments, which further amplify neutrophil proinflammatory responses. This mechanism, possibly required for effective host defense, may be relevant to complement involvement in neutrophil-mediated diseases.

Pauci-immune crescentic glomerulonephritis associated with ANCA of IgA class.

Pauci-immune renal vasculitis is associated strongly with antineutrophil cytoplasmic antibodies (ANCAs) of the immunoglobulin G (IgG) class, which are detected in 80% to 90% of affected patients. IgA ANCAs have been reported in association with various conditions, but never in the setting of pauci-immune vasculitis. A 28-year-old man with unexplained polyclonal hyper-IgA1 diagnosed in childhood presented with decreased kidney function, nephrotic syndrome, and microscopic hematuria. Kidney biopsy showed pauci-immune crescentic glomerulonephritis. Serum test results were negative for IgG ANCA by means of both indirect immunofluorescence and enzyme-linked immunosorbent assay techniques. Conversely, indirect immunofluorescence performed using anti-IgA antibody was strongly positive with a cytoplasmic ANCA pattern, and an enzyme-linked immunosorbent assay test had positive results for both antimyeloperoxidase and anti-proteinase 3 IgA. IgA ANCAs were not detected in 2 control serum samples from 1 patient with polyclonal hyper-IgA and 1 patient with monoclonal hyper-IgA. The patient received corticosteroids and 4 weekly perfusions of rituximab (375 mg/m2). After a 6-month follow-up, decreased kidney function and nephrotic syndrome persisted and IgA ANCA titers were unchanged. However, a control kidney biopsy showed a decrease in vasculitis activity. This first case of pauci-immune vasculitis associated with ANCA of the IgA class suggests the potential pathogenetic role of these peculiar antibodies. Additional studies are needed to determine whether IgA ANCAs, which are not routinely screened for, can be detected in patients with pauci-immune vasculitis either alone or in association with IgG ANCA.

The macrophage-derived neutrophil chemotactic factor, MNCF: a lectin with TNF-alpha-like activities on neutrophils.

The macrophage-derived neutrophil chemotactic factor (MNCF) is an alpha-galactoside-binding lectin, known to induce dexamethasone-insensitive neutrophil recruitment. We further characterized MNCF effects on neutrophils and showed that it shares with TNF-alpha the ability to delay apoptosis and to trigger degranulation. MNCF and TNF-alpha effects show similar kinetics and involve Src kinases and MAPKinases dependent pathways. They were, however, clearly distinguished, since the soluble TNF-receptor etanercept prevented TNF but not MNCF effects, while melibiose disaccharide inhibited MNCF but not TNF effects. Absorption of MNCF on detoxi-gel did not alter its properties, precluding an LPS contamination effect. By contrast, galectin-3 required LPS to activate neutrophils. Specific antibodies allowed to further demonstrate that MNCF and galectin-3 are two distinct molecules. Finally, MNCF- and IL-8-induced neutrophil activation differed by their kinetic and sensitivity to pertussis toxin. In conclusion, MNCF is a distinct neutrophil agonist, with pro-inflammatory activities involving its carbohydrate recognition domain.

Increased membrane expression of proteinase 3 during neutrophil adhesion in the presence of anti proteinase 3 antibodies.

We investigated membrane proteinase 3 (mPR3) expression during TNF-alpha-induced adhesion of neutrophils in the presence of anti-PR3 antibodies, a situation occurring during anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis. Three increasing levels of mPR3 expression were observed on the mPR3(+) neutrophil subset after stepwise cell activation. TNF-alpha activation without adhesion, TNF-alpha-induced adhesion, and adhesion in the presence of anti-PR3 mAb or human anti-PR3 ANCA resulted, respectively, in a two-, seven-, and 24-fold increase of mPR3 levels. In plasma, anti-PR3 antibodies poorly recognized suspended neutrophils, whereas they bound to mPR3 on adherent cells. mPR3 upregulation was also triggered by IL-8, formyl-methionyl-leucyl-phenylalanine (fMLP), and neutrophil adhesion to activated human umbilical vein endothelial cells. It involved beta2 integrins and Fcgamma receptor, because it was prevented by anti-CD18 antibodies and was not observed with anti-PR3 F(ab')(2). Furthermore, it was specific to anti-PR3 mAb, and no mPR3 upregulation was observed with anti-myeloperoxidase or anti-HLA-ABC mAb. Newly expressed mPR3 molecules, after TNF-induced adhesion, were mobilized from secretory vesicles (CD35(+)) and secondary granules (CD11b(+)). The adhesion- and antibody-dependent upregulations of mPR3 expression occurred with little azurophilic granule degranulation, no sign of apoptosis, and no further CD177 upregulation. In conclusion, this study describes an amplifying loop in polymorphonuclear neutrophil activation process, whereby ANCA are involved in the membrane expression of their own antigen during cell adhesion. This could explain the restriction of ANCA-associated vasculitis to small vessels, the main site of neutrophil adhesion.

Post-allogeneic haematopoietic stem cell transplantation membranous nephropathy: clinical presentation, outcome and pathogenic aspects.

BACKGROUND: Post-allogeneic haematopoietic stem cell transplantation (HSCT) membranous nephropathy (MN), a rare complication of HSCT, remains an ill-defined entity. We describe the clinical and biological characteristics and outcome of five patients with post-HSCT MN, review the previously reported cases and discuss the pathogenic aspects of this nephropathy. METHODS: Cases were identified by using a questionnaire sent to nephrologists and pathologists in French university and general hospitals. Medical records and kidney biopsy specimens were reviewed and relevant data were collected. Moreover, the IgG subclasses in glomerular deposits and the presence of chimeric renal cells were studied. RESULTS: Five patients were identified. All had a history of chronic graft-vs-host disease (cGVHD) and all had active manifestations of cGVHD at MN diagnosis. Mean time between HSCT and diagnosis of MN was 24.4 months. Renal insufficiency was present in four patients. Renal biopsy examination showed typical features of MN in all patients. IgG1 and IgG4 were the predominant IgG subclasses in the glomerular deposits. No chimeric glomerular cell was detected. Initial treatment for MN consisted in corticosteroids and immunosuppressors (ciclosporin, mycophenolate mofetil, rituximab, chlorambucil) in all patients. Complete remission of nephrotic syndrome (NS) occurred in two patients, partial remission in one patient, while treatment was inefficacious in one (data not available for one patient). Most interestingly, the evolution of NS paralleled the evolution of cGVHD in all patients. CONCLUSION: Our data suggest an association between cGVHD and post-HSCT MN. Treatment, mainly steroids and ciclosporin, should be aimed at the control of acute manifestations of cGVHD.

Inhibition of matrix metalloproteinase-9 by interferons and TGF-beta1 through distinct signalings accounts for reduced monocyte invasiveness.

Cytokines may provide signals for regulating human monocyte matrix metalloproteinase-9 (MMP-9) activity. In this study, we investigated the roles of interferons (IFN) type I/II and transforming growth factor-beta1 (TGF-beta1) in MMP-9-mediated invasiveness. MMP-9 antibody and inhibitor, IFNs and TGF-beta1 inhibited monocyte transmigration through Matrigel. IFNs and TGF-beta1 downregulated MMP-9 mRNA, protein and activity levels. The inhibitory action of IFNs was associated with the STAT1/IRF-1 pathway since the JAK inhibitor AG490 blocked STAT1 phosphorylation, IRF-1 synthesis and counteracted the blockade of MMP-9 release. TGF-beta1-mediated MMP-9 inhibition appeared STAT1/IRF-1-independent but reversed by the protein tyrosine kinase inhibitor tyrphostin 25. Our data point out the importance of IFNs and TGF-beta1 in the control of monocyte MMP-9-mediated extravasation.

Type III cryoglobulinemia complicated by renal cortical necrosis.

Renal involvement is rare in patients with type III cryoglobulinemia. We report a case of renal cortical necrosis in a patient with type III cryoglobulinemia. Renal function improved partially after treatment with plasma exchange, steroids, and cyclophosphamide. Renal magnetic resonance imaging was a valuable tool in the evaluation of the extent of renal cortical necrosis and improvement in renal vascularization after treatment.

ANCA-negative pauci-immune renal vasculitis: histology and outcome.

BACKGROUND: Pauci-immune renal vasculitis with focal glomerular necrosis and crescent formation is usually associated with anti-neutrophil cytoplasmic antibodies (ANCAs). However, ANCA's are absent in up to 10% of cases, which constitutes a rarely studied variant of renal vasculitis. METHODS: This retrospective multicentre cohort study analyzed the presenting features, renal histology and outcome in 20 patients with pauci-immune crescentic necrotizing renal vasculitis in whom indirect immunofluorescence did not detect ANCA. RESULTS: Renal histology revealed a high percentage of active glomerular lesions (50%), mainly cellular crescents, 28% of them with glomerular necrosis. Chronic tissue damage with glomerulosclerosis (21%) and diffuse interstitial fibrosis (40%) was already present at diagnosis, more prominent than in historical PR3-positive patients. Infiltrates of polymorphonuclear neutrophils in glomerular capillary loops were observed in 40% of all biopsies, mainly in necrotic lesions. The subsets of interstitially infiltrating leukocytes similar to ANCA-associated disease. Microscopic polyangiitis was diagnosed in 17 patients, Wegener's granulomatosis in two and renal-limited vasculitis in one. The patients median disease extent index (DEI) of 5 (range 4-11) reflected a systemic vasculitis. ANCA-negative vasculitis was not associated with infection or malignancy. Renal outcome was correlated to DEI (P = 0.032) and serum creatinine at diagnosis (P = 0.04). The mortality rate was high (35%) and closely related to age above 65 years at diagnosis (P = 0.014). Conclusions. The histological findings and prognosis in ANCA-negative renal vasculitis are comparable with those of ANCA-positive disease. Our data underline the importance of the exact diagnosis in an active vasculitic disease process even in the absence of ANCAs.

Renal and thymic pathology in thymoma-associated nephropathy: report of 21 cases and review of the literature.

BACKGROUND: Acquired thymic disease (malignant thymoma or thymic hyperplasia) is associated with various autoimmune diseases, such as myasthenia gravis (MG), pure red-cell aplasia (PRCA), pemphigus vulgaris or systemic lupus erythematosus (SLE). Renal disease has rarely been observed in association with thymoma. METHODS: This retrospective, multicentric study collected data on patients with thymic disease and biopsy-proven renal involvement. RESULTS: Twenty-one patients were studied (age: 49+/-14 years; male/female ratio: 8/13). Thymic pathology revealed mostly high-grade malignant thymoma (B2 and AB type); two cases were associated with non-malignant thymic hyperplasia. MG was found in nine out of 21 cases, SLE in three, PRCA in three and pemphigus in two. In 47% of these cases, nephropathy occurred after curative treatment of thymoma (108+/-83 months; range: 8-180 months), mainly based on surgical thymectomy associated with radiotherapy. Clinical and laboratory findings included nephrotic syndrome (75%), renal failure (50%), frequent presence of antinuclear antibodies and hypogammaglobulinaemia. Renal pathology showed minimal change disease in 14 patients and focal segmental glomerulosclerosis (FSGS) in one. Membranous nephropathy was observed in four cases, ANCA-associated glomerulonephritis in two and thrombotic microangiopathy in one. Most patients with minimal change disease or FSGS (11/13) were steroid-sensitive. Despite good response to steroids, 38% of patients died from thymoma and 17% developed end-stage renal failure. CONCLUSIONS: Glomerulopathy can be associated with thymoma or thymic hyperplasia. The present series shows that minimal change disease is the most frequent thymoma-associated glomerular lesion and that it may occur several years after thymectomy.

TNF-induced beta2 integrin activation involves Src kinases and a redox-regulated activation of p38 MAPK.

We previously demonstrated that the TNF-alpha-induced inside-out signaling leading to beta(2) integrin activation is redox regulated. To identify kinases involved in this pathway, the effects of kinase inhibitors on the expression of beta(2) integrin activation neoepitope (clone 24) were investigated. We show that both p38 MAPK (inhibited by SB203580) and Src kinases (inhibited by PP2) are involved in beta(2) integrin activation by TNF and oxidants in human neutrophils. Src kinases appeared constitutively active in resting neutrophils and not further activated by TNF or oxidants in nonadherent conditions. However, PP2 blocked both TNF-induced expression of the 24 epitope and cell adhesion promoted by the integrin activating anti-CD18 KIM185 mAb, showing that both the inside-out and the outside-in signaling involve Src kinases. p38 MAPK was activated by TNF and oxidants in nonadherent conditions i.e., with 10 mM EDTA. This activation in EDTA resulted in CD11b, CD35 and CD66 up-regulation and in an oxidative response, all blocked by SB203580 and PP2. p38 MAPK was not activated upon direct integrin activation by KIM185 mAb. Thus, p38 activation allows the study to distinguish the initial transduction pathway leading to beta(2) integrin activation from the signaling resulting from integrin engagement. Finally, p38 MAPK activation by TNF was blocked by diphenylene iodonium, an inhibitor of flavoprotein oxidoreductase, and by the free radical scavenger N-acetylcystein. Taken together, these results demonstrate, for the first time, that constitutively activated Src tyrosine kinases and a redox-regulated activation of p38 MAPK are involved in TNF inside-out signaling leading to beta(2) integrin activation.

The classification of glomerulonephritis in systemic lupus erythematosus revisited.

The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

Apoptosis-induced proteinase 3 membrane expression is independent from degranulation.

Proteinase 3 (PR3) and human neutrophil elastase (HNE) are serine proteinases stored in the azurophilic granules of neutrophils. In contrast to HNE, PR3 is the target of antineutrophil cytoplasm antibodies (ANCA) in Wegener's granulomatosis. The mechanisms leading to the membrane expression of PR3 and HNE are still unclear and appear to be critical to understand the pathophysiological role of ANCA. Stably transfected rat basophilic cell lines (RBL) with PR3 or HNE were used to analyze the PR3 and HNE secretion mechanisms and differentiate between them. RBL cells were lacking endogenous PR3 and HNE. They were stably transfected with HNE or PR3 or an inactive mutant of PR3 (PR3S203A). Using the calcium ionophore A23187 as a secretagogue, higher serine proteinase activity was secreted in the supernatant of RBL/HNE than in RBL/PR3. It is interesting that PR3 and PR3/S203A were also expressed at the plasma membrane, thus demonstrating that serine protease activity was not required for plasma membrane expression. In contrast, no expression of plasma membrane HNE could be detected in RBL/HNE. Apoptosis induced by etoposide was evaluated by DNA fragmentation, the presence of cytoplasmic histone-associated DNA fragments, and annexin V labeling. No membrane HNE was detected in RBL/HNE. In contrast, in RBL/PR3 and in RBL/PR3S203A, the membrane expression of PR3 and PR3S203A increased with etoposide concentrations and appeared closely related to annexin V labeling. Our data suggest that membrane PR3 originates from two distinct pools, the granular pool mobilized following degranulation or a plasma membrane pool mobilized upon apoptosis.

The expanding spectrum of renal diseases associated with antiphospholipid syndrome.

BACKGROUND: The association of thrombotic events and/or pregnancy complications with circulating antiphospholipid antibodies defines antiphospholipid syndrome (APS). In previous reports, renal involvement in APS consisted mainly of thrombotic vascular complications involving large vessels or intrarenal small-sized vessels (APS nephropathy). We report 9 cases of glomerulonephritis associated with APS. These cases are characterized by predominant pathological features distinct from vascular APS nephropathy. METHODS: We reviewed consecutive renal biopsies examined in 2 French university hospitals between 1980 and 2002 and identified renal biopsies performed in patients with primary APS. RESULTS: We identified 29 biopsies performed in patients with APS. Twenty biopsies showed characteristic features of APS nephropathy. In 9 cases, predominant pathological features distinct from vascular APS nephropathy were noted: membranous nephropathy (3 cases), minimal change disease/focal segmental glomerulosclerosis (3 cases), mesangial C3 nephropathy (2 cases), and pauci-immune crescentic glomerulonephritis (1 case). In 7 cases, the presentation of renal symptoms was subacute or chronic. Two patients experienced episodes of acute renal failure. At referral, median creatinine clearance was 50 mL/min (0.83 mL/s) (range, 18 to 117 mL/min [0.30 to 1.95 mL/s]). Proteinuria was noted in all cases (range, 1.5 to 15 g/d), with nephrotic syndrome in 4 cases. Lupus anticoagulant was present in all cases, and anticardiolipin antibodies, in 8 cases. Anti-DNA antibodies repeatedly were negative in all cases. Treatment consisted of antihypertensive therapy (6 cases), anticoagulant drugs (5 cases), steroids (4 cases), and antiplatelet drugs (3 cases). At last follow-up, renal function remained stable in 7 patients. Of 2 patients presenting with acute renal failure, 1 patient recovered normal renal function, whereas the other patient progressed to end-stage renal failure. CONCLUSION: The cases reported here represent a new aspect of the expanding spectrum of renal diseases encountered in association with APS.

Molecular cytogenetic aberrations in autosomal dominant polycystic kidney disease tissue.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder characterized by focal cyst formation from any part of the nephron. The molecular bases include germinal mutation of either PKD1 or PKD2 genes, enhanced expression of several protooncogenes, alteration of the TGF-alpha/EGF/EGF receptor (EGFR) axis, and disturbed regulation of proliferative/apoptosis pathways. To identify new locations of ADPKD related oncogenes and/or tumor suppressor genes (TSG), comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analyses were performed for a series of individual cysts (n = 24) from eight polycystic kidneys. By CGH, imbalances were detected predominantly on chromosomes 1p, 9q, 16p, 19, and 22q in all tissues. DNA copy number gain was seen on chromosomes 3q and 4q in five samples. The CGH data were supplemented by LOH analysis using 83 polymorphic microsatellite markers distributed along chromosomes 1, 9, 16, 19, and 22. The highest frequency of LOH was found on the 1p35-36 and 16p13.3 segments in cysts from seven samples. Allelic losses on 9q were detected in six, whereas deletions at 19p13 and 22q11 bands were observed in three polycystic kidneys. These results indicate that the deleted chromosomal regions may contain genes important in ADPKD initiation and progression.

[Secondary glomerular nephropathies]. / Glomérulopathies secondaires.

Secondary glomerular lesions are associated with various diseases; diabetes, systemic lupus erythematosus, primary cryoglobulinaemia, cryoglobulinemia and membranoproliferative glomerulonephritis secondary to hepatitis C virus (HCV), ANCA associated vasculitis and their forms limited to kidney (necrotic and crescentic GN), Goodpasture syndrome, HIV associated nephropathies, AL amyloidosis, AA amyloidosis (secondary amyloidosis), GN with non-amyloid organised deposits.

Renal involvement in monoclonal (type I) cryoglobulinemia: two cases associated with IgG3 kappa cryoglobulin.

Renal involvement has been described rarely in monoclonal (type I) cryoglobulinemia, although this complication is frequent among patients with mixed (type II or III) cryoglobulin. We report two patients with glomerulonephritis and monoclonal IgGkappa cryoglobulin. Both patients presented with nephrotic syndrome, microscopic hematuria, and impaired renal function. Hepatitis C serology was negative, bone marrow aspiration was normal, and the renal biopsy specimen showed membranoproliferative glomerulonephritis with glomerular subendothelial deposits of monoclonal IgGkappa. In both cases, circulating cryoglobulin and monotypic tissue deposits were found to be IgG3kappa, suggesting that this isotype may have a particular propensity to cause this type of membranoproliferative glomerulonephritis. Although 18 cases of type I cryoglobulinemia with biopsy-proven glomerulonephritis have been reported to date, this is the first characterization of immunoglobulin heavy-chain isotype in this disease.