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Biomedical subjects

R J Falk

Publications and source records attributed to R J Falk.

At least 109 records · Page 6Linked to original sources
PubMed1991

Wegener's granulomatosis, systemic vasculitis, and antineutrophil cytoplasmic autoantibodies.

Systemic vasculitis is often difficult to diagnose. The recent discovery of a new class of autoantibodies [antineutrophil cytoplasmic autoantibodies (ANCA)] provides clinicians with a serological test that strongly supports the diagnosis of the most common forms of systemic necrotizing vasculitis. The spectrum of patients with this form of vascular inflammation ranges from those with renal-limited glomerulonephritis to patients with multisystem disease, including Wegener's granulomatosis and polyarteritis nodosa.

Autoantibodies↗
PubMed1990

Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network.

OBJECTIVES: To determine the spectrum of clinical manifestations in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis; to determine renal and patient survival in these patients; to compare survival among patients treated with corticosteroids alone, corticosteroids plus intravenous cyclophosphamide or corticosteroids plus oral cyclophosphamide; and to assess the correlation of disease manifestations and treatment response with ANCA subtypes and serial autoantibody titers. DESIGN: Inception cohort study; mean follow-up of 24 months. SETTING: Collaborative network of 120 university and private practice nephrologists (The Glomerular Disease Collaborative Network). PARTICIPANTS: Seventy patients with ANCA and pauci-immune necrotizing and crescentic glomerulonephritis, of whom 59 were treated with either corticosteroids alone (14 patients), corticosteroids plus oral cyclophosphamide (30 patients), or corticosteroids plus intravenous cyclophosphamide (15 patients). MAIN RESULTS: Of the 70 patients, 18 had renal-limited disease (idiopathic crescentic glomerulonephritis); 15, nonpulmonary extrarenal disease consistent with polyarteritis nodosa; and 37, pulmonary disease consistent with Wegener granulomatosis or alveolar capillaritis. There were overlapping manifestations of disease between patients with autoantibodies producing a cytoplasmic pattern and patients with autoantibodies producing a perinuclear pattern; however, the perinuclear pattern occurred more frequently in patients with renal-limited disease. Renal and patient survival was 75% at 24 months, and no difference in survival was seen between patients with renal-limited disease and those with systemic disease. No differences in survival were seen between patients treated with oral cyclophosphamide and those treated with intravenous cyclophosphamide; however, the comparative data from patients treated with corticosteroids alone were inconclusive. In general, autoantibody titers correlated with response to treatment and disease activity, but there were exceptions. CONCLUSIONS: Patients with ANCA have various forms of necrotizing vascular inflammation, ranging from renal-limited disease to widespread systemic vasculitis, including polyarteritis nodosa and Wegener granulomatosis. Oral corticosteroids with either oral or intravenous cyclophosphamide appear to be equally effective therapy for ANCA-associated glomerulonephritis.

Adolescent↗
PubMed1990

Diagnosis and management of glomerulonephritis and vasculitis presenting as acute renal failure.

Acute and rapidly progressive renal failure is caused by a number of pathogenetically distinct types of glomerulonephritis, some of which are associated with systemic vasculitis. In a given patient, accurate diagnosis of the specific type of glomerulonephritis is essential for optimum treatment. Making a specific diagnosis usually requires renal biopsy or serologic analysis. The two categories of treatment for glomerulonephritis are (1) treatment for the pathophysiologic complications of glomerulonephritis, such as hypertension, fluid overload, and uremia, and (2) treatment for the inflammatory injury, which usually employs immunosuppression with steroids and cytotoxic drugs.

Acute Disease↗
PubMed1990

Adult minimal change glomerulopathy with acute renal failure.

Oliguric acute renal failure occurs in some adult patients with minimal change glomerulopathy. To look for clinical and pathologic factors that increase the risk for developing acute renal failure, 21 adults with minimal change glomerulopathy and a serum creatinine greater than 177 mumol/L (mean, 486 mumol/L; range, 194 to 1,344 mumol/L) (greater than 2.0 mg/dL [mean, 5.5 mg/dL; range, 2.2 to 15.2 mg/dL]) were compared with 50 adults with minimal change glomerulopathy and a serum creatinine less than 133 mumol/L (mean, 88 mumol/L; range, 53 to 124 mumol/L) (less than 1.5 mg/dL [mean, 1.0 mg/dL; range, 0.6 to 1.4 mg/dL]). Minimal change glomerulopathy patients with acute renal failure were older (59.5 v 40.3 years, P less than 0.001), and had higher systolic blood pressure (158 v 138 mm Hg, P = 0.001), more proteinuria (13.5 v 7.9 g/24 h, P = 0.01), and more arteriosclerosis in the renal biopsy specimen (1.7 + v 0.7 + on a scale of 0 to 4+, P = 0.005). Tubular epithelial simplification identical to that observed with ischemic acute renal failure (acute tubular necrosis) was observed in 71% of the patients with serum creatinine greater than 177 mumol/L (greater than 2.0 mg/dL) and 0% of those with less than 133 mumol/L (less than 1.5 mg/dL). All 18 patients with renal failure for whom follow-up data were available had recovery of function (mean creatinine, 539 +/- 301 mumol/L [6.1 +/- 3.4 mg/dL] at the time of biopsy and 106 +/- 27 mumol/L [1.2 +/- 0.3 mg/dL] at last follow-up), but sometimes only after weeks of dialysis support.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1990

Antineutrophil cytoplasmic autoantibodies and associated diseases: a review.

Antineutrophil cytoplasmic autoantibodies (ANCA) are specific for constituents of neutrophil primary granules and monocyte lysosomes. There are different types of ANCA with different specificities. By indirect immunofluorescence microscopy using alcohol-fixed neutrophils as substrate, two major categories of ANCA can be recognized, one with cytoplasmic staining (C-ANCA) and the other with artifactual perinuclear staining (P-ANCA). Some C-ANCA have specificity for proteinase 3 (PR3-ANCA) and some P-ANCA have specificity for myeloperoxidase (MPO-ANCA), but there are additional C-ANCA and P-ANCA specificities. ANCA are found in the blood of patients with necrotizing systemic vasculitis, such as Wegener's granulomatosis and polyarteritis nodosa, and patients with idiopathic crescentic glomerulonephritis. The glomerular lesion in patients with systemic and renal-limited ANCA-associated diseases is the same, ie, a pauci-immune necrotizing and crescentic glomerulonephritis. No matter where the vascular lesions of ANCA-associated disease are (eg, kidney, lung, gut, muscle, skin), they are characterized by necrotizing inflammation and a paucity of immune deposits. The distribution of disease correlates to a degree with the ANCA specificity, although there is substantial overlap. For example, patients with Wegener's granulomatosis most often have C-ANCA and patients with renal-limited disease most often have P-ANCA. In patients with P-ANCA-associated glomerulonephritis, approximately 90% of the P-ANCA have specificity for MPO. The clinical manifestations of ANCA-associated diseases often begin following a flu-like illness. The onset is most often in the winter and least often in the summer. The renal disease usually presents as rapidly progressive renal failure with nephritis. One of the most life-threatening components of the systemic involvement is pulmonary hemorrhage caused by a necrotizing alveolar capillaritis. Intravenous cyclophosphamide plus steroids is as effective as oral cyclophosphamide plus steroids for controlling ANCA-associated diseases. Using life-table analysis, the 2-year patient and renal survival rate in both patients with renal-limited and systemic disease is greater than 70%. There is evidence that in addition to being a useful serologic marker, ANCA are directly involved in the pathogenesis of the vascular injury in patients with ANCA-associated diseases. Although ANCA antigens are normally in the cytoplasm of neutrophils and monocytes, priming of these cells, as occurs following exposure to certain cytokines, results in the release of small amounts of ANCA antigens at the cell surface. In vitro, ANCA-IgG causes cytokine-primed neutrophils to undergo a respiratory burst and degranulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Algorithms↗
PubMed1990

Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are in the circulation of most patients with pauci-immune necrotizing vasculitis and pauci-immune crescentic glomerulonephritis. The current study demonstrates an effect of these autoantibodies on neutrophil function in vitro. ANCA cause normal human neutrophils to undergo an oxidative burst and degranulate. Both ANCA phenotypes (i.e., cytoplasmic-pattern ANCA and myeloperoxidase-specific ANCA) induce neutrophil activation. ANCA sera and purified immunoglobulins significantly increase the release of reactive oxygen species when compared with controls. ANCA, in a dose-dependent manner, induce the release of primary granule contents. These effects are markedly enhanced by priming neutrophils with tumor necrosis factor. Flow cytometry studies demonstrate the presence of myeloperoxidase on the surface of neutrophils after cytokine priming, indicating that primed neutrophils have ANCA antigens at their surfaces to interact with ANCA. These observations suggest an in vivo pathogenetic role for ANCA. We propose that, in patients with necrotizing vasculitis, ANCA-induced release of toxic oxygen radicals and noxious granule enzymes from cytokine-primed neutrophils could be mediating vascular inflammation.

Autoantibodies↗
PubMed1989

Reactivity of anti-neutrophil cytoplasmic autoantibodies with HL-60 cells.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) react with antigens in the cytoplasm of neutrophils and monocytes, and are found in the blood of patients with necrotizing vasculitis and pauci-immune necrotizing and crescentic glomerulonephritis. The standard techniques for ANCA analysis use human polymorphonuclear leukocytes (PMN) as a source for antigen. A comparison was made between ANCA reactivity with human PMN and HL-60 cells. Fifty-five ANCA-positive and 17 ANCA-negative sera were reacted with HL-60 cells in an indirect immunofluorescence microscopy assay to assess the ability of HL-60 cells to distinguish between positive and negative reactivity and between the two major types of ANCA. The HL-60 cell method agreed with a PMN method in all but one instance. In an enzyme immunoassay, HL-60 primary granules could be used to detect ANCA. Evidence is also presented that the perinuclear staining of HL-60 cells and neutrophils by ANCA with anti-myeloperoxidase specificity is caused by the nucleophilic properties of myeloperoxidase. Reactivity with HL-60 cells further elucidates the antigen specificity of both types of ANCA and indicates that HL-60 cells are a suitable tissue culture cell line for investigating the pathobiology of ANCA.

Autoantibodies↗
PubMed1989

Monoclonal antibodies to the apical chloride channel in Necturus gallbladder inhibit the chloride conductance.

Monoclonal antibodies raised by injecting Necturus gallbladder cells into mice were tested for their ability to inhibit the apical chloride conductance induced by elevation of cellular cAMP. Five of these monoclonal antibodies bound to the apical cells, as shown by indirect immunofluorescence microscopy, and inhibited the chloride conductance; one antibody that bound only to subepithelial smooth muscle, by indirect immunofluorescence microscopy, showed no inhibition of chloride transport. The channel or a closely related molecule is present in the membrane whether or not the pathway is open, since, in addition to inhibiting the conductance of the open channel, the antibody also bound to the membrane in the resting state and prevented subsequent opening of the channel. The antibody was shown to recognize, by ELISA, epitopes from the Necturus gallbladder and small intestine. Finally, by Western blot analysis of Necturus gallbladder homogenates, the antibody was shown to recognize two protein bands of Mr 219,000 and Mr 69,000. This antibody should permit isolation and characterization of this important ion channel.

Animals↗
PubMed1989

The pathobiology of the terminal complement complexes.

C5b and the other late-acting complement components can assemble the two terminal complexes (TCC) C5b-9 and SC5b-9. In addition to the lytic effects of C5b-9 it has been demonstrated that sublytic amounts of C5b-8 or C5b-9 can stimulate several important cellular activities. These effects may be important to explain the role of C5b-9 in the production and progression of several pathological conditions that has been demonstrated in experimental models of disease. With the help of antibodies that specifically recognize C9 neoantigens, deposits of TCC have been identified in human tissues, not only in immunological diseases but also in certain nonimmunological diseases. In the latter it has been shown that often there is no concordance between deposits of TCC and those of immunoglobulins and C3. Methods for measuring SC5b-9 in biological fluids have also been developed. Normal plasma was found to have low levels of SC5b-9. Increased plasma levels of SC5b-9 have been observed during the active phase of SLE nephritis, in certain infections and during cardiopulmonary bypass. Increased levels were also found in the cerebrospinal fluid of patients with inflammatory diseases of the central nervous system and in the synovial fluid of patients with rheumatoid arthritis. Autoantibodies to C9 neoantigens in plasma of certain patients with autoimmune, infectious or neoplastic diseases have recently been recognized. Additional work is needed to better delineate the potential usefulness of these findings for diagnosis and evaluation of disease activity.

Adult↗
PubMed1989

Luteal phase hyperprolactinemia during ovulation induction with human menopausal gonadotropins: incidence, recurrence, and effect on pregnancy rates.

Hyperprolactinemia may develop during ovulation induction with human menopausal gonadotropins and hCG (hMG/hCG). Because elevated serum prolactin (PRL) has several adverse effects on female reproductive function, this event has been implicated as a factor to explain the difference between ovulation and pregnancy rates in hMG/hCG treatment cycles. The incidence and severity of hyperprolactinemia in the luteal phase of hMG/hCG-stimulated cycles was investigated in a large series of patients. We analyzed 240 consecutive, ovulatory hMG/hCG cycles in 96 women from July 1984 to January 1986. All women had failed to conceive with clomiphene citrate, and had normal luteal phase PRL levels during unstimulated cycles. Daily serum total estrogens were determined during hMG administration. Serum progesterone and PRL were determined in the mid-luteal phase (7 days post-hCG administration). In 7.5% of the cycles, luteal phase PRL elevations were greater than 25 ng/mL. Only 2.5% of cycles had levels of PRL greater than 35 ng/mL. Hyperprolactinemia infrequently recurred in different cycles of the same patient (two of 16 patients, 12.5%). Cycles with hyperprolactinemia were found to have significantly higher preovulatory estrogen levels. Serum progesterone levels were not significantly decreased in cycles with elevated PRL. Pregnancy rates in cycles with and without hyperprolactinemia were similar (7.7 versus 11.1%, respectively; P greater than .05). We conclude that the development of luteal phase hyperprolactinemia during ovulation induction with hMG/hCG is an isolated event. High preovulatory estrogen levels may predispose to its development. Because hyperprolactinemia is uncommon and is usually mild, other factors must be responsible for the difference between ovulation and pregnancy rates using hMG/hCG.

Chorionic Gonadotropin↗