Primary systemic vasculitis.
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Antibodies, Antineutrophil Cytoplasmic↗
Biomedical subjects
D Adu
Publications and source records attributed to D Adu.
Cell adhesion molecule expression within human glomerular and kidney organ culture.
A glomerular and kidney organ culture method was developed to study cytokine inducibility of adhesion molecules and MHC antigen expression. Glomerular cells showed constitutive expression of intercellular cell adhesion molecule-1 (ICAM-1) and MHC class I and II antigens, but not vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or P-selectin. Expression of E-selectin on glomerular endothelial cells (ECs) was induced by interleukin-1 (IL-1), tumour necrosis factor (TNF), interferon-gamma (IFN-gamma) and granulocyte/ macrophage-colony stimulating factor (GM-CSF); this induction was inhibited by transforming growth factor beta (TGF beta) and by IL-4. P-selectin expression was never seen within glomeruli. VCAM-1 was constitutively expressed by Bowman's capsule and proximal tubules and was weakly induced on glomerular ECs by TNF and IL-4 in combination. Glomerular endothelial ICAM-1 expression was increased by IL-1, TNF, IFN-gamma, and GM-CSF, while TGF beta inhibited induction by TNF and IL-1. Expression of MHC class I and II antigens by glomerular ECs was constitutive; further upregulation of MHC class II by IFN-gamma was observed. These studies suggest that leukocyte-endothelial cell interactions that occur within the kidney follow broadly similar principles as are proposed to occur elsewhere in the body but, in addition, there are subtle differences that reflect local conditions.
Cell Adhesion Molecules↗
Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides.
OBJECTIVE: To develop and validate the Vasculitis Damage Index (VDI) for the standardized clinical assessment of damage in the systemic vasculitides. METHODS: Using a nominal group consensus approach, the Birmingham Vasculitis Group generated guiding principles for assessment of damage in all systemic vasculitides. Damage was defined as irreversible change resulting from scars. Consensus principles were developed into the VDI, including guidelines for use, a list of items of damage, and a glossary. RESULTS: For 100 surviving patients with systemic vasculitis, the median VDI score at last observation was 3 (range 0-8). Within the Wegener's granulomatosis subgroup, the median VDI score for 12 non-survivors was higher than for 47 survivors (non-survivors median score 7, interquartile range 5-8 versus survivors median score 4, interquartile range 2-5; P = 0.003). VDI scores for 100 patients with systemic vasculitis increased from initial presentation to last observation by a median score of 3 (range 1-4; P < 0.001). The VDI assesses more items and is more sensitive to change than other indices of damage (P < 0.001). Using the VDI, trained observers can produce moderately consistent damage scores. CONCLUSION: The VDI is a sensitive, reproducible, comprehensive, and credible clinical tool for quantifying damage. The data presented herein should enable further validation and testing of the VDI in specific vasculitic syndromes, and should facilitate the comparison of different therapies.
Humans↗
Association of vasculitic glomerulonephritis with membranous nephropathy: a report of 10 cases.
BACKGROUND: The concomitant occurrence of a vasculitic glomerulonephritis and membranous nephropathy in the same patient is unusual. We report data on 10 patients with this unusual combination. METHODS: Ten patients (nine males/one female; median age 63.5 years, range 30-70 years) presented between 1981 and 1995 with: acute renal failure (n = 3), nephrotic syndrome (n = 4), non-nephrotic range proteinuria and renal insufficiency (n = 3). The median serum creatinine at presentation was 296 mumol/l (range 65-1749 mumol/l). One patient had a vasculitic transformation from membranous nephropathy 5 years after the original presentation, coincident with an acute deterioration of renal function requiring dialysis; in all other patients the two glomerular disorders were seen together at presentation. Treatment was with oral prednisolone and cyclophosphamide (eight patients), of whom one also had plasma exchange; and oral prednisolone and azathioprine (one patient). Specific immunosuppressive treatment was withheld in one patient with histological evidence of chronic renal damage. Sera from four patients out of nine tested were positive for ANCA. RESULTS: After a median follow-up of 3.5 years (range 2 months-10 years), renal function had improved in three patients and remained stable in two. Two patients required renal replacement therapy. Three patients had died: one was ANCA-negative and died of a systemic vasculitis, and the other two died of sepsis. CONCLUSION: Membranous nephropathy complicated by a vasculitic glomerulonephritis: (1) has a more aggressive clinical course than membranous nephropathy alone, (2) appears to have an association with ANCA, (3) should be considered in those patients with an accelerated decline in renal function, and (4) may respond to treatment with immunosuppressive drugs.
Adult↗
Glomerulonephritis and non-Hodgkin lymphoma.
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Adult↗
Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis.
We report ten patients with rheumatoid arthritis (RA) who developed a focal segmental necrotizing glomerulonephritis (FSNGN) and extracapillary proliferation typical of vasculitic glomerulonephritis. Five patients also had extrarenal vasculitis. Renal presentation was with renal impairment (n = 9) (median creatinine 726 mumol/l, range 230-1592 mumol/l), microscopic haematuria (n = 8) and proteinuria (n = 10). Nine patients were seropositive for rheumatoid factor and nine had bone erosions. Serum from four of five patients tested by indirect immunofluorescence was positive for antineutrophil cytoplasmic antibody (ANCA) with perinuclear staining. Only three patients had penicillamine or gold therapy. Treatment was with prednisolone and cyclophosphamide (six patients, two of whom were also plasma-exchanged), prednisolone and azathioprine (two patients) and prednisolone alone (two patients). There was a marked improvement in renal function in eight patients. Two patients with dialysis-dependent renal failure recovered renal function, although in one patient this was transient and she required further dialysis 4 months later. Two other patients progressed to dialysis at 3 months and 1 year respectively. Four patients died, one remains dialysis-dependent, and four continue to have good renal function at 5 year follow-up (median creatinine 148.5 mumol/l, range 120-193 mumol/l). One patient was lost to follow-up at 5 years. FSNGN should be considered in all patients with RA and renal impairment, proteinuria and/or microscopic haematuria. This diagnosis appears to be more likely in patients with clinical extrarenal vasculitis, bone erosions or who are seropositive. In these cases, an urgent renal biopsy is indicated.
Adult↗
Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis.
Although cyclophosphamide and prednisolone are effective in treating systemic vasculitis, the optimum treatment regimes and duration of treatment are unknown. We randomized 54 patients aged 15-70 years (median 57.5 years) with systemic vasculitis (classical polyarteritis n = 8, microscopic polyarteritis n = 17, Wegener's granulomatosis n = 29) to treatment with either pulse cyclophosphamide and prednisolone (PCYP) (n = 24) or continuous oral and prednisolone and cyclophosphamide, with the latter followed after a median of 3 months (range 1.5-10 months) by azathioprine (CCAZP) (n = 30). Patients on CCAZP were more likely to develop leucopenia (13/30) than patients on PCYP, (7/24) although the difference was not significant. The numbers of infective episodes during follow up were comparable in the two groups at 1.7/patient for PCYP and 1.66/patient for CCAZP. Overall, 26/30 patients (87%) treated with CCAZP developed treatment-related toxicity, as did 17/24 patients (71%) treated with PCYP. After a median follow-up of 40.4 months (range 0.7-64.8), there was no difference in the frequency of deaths (PCYP 5, CCAZP 4), relapses (PCCYP 7, CCAZP 8), treatment failures (PCYP 4, CCAZP 4), improvement in disease activity scores or renal function. Survival at three years was 77% in patients treated with PCYP, and 90% in patients on CCAZP (p = 0.38). There was a tendency towards increased toxicity in patients treated with the continuous regimen.
Adolescent↗
Cytokines in haemolytic uraemic syndrome associated with verocytotoxin-producing Escherichia coli infection.
The proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) interleukin (IL)-1 beta, IL-6, and IL-8 were measured in plasma and urine samples from 19 children with verocytotoxin-producing Escherichia coli (VTEC) induced haemolytic uraemic syndrome (HUS) and 30 controls. TNF-alpha was detected in the plasma of two cases and one control; IL-6 in the plasma of one, and the urine of two cases, and in the plasma of one control. IL-1 beta and IL-8 were each identified in eight of the 19 cases and in one and two controls respectively. Urinary IL-8 was found in seven cases, four of whom had plasma concentrations below the limit of detection suggesting renal secretion of this cytokine. Cytokine concentrations did not correlate with peripheral blood neutrophil count at onset of disease. These data confirm the systemic release of cytokines responsible for the coordination of acute inflammatory processes in some children with VTEC induced HUS.
Adolescent↗
Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM.
Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.
Adult↗
IL-1 beta production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis.
Neutrophils accumulate in the acute blood vessel lesions of patients with autoimmune systemic vasculitis. They have been shown previously to produce the cytokine IL-1 beta in response to stimulation with TNF. This study demonstrates that neutrophils can be stimulated by anti-neutrophil cytoplasmic antibodies (ANCA), which are present in patients with systemic vasculitis, to express mRNA and protein for IL-1 beta. Both human ANCA and MoAbs to a variety of autoantigens recognized by ANCA, including proteinase 3, myeloperoxidase, bactericidal/permeability increasing protein and elastase, are effective. This response can be inhibited by actinomycin and cycloheximide, suggesting a requirement for de novo protein synthesis. IL-1 beta production can be inhibited by pooled human intravenous immunoglobulins but not by FK506 or cyclosporin A. These data suggest that ANCA in patients with active vasculitis may stimulate neutrophils to produce cytokines. It is hypothesized that cytokine production from neutrophils that accumulate in significant numbers in vasculitic lesions contribute to and augment the local inflammatory response by the activation of vascular endothelial cells and infiltrating leucocytes.
Antibodies, Antineutrophil Cytoplasmic↗
Glomerular vascular cell adhesion molecule-1 expression in renal vasculitis.
AIMS: To study the expression of cell adhesion molecules in the renal biopsy specimens of patients with systemic vasculitis and Henoch-Schönlein purpura (HSP); to correlate this with the severity of glomerular inflammation. METHODS: Renal biopsy specimens obtained from eight patients with untreated systemic vasculitis (four with Wegener's granulomatosis and four with microscopic polyarteritis), eight with HSP and nine controls (four with normal histopathology and five with thin glomerular basement membrane disease) were stained using the alkaline phosphatase anti-alkaline phosphatase method with monoclonal antibodies directed against intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. RESULTS: Biopsy specimens of normal kidneys expressed ICAM-1 in glomerular endocapillary cells, Bowman's capsule epithelium, interstitial cells and interstitial vascular endothelium, and VCAM-1 in Bowman's capsule epithelium, proximal tubular epithelium and interstitial vascular endothelium. No staining with antibody directed against E-selectin was seen in any of the biopsy specimens. Biopsy specimens of patients with a vasculitic glomerulonephritis (segmental necrotising glomerulonephritis) expressed VCAM-1 in glomerular endocapillary cells (four of eight patients with systemic vasculitis; two of eight patients with HSP). In patients with a systemic vasculitis glomerular VCAM-1 expression was associated with a more severe renal lesoin (44, 50, 60, and 65% of glomeruli involved) than in those not showing glomerular VCAM-1 expression (3, 3, 11, and 39% of glomeruli involved). CONCLUSION: Expression of VCAM-1 by glomerular endocapillary cells in renal biopsy specimens raises the possibility that recruitment of VLA-4 bearing leucocytes may contribute to glomerular injury in Wegener's granulomatosis and microscopic polyarteritis.
Adolescent↗
Hemodialysis in the treatment of acute renal failure in tropical Africa: a 20-year review at the Korle Bu Teaching Hospital, Accra.
From 1972 to 1992, 170 patients with acute renal failure (87 M, 83 F; mean age 32.51 +/- SE 0.945) underwent hemodialysis at the renal unit of the Korle Bu Teaching Hospital, Accra. Vascular access was established initially by arteriovenous shunt (133 cases), femoral venous cannulation (10 cases), and subclavian vein cannulation (27 cases). The overall mortality for acute renal failure (ARF) was 31.8% (54/170). The mortality for obstetric cases was 43.7% (14/32); for surgical cases, 33.3% (6/18); medical cases, 28.3% (13/32); and gynecologic (posthysterectomy) cases, 28.3% (2/7). The most important causes of death in ARF were pulmonary edema (42%), sepsis (20%), and cardiac tamponade (10.4%). Hemodialysis is now established as a form of treatment for ARF and a overall survival rate of 68.2% justifies the development of our program. With improvement of economies of developing countries and health insurance schemes, this form of treatment should be available in all developing countries.
Acute Kidney Injury↗
Blackwater fever and acute renal failure in expatriates in Africa.
From September 1976 to July, 1993, 7 patients---5 Europeans, 1 Filipino national, and 1 Korean---were admitted to the Renal Unit of Korle Bu Teaching Hospital in Ghana with acute renal failure due to severe malaria and intravascular hemolysis. All these patients had been in the Tropics 3 to 8 weeks and none were no malarial prophylaxis. All needed dialysis because of severe uremic symptoms. Four patients survived and 3 died. It is recommended that nationals from nonmalarial countries be counselled on the extreme importance of malarial prophylaxis when visiting Tropical areas where malaria is endemic.
Acute Kidney Injury↗
The nephrotic syndrome: does renal biopsy affect management?
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Adult↗
Low calcium dialysate and hyperparathyroidism.
A low calcium dialysate reduces hypercalcemia from calcium-containing phosphate binders and makes phosphate control possible without the use of aluminum salts. We asked whether this might, however, lead to hyperparathyroidism. We prospectively studied serum concentrations of parathyroid hormone levels (by an immunoreactive intact molecule assay) in 173 patients on continuous ambulatory peritoneal dialysis (CAPD) who were started on a low calcium dialysate (Ca2+ 1.25 or 1.00 mmol/L) because of hypercalcemia. Median follow-up was 13.2 months (range 1-28). Initial serum parathyroid hormone was [median(range)]: 70(5-1043) ng/L pre low calcium dialysate, and this rose to 130(5-914) ng/L at 0-6 months; 130(5-1030) ng/L at 6-12 months; 170(170-1400) ng/L at 12-18 months; and 130(5-1200) ng/L at 18-24 months (p = 0.0006). Twenty-two patients required a parathyroidectomy because of a sustained rise in parathyroid hormone that was not responsive to alfacalcidol and hypercalcemia. Initial serum parathyroid hormone was significantly higher in these patients at 359 (5-1073) ng/L as compared to a level of 69.5 (6-1147) ng/L in patients who did not have a parathyroidectomy (p = 0.0009). There was a significant sustained fall in mean serum corrected calcium from 2.77 (2.37-3.51) mmol/L to 2.53 (1.39-3.20) mmol/L at three months (p = 0.0006), a nonsignificant rise in mean serum alkaline phosphate from 179 (47-1858) mmol/L to 191 (55-1821) mmol/L (p = 0.15), and a fall in mean serum phosphate levels from 1.87 (0.59-3.18) mmol/L to 1.68 (0.45-3.6) mmol/L (p = 0.76). Our data suggest that the benefits of a low calcium dialysate in CAPD patients are balanced by an increased risk of hyperparathyroidism, and that this risk is higher in patients with an initially high serum parathyroid hormone level.
Adult↗
Soluble circulating cell adhesion molecules in haemolytic uraemic syndrome.
Plasma concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) were measured by enzyme-linked immunosorbent assay in four groups of children. Group 1 consisted of 20 patients with acute diarrhoea-associated haemolytic uraemic syndrome (D+HUS), the aetiology of HUS being verocytotoxin-producing Escherichia coli infection in each case. Controls consisted of 11 patients who had previously had D+HUS (group 2), 12 with chronic renal failure (group 3) and 8 healthy controls (group 4). When compared with healthy controls, the acute D+HUS group had higher sVCAM-1 (median 1,875 ng/ml, range 1,200-6,450 ng/ml vs. 1,200 ng/ml, range 975-2,125 ng/ml), von Willebrand factor antigen, (1.9 U/ml, range 0.85-5.1 U/ml vs. 0.55 U/ml, range 0.3-1.57 U/ml), white cell count (WBC, 14.5 x 10(9)/l, range 7.8-43.1 10(9)/l vs. 8.9 10(9)/l, range 5.7-10.8 10(9)/l) and neutrophil count (PMN, 10.1 x 10(9)/l, range 4.3-26.5 10(9)/l vs. 4.3 10(9)/l, range 3.7-6.6 10(9)/l), all P < 0.005, and sICAM-1 was reduced (230 ng/ml, range 130-340 ng/ml vs. 400 ng/ml, range 260-690 ng/ml), P < 0.05. Within the acute D+HUS group there was a significant correlation between sICAM-1 and PMN (r = 0.56, P < 0.01). There was no correlation between any adhesion molecule and plasma creatinine or von Willebrand factor. Comparing the acute HUS group with children with chronic renal failure, WBC (P < 0.001), PMN (P < 0.01) and sVCAM-1 (P < 0.01) were significantly elevated, but there was no difference between the von Willebrand factor (P = 0.08) or the sICAM-1 (P > 0.1). sVCAM-1 is elevated and sICAM-1 decreased in acute D+HUS. This pattern of altered adhesion molecule concentration is unlike that in adults with vasculitis and suggests that different endothelial regulatory factors are at play.
Acute Disease↗
Anti-epithelial (anti-A549) antibodies: their nature, specificity and relevance to transplantation.
Several studies have addressed the possible importance of anti-epithelial cell antibodies in kidney transplantation using the A549 cell line as an in vitro model. In this paper we report our results using for the first time an enzyme-linked immunosorbent assay (ELISA) to detect the anti-A549 cell antibodies. Sera from 129 kidney transplant patients were tested for IgM anti-epithelial cell antibodies directed against the A549 cell line prior to transplantation; only three sera were positive (2.3%). 101 of these patients were then followed-up post-transplantation; sera were collected routinely at 2, 6 and 12 weeks and at the time of rejection episodes. All samples were also tested for cytomegalovirus (CMV) IgM antibodies. Sixteen patients developed anti-A549 IgM antibodies, and there was no correlation with acute graft rejection. Anti-epithelial antibodies showed no binding to sections of normal kidney or biopsies of rejected kidneys. Eleven patients were positive for anti-CMV IgM antibodies. In nine cases both IgM anti-A549 and IgM anti-CMV antibodies were found, which was a highly significant association (p < 0.001). Analysis of A549 cellular proteins by immunoblotting gave evidence for the presence of CMV polypeptides in the cell lysate. Electron-microscopic examination of A549 cell preparations revealed intracellular particles which were compatible in size with CMV. Polymerase chain reaction analysis confirmed the presence of a specific CMV DNA sequence in A549 cells of several batches from different sources. Our data strongly suggest that the A549 cell line used in several published reports is infected with CMV and that in the majority of cases the anti-A549 'anti-epithelial' antibodies found in renal transplant patients are anti-CMV antibodies.
Adolescent↗
Circulating soluble adhesion molecules in inflammatory bowel disease.
OBJECTIVE: To determine levels of soluble forms of the cell adhesion molecules (CAM), ICAM-1, E-Selectin and VCAM-1 in relation to prevalence, treatment and disease activity in inflammatory bowel disease. PATIENTS AND METHODS: Plasma was obtained from patients with ulcerative colitis (n = 49), patients with ulcerative colitis who had undergone restorative proctocolectomy (n = 32, eight of whom had a clinical pouchitis), Crohn's disease patients (n = 34) and 24 healthy controls. RESULTS: Plasma soluble ICAM-1 levels [medians (ranges in ng/ml)] were significantly higher in patients with active ulcerative colitis [270 (90-510)], pouchitis [415 (310-670)] and active Crohn's disease [305 (200-630)] than in those with inactive ulcerative colitis [225 (140-425), P = 0.031], non-inflamed ileoanal pouch [260 (140-380), P = 0.0004] and inactive Crohn's disease [245 (90-520), P = 0.045], respectively, and controls. The soluble E-Selectin levels were also significantly higher in patients with active ulcerative colitis [55 (40-140)], pouchitis [90 (45-145)], and active Crohn's disease [78 (30-115)] than in those with inactive ulcerative colitis [45 (20-80, P = 0.003], non-inflamed ileoanal pouch [45 (20-90), P = 0.001] and inactive Crohn's disease [48 (25-90, P = 0.020], respectively, and controls. CONCLUSIONS: The present study suggests that increased levels of soluble ICAM-1 and soluble E-Selectin occur during active inflammatory bowel disease and pouchitis, which may be used as sensitive markers of continuing inflammation.
Adult↗