Protective role of mouse IgG1 in cryoglobulinaemia; insights from an animal model and relevance to human pathology.

Strait et al. described a novel mouse model of cryoglobulinaemia by challenging mice deficient in the immunoglobulin (Ig)G1 subclass (γ1(-) mice) with goat anti-mouse IgD [5]. The phenotype of wild-type mice was not remarkable, whereas γ1(-) mice developed IgG3 anti-goat IgG cryoglobulins as well as severe and lethal glomerulonephritis. Renal phenotype could not be rescued in γ1(-) mice by the deletion of C3, fragment crystalline γ receptor (FcγR) or J chain. On the other hand, early injection of IgG1, IgG2a or IgG2b inhibited the pathogenic effects of IgG3 in an antigen-dependent manner even in the absence of the FcγRIIb, an anti-inflammatory receptor. The authors concluded that the pathogenic role of IgG3 and the protective characteristic of IgG1 in this model were not explained by their abilities to bind to FcRs or effector molecules but are rather due to structural discrepancies enhancing the precipitation properties/solubility of IgG3/IgG1-containing immune complexes. The present article aims to discuss the current knowledge on IgG biology and the properties of IgGs explaining their differential propensity to acquire cryoglobulin activity.

ANCA-associated diseases and lung carcinomas: a five-case series.

Microscopic polyangiitis, granulomatosis with polyangiitis, Churg-Strauss syndrome and focal necrotizing glomerulonephritis are severe systemic vasculitides associated with circulating antineutrophil cytoplasmic antibodies (ANCA). Several studies reported that some malignancies can develop in these patients during follow-up, but few studies have considered the association and role of pre-existing cancers, at least in a fraction of patients. Herein, we report five patients with ANCA-associated diseases who had associated lung carcinomas or were diagnosed within 2 years after vasculitis onset. We discuss the putative role of tumor antigen in driving the auto-immune response.

[Criteria to indicate kidney biopsy in type 2 diabetic patients with proteinuria: Survey among French nephrologists]. / Critères d'indications de la biopsie rénale chez les patients diabétiques de type 2 protéinuriques : enquête auprès des néphrologues français.

Diabetic nephropathy is usually a presumptive diagnosis based on clinical and biological evidence. Renal biopsies are performed in diabetic patients with atypical findings evoking non-diabetic renal disease who could benefit from specific therapies. French speaking nephrologists were asked which criteria they retain to indicate renal biopsy in patients with type 2 diabetes and albuminuria>0.5g/day or equivalent through an online anonymous questionnaire. Among the suggested criteria were absence of diabetic retinopathy, hematuria, rapid decrease in GFR, short diabetes duration or rapid raise of proteinuria. 188 people answered the poll among whom interns (12%), fellows (13%), university hospital practitioners (26%), general hospital practitioners (24%), practitioners in a non-profit organization (13%), practitioners on private activity (10%), multi-modal practitioners (3%) and people without clinical activity (2%). Increasing proteinuria was retained as an indication criterion for renal biopsy by 51% of respondents, nephrotic syndrome by 56% of respondents, absence of diabetic retinopathy by 57% of respondents, short diabetes duration by 65% of respondents, rapid GFR decline by 75% of respondents and hematuria by 78% of respondents. These data highlight the high diversity of opinions on this topic and their discrepancies with guidelines and current literature regarding the association between non-diabetic renal disease and clinical and biological features. The lack of adhesion of nephrologists to guidelines was especially noteworthy regarding the absence of diabetic retinopathy. These results emphasize the need for studies focusing on biopsy indication criteria in patients with type 2 diabetes.

Malakoplakia as a cause of severe hypercalcemia through ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase expression: A case report.

RATIONALE: Malakoplakia is a rare disease characterized by the presence of nongranulomatous macrophage infiltration. In most cases, it affects the urinary tract. Malakoplakia can cause acute kidney injury when it is localized in the kidneys. PATIENT CONCERNS: Here, we report the case of a 65-year-old female patient with renal malakoplakia responsible for hypercalcemia. During her initial assessment, she was also diagnosed 25-OH vitamin D insufficiency, for which she was prescribed oral cholecalciferol. Three months later, she developed severe hypercalcemia with normal 25-OH vitamin D and parathyroid hormone levels and high 1,25-dihydroxyvitamin D levels. DIAGNOSES: After a superimposed granulomatous disease was excluded, malakoplakia cells were suspected to be responsible for the abnormal 25-hydroxyvitamin D3 1-alpha-hydroxylase activity, which was confirmed by immunohistochemistry. INTERVENTIONS: Cholecalciferol was stopped, the patient was rehydrated with intravenous physiological saline, and prednisone was initiated to decrease the enzyme activity. OUTCOMES: Six months later, she displayed normal serum calcium, 25-OH vitamin D and 1,25-dihydroxyvitamin D levels. LESSONS: This case illustrates that malakoplakia may exhibit ectopic 25-hydroxyvitamin D3 1-alpha-hydroxylase activity and cause severe hypercalcemia upon vitamin D supplementation. Therefore, such supplementation should not be given in malakoplakia patients without an actual deficiency and requires careful monitoring of serum calcium.

De Novo Donor-Specific Human Leukocyte Antigen Antibodies in Nonsensitized Kidney Transplant Recipients After T Cell-Mediated Rejection.

BACKGROUND: Local inflammation is a potential cause of humoral alloimmune responses in renal transplantation, and de novo donor-specific anti-human leucocyte antigen antibodies (dnDSAs) have been associated with a history of acute rejection. METHODS: We investigated the frequencies and consequences of dnDSAs after a first episode of acute T-cell-mediated rejection (index TCMR) in previously unsensitized kidney transplant recipients. RESULTS: Of the 1,054 patients who underwent kidney transplantation between September 2004 and December 2010 at our center, we identified 75 unsensitized patients with at least one TCMR. Index TCMRs were diagnosed 4.4 ± 6.8 months after transplantation. The dnDSAs were assessed using the highly sensitive single-antigen human leukocyte antigen bead assay 5.1 ± 3.9 months after the index TCMR and were detected in 16 patients (21%). Patients who developed dnDSAs were more likely to have experienced pre-transplant sensitizing events and were indistinguishable in their clinical, biologic, and histologic variables at the time of index TCMR, although the tubulitis scores tended to be higher (P = 0.079). These patients experienced a significantly higher incidence of subsequent antibody-mediated rejection episodes (P < 0.001), but reduced death-censored graft survival was not observed after a median follow-up of 5.5 years post-transplantation. Follow-up biopsies revealed increased antibody-mediated changes with significantly higher glomerulitis scores and numerically higher C4d staining scores. CONCLUSION: Monitoring anti-human leukocyte antigen antibodies after cellular rejection may be useful, especially among patients with a history of pretransplant exposure to alloantigens, to predict subsequent humoral events and their consequences.