Osvaldo Giachino

Hepatitis C virus infection and membranous glomerulonephritis.

Cristiana Rollino, MD, Divisione di Nefrologia e Dialisi, Ospedale Giovanni Bosco, Piazza del Donatore di Sangue 3, I-10154 Torino (Italy) Dear Sir, Chronic hepatitis B virus (HBV) infection is known to be associated with membranous glomerulonephritis (MGN), where it represents one of the etiologic factors identified up to now [1]. The frequency of association varies according to different authors and is particularly high in childhood [2]. HBs, HBe and HBc antigens have been identified in subepithelial deposits [3–5]. Whether other forms of hepatitis can also be associated with this nephropathy is still unknown. As new tests for the detection of anti-hepatitis C virus antibodies (HCV-Abs) have become available recently, we looked for a possible association between HCV and MGN. We tested sera of 27 adult patients (16 males, 11 females; mean age 49.8 ± 12.2 years) with biopsy-proven MGN. None of them exhibited systemic lupus erythe-matosus, diabetes mellitus, syphilis, malignancy or exposure to heavy metals or drugs known to induce MGN. HBV antigen and antibody were negative in all the patients. The presence of HCV-Abs was evaluated by the enzyme-linked immunosorbent assay ‘Abbott HCV EIA’, which employs a recombinant antigen of HCV. The neutralizing confirmatory Abbott test was used to bear out the positive results. Only 1 of 27 patients showed the presence of HCV-Abs in several sera; this result was corroborated by the confirmatory test. The onset of MGN in this patient occurred in July 1989. At the time of the admittance to our nephrology department (April 1990), laboratory investigations showed slight elevation of serum transaminases; alkaline phosphatase and prothrombin time were within the normal range, proteinuria was 4,400 mg/24 h, and renal function was normal. The patient was given a treatment with 3 × 1 g methylprednisolone pulses followed by oral prednisone 25 mg daily for 1 month and by chlorambucil 10 mg daily for the next month. The treatment was repeated 3 times and lasted on the whole 6 months [6]. At the end of the therapy, complete remission of the nephropathy (proteinuria 0.2 g/day) was achieved and transaminases were within the normal range. The relationship between hepatitis and occurrence of the nephrotic syndrome is not simply defined. At the time of the admittance to our department, we probably might have observed a late

Plasmapheresis in a Patient with Rapidly Progressive Idiopathic IgA Nephropathy: Removal of IgA-Containing Circulating Immune Complexes and Clinical Recovery

Primary IgA nephropathy is generally considered a benign disease, but progression to renal failure is not uncommon and a rapidly progressive course is observed in some cases, especially when extensive epithelial crescents are present. Circulating IgA-containing immune complexes (IgAIC) seem to play the most important pathogenetical role, hence the authors adopted plasmapheretic treatment in association with immunosuppressive drugs for 1 patient affected by primary IgA nephritis, with florid crescents and progressive renal failure. IgAIC decreased significantly after each plasma exchange and finally returned to normal values; over the same period urinary protein loss and heavy microscopic hematuria gradually disappeared and renal function was completely recovered.

Lab-on-a-chip: emerging analytical platforms for immune-mediated diseases.

Miniaturization of analytical procedures has a significant impact on diagnostic testing since it provides several advantages such as: reduced sample and reagent consumption, shorter analysis time and less sample handling. Lab-on-a-chip (LoC), usually silicon, glass, or silicon-glass, or polymer disposable cartridges, which are produced using techniques inherited from the microelectronics industry, could perform and integrate the operations needed to carry out biochemical analysis through the mechanical realization of a dedicated instrument. Analytical devices based on miniaturized platforms like LoC may provide an important contribution to the diagnosis of high prevalence and rare diseases. In this paper we review some of the uses of Lab-on-a-chip in the clinical diagnostics of immune-mediated diseases and we provide an overview of how specific applications of these technologies could improve and simplify several complex diagnostic procedures.

Long-term effects of methylprednisolone pulses and mycophenolate mofetil in IgA nephropathy patients at risk of progression.

BACKGROUND IgA nephropathy (IgAN) is a microcosm of glomerular lesions. Some histologic lesions are irreversible and progress toward obliteration of glomerular capillaries. Others are acute inflammatory processes potentially susceptible to reversal by means of immunosuppressive therapies. METHODS The effects of a combined schedule of steroids and mycophenolate mofetil (MMF) was prospectively examined in a subset of IgAN patients with acute inflammatory histologic changes associated with proteinuria (mean 2,400 mg/day, range 1,130-5,250), hematuria (76 red cells per high-power microscopic field, range 30-100) and renal failure (serum creatinine 1.6 mg/dL, range 1.2-2.9). Patients had diffuse mesangial proliferation with at least 10% florid crescents, mild to moderate degrees of glomerular sclerosis and interstitial changes, and both mesangial and capillary deposition of immunoreactants at immunofluorescence. Treatment consisted of 3 pulses of methylprednisolone (15 mg/kg) followed by oral prednisone (0.8 mg/kg body weight, tapered until discontinuation within 4 months) and MMF 2 g for 6 months. RESULTS Serum creatinine, proteinuria and microscopic hematuria significantly dropped at 6 months compared with baseline values (p=0.01) and remained lower at the end of follow-up 51 months (range 24-90) later (p<0.01, for proteinuria and hematuria; p=0.08, for serum creatinine). CONCLUSION Therapy with steroids and MMF may be considered in a subset of IgAN patients with florid glomerular changes, functional impairment and major urinary abnormalities, to prevent subsequent progression toward renal failure.

Mycophenolate mofetil and roscovitine decrease cyclin expression and increase p27kip1 expression in anti Thy1 mesangial proliferative nephritis

The response of mesangial cells to a phlogistic challenge includes cell proliferation and mesangial matrix expansion. Cell proliferation is a highly regulated process which includes enhancing factors such as cyclins, cyclin dependent kinases, and inhibitory proteins, such as p27kip1. The aim of the study was to evaluate the effects of Mycophenolate mofetil (MMF), and roscovitine (R), on the cell cycle regulatory system when administered in the florid phase of the experimental model of mesangial proliferative nephritis induced by the anti Thy‐1 antigen monoclonal antibody. Three days after nephritis induction, different groups were given MMF and R. Rats treated with MMF or R showed a slight decrease in mesangial proliferation and matrix expansion. Samples of cortical tissue were tested by ‘real time’ RT‐PCR in order to study gene expression of cyclins B, D1, D2, D3, E, and the cyclin inhibitor p27kip1. Localization of mRNA was evaluated by in situ hybridization. Real time RT‐PCR analysis showed a significant decrease in cyclins B, D1, D2, and D3 in rats treated with either MMF or R as compared to controls. Both MMF and R treatment induced a significant increase in p27kip1 mRNA expression. In situ hybridization showed a mesangial‐endothelial expression pattern in glomeruli. The number of labelled cells per glomerulus, the number of positive glomeruli in each examined slide as well as cyclin D2 and D3 signal intensity was significantly lower in rats treated with MMF or R as compared to controls, whereas MMF or R treatment up‐regulated p27kip1 mRNA expression. Immunohistochemical evaluation of p27kip1 aimed to examine the influence of MMF or R on protein expression confirmed up‐regulation.

Apheresis as rescue therapy in a severe case of sudden hearing loss

A 23-year-old man complained of progressive left ear hearing loss and tinnitus and was unsuccessfully treated with steroids and mannitol. Four months later he presented with sudden, severe, asymmetrical, bilateral sensorineural hearing loss. The results of the laboratory workup were normal except for antinuclear autoantibodies. Auditory brain stem responses showed absent peak and interpeak latencies on both sides. The combination of plasma exchange with high doses of steroids resulted in a definite improvement. Plasmapheresis combined with steroid administration can be used as secondline therapy in idiopathic, sudden sensorineural hearing loss.

Relationship between cryoglobulinemia-associated nephritis and HCV infection.

The pathogenetic mechanisms in hepatitis C virus (HCV)-related cryoglobulinemia are sustained by the chronic lymphocyte stimulation of HCV infection, and include the synthesis of IgM rheumatoid factor and tissue deposition of immunocomplexes, characterized by abnormal kinetics and an underlying lymphoproliferative disorder. Based on postulated pathogenetic mechanisms, therapeutic strategies include antiviral, immunosuppressive and immunomodulatory treatments. Combined interferon and ribavirin has shown a better response rate than interferon alone. Pegylated interferons are currently recommended in association with ribavirin. Advances in tolerance might be achieved by tailoring doses and treatment duration according to genotype and individual factors. Conventional immunosuppressive therapy has been widely used in patients with progressive renal involvement or relapsing disease. Rituximab is a promising alternative treatment option for severe cryoglobulinemic vasculitis and nephritis. Although the optimal treatment strategy in HCV-related cryoglobulinemia has not been determined yet, an algorithm based on the clinical severity of disease could be proposed, in which rituximab might be a first-line option in severe cases.