Kinetic analysis of changes in T- and B-lymphocytes after anti-CD20 treatment in renal pathology.

INTRODUCTION: The main objective of this study is to describe qualitatively and quantitatively the different immune lymphocyte phenotypes of patients with renal disease after treatment with anti-CD20. MATERIAL AND METHODS: Two cohorts of transplanted and autoimmune kidney patients were compared: (1) Those who began treatment with Rituximab, matched (for sex, age and general clinical parameters) with (2) Non-treated control kidney patients. Different analyses were performed: (A) B-lymphocyte subpopulations; (B) T-cell subpopulations; (C) serum levels of BAFF, APRIL, Rituximab and anti-Rituximab; (D) rs396991 polymorphism of CD16a and at different time points for each type of analysis: (i) at baseline, (ii) day 15, (iii) at three and (iv) six months post-antiCD20. RESULTS: (A) A depletion of all B cell subsets analysed was observed preferentially decreasing the CD40+memory B-cells, switched memory cells and plasmablasts. (B) A significant decreased percentage of CD4+T-lymphocytes was observed. A significant decrease of the percentage of memory T-cells and an increase in naïve T-cells was also observed. (C) A significant increase for APRIL was observed, as well as a positive correlation between the APRIL levels, and the differential of B-cells. (D) The presence of CD16a Valine-variant induced greater changes in the variations of total T-cell and T-naïve subpopulations. CONCLUSION: Our results highlight that the treatment of renal disease with Rituximab affects T-cells, particularly naïve/memory balance, while APRIL could be also a secondary marker of this treatment. The sequential analysis of phenotypic alterations of B- and T-cells could help patient management, although further studies to identify periods of remission or clinical relapse are warranted.

Long-term outcome of antineutrophil cytoplasmic antibody-associated small vessel vasculitis after renal transplantation.

The survival after renal transplantation of patients with antineutrophil cytoplasmic antibody (ANCA)-associated to systemic vasculitis is as good as in other diseases, although most of the reports are based on small numbers of patients. Furthermore, it is not known whether comorbidities (cardiovascular [CV] disease and cancer) are more frequent than in general population. We report our experience and the analysis of the published data on this topic. The outcome after transplantation in 49 patients with ANCA-associated small vessel vasculitis was compared with a control group. The relapse rate of vasculitis was 0.01 per patient per year. Comparison with the control patients revealed no difference in long-term outcome, CV mortality or incidence of malignancies. In the published literature, patients with ANCA at transplantation and with Wegener's granulomatosis are at greater risk of relapse. Taking our own results together with the review of the literature, we conclude that patient and graft survival rates compare favorably with those in control group that the recurrence rate is very low and that there is no increase in the incidence of cancer or in CV mortality. Patients with ANCA at transplantation and with Wegener's granulomatosis have a higher relapse rate.

TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis.

BACKGROUND: Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. METHODS: TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. RESULTS: Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. CONCLUSIONS: We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.

Vasculitis syndromes: LAMP-2 illuminates pathogenesis of ANCA glomerulonephritis.

The discovery that antibodies to a bacterial antigen can cross-react with a mammalian protein to cause pauci-immune necrotizing and crescentic glomerulonephritis opens up new possibilities for the diagnosis and treatment of this condition.

Immunotherapy for antineutrophil cytoplasmic antibody-associated vasculitis: challenging the therapeutic status quo?

Anti-neutrophil cytoplasmic antibodies (ANCA) are IgG antibodies directed against antigenic constituents of neutrophils contained in the azurophilic granules and monocyte lysosomes. Systemic vasculitis with ANCA [ANCA-associated vasculitides (AAV)] is a subgroup of life-threatening inflammatory disorders affecting small- to medium-sized vessels; immunosuppressants and glucocorticoids represent the current therapeutic mainstay. Although these agents have improved patients' survival, 25% present with severe adverse events, and standard therapy does not sustain remission. Therefore, an unmet need for safer and more effective therapies has prompted interest in biological agents. Continuous advances in the knowledge of AAV pathogenesis are paving the way to new biologicals that are now awaiting testing.

Treatment of antineutrophil cytoplasmic antibody associated vasculitis: a systematic review.

CONTEXT: Immunosuppressive therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have greatly advanced patient survival but have turned ANCA-associated vasculitis (AAV) into chronic, relapsing disorders. Long-term treatment and disease-related morbidity are major threats. The last decade has seen a collaborative international effort to determine effective treatment. OBJECTIVE: To analyze the reported evidence on AAV therapy in order to provide physicians with a rational approach for dealing with various clinical scenarios. DATA SOURCES: We searched English-language articles on the medical treatment of AAV published between 1966 and March 2007 using MEDLINE. Articles from the reference lists of the most relevant articles retrieved were also analyzed. STUDY SELECTION: Studies of current available drug treatments or medical interventions for patients with AAV were included. Duplicate publications, case reports, and uncontrolled trials and series including fewer than 10 patients were excluded. DATA SYNTHESIS: We included 2 meta-analyses, 20 randomized controlled prospective trials, and 62 uncontrolled trials with more than 10 patients or observational studies. Outcome measures and treatment protocols were heterogeneous across trials. Cotrimoxazole can be used alone or in combination with corticosteroids to induce and maintain remission in cases of isolated upper respiratory tract involvement. To induce remission, methotrexate plus corticosteroids can be used instead of cyclophosphamide for patients with generalized, non-organ-threatening disease. When methotrexate is used as maintenance therapy, the likelihood of relapse is high and rigorous monitoring is mandatory. Pulse cyclophosphamide with corticosteroids can be used to induce remission in patients with generalized organ-threatening disease. The combination of azathioprine and daily prednisone is effective in maintaining remission. Plasma exchange is at present the best complement to immunosuppressants in advanced renal disease. In Churg-Strauss syndrome, treatment can be started with high doses of corticosteroids, tapering them when the clinical situation improves. In patients with a high risk of death, cyclophosphamide should be introduced. CONCLUSIONS: Although AAV therapies should be tailored to the patient's specific clinical situation, evidence for treatment of several disease states is lacking. There is a need for safer and more effective drugs.