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Cryoglobulinemia refers to the presence in serum of immunoglobulins, that reversibly precipitate at low temperatures. Cryoglobulins are classified according to their immunochemical properties as type I, composed of a single monoclonal immunoglobulin, and types II and III, referred as mixed cryoglobulinemia (MC), composed by a mixture of monoclonal (type II) and polyclonal (type III) IgM that have rheumatoid factor activity and bind to polyclonal IgGs. MC is a systemic vasculitis with cutaneous and multiple organ involvement including chronic hepatitis, membrano-proliferative glomerulonephritis, and peripheral neuropathy. In more than 90% of patients, MC is associated with chronic hepatitis C virus (HCV) infection, which is considered the triggering factor of the disease. Patients with HCV-related MC may be managed by means of etiological, pathogenetic or symptomatic therapeutic modalities. The choice of the more appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement. This paper reviews the currently available therapeutic strategies for MC syndrome, emphasizing the importance of HCV eradication, and the safety/efficacy of new biologic therapies for selective control of cryoglobulin-producing B-cells.

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.

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.

In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure to lower than usual targets? We aimed to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease.We undertook a multicentre, randomised controlled trial of patients with non-diabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5-5 mg/day). We randomly assigned participants either conventional (diastolic90 mm Hg; n=169) or intensified (systolic/diastolic130/80 mm Hg; n=169) blood-pressure control. To achieve the intensified blood-pressure level, patients received add-on therapy with the dihydropyridine calcium-channel blocker felodipine (5-10 mg/day). The primary outcome measure was time to end-stage renal disease over 36 months' follow-up, and analysis was by intention to treat.Of 338 patients who were randomised, three (two assigned intensified and one allocated conventional blood-pressure control) never took study drugs and they were excluded. Over a median follow-up of 19 months (IQR 12-35), 38/167 (23%) patients assigned to intensified blood-pressure control and 34/168 (20%) allocated conventional control progressed to end-stage renal disease (hazard ratio 1.00 [95% CI 0.61-1.64]; p=0.99).In patients with non-diabetic proteinuric nephropathies receiving background ACE-inhibitor therapy, no additional benefit from further blood-pressure reduction by felodipine could be shown.

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.

Summary Background Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1, reported here, 24 h proteinuria was 1 g or more but less than 3 g per 24 h. Methods In stratum 1 of this double-blind trial 186 patients were randomised to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg. The primary endpoints were change in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (⩾3 g/24 h). Median follow-up was 31 months. Findings The decline in GFR per month was not significantly different (ramipril 0·26 [SE 0·05] mL per min per 1·73m 2 , control 0·29 [0·06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs 18/87) for a relative risk (RR) of 2·72 (95% CI 1·22–6·08); so was progression to overt proteinuria (15/99 vs 27/87, RR 2·40 [1·27–4·52]). Patients with a baseline GFR of 45 mL/min/1·73 m 2 or less and proteinuria of 1·5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13% in the ramipril group and increased by 15% in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2. Interpretation In non-diabetic nephropathies, ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria.

Portal hypertension is caused by an increased resistance to portal outflow and an increased portal blood inflow. Portal hypertension is associated with an abnormal distribution of the blood volume, which is increased in the splanchnic territory and reduced in the non-splanchnic compartments. The relative underfilling of the arterial circulation is responsible for the sodium and water retention, which is a consequence of the baroceptor-mediated activation of vasoconstrictor and antinatriuretic factors triggered to restore circulatory integrity.

Mixed cryoglobulinemia is a chronic immune complex-mediated disease strongly associated with hepatitis C virus (HCV) infection. Mixed cryoglobulinemia is a vasculitis of small and medium-sized arteries and veins, due to the deposition of complexes of antigen, cryoglobulin and complement in the vessel walls. The main clinical features of mixed cryoglobulinemia vasculitis include the triad of palpable purpura, arthralgias, and weakness, and other pathological conditions such as glomerulonephritis, peripheral neuropathy, skin ulcers, and widespread vasculitis. The treatment of HCV-related mixed cryoglobulinemia is difficult due to the multifactorial origin and clinical polymorphism of the syndrome. It can be directed to eradicate the HCV infection, suppress the B-cell clonal expansion and cryoglobulin production, or ameliorate symptoms. The choice of the most appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement.

The most frequent renal involvement in patients with chronic hepatitis C virus (HCV) infection is cryoglobulinemic glomerulonephritis, with type I membranoproliferative glomerulonephritis (MPGN) being the predominant histological pattern. The pathogenesis of HCV-related cryoglobulinemic MPGN is unknown, but the glomerular damage may be due to the deposition of immune complexes of HCV, IgG, and IgM rheumatoid factors. Clinically, cryoglobulinemic MPGN may range from isolated proteinuria to overt nephritic or nephrotic syndrome, with variable progression to chronic renal insufficiency. The management of cryoglobulinemic MPGN is difficult; the eradication of HCV by means of antiviral therapy (peginterferon plus ribavirin) leads to clinical remission in a proportion of patients, but severe renal disease may be resistant to antiviral therapy. In such cases, corticosteroids and immunosuppressive agents have been used to decrease cryoglobulin production and improve the vasculitic manifestations, but long-lasting remission of the renal disease is uncommon. Here we describe four patients with HCV-related cryoglobulinemic MPGN and the strategies used for their management. The principal message provided by these illustrative cases is that antiviral therapy alone can be the first-line treatment for patients with mild-to-moderate kidney involvement, whereas a short-term course of corticosteroids and cytotoxic agents followed by antiviral therapy may be a reasonable therapeutic strategy for patients with severe/active renal disease.

Churg-Strauss syndrome (CSS) is a rare systemic disease characterized by necrotizing vasculitis and peripheral eosinophilia. Cardiac involvement is considered common and is given a high rank among the causes of morbidity and mortality. The aim of this study was an update on the cardiac manifestations of this syndrome using a noninvasive approach. Sixteen patients with CSS were compared with a gender- and age-matched group of 20 healthy subjects. All patients but 1 were receiving treatment (steroids and/or immunosuppressive drugs). According to the Birmingham vasculitis activity score, 12 patients were in an active phase, and 4 were in drug-induced remission. All subjects underwent M-B-mode echocardiography and Doppler tissue echocardiography. Heart failure, life-threatening arrhythmias, and other prominent manifestations of heart disease were not observed. No differences were found in left ventricular diameter, volume, mass, or ejection fraction. The 2 groups did not differ in right ventricular diameter and pulmonary pressure. Few and nonspecific changes were detected by 2-dimensional echocardiography, including subclinical pericardial effusion and mitral regurgitation, in fewer than half the subjects. Subjects with CSS showed an impairment of ventricular relaxation. Changes were more prominent in the right ventricle. The peak velocity (PV) of early diastolic tricuspid inflow (E) was about 8% less than in controls, and the velocity of late diastolic inflow (A) was 35% greater. The E/A PV ratio was, on average, 33% less. In the left ventricle, E PV was 11% less and A PV 11% greater. The E/A ratio was decreased by 22%. Doppler analysis of tissue kinetics confirmed these indications. In the right ventricle, E PV was decreased by 10% and A PV was increased by 20% in the patient group. The E/A PV ratio was decreased by 29%. In the left ventricle, in which different sites were sampled, the average changes were −15%, +1%, and −23%, respectively. In the left ventricle, the velocity of systolic contraction was also decreased by 12%. Because of the small group size, only some of these differences were statistically significant. In conclusion, these moderate changes, devoid of clinical correlates, contrast with early reports emphasizing cardiac morbidity and poor prognosis in this syndrome.

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. MC is a non-neoplastic B cell lymphoproliferative process induced by HCV in an antigen-driven mechanism. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. Glomerulonephritis is predominantly associated with MC, and almost always takes the form of membranoproliferative glomerulonephritis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. The treatment of these virus-related diseases must be individualized on the basis of the severity of clinical symptoms. Antiviral therapy with interferon alpha and ribavirin (the currently recommended treatment of HCV infection) may be successful in patients with mild-to-moderate disease, but sustained responses are uncommon. In case of severe and rapidly progressive disease, although it is capable of suppressing viremia and cryoglobulinemia, antiviral therapy is not fully effective in controlling the inflammatory and self-perpetuating reaction consequent to the deposition of cryoglobulins in the glomeruli and vessel walls. In such cases, a short course of steroids and cytotoxic drugs (with or without plasmapheresis) may be needed to improve the vascular manifestations and decrease the production of cryoglobulins. Once the acute disease flare has been controlled, antiviral therapy may be administered to eradicate HCV, the causative agent of the cryoglobulinemic syndrome. In patients in whom antiviral therapy is ineffective, contraindicated or not tolerated, rituximab, a monoclonal anti-CD20 antibody, may be an alternative to standard immunosuppression.

Churg-Strauss syndrome (CSS) is a rare systemic vasculitis occurring in patients with a history of asthma or allergy and eosinophilia. Although lungs, skin, and peripheral nervous system are the most common sites of involvement, many other organs, including heart, kidneys, and gastrointestinal tract, can be affected. CSS is an eosinophil-mediated disease, but its pathophysiology is not fully known. There are no specific laboratory tests for CSS. The main laboratory characteristics are peripheral blood eosinophilia, elevated serum IgE levels, and the presence of an inflammatory syndrome. Antineutrophil cytoplasmic antibodies directed against myeloperoxidase are positive in approximately one-half of patients. The diagnosis of CSS rests on the association of the clinical features of the disease with its histologic hallmarks. The biopsy of affected tissues may show a spectrum of histologic changes, including leukocytoclastic or necrotizing vasculitis, eosinophilic tissue infiltration, vascular and extravascular granulomas. The involved vessels are small arteries, veins, arterioles, venules, and capillaries. Corticosteroids, sometimes in combination with a cytotoxic agent, such as cyclophosphamide, are the most effective treatment of CSS. Intravenous immunoglobulins or interferon-alpha may be useful for patients refractory to conventional treatment.

A relationship between the urinary albumin excretion rate (UAE) and different types of tumors has been previously described but little is known about UAE and renal cell cancer (RCC). We evaluated the prognostic significance of UAE and its correlation with tumor clinicopathological findings in patients with RCC treated with recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha). Because rIL-2 and rIFN-alpha increase glomerular permeability, we also determined whether the first immunotherapy cycle induced a significant increase in UAE and whether it was related to tumor parameters.A total of 51 consecutive patients with RCC were enrolled. Inclusion criteria were patient age at diagnosis younger than 70 years and serum creatinine less than 1.8 mg/dl. Patients with central nervous system metastases and diabetes mellitus were excluded. Nephrectomy was followed by systemic treatment with 1-month cycles of low dose rIL-2 and rIFN-alpha, which were repeated every 4 months, UAE was determined before and after the first treatment cycle.Univariate analysis showed that pre-cycle and post-cycle UAE greater than 30 mg/24 hours significantly influenced survival (p = 0.006 and 0.007, respectively). A multivariate model adjusted for age at onset, performance status, post-cycle UAE, tumor stage and grade, and metastases showed that pre-cycle UAE greater than 30 mg/24 hours had an independent prognostic role (p = 0.011). The first treatment cycle increased UAE 81.8% vs baseline (p = 0.002). The post-cycle vs pre-cycle increase was significant in patients with stages III-IV (p = 0.003) and grades 3-4 (p = 0.028) tumors. Pre-cycle and post-cycle UAE were significantly higher in stages III-IV than in stages I-II cases (p = 0.030 and 0.007, respectively).UAE is an independent prognostic factor that is related to disease stage in patients with RCC.

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. In HCV-infected patients with MC, renal involvement worsens the overall prognosis because of a high incidence of infection or cardiovascular disease. The relationship between MC and HCV infection has prompted the use of antiviral therapy. Two patients with chronic HCV infection, type-II MC and membranoproliferative glomerulonephritis (MPGN), presenting as nephrotic syndrome were treated with interferon (IFN)-alpha (3 MU 3 times per week) and ribavirin (15 mg/kg daily) for 6 months. Laboratory tests included measurement of anti-HCV antibodies, HCV RNA, and HCV genotyping, and characterization of circulating cryoglobulins. A pretreatment renal biopsy was performed, and the histopathologic lesions were scored according to the index of disease activity. Viremia and cryoglobulinemia were suppressed in both patients. However, a complete remission of proteinuria was observed in 1 patient only. The evaluation of the renal biopsy specimens revealed a mild MPGN (activity score: 5/24) in the patient with remission of proteinuria and a severe MPGN (activity score: 15/24) in the patient who maintained a nephrotic-range proteinuria. Although a fully satisfactory treatment is not yet available, we feel that a reasonable therapeutic strategy for HCV-infected patients with MC nephritis could be as follows: (1) antiviral treatment alone for patients with a low-grade kidney involvement, and (2) a short-term course of steroids and cytotoxic drugs followed by antiviral therapy for acute exacerbations and/or rapidly progressive GN.

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

Background. In this study we investigated whether the increase in proteinuria induced by an oral protein load may be prevented by the angiotensin-converting enzyme inhibitor (ACEI) captopril in patients with nephrotic syndrome, and whether the effects of captopril on renal haemodynamics and/or glomerular selectivity are comparable to those obtained with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin and the calcium-channel blocker (CaCB) nifedipine. Methods. Twelve subjects underwent the following treatments : (1) low-protein meal (0.2 g protein/kg body wt), (2) high-protein meal (1.3 g protein/kg body wt), (3) high-protein meal plus oral captopril (50 mg), (4) high-protein meal plus oral nifedipine (10 mg), (5) high-protein meal plus oral indomethacin (50 mg). Urine and blood samples were obtained after meals and tested for total protein, immunoglobulin G and albumin. GFR and renal plasma flow (RPF) were calculated from iothalamate and p-aminohippuric acid clearances respectively. Results. Mean arterial pressure decreased significantly after both captopril (-4%, P=0.001) and nifedipine (-5%, P=0.0019). Compared with the low-protein meal, mean values of GFR and RPF increased significantly after the high-protein meal alone (+21%, P= 0.0002 ; +10%, P=0.0491 respectively) and after captopril (+18%, P=0.0025 ; +24%, P=0.0034 respectively) or nifedipine administration (+30%, P=0.0001 ; +21%, P=0.0036 respectively), whereas they remained unchanged after the high-protein meal plus indomethacin administration. FF did not change significantly under the five experimental conditions. The increase in urinary protein excretion induced by the meat load (total protein +18%, P=0.0102 ; albumin +26%, P= 0.0316 ; IgG +28%, P=0.0203) was entirely blocked by both captopril and indomethacin, whereas it was further increased by nifedipine administration. Conclusions. Both captopril and indomethacin, but not nifedipine, are able to prevent the increase in urinary protein excretion rate following a meat meal. The antiproteinuric effect of captopril is comparable to that of indomethacin, but the renal haemodynamic changes induced by these drugs differ considerably, because the filtration capacity and the renal functional reserve were preserved by captopril and decreased by indomethacin. The reduction in systemic blood pressure following administration of both captopril and nifedipine does not account for changes in proteinuria, since, with a similar degree of blood pressure lowering, urinary protein excretion is reduced by captopril and increased by nifedipine.