[Eosinophilic fasciitis; the importance of early detection for optimal outcomes]. / Eosinofiele fasciitis, het belang van een tijdige herkenning voor de genezing.

Eosinophilic fasciitis (EF) is a disease with unknown aetiology, although an immunologic pathogenesis is suspected. The characteristic features of this inflammatory disease include scleroderma-like skin indurations, predominantly on the extremities, and peripheral blood eosinophilia. Internal organs are generally not affected. Initiation of systemic glucocorticoid therapy at an early stage results in a good response and remission of symptoms. This is illustrated in 3 cases of EF to demonstrate the importance of early detection in this disease.

Secretory immunoglobulin A (IgA) responses in IgA nephropathy patients after mucosal immunization, as part of a polymeric IgA response.

Secretory immunoglobulin A (SIgA), although generated at mucosal surfaces, is also found in low concentrations in the circulation. Recently, SIgA was demonstrated in mesangial deposits of patients with immunoglobulin A nephropathy (IgAN), suggesting a role in the pathogenesis. This finding is in line with the belief that high molecular weight (HMW) immunoglobulin A (IgA) is deposited in the kidney. However, there is little information on the size distribution of antigen-specific IgA in circulation upon mucosal challenge. In this study we measured antigen-specific IgA, including SIgA, in serum following challenge of IgAN patients and controls via intranasal vaccination with a neoantigen, cholera toxin subunit B (CTB). We size-fractionated serum and nasal washes to study the size distribution of total IgA, SIgA and CTB-specific IgA. Finally, we compared the size distribution of antigen-specific IgA after mucosal immunization with the distribution upon systemic immunization. A significant induction of antigen-specific SIgA was detectable in serum of both patients with IgAN and controls after mucosal immunization with CTB. Independent of the route of immunization, in both groups the antigen-specific IgA response was predominantly in the polymeric IgA fractions. This is in contrast to total IgA levels in serum that are predominantly monomeric. We conclude that mucosal challenge results in antigen-specific SIgA in the circulation, and that the antigen-specific IgA response in both IgAN patients and in controls is of predominantly HMW in nature. No differences between IgAN patients and controls were detected, suggesting that the size distribution of antigen-specific IgA in the circulation is not disturbed specifically in IgAN patients.

Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial.

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.

Adequacy of peritoneal dialysis and the importance of preserving residual renal function.

The well-being and survival of dialysis patients not only depend on the removal of waste products and excess fluid, but also on the prevention of cardiovascular complications by maintaining normovolaemia and adequate blood pressure and avoidance of ectopic calcification. Also, the maintenance of nutritional status and adequate removal of middle molecules are amongst the most important issues in long-term renal replacement therapy. In this review, attention is given to optimal peritoneal small solute clearance and Kt/V and to the evidence concerning the role of residual renal function. In addition, factors that can influence this residual function are also discussed.

Health-related quality of life in patients with systemic lupus erythematosus: development and validation of a lupus specific symptom checklist.

Reliable and sensitive measures are needed to evaluate the quality of life (QoL) in patients with systemic lupus erythematosus (SLE). No lupus specific questionnaires are available. This study describes the development and validation of a disease-specific questionnaire for lupus patients, which assesses the presence and burden of 38 disease- and treatment-related symptoms: the SLE Symptom Checklist (SSC). Reliability and reproducibility were tested in respectively 87 and 28 stable SLE patients. The internal consistency (Cronbach's alpha coefficients 0.89) and test-retest reliability (Pearson product-moment correlation coefficient between 0.67 and 0.87) were satisfactory. Concurrent validity was supported by significant, but moderate correlations with other measures of subjective well-being and functional status. Responsiveness was measured in 17 patients with lupus nephritis treated with cyclophosphamide, at start of therapy and 1 year thereafter. A significant change in number of symptoms and total distress level was found. It is concluded that the SSC has satisfactory psychometric properties and appears suitable for both clinical and research purposes.

Can renal dysfunction after infra-renal aortic aneurysm repair be modified by multi-antioxidant supplementation?

BACKGROUND: Renal failure after lower torso ischemia is a serious problem, partly caused by hypotension and indirect reperfusion injury. This injury is partly due to the formation of oxygen free radicals by activated neutrophils. This injury results in albuminuria and renal function impairment. There are indications that free radical damage in indirect reperfusion injury can be diminished by administering extra antioxidants before and during reperfusion. METHODS: In this prospective randomised study we have looked at the influence of a multi-antioxidant supplementation on renal function in patients undergoing an elective open infrarenal abdominal aneurysm repair. The patients received either standard treatment (n=22) or standard treatment with additional antioxidants perioperatively (Allopurinol, vitamin E and C, N-acetylcysteine and mannitol). For renal function we have looked at the albumin/creatinine ratio in urine and 24 hr creatinine clearance. RESULTS: Despite significantly increased serum total antioxidant capacity, the group receiving extra antioxidants showed no decrease in the albumin/creatinine ratio in urine. There was however a significantly higher creatinine clearance in this group at day 2. CONCLUSIONS: The results indicate that the diminished renal function after infrarenal aneurysm repair may be influenced by antioxidant therapy.

Hemolytic uremic syndrome after capnocytophaga canimorsus (DF-2) septicemia.

A 66-year-old man developed a hemolytic uremic syndrome (HUS) with acute renal failure, thrombocytopenia, fragmented red cells in the blood film and elevated serum LDH following a capnocytophaga canimorsus (DF-2) infection after a dog bite. He was treated with antibiotics, plasmapheresis and hemodialysis. Although hematologic values improved, the patient remained hemodialysis-dependent for six months. In the literature several cases of renal failure following capnocytophaga canimorsus septicemia have been described, caused by hypotension or disseminated intravascular coagulation (DIC). In our patient there were no signs of hypotension or extensive DIC. A few case reports described HUS and thrombotic thrombocytopenic purpura (TTP) following DF-2 sepsis.

[Immediate recovery from acute renal insufficiency after abdominal decompression]. / Onmiddellijk herstel van acute nierinsufficiëntie na abdominale decompressie.

A 61-year-old man received an aorto-iliac reconstruction after he was admitted because of a ruptured abdominal aortic aneurysm. Postoperatively, he developed cardiopulmonary insufficiency with anuria. After the intra-abdominal pressure had risen to 40 cmH2O (measured by a urinary bladder catheter), it was decided to perform a relaparotomy. Immediately after abdominal decompression--without correction of any other intra-abdominal pathology--the diuresis increased and several other cardiopulmonary parameters improved significantly. When a critically ill patient shows a rapid increase of the intra-abdominal pressure above a critical level an acute abdominal compartment syndrome may develop. This syndrome consists mainly of potentially fatal cardiopulmonary and renal insufficiency, for which (re)laparotomy with abdominal decompression is the only correct treatment.

Renal replacement therapy in the elderly.

BACKGROUND AND METHODS: In a retrospective study the medical records of 122 patients aged over 65 years at the start of renal replacement therapy (RRT) in our dialysis centre were analysed. RESULTS: The mean age at the start of RRT was 72.7 +/- 5.7 years (range 65.0-90.3). Seventy-six percent were treated with haemodialysis, 21% with haemofiltration and 3% with continuous ambulatory peritoneal dialysis. There was no significant difference in survival between the different modes of treatment. The median survival was 23.8 months, the actuarial survival rates at 2, 5 and 7 years were 50, 27 and 18%, respectively. Patients aged between 65 and 75 years had a median survival of 36.4 months, patients above 75 years of 12.5 months (P = 0.009). Patients with tubulo-interstitial nephritis had a significantly longer survival than patients with other renal diseases. When chronic obstructive pulmonary disease or peripheral vascular disease was present, there was a significantly shorter survival. There was no difference in survival between patients with malignancy, cardiac diseases, diabetes mellitus or cerebrovascular diseases before the start of RRT and others. After the start of RRT there was a significant increase of infectious and psychiatric disease. During the study period 70% died, most frequently from cardiovascular causes (28%), discontinuation of dialysis treatment (28%) or infection (19%). CONCLUSIONS: We think that both survival and quality of life in elderly patients during RRT are acceptable, and that neither age nor comorbidity should be a contraindication to RRT.

Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy.

Twelve IgA nephropathy (IgAN) patients and 18 controls were immunized with novel protein antigens, cholera toxin subunit B (CTB) via the nasal route and keyhole limpet hemocyanin (KLH) subcutaneously. Antibody secreting cells and antibody response in body fluids were determined by ELISPOT assay and ELISA, respectively. Analysis of variance showed, in contrast to controls (P < 0.001), no CTB-specific IgA response in the nasal washes of patients with IgAN. Significantly lower numbers of CTB-specific antibody-secreting cells in peripheral blood (P < 0.001) and CTB-specific antibodies in plasma (P < 0.005) were found in IgAN, both restricted to the IgA1 subclass. The proportions of CTB-specific IgA1-secreting cells in bone marrow aspirates correlated significantly with the corresponding ratios in plasma, with significantly lower values (P < 0.005) in IgAN as compared to controls. These results support the existence of a "mucosa-bone marrow axis" in humans, but no dysregulation of this axis was found in IgAN. The deficient mucosal IgA immune response to CTB observed in this study after primary mucosal immunization indicates that patients with IgAN have a defective immune response when challenged intranasally. These patients may depend on more frequent and/or prolonged antigen encounter at mucosal sites before efficient mucosal immunity is established. Repeated seeding of antigen-specific cells to secondary lympoid organs could result secondarily in the relative hyperresponsiveness found in IgAN upon reactivation by parenteral immunization.

Immunoglobulin A subclass measurement in serum and saliva: sensitivity of detection of dimeric IgA2 in ELISA depends on the antibody used.

The existence of two IgA subclasses in humans has been reliably shown by biochemical, immunochemical and genetic means. IgA is unique among immunoglobulins in the regular occurrence of both monomeric and polymeric forms. In order to be able to study the relationship between monomeric and polymeric IgA1 and IgA2 concentrations in the circulation and mucosal compartment i.e. secretions, it is essential that the methods used are not biased by the molecular size of the IgA under investigation. We validated IgA and IgA subclass measurements in serum and saliva by sandwich enzyme-linked immunosorbent assay (ELISA). Coating reagents were specific mAbs against IgA (clone 4E8), IgA1 (clone 69-11.4) or IgA2 (clone 16-512-H5 and clone IF8.58). Pooled normal human serum and purified dimeric IgA1 (d-IgA1) or IgA2 (d-IgA2) myeloma proteins were used to standardize the assays. Polymeric and monomeric forms of IgA in sera from volunteers and patients with myelomatosis were assayed in fractions separated by high performance liquid chromatography (HPLC). Dithioerythritol (DTE) was used to determine the influence of the quarternary structure of IgA on its detection by mAbs. We found that mAbs 4E8, 69-11.4 and 16-512-H5 reliably measured d-IgA, d-IgA1 and d-IgA2 respectively, independent of the standard employed. Clone IF8.58 underestimated the concentration of d-IgA2 (correction factor +/- 2) with increased sensitivity in the presence of DTE. This difference is probably explained by the composition of the immunogen against which the mAb was raised. We conclude that no reliable conclusions can be made concerning the subclass ratio in biological fluids unless the monoclonal antibodies used have been appropriately validated.

Therapy of proliferative lupus glomerulonephritis: a prospective trial in The Netherlands.

Proliferative glomerulonephritis is a severe clinical manifestation of systemic lupus erythematosus, and it remains a major determinant of morbidity and mortality in this disease, despite the progress that has been made by treating patients with a combination of corticosteroids and cytotoxic drugs. Earlier controlled clinical trials have demonstrated the superior efficacy of a combination of pulse cyclophosphamide with steroids over treatment with steroids alone. However, cyclophosphamide carries a substantial risk of short-term and long-term toxicity in this predominantly young population, and previous trials have not convincingly shown any benefit over the milder treatment with a combination of azathioprine and steroids. We propose to conduct a Dutch multicentre trial to test whether similar renal survival can be achieved with an azathioprine-based regimen, compared to the widely used cyclophosphamide treatment, with a possibly lower risk of adverse effects.

Binding of dimeric and polymeric IgA to rat renal mesangial cells enhances the release of interleukin 6.

The mesangium plays a crucial role in processes of inflammation in the kidney. Since deposits of IgA in the mesangium in patients with IgA nephropathy suggest a role for IgA in the inflammatory process, we investigated whether IgA is able to bind to cultured rat mesangial cells (MC) in vitro and induce activation of MC. As a source of IgA, monomeric (mIgA), dimeric (dIgA) and polymeric IgA-alpha-DNP (pIgA) rat monoclonal antibodies were used. FACS analysis indicated binding of dIgA and pIgA to MC while only a small percentage of the cells exhibited binding of mIgA. Additional experiments employing radiolabeled IgA revealed a time- and dose-dependent binding of 125I-dIgA and 125I-pIgA with 6 x 10(6) binding sites for dIgA with an affinity of 5.5 x 10(6) M-1 and 7.2 X 10(6) binding sites/cell for pIgA with an affinity of 1.2 x 10(6) M-1. As compared to 125I-dIgA and 125I-pIgA, little binding of 125I-mIgA to MC occurred; the binding of dIgA and pIgA was not influenced by excess cold BSA, IgG or asialofetuin. Since some studies have suggested that fibronectin might interact with IgA, the binding of IgA to MC in the presence or absence of fibronectin or the RGD fragment was also analyzed. However no influence of fibronectin or the RGD fragment on binding of dIgA and pIgA to MC was observed. As a measure for activation of MC by IgA, the production of IL-6 by MC was analyzed. Dimeric IgA and pIgA both induced a dose-dependent increase of IL-6 production by MC.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of the immune response by nasal immunization.

Intranasal immunization results in both a mucosal and a systemic immune response in humans. Intranasal tetanus toxoid immunization in humans causes an increased serum IgA1 antibody response to tetanus toxoid following a subsequent intramuscular immunization. We hypothesized that intranasal priming with a novel protein antigen, keyhole limpet hemocyanin (KLH), would similarly result in an up-regulated systemic IgA response after a subsequent systemic immunization. To test this hypothesis, five healthy adults received a primary series of intranasal KLH immunizations followed 3 months later by a subcutaneous KLH immunizations Eight healthy adults received only a subcutaneous KLH immunization and served as controls. The nasal immunization resulted in a brisk and sustained serum IgM, IgA, and IgG antibody response and a mucosal IgA response. The subcutaneous immunization alone resulted in a serum antibody response and the development of delayed type hypersensitivity by skin testing. When the nasally primed subjects received a subsequent subcutaneous immunization there was a decline in the serum concentration of IgA and IgG antibodies to KLH. In addition, the nasally primed subjects failed to develop delayed type hypersensitivity to KLH following subcutaneous immunization. These data suggest that the nasal mucosa can induce a mucosal and systemic response; however, it may also suppress a subsequent immune response to systemic immunization.