Cryoglobulinemic glomerulonephritis: an extrahepatic manifestation of hepatitis C virus (HCV) infection

A 66-year-old woman was admitted to our Department for evaluation of a nephrotic syndrome. Physical examination revealed ankle edema, palpable purpura of the legs and hypertension. There was no hepatosplenomegaly. The main laboratory findings were haemoglobin 11.4 g/dl, serum creatinine 1.4 mg/dl, proteinuria 3.5 g/day with reduced serum albumin (3.1 g/dl), rheumatoid factor (RF) activity 125 IU/ml, and serum C4 levels 2.3 mg/dl. Cryocrit was 24%, with type II (IgG-IgM-κ) cryoglobulins. The patient was positive for HCV antibodies and serum HCV RNA; the genotype was 1b. A percutaneous renal biopsy showed a cryoglobulinemic membranoproliferative glomerulonephritis with moderate histologic severity. The primary goal in patients with mild-to-moderate disease is viral clearance, so combination therapy with interferon-α (3 MU thrice weekly) and ribavirin (800 mg/day) was started. Twelve weeks later, serum HCV RNA had disappeared, a result that was confirmed at the end of antiviral therapy in week 48, and during the post-treatment follow-up. Proteinuria returned to the normal range, cryoglobulins decreased to undetectable levels and serum C4 levels normalized. RF activity decreased, but remained above normal. The message provided by this illustrative case is that antiviral therapy represents the first-line treatment for HCV-related cryoglobulinemic patients with mild-to-moderate kidney involvement, because it provides the best chance of viral clearance and subsequent disease improvement

Adult idiopathic subglottic stenosis: a diagnostic and therapeutic challenge

Annali Italiani di Medicina Intern

Hypertension as an Etiopathological Factor in the Development of Cerebral Atrophy in Hemodialyzed Patients

Twenty-five patients on long-term regular hemodialysis treatment (RDT) at our dialysis unit who underwent diagnostic cerebral computed tomography (CCT) participated in a study aimed at clarifying the pathogenesis of cerebral atrophy occasionally found at their original scan. The upper age limit was 55 years to exclude the physiological involutive brain changes occurring with age. Cerebral atrophy (CA), as defined morphologically (enlargement of cerebral sulci or an increased Evan’s Index), was detected in all cases. Seventeen patients underwent magnetic resonance imaging (MRI) to define possible white matter changes more accurately. No significant correlation was found between the degree of atrophy and the following uremia-altered hematoseric parameters: creatinine, hematocrit, cholesterol, triglyceridemia, albumin, PTH, calcium, inorganic phosphate. There was no correlation between degree of atrophy and number of months the patients had been on RDT or time that passed between the finding of a creatinine clearance !30 ml/min and the start of RDT. Very high correlations were found between the degree of CA and predialytic blood pressure values, and between CA and the duration of hypertension (n = 13, r = 0.66, p ! 0.013). Thus, hypertension seems to be an early cause of cerebral parenchymal damage in RDT patients, and should be promptly corrected

Outcome and prognostic factors during the course of primary small-vessel vasculitides.

Objective. Toidentify the prognostic factors of relapse and/or death during the course of primary smauvessel vasculitides (PSVV), and to differentiae their prognostic relevance by the type of vasculitis. Methods. Sventy-five patients were retrospectively followed up after diagnosis: 36 with Wegener’s granulomatosis (WG), 23 with Churg-Strauss syndrome (CSS), and 16 with microscopic polyanglitis. Cox regression analisys was used to identify the significant predictors of replase and death. Results. Gastrointestinal (GI) involvement was associated with an increased risk of replase, mainly in the patients with CSS, whereas renal disease and perinuclear antineutrophil cytoplasmic antibody positivity were correlated with a lower risk of replase. Presence of nasal Staphylococcus aureus tended to increase the risk of replase in CSS (hazard ratio (HR) 4.45, p=0.087), but to decrease it in WG (HR 0.12,p =0.066). Olger age, renal and hepatic involyement, erythrocyte sedimentation rate > 100 mm/h, and serum creatinine level 1.5 mg/dl were alol related to higher risk of death in univariate analysis; however, only cerebral (HR 8.52, p = 0.021) and hepaticinvolvement (HR 4.40, p=0.028 and serum creatinine level > 1.5 mg/dl (HR 5.72,p = 0-044) were independently correlated with an favorable prognosis for survival. The risk of death associated with eact of these indicators did non depend on the form of PSVV. Conclusion. Gli involvement increases the risk of relapse in CSS, whereas the prognostic significance of nasal S. aureas in terms of relapse seems to be opposite in patients whit CSS and those whit WG. Patients with cerebral, hepatic, and renal involvement have the poorest prognosis for survival. Our data do not show that the prognostic relevance of these factors depends on the from of PSVV )J. Rheumatol First Release June 15 20’06

Antiviral Therapy for HCV-Associated Cryoglobulinemic Glomerulonephritis: Case Report and Review of the Literature

We describe the case of a 51-year-old woman with HCV-associated cryoglobulinemic glomerulonephritis (GN). She presented mild deterioration of kidney function, non-nephrotic proteinuria, and active urinary sediment. Kidney biopsy showed features of membranoproliferative changes with some sclerosis. Sustained viral response (SVR) was obtained by 6 months of antiviral therapy (peg-IFN-α2a plus ribavirin). SVR was linked with improvement of kidney function and remission of proteinuria. Clinical and virological remission persists over a 25-month follow-up. This case report emphasizes efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis – preliminary but encouraging results exist. We identified by systematic review of the literature 9 studies (156 unique patients); the pooled estimate of frequency of sustained virological response after IFN-based therapy was 0.49 (95% confidence interval, CI: 0.21, 0.77; p < 0.0005; random effects model). Heterogeneity was found (I2 = 98.9%, p < 0.0001). Two possible regimens should be considered for the treatment of HCV-associated cryoglobulinemic GN according to the clinical presentation. Immunosuppressive therapy is recommended for HCV-related kidney disease having aggressive course, and recent evidence supports rituximab (RTX) use with a reduced exposure to corticosteroids. We identified six studies (66 unique patients) on RTX therapy for HCV-associated kidney disease; at the end of RTX therapy, the pooled estimate of the mean decrease in proteinuria was 1.4 g/24 h (95% CI: 0.75, 2.05, p < 0.001); The p test for heterogeneity gave a value of 0.94 (I2 = 0). Several questions related to RTX use remain. HCV-induced GN is uncommon among CKD patients of developed countries, and this clearly hampers prospective controlled clinical trials aimed to evaluate efficacy and safety of antiviral or immunosuppressive therapy in this population

The LRRK2 variant E193K prevents mitochondrial fission upon MPP+ treatment by altering LRRK2 binding to DRP1

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson’s disease (PD). LRRK2 is a complex protein that consists of multiple domains, including 13 putative armadillo-type repeats at the N-terminus. In this study, we analyzed the functional and molecular consequences of a novel variant, E193K, identified in an Italian family. E193K substitution does not influence LRRK2 kinase activity. Instead it affects LRRK2 biochemical properties, such as phosphorylation at Ser935 and affinity for 14-3-3ε. Primary fibroblasts obtained from an E193K carrier demonstrated increased cellular toxicity and abnormal mitochondrial fission upon 1-methyl-4-phenylpyridinium treatment. We found that E193K alters LRRK2 binding to DRP1, a crucial mediator of mitochondrial fission. Our data support a role for LRRK2 as a scaffolding protein influencing mitochondrial fission