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Background and objectives Complement alternative pathway (cAP) activation has recently been recognized as a key pathogenic event in ANCA-associated vasculitis (AAV). cAP dysregulation is also a major determinant of thrombotic microangiopathies (TMA), which can in turn complicate AAV. We explored the prognostic significance of cAP activation and of histologic evidence of TMA in a cohort of patients with renal AAV. Design, setting, participants, & measurements We studied 46 patients with AAV diagnosed between January 1990 and December 2011 at the Nephrology Unit of Parma University Hospital; 30 of them had undergone renal biopsy. We analyzed serum levels of C3 (sC3) and C4 (sC4) and, for 19 patients who had frozen plasma, plasma Bb and C5b-9 levels. We also reviewed all kidney biopsy specimens, specifically searching for histologic signs of TMA, and performed immunofluorescence or immunohistochemistry for C3d, C4d, Bb and C5b-9. Results sC3 was below the lower limit of normal in 35% of the patients, whereas C4 was low in only 2%. Patients with low sC3 tended to be older (P=0.04) and to have lower eGFR at diagnosis (P=0.06). The median follow-up was 78 months (interquartile range, 18–135 months); 18 patients reached ESRD (10 of 14 and 8 of 26 in the low and normal sC3 groups, respectively). Death-censored renal survival was lower in the low sC3 group than in the normal sC3 group (log-rank test, P=0.01). Eight of the 30 patients who had undergone biopsy (27%) had histologic signs of TMA; these signs were more frequent in patients with low sC3 (5 of 10 versus 3 of 20; P=0.04). Notably, patients with histologic signs of TMA had a dramatically worse death-censored renal survival than patients without TMA (log-rank test, P=0.01), with ESRD occurring in 8 of 8 patients with TMA versus 8 of 22 patients without TMA. Conclusions Low sC3 levels and histologic signs of TMA are associated with a poor renal prognosis in patients with AAV.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, to whose pathogenesis neoplastic and immune-mediated mechanisms contribute. Mammalian target of rapamycin (mTOR)-inhibitors have antiproliferative and immunosuppressive properties. We tested in this study, the efficacy and safety of the mTOR-inhibitor sirolimus (SRL) plus prednisone (PDN) in patients with ECD. PDN was given initially at 0.75 mg/kg per day, tapered to 5 to 2.5 mg per day by month 6. Target SRL blood levels were 8 to 12 ng/mL. Treatment was continued for at least 24 months in patients who showed disease stabilization or improvement. Ten patients were enrolled; 8 achieved stable disease or objective responses, whereas 2 had disease progression. Responses were mainly observed at the following sites: retroperitoneum in 5/8 patients (62.5%), cardiovascular in 3/4 (75%), bone in 3/9 (33.3%), and central nervous system (CNS) in 1/3 (33.3%). The median follow-up was 29 months (interquartile range, 16.5-74.5); 2 patients died of progressive CNS disease and small-cell lung cancer, respectively. Treatment-related toxicity was mild. Using immunohistochemistry and immunofluorescence on ECD biopsies, we detected expression in foamy histiocytes of the phosphorylated forms of mTOR and of its downstream kinase p70S6K, which indicated mTOR pathway activation. In conclusion, SRL and PDN often induce objective responses or disease stabilization and may represent a valid treatment of ECD. The trial is registered at the Australia-New Zealand Clinical Trial Registry as #ACTRN12613001321730.

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease often associated with autoimmune disorders. Whether IRF is associated with Hashimoto's thyroiditis (HT) is poorly understood and only addressed by case-reports. We evaluated the prevalence of HT in a large IRF cohort and in matched controls.We studied 73 consecutive patients with new-onset IRF and 71 controls. The association between HT and IRF was cross-sectionally evaluated in a referral center. Longitudinally, thyroid function tests were also performed. Serum concentrations of FT4, TSH, and anti-thyroperoxidase antibodies (AbTPO) were evaluated together with thyroid ultrasound (US). Lymphocytic infiltrates were characterized in thyroid nodule fine needle aspirates (FNAB). In patients undergoing thyroidectomy, thyroid histology was also reviewed.A higher prevalence of AbTPO positivity (P0.03) and US findings suggestive of autoimmune thyroiditis (US-AIT) (P0.0001) were found in IRF patients compared to controls. In the logistic regression analysis, the risk of AbTPO-diagnosed HT and that of US-AIT was significantly higher in IRF patients than in controls (ORs, 3.56, 95% CI 1.48-8.59, P=0.004 and 4.74, 95% C.I., 2.34-9.61, P0.0001 in AbTPO-diagnosed HT and US-AIT, respectively). Thyroid histology in IRF patients showed either classical or the fibrous variant of HT. At the end of the follow-up (median, 45 and 36 months in patients and controls, respectively), 25% of IRF patients and 3% of controls were receiving l-thyroxine.IRF patients have a higher risk of HT compared to controls. Thyroid function should be monitored in patients with IRF.

Retroperitoneal fibrosis (RPF) is an uncommon disease characterized by a fibrous reaction that takes place in the peri-aortic retroperitoneum and often entraps the ureters causing obstructive uropathy. RPF is idiopathic in the majority of cases, but can also be secondary to malignancies, infections, drugs, radiotherapy, and rare histiocytic disorders such as Erdheim–Chester disease. Idiopathic RPF is an immune-mediated disease, which can either be isolated, associated with other autoimmune diseases, or arise in the context of a multifocal fibro-inflammatory disorder recently renamed as IgG4-related disease. The differential diagnosis between idiopathic, IgG4-related and secondary RPF is crucial, essentially because the therapeutic approaches – especially of idiopathic vs. secondary RPF – can be dramatically different. This review focuses on the clinical, laboratory and imaging features of the different RPF forms, and also provides an overview of the available treatment options.

Objectives The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. Methods In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. Results Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. Conclusions MTX may be effective and safe for remission-maintenance in AAV. Trial registration clinicaltrials.gov NCT00751517.

Pretransplant donor biopsy (PTDB)-based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score

Introduction: Idiopathic retroperitoneal fibrosis (RPF) is a rare condition hallmarked by a periaortic fibro-inflammatory tissue that often causes ureteral obstruction. Its clinical manifestations include abdominal or back pain, systemic symptoms such as fatigue, weight loss and fever and, less frequently, constipation, testicular pain, claudicatio and edema of the lower limbs. The primary goal of treatment is the relief of ureteral obstruction and the regression of the fibro-inflammatory process. The treatment is still empiric because, to date, there is only one randomized controlled trial. Patients often need long-term therapy because this disease may have a chronic-relapsing course. Areas covered: This review summarized current strategies for the treatment of idiopathic RPF. An overview of the different therapeutic protocols is provided and the most relevant published references have been considered. Expert opinion: Idiopathic RPF is potentially curable with the available treatments. It usually respond...

Background Primary or secondary glomerulonephritis has been anecdotally reported in association with atypical haemolytic uraemic syndrome (aHUS). We here report a series of six patients who developed aHUS and glomerulopathy, and review the literature on aHUS and glomerulonephritis. Methods Out of all patients diagnosed at our unit with biopsy-proven glomerular diseases between March 2007 and October 2011, selected cases developing aHUS during the follow-up are presented. The following tests were performed in all six patients: serum C3 and C4 levels, ADAMTS13 activity, CFH levels and anti-CFH autoantibodies and genetic screening for CFH, MCP, CFI, C3 and CFHR1-3 mutations and risk haplotypes associated with aHUS. Results Two hundred and forty-eight patients received a biopsy-proven diagnosis of glomerulopathy and were followed for a median of 31 months (range 2-58). Of these, six developed aHUS, within a median of 15 months (range 1-36) of their initial diagnosis of glomerulopathy. One of these patients had focal segmental glomerulosclerosis (FSGS), two membranoproliferative glomerulonephritis (MPGN) type I, one C3 glomerulonephritis and two systemic small vessel vasculitis [one granulomatosis with polyangiitis (Wegener's), one Henoch-Schoenlein purpura]. Five patients (one of them heterozygous for a CFH mutation) carried, in homo- or heterozygosity, the risk haplotype CFH-H3 (CFH tgtgt), previously described to be associated with aHUS, while another one patient was homozygous for the MCPggaac risk haplotype predisposing to aHUS when present on both alleles. Conclusions Different types of glomerulopathies can be complicated by aHUS. Several mechanisms can contribute to this association, such as nephrotic-range proteinuria, mutations or aHUS-risk haplotypes involving genes encoding alternative complement regulatory proteins in some patients and inflammatory triggers associated with systemic immune-mediated diseases.

Objectives We report a case of orofacial granulomatosis successfully treated with low-level laser therapy (LLLT). Study design LLLT was delivered through a diode laser device (Lasemar Eufoton, Trieste, Italy) with the use of a 4-cm defocalized lens and power of 1 W. Treatment was administered in sessions of 5 irradiations of 1 minute each, with a 1-minute interval between 2 subsequent irradiations (power density 0.08 W/cm 2 ; fluence/application: 4.8 J/cm 2 ; fluence/session: 24 J/cm 2 ). Laser therapy was repeated 12 times (3 times per week). Results After 2 weeks of LLLT applications, the patient reported an improvement of symptomatology as well as a decrease of labial swelling. Complete healing was observed after 1 month. The patient was followed for 2 years. No recurrence of swelling was observed during the follow-up. Conclusions Advantages of the LLLT approach include an absence of side effects, analgesic properties (usually reported after first application), and good patient compliance.

Background context Fungal spondylodiscitis is often because of Candida albicans or other common Candida species, whereas unusual strains such as Candida sake are often thought to be nonpathogenic. Purpose To report the first case of spondylodiscitis caused by C sake and its outcome after antimycotic therapy; as the disease occurred in a patient undergoing hemodialysis (HD), we also discuss the potential conditions related to the uremic state and to HD itself, which may predispose to spondylodiscitis. Study design/setting Case report. Methods Report of the patient's clinical findings and review of the literature concerning spondylodiscitis in HD patients and infections caused by C sake . Results The patient was a 48-year-old woman with end-stage renal disease (ESRD) undergoing HD who presented with back pain; spine computed tomographic (CT) scans showed lumbar spondylodiscitis with large bilateral abscesses in the psoas muscles, with an imaging appearance resembling that of Pott's disease. Surprisingly, C sake was isolated from the cultures of the liquid obtained by CT-guided aspiration of both abscesses, and fluconazole therapy was strikingly effective in inducing abscess regression and healing of spondylodiscitis. Conclusions In patients with chronic disorders such as ESRD, spondylodiscitis can also be caused by rare fungal strains that are usually thought to be nonpathogenic; a correct diagnostic workup is essential, as such forms can promptly respond to common antimycotic agents.

Central nervous system (CNS) lymphoma is a rare posttransplant lymphoproliferative disorder (PTLD), which usually has a poor outcome. To date, no specific conditions predisposing to this complication have been identified. We here describe the case of a renal transplant patient who was initially diagnosed as having Epstein-Barr virus (EBV)-associated leukoencephalopathy and ultimately developed EBV-positive CNS lymphoma. The patient was a young lady who, 2 years after transplantation, presented with focal neurological and electroencephalographic abnormalities and diffuse white matter lesions on brain magnetic resonance imaging. EBV-DNA was detected in the cerebrospinal fluid (CSF) by polymerase chain reaction. After acyclovir therapy and immunosuppressive drug tapering, the symptoms and electroencephalographic abnormalities subsided, and EBV-DNA disappeared from the CSF. Ten years later, a bulky cerebral mass was found. After excision, a diagnosis of EBV-positive, Hodgkin-like monomorphic B-cell PTLD was made. This case illustrates the potential pathophysiological relationships between EBV infection, leukoencephalopathy and CNS lymphoma; although a long time elapsed from the initial neurological illness to CNS lymphoma, a link between these two conditions cannot be excluded. Therefore, a careful long-term follow-up of EBV-related encephalopathy is advisable.

Objective: We report the results obtained using an original immunotherapy schedule featuring chronically administered low-dose interleukin-2 (IL-2) and interferon-α (IFN-α) in patients with metastatic renal cell carcinoma (mRCC), and we assess treatment efficacy according to the patients’ prognostic profiles. Methods: 138 consecutive patients were enrolled, and received IL-2 (1 million IU/m2) subcutaneously twice daily on days 1 and 2, and once daily on days 3–5 of each week, and IFN-α (1.8 million IU/m2) intramuscularly once daily on days 3 and 5. Each cycle consisted of 4 consecutive weeks and was repeated indefinitely at 4-month intervals regardless of response. The patients’ baseline risk profile was assessed using Negrier’s stratification system. Results: The overall response rate was 10.9% (95% CI 6.7–17.2), and median overall survival was 19.6 months (95% CI 14.2–28.2). Treatment-related toxicity was mostly WHO grade 2 or below. Survival in the low-, intermediate- and high-risk groups was significantly different (p for trend Conclusion: Chronically administered low-dose IL-2 and IFN-α may be a safe and effective option for low-risk mRCC patients.

Objectives: Churg-Strauss syndrome (CSS) is a systemic vasculitic disorder of unknown etiology that affects small-to-medium-size blood vessels. Patients affected by CSS frequently show ear, nose, and throat manifestations, which are often present at the time of disease onset. The purpose of this study was to determine the frequency of nasal polyposis in a series of 29 patients with CSS and to correlate the nasal findings to the total health situation of these patients. Study Design: Retrospective analysis. Setting: Department of Otolaryngology and Department of Clinical Medicine, Nephrology and Health Science, University of Parma. Methods: Twenty-nine patients with CSS were identified. Of the 29 patients, 17 (58.6%) had nasal polyposis and were enrolled in this study. The nasal polyps were graded according to the Lund and Mackay endoscopic and radiological classifications. Results: At diagnosis, endoscopic intranasal evaluation identified nasal polyposis of grade 3 in nine cases (52.9%), grade 2 in six cases (35.2%), and grade 1 in the remaining case (5.8%). After corticosteroid and immunosuppressive therapy, clinical remission was achieved in 14 patients (82.3%), whereas 3 patients experienced a relapse. Posttreatment endoscopic evaluation showed a permanent disappearance (grade 0) of nasal polyps in eight patients (47%). The other nine patients (52.92%) were found to have a small polyp situated in the middle meatus (grade 1). Conclusions: Nasal polyposis in patients with CSS may represent the initial phase of the syndrome, though patients often have concurrent pulmonary disease. Corticosteroid therapy either alone or combined with immunosuppressive drugs usually yielded improvement or stabilization.

Objective: To compare the clinical aspects of peripheral neuropathy associated with Wegener’s granulomatosis (WG), Churg–Strauss syndrome (CSS) and microscopic polyangiitis (MP). Methods: Cohort study conducted in a single university hospital. Patients were included when a definite diagnosis of WG, CSS or MP was made according to the current classification criteria in our hospital, between 1999 and 2006. All patients underwent periodically clinical and electrophysiological screening for peripheral neuropathy, assessment of disability, and clinical and laboratory evaluation during a mean follow-up of 38 months. Results: Sixty-four consecutive patients diagnosed with WG (26 patients), CSS (26 patients) and MP (12 patients) were recruited. Peripheral neuropathy occurred in 27/64 patients: six with WG, 15 with CSS and six with MP. Neuropathy occurred earlier in the disease history in CSS and MP compared with WG. Among patients with WG, those who developed peripheral neuropathy during follow-up were older than those without neuropathy both at the time of onset and of diagnosis of vasculitis. Distal symmetric polyneuropathy was present in 11 patients, and single or multiple mononeuropathy in 16. Patients with WG had a less severe form of mononeuritis multiplex than CSS or MPA patients. Disability and pain were greater in patients with mononeuropathy, although one-third of them were painless. Relapses of neuropathy were extremely infrequent. Conclusions: Peripheral neuropathy in WG occurs less frequently, later in the disease course and in a milder form than in CSS and MP. Single or multiple mononeuropathy associated with these subsets of vasculitis can often be painless.

BACKGROUND: Churg-Strauss syndrome (CSS) is a rare disorder characterized by asthma, eosinophilia, and systemic vasculitis. Renal involvement is not regarded as a prominent feature, and its prevalence and severity vary widely in published reports that usually refer to small series of selected patients. METHODS: We examined the prevalence, clinicopathologic features, and prognosis of renal disease in 116 patients with CSS. RESULTS: There were 48 men and 68 women with a mean age of 51.9 years (range, 18 to 86 years). Signs of renal abnormalities were present in 31 patients (26.7%). Rapidly progressive renal insufficiency was documented in 16 patients (13.8%); urinary abnormalities, 14 patients (12.1%); and chronic renal impairment, 1 patient. There were 3 additional cases of obstructive uropathy. Sixteen patients underwent renal biopsy, which showed necrotizing crescentic glomerulonephritis in 11 patients. Other diagnoses were eosinophilic interstitial nephritis, mesangial glomerulonephritis, and focal sclerosis. Antineutrophil cytoplasmic antibody (ANCA) was positive in 21 of 28 patients (75.0%) with nephropathy versus 19 of 74 patients without (25.7%; P < 0.001). In particular, all patients with necrotizing crescentic glomerulonephritis were ANCA positive. After a median follow-up of 4.5 years, 10 patients died (5 patients with nephropathy) and 7 patients developed mild chronic renal insufficiency. Five-year mortality rates were 11.7% (95% confidence interval, 3.9 to 33.3) in patients with nephropathy and 2.7% (95% confidence interval, 0.7 to 10.7) in those without (P = 0.10). CONCLUSION: Renal abnormalities are present in about one quarter of patients with CSS. The prevailing picture is ANCA-associated necrotizing crescentic glomerulonephritis; however, other forms of nephropathy also may occur. Outcome and long-term follow-up usually are good.

Objective Patients with chronic periaortitis (CP) often show clinical and laboratory findings of a systemic autoimmune disorder. The aim of the present study was to investigate the role of the HLA system in CP. Methods Low-resolution genotyping for HLA–A, HLA–B, and HLA–DRB1 loci and genotyping of TNFA(-238)A/G and TNFA(-308)A/G single nucleotide polymorphisms were performed in 35 consecutive patients with CP and 350 healthy controls. Results The HLA–DRB1*03 allele frequency was strikingly higher in patients with CP than in controls (24.28% versus 9.14%; χ2 = 15.50, P = 0.000084, corrected P [Pcorr] = 0.0012, odds ratio [OR] 3.187, 95% confidence interval [95% CI] 1.74–5.83); the HLA–B*08 allele frequency was also higher in patients than in controls (17.14% versus 6.28%; χ2=11.12, P = 0.0008, Pcorr = 0.0269, OR 3.085, 95% CI 1.54–6.16). The A*01 allele frequency was significantly different (P = 0.0463), but the statistical significance was lost after correction for multiple testing (Pcorr = 0.5088). TNFA(-238)A allele and TNFA(-308)A allele frequencies were not significantly different (P = 0.512 and P = 0.445, respectively). Comparison of the main clinical and laboratory findings suggestive of a systemic autoimmune disease (e.g., acute-phase reactants, constitutional symptoms, other autoimmune diseases associated with CP) between the HLA–DRB1*03–positive and the HLA–DRB1*03–negative patients showed that the former group had significantly higher levels of C-reactive protein (P = 0.045) at disease onset, although this difference was not statistically significant after correction for multiple tests (Pcorr = 0.369). Conclusion The HLA system plays a role in susceptibility to CP. The strong association between CP and HLA–DRB1*03, an allele linked to a wide range of autoimmune conditions, further supports the view that CP may represent a clinical manifestation of an autoimmune disease.

Ear, nose and throat (ENT) involvement is common in Churg-Strauss syndrome (CSS), usually manifesting as allergic rhinitis and chronic rhinosinusitis with or without polyps. Otolaryngologists may play a pivotal role in making an early diagnosis of this disease.CSS is a systemic vasculitic disorder that affects small to medium-sized blood vessels. Although the cause of CSS remains unknown, tissue damage seems more likely to be mediated by activated eosinophils. Patients affected by CSS frequently have ENT manifestations, which are often present at the time of disease onset and may represent relevant clues for the diagnosis. Thus, our objective was to present the ENT manifestations at the onset, at the diagnosis and at some point during the course of the disease in a series of patients with CSS collected at a single center.Twenty-eight patients with CSS, as defined according to the 1990 American College of Rheumatology classification criteria, were identified. Twenty-one (75%) of these patients had ENT involvement. We evaluated the clinical course, laboratory data, histologic findings, treatment and outcomes.Of the 21 patients, 13 (61.9%) had ENT involvement at asthma onset and 8 (38%) at diagnosis or during follow-up. The most common ENT manifestations were allergic rhinitis in 9 (42.8%) patients and nasal polyposis in 16 (76.1%). Three (14.2%) patients developed chronic rhinosinusitis without polyps, three (14.2%) had nasal crusting, one (4.7%) serous otitis media, one (4.7%) purulent otitis media, two (9.5%) progressive sensorineural hearing loss, and one (4.7%) unilateral facial palsy. Corticosteroid therapy associated with immunosuppressive drugs usually yielded improvement or stabilization.

Retroperitoneal fibrosis (RPF) is usually idiopathic but sometimes secondary to underlying diseases. In this report, we describe a case of apparently idiopathic RPF associated with a mediastinal tuberculous adenopathy. After a course of antituberculous treatment, a complete resolution of both adenopathy and RPF was observed. We discuss the potential pathogenetic mechanisms linking the 2 diseases.

Background/Aims: To verify whether human IgG induces proinflammatory activation of human proximal tubular epithelial cells (PTEC) independent of the metabolic overload of protein reabsorption. Methods: Cultured PTEC were incubated with normal IgG, IgG from systemic lupus erythematosus (SLE) patients, albumin or transferrin. IL-6 secretion and extracellular regulated kinase (ERK) activation (dual-phosphorylated ERK) were measured by ELISA and by Western blotting of PTEC extracts, respectively; renal biopsy specimens from patients with IgG and non-IgG proteinuria were analyzed by immunohistochemistry and in situ hybridization to detect ERK-P and IL-6. Results: Normal and SLE IgG, but not albumin or transferrin, induced an early significant increase in IL-6 secretion by PTECs. Also ERK activation was found after 1-hour incubation of PTEC with IgG, but not with control medium and albumin-treated PTEC. Activated ERK and IL-6 were found to colocalize in tubular cells in the kidney specimens of patients with IgG proteinuria only. Conclusion: IgG-dependent early activation of ERK and increased IL-6 secretion in PTEC suggest that IgG filtered during nonselective proteinuria may play a specific role in tubulointerstitial disease. Such a role could be particularly relevant in diseases associated with abnormal IgG pool compositions, such as SLE. Preliminary results on human renal biopsy specimens suggest that our in vitro observations may also be relevant in vivo.

Purpose of review Chronic periaortitis includes idiopathic retroperitoneal fibrosis, perianeurysmal retroperitoneal fibrosis, and inflammatory abdominal aortic aneurysms. This review analyses the different aspects of the disease and highlights evolving concepts concerning its pathogenesis, diagnosis, and management. Recent findings It has recently been reported that asbestos exposure is a major risk factor for idiopathic retroperitoneal fibrosis. An increasing number of studies showing an association with autoimmune diseases clearly support the hypothesis of a close link between autoimmunity and chronic periaortitis. Furthermore, various findings (eg, constitutional symptoms, the involvement of other organs, high acute-phase reactant levels) support the hypothesis that chronic periaortitis may be a manifestation of a systemic disease and challenge the well-known theory of a local immune response to antigens in atherosclerotic plaque. In addition to CT and MRI, which are the diagnostic modalities of choice, positron emission tomography may be useful in monitoring disease activity and response to therapy. Although there is a lack of prospective randomized trials, recent studies have highlighted the role of steroids, immunosuppressive agents, and tamoxifen in the medical treatment of chronic periaortitis. Summary Chronic periaortitis is a rare disease with protean manifestations but, if correctly diagnosed, can be successfully managed. It should be approached in the setting of a systemic process, and clinicians must be aware that other organs may be affected. Its clinical course is chronic-relapsing, so a careful follow-up is essential. Further studies are needed to investigate the pathogenetic mechanisms and the most appropriate therapeutic options.

To investigate the possible interaction between occupational risk factors and genotype for glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in renal cell cancer (RCC).One hundred patients with RCC and 200 outpatient controls were enrolled at Parma University Hospital. The polymorphisms of glutathione S-transferase M1-1 (GSTM1) and T1-1 (GSTT1) were investigated by PCR; occupational history was collected by a structured questionnaire.Subjects with GSTM1 present genotype showed higher risks for RCC, compared to GSTM1 null subjects, if exposed to metals (OR 2.73; 95% CI 0.91 to 8.22 v 1.14; 95% CI 0.46 to 2.82) or pesticides (OR 3.46; 95% CI 1.12 to 10.74 v 1.59; 95% CI 0.48 to 5.34). The GSTT1 present genotype also enhanced the risk (about twofold) of RCC among subjects exposed to solvents and pesticides, compared with those GSTT1 null.Results support the hypothesis that GSTM1 and GSTT1 polymorphisms can interact with several occupational exposures to significantly modify the risk of RCC among exposed subjects.

Background Chronic periaortitis includes idiopathic retroperitoneal fibrosis, inflammatory aneurysms of the abdominal aorta, and perianeurysmal retroperitoneal fibrosis. It is considered to be due to advanced atherosclerosis, but is often associated with systemic autoimmune disorders. Methods We studied 16 consecutive patients who were diagnosed with chronic periaortitis by computed tomography. Each patient underwent a physical examination, routine laboratory tests, measurement of autoantibodies, thyroid echotomography, and chest radiography. Aortic wall or periaortic retroperitoneal samples from 9 patients who underwent surgery were available for histologic examination and immunohistochemical characterization of the inflammatory infiltrate. Results Twelve patients had constitutional symptoms, 14 had an elevated erythrocyte sedimentation rate, and 13 had an elevated C-reactive protein level. Antinuclear antibodies were positive in 10 patients. Three patients had autoimmune thyroiditis, and 1 had seropositive rheumatoid arthritis. Antineutrophil cytoplasmic antibodies were positive in 3 patients who presented with rapidly progressive renal failure. Pathologic examination of the aortic and periaortic specimens revealed moderate to severe inflammatory infiltration, mainly consisting of B cells and CD4 + T cells. Vasculitis with fibrinoid necrosis involving the aortic vasa vasorum and the small and medium retroperitoneal vessels was found in seven of the nine histologic samples. Conclusion These clinical and pathologic features support the hypothesis that, at least in some patients, chronic periaortitis is a systemic autoimmune disease, perhaps involving a vasculitic process of small and medium vessels.

Chronic periaortitis (CP) is a rare condition, hallmarked by periaortic fibro-inflammatory tissue which often causes ureteral obstruction, and encompasses idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysm (IAAA). CP usually responds to glucocorticoids, but some patients may be steroid-refractory or not tolerate standard glucocorticoid doses. For such cases, valid therapeutic alternatives are lacking.1 2 Combinations of prednisone and immunosuppressants (eg, cyclophosphamide, mycophenolate mofetil) are not of proven superiority to prednisone alone, and their effectiveness in refractory CP is unknown.3 4 Because B cells abundantly infiltrate CP lesions,5 and CP is often associated with autoimmune diseases,6 we used rituximab in two patients with CP, one refractory to conventional treatments, and the other with contraindications to standard-dose glucocorticoids. Our first patient, a 49-year-old woman, was hospitalised for malaise and back pain. Abdominal CT revealed a soft-tissue-density periaortic mass suggesting CP, a diagnosis confirmed by laparoscopic biopsy (figure 1). The patient responded to prednisone (initial dose, 1 mg/kg/day), with symptom remission and reduction in CP thickness, but relapsed with back pain and CP enlargement when the prednisone dose was 5 mg/day (8 months after treatment initiation). …

Objective Fibroblast activation is a crucial event in the development of systemic sclerosis (SSc). Antifibroblast autoantibodies (AFAs), detectable in the sera of SSc patients, are able to induce a proinflammatory phenotype on cultured fibroblasts. This study was undertaken to investigate the mechanisms of the interaction between AFAs and living fibroblasts. Methods We coupled to fluorescein 1) IgG purified from AFA-positive and AFA-negative SSc sera (as assessed by cellular enzyme-linked immunosorbent assay) and 2) single healthy donor and pooled normal IgG. The interaction of IgG with living cultured fibroblasts from healthy individuals and from a patient with SSc was visualized by real-time confocal microscopy. Intracellular colocalization of caveolin and internalized AFA-positive IgG was assessed by immunofluorescence. Results AFA-positive IgG bound to living fibroblasts and was internalized with a cytoplasmic fibrillar pattern, in contrast to AFA-negative IgG. In the IgG tested, no correlation with antinuclear antibody activity was found. Preincubation of fibroblasts with normal IgG did not affect internalization. Internalized AFA-positive IgG colocalized with caveolin, and internalization was entirely inhibited by disassembling fibroblast caveolae with filipin. Conclusion The finding that both normal and pathologic fibroblasts specifically internalized AFA-positive, but not AFA-negative, IgG demonstrates that AFAs in SSc patient sera interact with constitutively expressed membrane molecules on fibroblasts, via an Fc-independent mechanism. The results of colocalization and inhibition experiments suggest that microdomains containing caveolin are involved in the interaction between AFAs and fibroblasts. These data, together with the reported ability of AFAs to activate fibroblasts, provide evidence for a role of AFAs in the pathogenesis of SSc.

Retroperitoneal fibrosis (RPF) is a disease of unknown aetiology that has sometimes been reported in association with connective tissue disorders and systemic vasculitis. We report here two cases of antineutrophil cytoplasmic antibody (ANCA)-positive RPF showing clinical evidence of rapidly progressive glomerulonephritis. Although treatment with prednisone and cyclophosphamide led to a remission of RPF in both cases, renal function was restored in only one patient and the other progressed to chronic renal failure. The paper reviews the literature concerning ANCA-positive RPF and discusses the relationship between ANCA-positive vasculitis and RPF.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disorder, belonging to the small vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, defined as an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium-sized vessels, associated with asthma and eosinophilia. EGPA pathogenesis is not well known: HLA-DRB1*04 and *07, HLA-DRB4 and IL10.2 haplotype of the IL-10 promoter gene are the most studied genetic determinants. Among the acquired pathogenetic factors, the exposure to different allergens, infections, vaccinations, drugs, and silica exposure have been involved. Eosinophils are the most characteristic cells in EGPA and different studies have demonstrated their role as effector and immunoregulatory cells. EGPA is considered as a disease with a prevalent activation of the Th-2 cellular-mediated inflammatory response and also humoral immunity plays an important role. A link between B and T inflammatory responses may explain different disease features. EGPA typically develops into three sequential phases: the allergic phase, distinguished by the occurrence of asthma, allergic rhinitis, and sinusitis, the eosinophilic phase, in which the main pathological finding is the eosinophilic organ infiltrations (e.g., lungs, heart, and gastrointestinal system), and the vasculitic phase, characterized by purpura, peripheral neuropathy, and constitutional symptoms. ANCA (especially pANCA anti-myeloperoxidase) are present in 40–60% of the patients. An elevation of IgG4 is frequently found. Corticosteroids and cyclophosphamide are classically used for remission induction, while azathioprine and methotrexate are the therapeutic options for remission maintenance. B-cell depletion with rituximab has shown promising results for remission induction.

This review of clinical and experimental studies aims at analysing the interplay between graft endothelium and host immune system in renal transplantation, and how it affects the survival of the graft. Graft endothelium is indeed the first barrier between self and non-self that is encountered by host lymphocytes upon reperfusion of vascularised solid transplants. Endothelial cells express all the major sets of antigens that elicit host immune response, and therefore represent a preferential target in organ rejection. Some of the antigens expressed by endothelial cells are target of the antibody-mediated response, such as the AB0 blood group system, the HLA and MICA systems, and the endothelial cell-restricted antigens; for each of these systems, the mechanisms of interaction and damage of both preformed and de novo donor-specific antibodies are reviewed along with their impact on renal graft survival. Moreover the rejection process can force injured endothelial cells to expose cryptic self-antigens, toward which an auto-immune response mounts, overlapping to the allo-immune response in the damaging of the graft. Not only are endothelial cells a passive target of the host immune response, but also an active player in lymphocyte activation; therefore their interaction with allogenic T-cells is analysed on the basis of experimental in vitro and in vivo studies, according to the patterns of expression of the HLA class I and II and the co-stimulatory molecules specific for cytotoxic and helper T-cells. Finally, as the response that follows transplantation has proven to be not necessarily destructive, the factors that foster graft endothelium functioning in spite of rejection, and how they could be therapeutically harnessed to promote long-term graft acceptance, are described: accommodation that is resistance of endothelial cells to donor-specific antibodies, and endothelial cell ability to induce Foxp3+ Regulatory T-cells, that are crucial mediators of tolerance.

In recent years, black fungi have been increasingly reported as causing opportunistic infections after solid organ transplantation. Here, we report a case of insidious, relentless, and multifocal Exophiala xenobiotica infection in a kidney transplant recipient that eventually required multiple surgical excisions along with oral and intravenous antifungal combination therapy using liposomal amphotericin B and posaconazole. We compare the present case with all previously reported cases of Exophiala infection after kidney transplantation.

Objective Chronic periaortitis (CP) is a rare disease characterized by fibro-inflammatory tissue surrounding the abdominal aorta and the iliac arteries. Anecdotal reports have shown that CP may also involve other vascular districts, particularly the thoracic aorta. The aim of this study was to investigate the thoracic aorta and epiaortic artery involvement in CP. Methods Patients were eligible if they had undergone imaging studies assessing inflammatory involvement of the thoracic aorta and its major branches (e.g. contrast CT, MRI or PET-CT). We explored the patterns of thoracic vessel involvement and compared the clinical characteristics of patients with and without thoracic disease. Where available, we also reviewed the thoracic vascular/perivascular tissue biopsies. Results Of 153 CP patients seen between 1999 and 2012, 77 were eligible. Of these, 28 (36%) had thoracic involvement: 15 (54%) had thoracic periaortitis, with 7 also showing epiaortic artery involvement; 6 (21%) had periaortitis surrounding a thoracic aortic aneurysm, 2 of them with epiaortic artery involvement; 7 (25%) had a thoracic aortic aneurysm without periaortitis. Patients with thoracic disease were more frequently female (P = 0.01), were older (P = 0.001) and had a higher frequency of pain and constitutional symptoms (P = 0.02). Thoracic (peri)vascular biopsies revealed adventitial and peri-adventitial fibro-inflammatory patterns similar to those observed in abdominal CP. Conclusion In about one-third of patients, CP also involves the thoracic aorta and the epiaortic arteries, which supports the hypothesis of a systemic inflammatory disease of the large arteries.

We aimed to determine the immunological effects of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha) in patients bearing advanced renal cell carcinoma.Twenty-seven patients received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular rIFN-alpha twice weekly, for 4 consecutive weeks. The cycle was repeated indefinitely at regular 4-month intervals, for all patients. rIL-2 (1 x 10(6) IU/m2) was administered every 12 h on days 1 and 2 and once a day on days 3-5 of each week; rIFN-alpha (1.8 x 10(6) IU/m2) was given on days 3 and 5. In the enrolled patients, total and differential white blood cell counts, phenotypic analysis of some lymphocyte subsets, and soluble IL-2 receptor (sIL-2R), were investigated before and after each of the first six cycles of therapy (about 24 months of follow-up).The cycles of immunotherapy induced a significant increase of total lymphocytes (37%, P0.001), eosinophils (222%, P0.001), CD25+ cells (27%, P=0.004), sIL-2R (174%, P0.001) and natural killer (NK) cells (CD3-CD56+) (61%, P0.001); the subset that expresses CD56 with high density (CD56+ bright) expanded more (233%, P0.001) than the subset expressing the same marker with low density (CD56+ dimmer) (15%, P = 0.043). Unlike the previous subsets, the treatment decreased significantly T-lymphocytes with NK cell marker (CD3+ CD56+) (28%, P = 0.011). No significant differences of effectiveness were found among the subsequent treatment cycles, except for CD25+ cells and sIL-2R (P = 0.036 and P = 0.005, respectively): the increase induced by immunotherapy was maximum after the first cycle and decreased progressively thereafter.Long-term repeated cycles of low-dose immunotherapy induced repeated and significant expansion of one of the most important lymphocyte subsets for the non-MHC-restricted immune response to the tumour mass: CD3-CD56+ cells.

BACKGROUND The objective of this study was to evaluate response, toxicity, and immunologic effects of an original immunotherapy schedule based on repeated cycles of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-α (rIFNα) in patients with metastatic renal cell carcinoma (mRCC). METHODS Fifty patients who underwent nephrectomy received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular rIFNα twice weekly for 4 consecutive weeks. The cycle was regularly repeated indefinitely at 4-month intervals in all patients, irrespective of their response. rIL-2 (1 × 106 IU/m2) was administered every 12 hours on Days 1 and 2 and once per day on Days 3–5 of each week; rIFNα (1.8 × 106 IU/m2) was given on Days 3 and 5. Toxicity was graded according to the World Health Organization (WHO) criteria. Forty percent of the patients had only one metastatic disease site at the time of treatment. The Kaplan–Meier method was used to estimate survival, and an analysis of variance was used to evaluate the effects on leukocytes and lymphocyte subsets over time. RESULTS A total of 241 cycles were administered. One patient achieved a complete response, and five patients achieved a partial response. Five patients had stable disease, and 30 patients had progressive disease. Nine patients were not evaluable for response. The overall response rate was 12% (95% confidence interval, 3–21%) on the basis of an intent-to-treat analysis. The 36-month survival probability for all 50 patients was 47%. Treatment-related toxicity was limited to WHO Grades 1 and 2. Both lymphocyte and eosinophil levels significantly increased after all cycles (by 42% and 353%, respectively). The treatment also induced significant increases in the CD25 positive (24%), CD56 positive (28%), and CD3 negative/CD56 positive (54%) lymphocyte subsets. CONCLUSIONS Long-term, repeated treatment with low doses of rIL-2 and rIFNα is feasible in patients with mRCC. The schedule induces clinical response rates and survival probabilities are similar to those obtained using higher doses. Cancer 2001;92:2286–96. © 2001 American Cancer Society.

Renal involvement during graft-versus-host disease following haematopoietic cell transplantation for multiple myeloma has never been described. We report a case of a recipient who developed nephrotic syndrome and membranous glomerulonephritis 22 months after the graft and 6 months after cyclosporine withdrawal. Symptoms resolved when immunosuppressive therapy was reinstituted.

U.Maggiore,M.C.Medici,A.Vaglio,C.Buzio.Increasedviralloadafterintravenous immunoglobulintherapy for BKvirus-associatednephropathy:acase report.TransplInfectDis2010:12:470^472.Allrightsreservedaccepted for publication 7 December 2009Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14,E-mail: umaggiore@ao.pr.itTo the EditorIntravenous immunoglobulins (IVIG) have been proposedas a treatment for BK virus-associated nephropathy(BKVAN), based on their alleged anti-in£ammatory andBKVneutralizing activities (1).While it appears reasonableto exploit their anti-in£ammatory activity for treatingBKVAN with a marked in£ammatory component, with orwithout coexisting rejection (2), the BKV neutralizingeiect of IVIG appears questionable, as recent studieshave shown that BKV active replication occurs despitemarkedly high levels of BKV-speci¢c immunoglobulin G(IgG)(3^5).TheevidenceinfavoroftheuseofIVIGcomesfromtheinitial experience with 8 cases of BKVAN and from othersubsequent reports (1,6). However, in none of these studieswas the viral load monitored by quantitative polymerasechainreaction(PCR)assayimmediatelyafterIVIGtherapy,andthereforenodirectevidencewasprovidedtodeterminethe eiectof IVIG onviralclearance.InthisletterwedescribeapatientsuieringfromBKVANwhomwetreatedwithtaperingofimmunosuppressionandwith IVIG. In this patient, we performed serial measure-mentsofplasmaBKviralloadbeforeandafterIVIGadmin-istration.

In order to study the relationship between the long term renal haemodynamic effects of calcium antagonists and hypertensive renal damage, 8 patients with mild to moderate essential hypertension (6 males and 2 females, aged 19 to 60 years) underwent measurement of 24-hour microalbuminuria (urinary albumin excretion), mean blood pressure, effective renal plasma flow (para-aminohippuric acid clearance) and glomerular filtration rate (inulin clearance) before and after 12 to 16 months’ treatment with amlodipine 10mg once daily. Mean blood pressure fell from 125 ± 7mm Hg at baseline to 101 ± 3mm Hg during treatment with amlodipine (p < 0.001). Effective renal plasma flow did not change (633 ± 51 ml/min · 1.73m2 to 626 ± 46 ml/min · 1.73m2), while renal vascular resistance decreased from 8.5 ± 0.6 dyn · sec · cm−5 to 7.0 ± 0.4 dyn · sec · cm−5 (p = 0.01). Glomerular filtration rate rose significantly (109 ± 7 ml/min · 1.73m2 at baseline to 122 ± 4 ml/min · 1.73m2, p < 0.02 after amlodipine treatment) and urinary albumin excretion decreased from 17.4 ± 4.2 mg/24h to 7.2 ± 1.5 mg/24h (p < 0.05). Our findings show that long term treatment with amlodipine is followed by sustained renal vasodilation, an increase in glomerular filtration rate and, consequently, an increase in filtration fraction. However, despite the long term increase in glomerular filtration, urinary albumin excretion falls substantially. We suggest that long term renal protection afforded by amlodipine may occur independently of its effects on glomerular haemodynamics.

The immune cell function assay (ICFA) and de novo anti-donor-specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3-year follow-up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy-proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1-2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted-odds ratio of de novo DSA associated with prior infections: 6.03 [95% CI, 1.64-22.06; p = 0.007]). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease, characterised by a fibroinflammatory tissue surrounding the aortoiliac axis and frequently entrapping the ureters.1 ,2 Glucocorticoids effectively induce remission, but 24% to 72% of patients relapse, half of them repeatedly.3 ,4 Immunosuppressants and glucocorticoids are usually required in relapsing IRF but no studies are available. In this prospective, open-label trial we enrolled 16 relapsing patients with IRF (July 2004 to April 2011) aged 18–85 years and with an estimated glomerular filtration rate (eGFR)>50 ml/min5 after ureteral decompression (if required), and treated them with methotrexate and prednisone for 12 months. Relapse was defined in case of mass enlargement, hydronephrosis, or disease-related symptoms associated with high inflammatory markers.3 Prednisone was given at 0.5–1 mg/kg/day depending on flare severity, tapered to 12.5–10 mg/day by month 3, 7.5–5 mg/day by month 6 and maintained at 5–2.5 mg/day until month 12. Methotrexate was given at 15–20 mg/week until month 12. After month 12, the clinician was free to continue or withdraw the treatment. The primary endpoint was remission (at month 12) defined as a stable, reduced mass and absence of hydronephrosis, disease-related symptoms and normal inflammatory markers.3 Secondary endpoints were changes in erythrocyte sedimentation …

OBJECTIVE: Chronic periaortitis (CP) is a rare disease that is characterised by fibro-inflammatory tissue surrounding the abdominal aorta and has both non-aneurysmal (idiopathic retroperitoneal fibrosis [IRF]) and aneurysmal forms (inflammatory abdominal aortic aneurysm [IAAA]). We investigated whether toll-like receptor 4 (TLR-4) and vascular endothelial growth factor (VEGF) polymorphisms were associated with susceptibility to, and the clinical features of CP. METHODS: One hundred and two CP patients and 200 healthy controls were molecularly genotyped for TLR-4 gene polymorphism (+896 A/G) (rs4986790), VEGF mutations +936 C/T (rs3025039) and -634 C/G (rs2010963), and an 18 base pair (bp) insertion/deletion (I/D) polymorphism at -2549 of the VEGF promoter region. The patients were grouped on the basis of the type of CP (IRF or IAAA), and the presence or absence of established atherosclerotic disease (ischemic heart disease, cerebrovascular disease, and peripheral arterial disease). RESULTS: There were no significant differences in the distribution of the studied polymorphisms between the patients and controls. However, carriage of the +936 T allele was significantly more frequent in the patients with IRF than in those with IAAA (26.5% vs 5.3%; p = 0.046; OR 6.49 [95% CI 0.82-51.54]). There were significantly more carriers of the I allele among the patients with ureteral obstruction (83.8% vs 58.8%; p = 0.006; OR 3.63 [95% CI 1.42-9.28]) and those who received conservative treatment (48.5% vs 23.5%; p = 0.015; OR 3.06 [95% CI 1.22-7.721]) than among those without, and II homozygosity was significantly more frequent in the patients with deep vein thrombosis than in those without (30.4% vs 11.7%, p = 0.031; OR 3.31 [95% CI 1.07-10.21]). CONCLUSION: The VEGF +936 C/T polymorphism may be associated with an increased risk of developing the non-aneurysmal IRF form of CP. Carriers of the I allele and II homozygosity are respectively at increased risk of developing ureteral obstruction and deep vein thrombosis.

Introduction Evaluation of kidney transplant candidates is based on strict exclusion of major pathologies, such as neoplastic disease. The aim of this study is to evaluate epidemiological and clinical impact of tumor disease in an Italian renal transplant waiting list and to propose a screening schedule for neoplastic detection. Materials and methods We retrospectively observed data of patients enrolled on the Emilia-Romagna kidney transplant waiting list between 1st August 2008 and 31st December 2010, evaluating the different causes of getting out from the list, the histologic type and incidence of cancer and the correlation between cancer onset and clinical features. The ratio of observed to expected cancer numbers (standardized incidence ratio, SIR), was estimated. Results We observed 2345 patients; 1297 got out from the waiting list; 57 of them (4,4%) got out because the onset of tumor. The overall incidence rate of cancer was 1354.8 (x 100000 person-year) (1045.9 person-year in patients awaiting for first transplant(FT), 1851.5 person-year in patients awaiting for second transplant(ST)). The overall prevalence of cancer was 2,43% (2.2% in FT, 3.4% in ST) with a SIR of 1.8; In our population the prevalence of cancers related to ESKD was 52.6% with a SIR of 15.8. Conclusion Kidney transplant waiting list patients present a higher incidence and prevalence of cancer compared to general population; it could be important to evaluate them for ESKD related malignancies because of their high incidence.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA) is a systemic small-vessel vasculitis associated with asthma and eosinophilia. Histology of EGPA shows tissue eosinophilia, necrotizing vasculitis, and eosinophil-rich granulomatous inflammation. EGPA commonly presents with upper airway tract and lung involvement, peripheral neuropathy, cardiac and skin lesions. Antineutrophil cytoplasmic antibodies (ANCA) are positive in ~40% of the cases and more often in patients with clinical manifestations due to small-vessel vasculitis. The pathogenesis of EGPA is multifactorial: the disease can be triggered by exposure to allergens or drugs, but a genetic background has also been recognized, particularly an association with HLA-DRB4. Th2 responses are prominent, with up-regulation of IL-4, IL-13, and IL-5; however, Th1 and Th17 responses are not negligible. Eosinophils are activated, have a prolonged lifespan and probably cause tissue damage by releasing their granule proteins; their tissue recruitment can be regulated by chemokines such as eotaxin-3 and CCL17. Humoral immunity is also dysregulated, as demonstrated by prominent IgG4 and IgE responses. EGPA promptly responds to glucocorticoid therapy, although combinations of glucocorticoids and immunosuppressants (e.g., cyclophosphamide, azathioprine) are eventually required in most cases. Newer therapeutic options include the anti-IL5 antibody mepolizumab, whose efficacy has been described in small clinical trials, and the B-cell-depleting agent rituximab, reported in several case series.

Aims and Background The exact mechanism by which recombinant interleukine-2 and interferon-a modulate the immunological response, inducing long-term responses in metastatic renal cell carcinoma, is still not clear. The aim of the study was to analyze the modifications in peripheral blood lymphocytes during cycles of low-dose immunotherapy as a marker of the biological response to the treatment in 146 patients with renal cell carcinoma (advanced and localized disease). Methods and Study Design Peripheral blood lymphocytes were evaluated before and after every cycle of treatment. Results We found a statistically significant overall difference between pre- and post-cycle values (mean increase of 39%). The differences between pre- and post-cycle lymphocyte counts for each cycle were significant. Also, the post-cycle lymphocyte count of each cycle remained higher than the baseline value. Furthermore, pre-cycle lymphocyte counts of each cycle were still higher than the baseline value, with no difference between a pre-cycle lymphocyte mean value and the other one (except that between the first and second cycle). From the end of each cycle, but before starting the next one, the absolute value of lymphocytes fell on the average by 15–30%, concurring with the fact that, even starting from pre-cycle values higher than baseline, the immune system remains sensitive to chronically repeated stimulation by immunotherapy. We also found that non-metastatic patients had a higher number of peripheral blood lymphocytes than metastatic patients, whereas the latter had a lower immune response to therapy. Conclusions The results support the idea that “maintenance” immunotherapy may not develop resistance over time in terms of biological response and thus may have a role as chronic therapy in combination with other drugs such as target therapy. We suppose that the immune system of patients with metastases is in a state of relative impairment, resulting in less sensitivity to immunostimulating agents.