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J Savige

Publications and source records attributed to J Savige.

At least 37 records · Page 2Linked to original sources
PubMed1999

International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)

Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms. Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

A comparison of the clinical and laboratory features of thin basement membrane disease (TBMD) and IgA glomerulonephritis (IgA GN).

AIM: The aim of this study was to determine the clinical and laboratory characteristics that distinguished thin basement membrane disease (TBMD) from IgA glomerulonephritis (IgA GN) at presentation and at follow-up. PATIENTS AND METHODS: Seventy-one patients with TBMD and 31 with IgA GN were studied. Males accounted for 11/71 (15%) patients with TBMD, and 20/31 (65%) of those with IgA GN (p < 0.001). RESULTS: At presentation, patients with TBMD had hematuria (42%) or proteinuria (42%), and sometimes both (24%), while those with IgA GN usually had both hematuria and proteinuria (71%, p < 0.0001). Furthermore, patients with IgA GN were more likely to have higher urinary RBC counts (p < 0.001), and more proteinuria (p < 0.001) than those with TBMD. An elevated serum creatinine or blood pressure did not distinguish between TBMD and IgA GN at presentation. At review, fewer individuals with IgA GN had elevated levels of urinary RBC and protein, and the proportions were not different from those in patients with TBMD. This was presumably because the acute episode had resolved. CONCLUSION: The outcome was worse in patients with IgA GN, with 8/31 (26%) having an elevated serum creatinine and 3/31 (10%) with end-stage renal failure, compared with an elevated serum creatinine in 3/61 (5%) patients with TBMD (p < 0.02) and no patients with renal failure (p < 0.05).

Adolescent↗
PubMed1998

Anti-glomerular basement membrane (GBM)-antibody-mediated disease with normal renal function.

BACKGROUND: This study compared the clinical and laboratory characteristics of patients with anti-glomerular basement membrane (GBM) disease and normal renal function, with those of patients with anti-GBM disease where there was renal impairment. METHODS: The medical records of the 14 patients who had presented with anti-GBM disease to our hospital in the past 20 years were reviewed. RESULTS: Five (36%) had a normal serum creatinine or creatinine clearance at presentation. Other features were haemoptysis (2/5, 40%), macroscopic haematuria (2/5, 40%) or systemic symptoms (1/5, 20%). All five (100%) had some degree of haematuria, four (80%) had proteinuria of at least 1 g/day, and none was hypertensive. Anaemia, a raised WCC, or elevated ESR (> 35 mm/h) occurred less often than in patients with impaired renal function (P<0.05). Two of the five (40%) with normal renal function had circulating anti-GBM antibodies, which were present at low or moderate levels; but seven of the nine with renal impairment (77%) had circulating antibodies, with high levels in five. Renal biopsies from patients with normal renal function were normal (1/5, 20%), showed mesangial proliferation (4/5, 80%) or had more than 20% glomeruli sclerosed (1/5, 20%). Complement deposition was present in 2/4 biopsies (50%). The kidneys from patients with renal impairment had crescents in more than 50% glomeruli (9/9, 100%), and four had more than 20% glomeruli sclerosed (44%). All four kidneys from patients with renal impairment that were examined had complement deposits (100%). Treatment was identical in both groups; patients with normal renal function were followed for a median of 48 months, and those with renal impairment for 180 months. There were no further episodes of haemoptysis, haematuria, or other symptoms of relapse in either group. All five patients with normal renal function are alive, and the serum creatinine is less than 0.2 mmol/l in all (100%), but haematuria persists in one (20%), and proteinuria >1 g/day in two (40%). Eight of the nine (89%) patients with impaired renal function survive, but all are currently being dialysed or have had a renal transplant. CONCLUSION: Patients with anti-GBM disease with normal renal function are not uncommon, and often have a good prognosis. There is less renal damage, possibly because of lower levels of circulating anti-GBM antibodies and less glomerular complement deposition.

Adolescent↗
PubMed1998

Antineutrophil cytoplasmic antibody (ANCA)-positive cutaneous leucocytoclastic vasculitis associated with antithyroid therapy in Graves' disease.

Presented is a case of a 27-year-old male with Graves' disease on long-term propylthiouracil treatment who, when changed to carbimazole, rapidly developed a petechial and purpuric eruption on the legs, which subsequently flared on treatment with radioiodine. The clinical diagnosis of leucocytoclastic vasculitis was confirmed on skin biopsy. High-titre antineutrophil cytoplasmic antibodies in a perinuclear pattern (P-ANCA) were identified. No anti-myeloperoxidase activity was noted; therefore, the P-ANCA were classified in the atypical group. The target antigens, as determined by enzyme-linked immunosorbent assay, were lysozyme, lactoferrin and bactericidal/permeability increasing protein. Propylthiouracil and carbimazole are chemically related antithyroid drugs. There are reports of typical and atypical P-ANCA-positive cutaneous vasculitis due to propylthiouracil. Cutaneous vasculitis associated with atypical P-ANCA has not been noted previously to be temporally related to carbimazole use. The consideration of thionamides as possible aetiological agents in cases of P-ANCA-positive drug-induced vasculitis is suggested.

Adult↗
PubMed1997

Ocular abnormalities in thin basement membrane disease.

AIM/BACKGROUND: Alport syndrome is an X linked disease that results in renal failure, deafness, and ocular abnormalities including a dot and fleck retinopathy and anterior lenticonus. The ultrastructural appearance of the glomerular basement membrane in thin basement membrane disease (TBMD) resembles that seen in some patients with Alport syndrome, and in some cases this disease is inherited too. The aim of this study was to determine whether patients with TBMD have any ocular abnormalities. METHODS: The eyes of 17 unrelated individuals with TBMD were studied by slit-lamp, including biomicroscopic fundus examination with a 78 D lens, by direct ophthalmoscopy, and by fundal photographs. The findings were compared with those in patients with IgA glomerulonephritis or Alport syndrome, and in normals. RESULTS: No patient with TBMD had a dot and fleck retinopathy or anterior lenticonus. A corneal dystrophy (n = 2) or pigmentation (n = 1), and retinal pigment epithelial clumping and maculopathy (n = 1) were noted. Corneal, lens, and retinal dots were found in five (29%), three (18%), and 16 (94%) patients, respectively, but these were also demonstrated in individuals with other renal diseases and in normal individuals. CONCLUSIONS: The dot and fleck retinopathy and anterior lenticonus typical of Alport syndrome do not occur in TBMD. The protein abnormality and genetic defect in TBMD are not known, but the lack of ocular lesions suggests that the abnormal protein in this disease is more sparsely distributed or less important in the basement membranes of the eye than of the kidney. Alternatively, the protein may be less affected by the mutations responsible for TBMD.

Adolescent↗
PubMed1997

Alport syndrome. A review of the ocular manifestations.

Alport syndrome has a prevalence of 1/5000, and 85% of patients have the X-linked form, where affected males develop renal failure and usually have a high-tone sensorineural deafness by the age of 20. The typical ocular associations are a dot-and-fleck retinopathy which occurs in about 85% of affected adult males, anterior lenticonus which occurs in about 25%, and the rare posterior polymorphous corneal dystrophy. The retinopathy and anterior lenticonus are not usually demonstrated in childhood but worsen with time so that the retinal lesion is often present at the onset of renal failure, and the anterior lenticonus, later. The demonstration of a dot-and-fleck retinopathy in any individual with a family history of Alport syndrome or with end-stage renal disease is diagnostic of Alport syndrome. The presence of anterior lenticonus or posterior polymorphous corneal dystrophy in any individual is highly suggestive of the diagnosis of Alport syndrome. Additional ocular features described in X-linked Alport syndrome include other corneal dystrophies, microcornea, arcus, iris atrophy, cataracts, spontaneous lens rupture, spherophakia, posterior lenticonus, a poor macular reflex, fluorescein angiogram hyperfluorescence, electrooculogram and electroretinogram abnormalities, and retinal pigmentation. All mutations demonstrated to date in X-linked Alport syndrome have affected the COL4A5 gene which encodes the alpha 5 chain of type IV collagen. This protein is probably common to the basement membranes of the glomerulus, cochlea, retina, lens capsule, and cornea. However, the alpha 3(IV) and 4(IV) as well as the alpha 5(IV) collagen chains are usually absent from the affected basement membranes, because the abnormal alpha 5(IV) molecule interferes with the stability of all three. The loss of these collagen molecules from the affected basement membranes results in an abnormal ultrastructural appearance. The ocular and other clinical features of autosomal recessive Alport syndrome are identical to those seen in X-linked disease, while retinopathy and cataracts are the only ocular abnormalities described in the rare autosomal dominant form of Alport syndrome. There are no ocular associations of thin basement membrane disease which is a common disease that probably represents the heterozygous expression of X-linked or autosomal recessive Alport syndrome.

Animals↗
PubMed1997

Ocular manifestations of autosomal recessive Alport syndrome.

Ocular abnormalities are common in X-linked Alport syndrome, but they have not been studied in patients with the rarer autosomal recessive disease. We have examined the eyes of a family with autosomal recessive Alport syndrome. Four of the eight offspring of a consanguineous marriage had renal failure and deafness by the age of 20 years. The diagnosis of Alport syndrome was confirmed on the ultrastructural demonstration of a lamellated glomerular basement membrane (GBM) in one affected family member. Autosomal recessive inheritance was suggested by the lack of linkage to the COL4A5/COL4A6 locus, and by linkage to the COL4A3/COL4A4 locus. All four affected family members had anterior lenticonus (or had had a lens replacement for this) and the three who were examined had a dot-and-fleck retinopathy. Neither of the two unaffected offspring who were examined nor the father had these abnormalities. The ocular manifestations of autosomal recessive Alport syndrome are probably identical to those for the X-linked form. Although the mutations in these diseases affect genes for different type IV collagen chains, these chains occur together in the basement membranes of the kidney, eye and ear, and abnormalities in any one may result in the same clinical phenotype.

Adult↗
PubMed1997

Classical polyarteritis nodosa and microscopic polyarteritis with medium vessel involvement--a comparison of the clinical and laboratory features.

Microscopic polyarteritis may involve medium-sized and small blood vessels as well as arterioles, venules and capillaries. We have compared the clinical and laboratory features in patients with microscopic polyarteritis and medium vessel involvement, with the features found in patients with polyarteritis nodosa affecting medium vessels alone. In a 9-year period, 21 patients presented to our hospital with a form of polyarteritis. Seven had microscopic polyarteritis demonstrated histologically (6/7, 86%) and associated with dysmorphic urinary red cells (7/7, 100%), as well as medium vessel vasculitis demonstrated histologically (7/7) or by angiography (1/7, 14%). Five patients had polyarteritis nodosa with medium vessel vasculitis demonstrated histologically (3/5, 60%) or by angiography (2/5, 40%); and no evidence of a glomerular vasculitis on biopsy (2/7, 29%) or in the urinary sediment (0/7, 0%). The remaining 9 patients had microscopic polyarteritis but medium vessel involvement was not excluded by angiography. All patients with microscopic polyarteritis and medium vessel involvement had glomerular hematuria (> 100,000 glomerular RBC/ml), proteinuria > 0.5 g/24 hours), and an elevated serum creatinine (0.166 to 0.811 mmol/l). Other symptoms included fever (6/7, 86%), night sweats (5/7, 71%), gastrointestinal bleeding (4/7, 57%), proximal myopathy (3/7, 43%) and peripheral neuropathy (3/7, 43%). One patient (1/7, 14%) had hypertension. Anemia (6/7, 86%), a raised ESR (6/7, 86%), thrombocytosis (6/7, 86%), hypoalbuminemia (6/7, 86%) and abnormal liver function tests (6/7, 86%) were common. Two patients (29%) had an eosinophilia. All 5 individuals who were tested for ANCA were positive (2cANCA, 2pANCA and one pattern not described). In contrast, in patients with polyarteritis nodosa and medium vessel involvement alone, an elevated ESR was common (4/5, 80%) but fever (1/5, 20%), night sweats (0/5, 0%), proximal myopathy (1/5, 20%) and peripheral neuropathy (1/5, 20%) were seen infrequently; hypertension (1/5, 20%) and eosinophilia (1/5, 20%) were also uncommon; and ANCA were not demonstrated (0/3, 0%). Medium-sized vessel involvement is common in patients with microscopic polyarteristis, and these patients are more likely to have renal involvement and systemic symptoms, and be ANCA-positive, than patients with polyarteritis nodosa alone. Gastrointestinal symptoms are often seen in both groups.

Adult↗
PubMed1996

Clinical features in two patients with IgA glomerulonephritis and thin-basement-membrane disease.

BACKGROUND: Both IgA glomerulonephritis (IgA gn) and thin basement membrane disease (TBMD) are common forms of glomerulonephritis. Patients with these conditions may present with identical clinical features, but higher urinary RBC counts, heavier proteinuria, and impaired renal function are more common in patients with IgA gn. Because IgA gn and TBMD are common, some patients will have both diseases. SUBJECTS: We describe the clinical features of two individuals with both Iga gn and TBMD, and compare them with the clinical and laboratory characteristics in patients with TBMD (n=15) or IgA gn (n=32) alone. RESULTS: IgA gn was found in two individuals of the 110 with TBMD who were studied. They both had haematuria with >/100 000 RBC/ml and proteinuria >0.2/day (one had more than 1 g/day). These features were more consistent with Iga gn than TBMD alone. However, both individuals had normal serum creatinine and creatinine clearance at presentation. Additional clinical features were macroscopic haematuria in one and hypertension in both. CONCLUSIONS: IgA deposits are not uncommon in patients with TBMD, and these patients have clinical features that resemble those seen in IgA gn rather than TBMD. Patients with both IgA gn and TBMD do not necessarily have the worse prognosis noted in some patients with Iga gn.

Basement Membrane↗
PubMed1996

Polyarteritis nodosa and antiglomerular basement membrane disease without antineutrophil cytoplasm antibodies.

Antiglomerular basement membrane (GBM) antibodies have been described previously in patients with microscopic polyarteritis but not in patients with polyarteritis nodosa alone. Where anti-GBM antibodies occur in microscopic polyarteritis, antineutrophil cytoplasm antibodies (ANCA) are usually present. We describe here a patient with polyarteritis nodosa and anti-GBM antibodies in whom ANCA could not be demonstrated. A 72-year-old woman presented with abdominal pain, diarrhoea and acute renal failure. A renal biopsy showed crescentic glomerulonephritis and linear immunofluorescence of the GBM consistent with anti-GBM disease. In addition, there was evidence of large-and medium-sized vessel vasculitis on abdominal angiography, performed because of persisting abdominal pain. There was no small vessel vasculitis on histological examination of the renal biopsy and ANCA could not be demonstrated by indirect immunofluorescence or ELISA.

Acute Kidney Injury↗
PubMed1995

Bull terrier hereditary nephritis: a model for autosomal dominant Alport syndrome.

Bull terrier hereditary nephritis is inherited as an autosomal dominant disease and causes renal failure at variable ages in affected dogs. The aims of this study were to compare the clinical, ultrastructural and immunohistochemical features of bull terrier hereditary nephritis with the characteristics of the human forms of Alport syndrome. Many animals with bull terrier hereditary nephritis have hematuria, and some have anterior lenticonus. However, deafness is not associated with the renal disease, and affected dogs do not have the large platelets that are occasionally seen in patients with autosomal Alport syndrome. The glomerular capillary basement membrane (GCBM) in affected bull terriers has an identical ultrastructural appearance to that seen in X-linked Alport syndrome, with lamellations and intramembranous electron-dense deposits. However, both the Goodpasture and the Alport antigens, which represent parts of the alpha 3(IV) and alpha 5(IV) collagen chains, respectively, are present in the GCBM of affected dogs. Bull terrier hereditary nephritis represents an animal model for autosomal dominant Alport syndrome, and can be used to further examine how genetic mutations affect a basement membrane protein and the corresponding membrane structure.

Animals↗
PubMed1995

Epitope mapping of anti-proteinase 3 and anti-myeloperoxidase antibodies.

Anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO) autoantibodies are present in many patients with Wegener's granulomatosis (WG) and microscopic polyarteritis. The aim of this study was to determine whether these antibodies bound to linear peptide sequences on their target antigens. If common linear epitopes were demonstrated, then these could be manufactured and used in diagnostic ELISAs for anti-PR3 and anti-MPO antibodies. In addition, any homology between these epitopes and bacterial or viral sequences might implicate those microorganisms in the development of these antibodies and the pathogenesis of the associated diseases. The presence of linear epitopes on PR3 and MPO was suggested by the binding of the corresponding autoantibodies to these proteins after they had been reduced with beta-mercaptoethanol (beta-ME) and denatured with SDS or boiling, and digested with proteases. Four of the 22 sera with anti-PR3 antibodies bound to PR3 in Western blots after treatment with SDS, beta-ME and boiling for 5 min. Thermal denaturation reduced the amount of binding more than other forms of denaturation. One serum with anti-PR3 antibodies bound to Lys-C and Glu-C-digested PR3 in dot blots. Linear epitopes could not be further defined by their binding in an ELISA using overlapping peptides corresponding to the PR3 molecule because of non-specific binding. Three of the five sera with anti-MPO antibodies bound to MPO in Western blots after treatment with SDS, beta-ME and boiling for 5 min. One serum with anti-MPO antibodies bound to Lys-C and Glu-C-digested MPO in dot blots. Again, linear epitopes could not be further defined using an ELISA with overlapping peptides because of non-specific binding. Some anti-PR3 and anti-MPO antibodies are likely to recognize linear epitopes, but these cannot be defined by use of a PIN ELISA system.

Amino Acid Sequence↗
PubMed1995

Lupus anticoagulant in anti-neutrophil cytoplasmic antibody-associated polyarteritis.

Lupus anticoagulant has been described in association with many autoimmune disorders. Here we describe its occurrence in a patient with ANCA-associated microscopic polyarteritis with medium vessel involvement. A 62-year-old man presented with mononeuritis multiplex and abdominal pain and was demonstrated to have multiple aneurysms on visceral angiography, consistent with the diagnosis of medium vessel vasculitis or classical polyarteritis nodosa. In addition he had active tuberculosis. He developed a deep venous thrombosis at this admission and, on one occasion, had a prolonged APTT but this was not confirmed to be due to a lupus anticoagulant. Two years later when the patient was readmitted with fevers, headaches and nasal discharge, both ANCA and a lupus anticoagulant were demonstrated in his serum, although there was no evidence of a venous thrombosis. Six months later the patient was demonstrated for the first time to have dysmorphic urinary RBC consistent with glomerular bleeding; at the same time he developed a deep venous thrombosis. ANCA was still present, but the lupus anticoagulant could not be detected. The patient was treated with cyclophosphamide and prednisolone and a Greenfield filter inserted into his inferior vena cava.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1994

Albipunctatus retinopathy in inherited interstitial nephritis.

We describe here a patient with familial interstitial nephritis and albipunctatus retinopathy. Albipunctatus is often seen in patients with Alport syndrome, which is an X-linked disorder characterised in affected males by renal failure by the age of 25, high-tone sensorineural deafness, anterior lenticonus and albipunctatus. The diagnosis of Alport syndrome depends on the electron microscopic appearance of a trabeculated glomerular basement membrane (GBM); and mutations have been demonstrated in the gene for the alpha 5 chain of type IV collagen. In the familial interstitial nephritis described here, the inheritance was autosomal dominant, renal failure developed in middle age, and there was no associated hearing loss or anterior lenticonus. The finding of albipunctatus retinopathy in this patient suggests that the genetic mutation responsible involves a protein common to both retinal and interstitial basement membranes. In addition, we conclude that the demonstration of albipunctatus in an individual with familial nephritis does not necessarily indicate that the underlying disease is Alport syndrome.

Basement Membrane↗
PubMed1993

Studies to demonstrate inhibition of functional activity of neutrophil lysosomal enzymes with ANCA.

Many autoantibodies that have enzymes as their targets bind to the catalytic sites and inhibit enzymatic activity. We have established functional assays for the targets of anti-neutrophil cytoplasm antibodies (ANCA) in order to determine whether these antibodies are directed against the corresponding catalytic sites. Anti-proteinase 3 activity was measured by the cleavage of alpha-naphthyl acetate; myeloperoxidase activity by peroxidation of monochlorodimedon or guaiacol using hydrogen peroxide; and elastase activity by a fluorimetric assay of the hydrolytic product of N-succ (ala)3 amido-methyl coumarin. The addition of immunoglobulin from patients with ANCA to these assays did not result in inhibition of functional activity of the corresponding enzyme when compared with normal immunoglobulin. Furthermore the removal of specific immunoglobulin by solid phase adsorption to the corresponding antigen did not result in an increase in enzymatic activity compared with the starting material. However preliminary results suggest that anti-neutrophil proteinase 3 binding may be inhibited in a solid-phase ELISA by preincubation with a peptide corresponding to the catalytic site.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1991

Hereditary abnormalities of renal basement membranes.

The glomerular and tubular basement membranes are the principal barriers to filtration and re-absorption of water and molecules in the nephron. They are composed primarily of type IV collagen, laminin, fibronectin, sulphated proteoglycans and collagen type I. Three common inherited diseases are associated with abnormalities of basement membrane proteins: Alport's syndrome, thin basement membrane disease (TBMD) and adult polycystic kidney disease. In this review we describe the application of molecular biological techniques to the study of these conditions. Classic Alport's syndrome is an X-linked disorder with a lamellated glomerular basement membrane (GBM) which typically results in renal failure in males. Studies with sera from patients with Goodpasture's syndrome, or monoclonal antibodies specific for the Goodpasture antigen, show that the Goodpasture antigen is absent or masked in the kidneys of individuals with Alport's syndrome. There is some evidence to suggest that the Goodpasture antigen is best represented by the non-collagenous domain of the alpha 3 chain of type IV collagen, but that other non-collagenous regions may also contribute to the antigen. It is through these non-collagenous regions that the type IV collagen chains form the typical network, and the abnormality in Alport's syndrome interferes with this network formation. However, we have recently demonstrated that the gene for the non-collagenous domain of the alpha 3 collagen chain is present in individuals with Alport's syndrome. Furthermore, other groups have shown a defect in a novel type IV collagen chain, the alpha 5 chain, in 3 unrelated cases of Alport's syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Basement Membrane↗