The nature of clinical trials in nephrology.
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Clinical Trials as Topic↗
Biomedical subjects
W K Bolton
Publications and source records attributed to W K Bolton.
Analyzing pulsatile endocrine data in patients with chronic renal failure: a brief review of deconvolution techniques.
Deconvolution analysis provides an important new technique to evaluate underlying hormone secretory rates quantitatively based upon serially measured plasma hormone concentrations with or without prior knowledge of the half-time of hormone disappearance from the blood. Information about endocrine gland secretion is particularly important in chronic renal failure, wherein the decreased metabolic clearance rates of various hormones would otherwise confound the interpretation of plasma hormone concentrations. Here we review two particularly useful techniques of deconvolution, one of which is a waveform-defined algorithm and the other waveform independent. The first method can be used to estimate both hormone half-life and secretory rates in vivo. The second methodology allows calculation of in vivo hormone secretion rates without assuming any special form for the secretion event, but requires a priori knowledge of hormone half-life. We illustrate examples of these two deconvolution approaches, and discuss why the interpretations of hormone concentration measurements in earlier studies (where deconvolution methods were not employed) must be viewed with caution. Based on such considerations, additional investigations of in vivo hormone secretory pathophysiology will be required in children and adults with chronic renal failure.
Endocrine Glands↗
Heparin skin necrosis: delayed occurrence in a patient on hemodialysis.
A case of skin necrosis in a patient receiving intravenous (IV) heparin during routine intermittent hemodialysis is reported. Multiple erythematous, tender lesions developed over the abdomen and thighs and rapidly became necrotic. Biopsies showed fibrin thrombi in the dermal venules and capillaries, but no cellular infiltrate. The patient was in her third month of regular hemodialysis. Skin necrosis associated with the use of heparin usually occurs within 2 weeks of beginning heparin therapy and has not been reported in patients receiving heparin with hemodialysis. Possible mechanisms, including acquired antithrombin III deficiency leading to heparin-induced skin necrosis, are discussed.
Abdomen↗
Neuroendocrine alterations in the somatotrophic axis in chronic renal failure.
Both secretion and metabolic clearance of GH in health and disease are subject to regulation by an array of metabolic, nutritional, physical activity, age, and body composition cues. Moreover, both GH and its mediators (e.g. IGF-I) are bound in plasma by one or more high-affinity binding proteins. Accordingly, carefully designed clinical and basic investigations are required to examine and clarify the diverse alterations in the dynamics of the somatotrophic axis that accompany the syndrome of CRF with its attendant attenuation of normal anabolism, growth and development.
Carrier Proteins↗
IgA antineutrophil cytoplasmic antibody in Henoch-Schönlein purpura.
Sera from 29 children with acute Henoch-Schönlein purpura were tested for IgA antineutrophil cytoplasmic antibody (ANCA) and for IgA rheumatoid factor (RF). All sera were negative for IgA ANCA by indirect immunofluorescence, but 13 of 29 patients had weakly positive results for IgA ANCA when tested using an enzyme immunoassay. Sixteen of 29 children were IgA RF seropositive. IgA RF seropositive patients had significantly higher titers of IgA ANCA as compared with IgA RF seronegative patients (p = 0.0002). Indeed, of the 16 patients who were IgA RF seropositive, 13 also had positive tests for IgA ANCA, while none of the IgA RF seronegative patients had positive tests for IgA ANCA (p = 0.00001). Removal of IgA RF from eight sera by adsorption with immobilized IgG produced comparable reductions in the titers of both IgA RF and IgA ANCA. We conclude that IgA ANCA is not an important serologic marker in Henoch-Schönlein purpura, but the presence of serum IgA RF may produce weak false-positive results for IgA ANCA in some patients.
Antibodies, Antineutrophil Cytoplasmic↗
Isolation and characterization of chicken mesangial cells.
Experimental autoimmune glomerulonephritis (EAG) in chickens appears to be mediated by cellular immunity and is associated with mesangial proliferation. We have developed techniques for the culture of chicken mesangial cells to study factors in vitro which lead to this proliferation. Chicken glomeruli isolated by sieving collagenase-treated whole kidney homogenates were cultured in Waymouth's medium MB 752/1 supplemented with 20% decomplemented fetal calf serum and 1 unit/ml insulin. Propagated cells share the following characteristics with mammalian mesangial cells: stellate and spindle-shaped morphology with an extensive microfilamentous system by light and electron microscopy; resistance to aminonucleoside of puromycin; susceptibility to mitomycin C; growth in L-valine-free medium; absent staining for factor VIII-related antigen, chicken T cell and Ia antigen; positive staining for fibronectin, myosin, alpha-actinin and desmin, and angiotensin II binding and induction of contraction. Unlike cultured mammalian mesangial cells, chicken mesangial cells avidly phagocytize latex beads and display multilamellar residual bodies on electron microscopy indicative of phagocytic activity. They differed from fibroblasts which were non-phagocytic, had different growth patterns, fluorescence staining and ultrastructural morphology. To our knowledge, this is the first description of the culture of chicken mesangial cells. This in vitro system should allow further studies of pathogenetic processes involved in the production of EAG with elucidation of mechanisms relevant to human disease.
Angiotensin II↗
Treatment and prognosis of renal and systemic vasculitis.
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Acute Disease↗
Mechanisms of glomerular injury: injury mediated by sensitized lymphocytes.
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Animals↗
An evaluation of diabetic and pseudodiabetic glomerulosclerosis.
Diabetic glomerulosclerosis must be either a primary manifestation or a secondary consequence of the metabolic abnormalities of diabetes. Several earlier reports have attempted to support the former hypothesis by describing cases of pathognomonic renal lesions in nondiabetic subjects; however, the clinical and pathologic data in these reports are inconclusive. We have reviewed our experience at the University of Virginia Hospital with 447 percutaneous renal biopsies performed over a period of four years from July 1973 through July 1977. Of these cases, only two appeared to represent diabetic glomerulosclerosis occurring in nondiabetic subjects. Upon further investigation, one case provided to be light chain disease demonstrated by immunofluorescence staining. The other case, on repeat renal biopsy, proved to be membranoproliferative glomerulonephritis. We conclude that a diagnosis of diabetic glomerulosclerosis must be viewed with suspicion in nondiabetic subjects. Suspected cases should be labeled pseudodiabetic glomerulosclerosis and investigated further.
Adult↗
Intravenous pulse methylprednisolone therapy of acute crescentic rapidly progressive glomerulonephritis.
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Acute Disease↗
Crescentic glomerulonephritis without immune deposits: clinicopathologic features.
Of 46 patients with acute crescentic glomerulonephritis involving 20 to 90% of glomeruli, 16 had no definable systemic disease and no significant glomerular immune deposits by immunofluorescent or electron microscopy. Anti-GBM antibody and circulating immune complexes were further excluded by radioimmunoassay and Raji cell assay in all patients tested. Clinical features included a 10:6 male:female ratio, mean age of 58 years (range, 13-77), disease duration of less than 3 months, rapidly deteriorating renal function, and frequent pulmonary manifestations. Nine patients had oliguria, serum creatinine concentrations over 6 mg/100 ml, and required dialysis, but three of these patients subsequently recovered renal function. These three patients and seven patients with creatinine concentrations of less than 6 mg/100 ml have not progressed to chronic renal failure. In this series, idiopathic acute crescentic glomerulonephritis without immune deposits was more common than was immune complex or anti-GBM nephritis. The clinical, laboratory, and pathologic characteristics of these patients were similar to those reported in anti-GBM and immune-complex-induced glomerulonephritis. These observations expand the spectrum of rapidly progressive crescentic glomerulonephritis. They suggest that glomerular immune deposits may be less important than other factors in determining the extent of renal injury and subsequent clinical course in crescentic glomerulonephritis.
Adolescent↗
Membranous nephropathy: a radioimmunologic search for anti-renal tubular epithelial antibodies and circulating immune complexes.
In an effort to elucidate immunopathogenic of membranous nephropathy (MN), freshly collected sera from patients with biopsy proven MN were assayed of circulating immune complexes (ICs) by the Raji cell method and for anti-renal tubular epithelial (RTE) antibodies by a newly established radioimmunoassay (RIA) and by indirect immunofluorescence. 6 of 26 MN patients tested by the Raji cell assay had detectable circulating ICs. However, 5 of these 6 patients had other medical conditions which might also explain the IC reactivity. 29 MN patients and 11 patients with other glomerular diseases had no demonstrable circulating anti-RTE antibodies. This study suggests that if RTE antigens possess a nephritogenic potential for man it is probably only rarely expressed. The inconstant detection of circulating immune complexes in idiopathic MN raises an speculation as to their immunopathogenic significance.
Adult↗
Chronic interstitial nephritis and mixed cryoglobulinemia associated with drug abuse.
Two cases of chronic interstitial nephritis with renal insufficiency were associated with mixed cryoglobulinemia and parenteral drug abuse. Previously recognized causes of interstitial nephritis were not present in either case. Despite extensive interstitial inflammatory infiltrates, no substantial glomerular abnormalities or immune deposits were present in either patient. One patient had a history of intravenous injection of suspended methadone tablets containing talc crystals, and there was evidence of talc embolization in biopsy specimens of liver, spleen, and kidney. Interstitial nephritis associated with drug abuse has not been previously described to our knowledge, but the association in these cases seems not to have been fortuitous and warrants consideration in the evaluation of both parenteral drug abusers and patients with unexplained interstitial nephritis.
Adult↗
Massive proteinuria and acute renal failure in a patient with acute silicoproteinosis.
Acute pulmonary silicoproteinosis, massive proteinuria and fatal renal failure developed in a 23 year old male sandblaster. Examination of the kidney by immunofluorescence revealed granular deposits of immunoglobulin M (IgM) and the third component of complement (C3) along the glomerular basement membrane. Light microscopy disclosed mild proliferative glomerulonephritis with loss of colloidal iron staining for sialoprotein, and electron microscopy disclosed an increased density of epithelial cytoplasm, altered lysosomes and endothelial cell microtubular structures. The silicon content of the kidney was 264 parts per million (ppm), but particles of silicon were not demonstrated by electron microscopy. No primary or systemic causes of renal diseases were elucidated. The renal dysfunction apparently resulted from acute renal silicon toxicity, a new complication of acute pulmonary silicoproteinosis.
Acute Kidney Injury↗
Study of chemical sympathectomy in endotoxin-induced lethality and fibrin depostion.
Shock and the generalized Shwartzman reaction are well known features of endotoxin which have been shown to involve the sympathetic nervous system. The mechanism of sympathetic nervous system involvement with endotoxin injection was studied in rabbits chemically sympathectomized with 6-hydroxydopamine. Endotoxin, in doses producing a spectrum of morbidity and mortality in normal rabbits, was administered i.v. to chemically sympathectomized, normal, and unilateral renal surgically sympathectomized animals. Chemical sympathectomy produced a significant depletion of tissue norepinephrine which, in endotoxin recipient animals, was associated with a significantly lower mortality rate and greatly decreased fibrin deposition in the lungs and kidneys, despite intravascular coagulation. Unilateral renal sympathectomy afforded protection to the ipsilateral kidney, but data on mortality and systemic fibrin deposition were similar to those reported for normal rabbits given endotoxin. Six-hydroxydopamine prevents significant tissue injury secondary to endotoxin in this experimental model. In addition, the data provide direct evidence that an intact reactive sympathetic nervous system is essential for development of lethal toxicity and generalized Shwartzman reaction due to endotoxin.
Animals↗
Pharmacokinetics of cefaclor and cephalexin: dosage nomograms for impaired renal function.
The pharmacokinetics of cefaclor and cephalexin were characterized in patients with creatinine clearances ranging from 0 to 147 ml/min. Each of 24 fasted subjects received a single 500-mg oral dose of cefaclor, and 13 of these subjects later received 500 mg of cephalexin. Serum and urine levels of the antibiotics were measured by bioassay. The serum half-lives were highly correlated with corrected creatinine clearance (cefaclor r = 0.92, cephalexin r = 0.94). Linear regression estimates of the half-life of cefaclor were 2.3 h in the anephric patient and 40 min in the patient with a corrected creatinine clearance of 100 ml/min. For cephalexin, corresponding half-lives were 15.4 h and 58 min. We present a dosage nomogram for calculating the appropriate adjustments to the loading dose based on patient weight and maintenence dose based on corrected creatinine clearance.
Adult↗
Nephrotic syndrome and focal glomerular sclerosis in aging man.
Focal glomerular sclerosis (FGS) with the nephrotic syndrome is a disecades. Less than 2% of reported patients are older than 60 years of age, and to our knowledge no patients over 70 years of age have been described. The present report documents with renal biopsies the occurrence of FGS and the nephrotic syndrome in 4 patients with an average age of 70 years, 3 being septuagenarians. We suggest that FGS in these patients may represent a disease of senescence, and that FGS in younger patients may result from accelerated glomerulotubular senescence.
Adult↗
Bovine serum albumin chronic serum sickness nephropathy in rats.
We administered bovine serum albumin (BSA) 1 or 3 mg i.v. into hyper-immune Sprague-Dawley rats weekly for up to 6 months. Animals with free circulating antibody 1 h after BSA developed mesangial deposits of IgG and C-3 without proteinuria. Rats without free antibody at 1 h developed either mesangial or mesangial and glomerular basement membrane (GBM) deposits. Rats given 3 mg BSA tended to have GBM deposits, proteinuria and undetectable antibody at 1 h. By electronmicroscopy, all rats had mesangial and subendothelial dense deposits, while those with GBM lesions had intramembranous and subepithelial deposits with foot process obliteration. Light microscopic evaluation of kidney tissue revealed only mild histological changes similar to those in age-matched control rats. The present studies demonstrate that prolonged i.v. administration of BSA into rats results in the development of a chronic non-inflammatory nephropathy. Despite certain parallels to chronic serum sickness nephropathy in rabbits, species differences appear to modify the nephropathy in rats.
Animals↗