Lesson of the week: cholesterol emboli syndrome.
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Acute Kidney Injury↗
Biomedical subjects
C D Pusey
Publications and source records attributed to C D Pusey.
Nephrotoxicity of intravenous immunoglobulin.
Individual case reports have documented nephrotoxicity of intravenous immunoglobulin (IVIG) preparations, but the true incidence of renal dysfunction is unknown and many data sheets do not include renal impairment as a side-effect of these preparations. We determined the incidence of renal impairment in an unselected cohort of patients receiving two different preparations of IVIG over 20 months, administering 287 courses of IVIG to 119 patients for a variety of indications, including thrombocytopenia, systemic lupus erythematosis, neuropathy, Guillain-Barre syndrome and infections. Two different preparations of IVIG were used, Vigam (BPL) and Sandoglobulin (Novartis), which differ in the concentration of sucrose added as a stabilizer. Eight patients showed deterioration in renal function (6.7%), and in two, no renal recovery occurred (1. 7%). There were no significant differences in the patient characteristics or dose or preparation of IVIG administered to those patients with or without changes in serum creatinine. There was no association between the amount of sucrose in the IVIG and development of renal failure. IVIG (regardless of the sucrose content) is associated with renal impairment which may be irreversible, with a maximum incidence of 6.7%. All patients should have their renal function monitored during the use of IVIG.
Adult↗
Vasculitis-aims of therapy. An overview.
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Humans↗
Type IV phosphodiesterase inhibitor is effective in prevention and treatment of experimental crescentic glomerulonephritis.
BACKGROUND: Tumour necrosis factor alpha (TNF-alpha) has an important role in acute glomerular inflammation. Rolipram, a type IV phosphodiesterase inhibitor, has multiple anti-inflammatory effects including inhibition of TNF-alpha synthesis. METHODS: We investigated the effects of rolipram in prevention and delayed treatment of crescentic glomerulonephritis in Wistar Kyoto rats. Glomerulonephritis was induced by injection of nephrotoxic serum. RESULTS: In the preventive study, rolipram (6.25 mg/kg i.p. twice daily) was started 2.5 h before injection of nephrotoxic serum. Rolipram reduced the expression of TNF-alpha in glomeruli and renal tubules and abrogated glomerular injury on day 4 (99.7% reduction in albuminuria and 96.4% reduction in fibrin deposition). In the delayed-treatment experiment, rolipram was started 4 days after injection of nephrotoxic serum. Rolipram reduced renal excretion of TNF-alpha by 63% on day 7. TNF-alpha was not detected in the sera of treated or control rats. Delayed treatment was effective in crescentic glomerulonephritis, as shown by reduction in albuminuria by 38.1%, fibrin deposition by 60.8%, and crescent formation by 67% on day 7. CONCLUSIONS: Rolipram is effective both in prevention and treatment of experimental crescentic glomerulonephritis. This was associated with a reduction of renal production of TNF-alpha.
Animals↗
CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis.
Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The role of T cells in the pathogenesis of EAG remains unclear. T-cell costimulation is provided by ligation of CD28 with either B7.1 (CD80) or B7.2 (CD86) on antigen-presenting cells, and can be inhibited by a soluble form of CTLA4 (CTLA4-Ig) that binds to both B7.1 and B7.2. We examined the effect of CD28-B7 blockade on the development of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectively blocks B7.1. Native CTLA4-Ig treatment ameliorated EAG by several measures, including the levels of circulating anti-GBM antibodies, albuminuria, the deposition of IgG and fibrin in the glomeruli, the severity of glomerular abnormalities, and the numbers of infiltrating T cells and macrophages. Y100F-Ig resulted in a similar reduction in the severity of nephritis, but produced no overall reduction in circulating anti-GBM antibodies, although there was a reduction in IgG2a antibodies. We concluded that CD28-B7 blockade reduced autoantibody production and cellular infiltration of glomeruli, and prevented target organ injury. Our results suggest a key role for B7. 1 in costimulation of Th1-like autoimmune responses in the rat, and show that glomerular injury in EAG is largely dependent on cell-mediated mechanisms.
Abatacept↗
Nephropathy caused by Chinese herbs in the UK.
The use of Chinese herbal remedies is increasing in the UK. We report the presence of a nephrotoxic compound in herb samples, which led to end-stage renal failure in two patients. We suggest that use of these products is regulated more tightly.
Aristolochic Acids↗
Endothelial expression of VCAM-1 in experimental crescentic nephritis and effect of antibodies to very late antigen-4 or VCAM-1 on glomerular injury.
The migration of leukocytes into glomeruli in crescentic glomerulonephritis is fundamental to pathogenesis, and offers important therapeutic opportunities. We addressed the importance of VCAM-1, and its leukocyte ligand very late antigen-4 (VLA-4), in such leukocyte migration. In a rat model of nephrotoxic nephritis, glomerular expression of VCAM-1, studied by immunohistochemistry, was up-regulated by day 6 of nephritis. To quantify kidney endothelial VCAM-1 expression, a differential radiolabeled mAb technique was used, which demonstrated that protein expression was not up-regulated by day 2 of nephritis, but rose threefold between days 2 and 5, and remained elevated until at least day 28. An in vivo study was then performed, using blocking mAbs to either VCAM-1 or VLA-4, starting mAb treatment on the day prior to disease induction, and continuing until animals were sacrificed at day 7. mAbs to VLA-4 significantly attenuated renal injury (albuminuria, glomerular fibrinoid necrosis, and crescent formation), but mAbs to VCAM-1 had no significant effect. Surprisingly, the number of leukocytes within glomeruli was unaffected by anti-VLA-4 mAb therapy, despite the reduction in renal injury. Paradoxically, classical markers of macrophage activation were increased in the anti-VLA-4- and anti-VCAM-1-treated animals. This study demonstrates that kidney endothelial VCAM-1, in contrast to ICAM-1, is not up-regulated by day 2 of nephrotoxic nephritis, and plays little part in early leukocyte influx into glomeruli. However, VLA-4 is an important mediator of glomerular injury, operating after transendothelial leukocyte migration, and presumably binding to alternate ligands within the kidney.
Albuminuria↗
Interleukin-4 ameliorates crescentic glomerulonephritis in Wistar Kyoto rats.
BACKGROUND: Activated macrophages play a central role in crescentic glomerulonephritis. Interleukin-4 (IL-4) down-regulates many macrophage proinflammatory activities. We therefore studied the effect of IL-4 on glomerular injury in a model of crescentic glomerulonephritis in the Wistar Kyoto rat. METHODS: Glomerulonephritis was induced by i.v. administration of rabbit antirat glomerular basement membrane antiserum (nephrotoxic serum, NTS). In experiment 1, IL-4 was given from two hours before NTS until day 6. In experiment 2, rats were treated from day 0 to 7 and were then monitored until killed on day 28. In experiment 3, IL-4 was given from day 4 to 7. RESULTS: Continuous IL-4 treatment (experiment 1) significantly (P = 0.001) reduced proteinuria (3 +/- 1 mg per 24 hr vs. 56 +/- 7), fibrinoid necrosis (0.06 +/- 0.04 quadrants/glomulus vs. 1.2 +/- 0.1), macrophage infiltration (6.7 +/- 2.6 cells/glom vs. 33 +/- 2.5), CD8+ cells (1.5 +/- 0.6 cells/glom vs. 6.2 +/- 1.1), inducible nitric oxide synthase positive cells (0.04 +/- 0.04 cells/glom vs. 3.7 +/- 0.6), proliferating cell nuclear antigen positive cells (3.2 +/- 1 cells/glom vs. 15 +/- 2.3), and glomerular intercellular adhesion molecule-1 expression. Follow-up after seven days of treatment (experiment 2) showed that at four weeks, creatinine clearance was higher in treated rats (1.1 +/- 0.1 ml/min vs. 0.4 +/- 01, P = 0.011), and both glomerular scarring (P = 0.006) and tubular atrophy (P = 0.006) were less. Delayed treatment (experiment 3) reduced proteinuria (41 +/- 5 mg per 24 hr vs. 97 +/- 9, P = 0.004) and fibrinoid necrosis (0.39 +/- 0.05 quadrants/glom vs. 1.6 +/- 0.1, P = 0.004). There was no difference in macrophage infiltration, but inducible nitric oxide synthase positive cells were reduced (0.6 +/- 0.1 cells/glom vs. 1.8 +/- 0.4, P = 0.01) as were ED3+ cells (0.18 +/- 0.06 cells/glom vs. 1.86 +/- 0.21, P = 0.004). CONCLUSION: In this model of crescentic glomerulonephritis, early IL-4 treatment abolished proteinuria and markedly reduced glomerular inflammation. If treatment was stopped after seven days, there was continuing benefit on glomerular and tubulointerstitial scarring and creatinine clearance at four weeks. If treatment was delayed until inflammation was established, there was still a reduction of injury, but without an alteration of macrophage numbers, suggesting that IL-4 may be acting, in part, to reduce macrophage activation.
Animals↗
Development of scarring and renal failure in a rat model of crescentic glomerulonephritis.
BACKGROUND: The aim of this study was to develop and characterize a rat model of crescentic glomerulonephritis which progresses to glomerulosclerosis and renal failure. METHODS: Glomerulonephritis was induced in Wistar Kyoto rats by a single injection of rabbit anti-glomerular basement membrane antiserum. Albuminuria and serum creatinine were monitored. Kidneys were examined, from 2.5 h to 44 days, using light-microscopy and immunohistochemistry. To characterize the glomerular inflammatory infiltrate, glomeruli were digested to single cells and analysed by fluorescence-activated cell sorter (FACS) and by immunohistochemistry on cytospins. RESULTS: Rats developed albuminuria by 4 days and increased serum creatinine by day 18. Histology showed glomerular fibrinoid necrosis by day 4 and cellular crescents in a mean of 63% of glomeruli by day 11. By 6 weeks, rats had developed renal failure (mean creatinine >300 micromol/l) with 94% of the glomeruli showing glomerulosclerosis. The kidneys were also affected by severe interstitial nephritis and tubular loss. The glomeruli were infiltrated by monocytes/ macrophages (ED1+) and CD8+ (OX8+) cells. FACS analysis showed that CD8+ cells did not express T-cell markers (CD3, TCRalphabeta or TCRgammadelta) or the NK-cell marker (NKR-P1). FACS analysis of peripheral blood mononuclear cells demonstrated a population of monocytes reactive with OX8, and double-labelling of cytospin preparations of glomerular digests showed that a proportion of the CD8+ cells were a subset of ED1+ monocyte/macrophages. CONCLUSIONS: We have characterized a reproducible model of crescentic glomerulonephritis which rapidly progresses to chronic renal failure with glomerulosclerosis and tubulo-interstitial scarring. This model will be useful for testing new therapeutic approaches in crescentic glomerulonephritis.
Animals↗
Images in clinical medicine. Tuberous sclerosis.
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Adolescent↗
Recombinant alpha-chains of type IV collagen demonstrate that the amino terminal of the Goodpasture autoantigen is crucial for antibody recognition.
Goodpasture's disease, an autoimmune disorder causing severe glomerulonephritis and pulmonary haemorrhage, is characterized by antibodies to the glomerular basement membrane (GBM). The principal target antigen has been identified as the carboxyl terminal non-collagenous (NC1) domain of the alpha3-chain of type IV collagen. Anti-GBM antibodies appear to recognize one major epitope that is common to all patients, and is largely conformational. We have analysed antibody binding to recombinant alpha(IV)NC1 domains using a construct and expression system shown to produce correctly folded antigen that is strongly recognized by autoantibodies. In this system, as with the native antigen, alpha3(IV)NC1 was bound strongly by antibodies from all patients, whereas the closely related alpha1(IV) and alpha5(IV)NC1 domains, similarly expressed, showed no such binding. A series of chimeric NC1 domains, between human alpha3(IV) and alpha1(IV), and between human and rat alpha3(IV), were expressed as recombinant molecules, and were recognized by autoantibodies to varying degrees. Strong binding required the presence of human alpha3(IV) sequence in the amino terminal region of both sets of chimeric molecules. This work strongly suggests that the amino terminal of alpha3(IV)NC1 is critical for antibody recognition, whereas the carboxyl terminal end of alpha3(IV)NC1 has a less important role.
Animals↗
Experimental autoimmune glomerulonephritis (EAG) induced by homologous and heterologous glomerular basement membrane in two substrains of Wistar-Kyoto rat.
BACKGROUND: Goodpasture's, or antiglomerular basement membrane (GBM), disease presents with rapidly progressive glomerulonephritis, and is caused by auto-immunity to the NC1 domain of the alpha 3 chain of type IV collagen. In order to investigate mechanisms involved in the induction and regulation of glomerulonephritis, experimental models of Goodpasture's disease have been developed in the rat which share many characteristics with the human disease. Induction of experimental autoimmune glomerulonephritis (EAG) involves immunization of susceptible strains with either heterologous or homologous GBM in FCA. However, pathological changes have tended to be mild and/or variable, except in certain protocols using Wistar-Kyoto (WKY) rats. METHODS: We studied the susceptibility of inbred WKY rats from two different suppliers to the development of EAG. These substrains of rat had different MHC haplotypes (WKY/CR, RT1-1; WKY/Olac, RT1-k), so we proposed that they might show differences in their immune response to GBM antigens. Both substrains were immunized with sheep GBM, pH 7, or rat GBM buffered to pH 3, pH 5 or pH 7. RESULTS: All immunized rats developed circulating anti-GBM antibodies detectable at 14 days and rising until 28 days, at which time there was linear deposition of IgG on the GBM. WKY/CR rats developed severe focal segmental proliferative and necrotizing glomerulonephritis, with heavy albuminuria, following immunization with rat GBM, pH 7, but only moderate disease following sheep GBM. WKY/Olac rats showed a more variable response, with moderate disease following both rat and sheep GBM. Immunization of either substrain with rat GBM, pH 5, produced a response similar to that with rat GBM, pH 7, but disease was mild following rat GBM, pH 3. CONCLUSION: EAG in the WKY rat varies in severity according to the substrain of animal and preparation of GBM used for immunization. The model with the most severe and consistent changes was that induced in the WKY/CR rat by rat GBM at pH 7. This model of EAG will be of value for investigating mechanisms of autoimmunity and inflammation in glomerulonephritis, and for attempting novel forms of immunotherapy prior to trials in man.
Albuminuria↗
Sequence analysis of the 'Goodpasture antigen' of mammals.
BACKGROUND: Autoimmunity to the NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1), the Goodpasture antigen, is the cause of spontaneous human antiglomerular basement membrane (anti-GBM) disease, and of anti-GBM nephritis in several animal models. METHODS: We have derived amino acid sequences from alpha3(IV)NC1 for a number of mammalian species (monkey, sheep, pig, dog, rabbit, and rat) by RT-PCR and cDNA cloning. The GBM of some species was studied comparatively for binding to Goodpasture autoantibodies. RESULTS: From this work and other data the sequences of nine mammalian species can be aligned. Regions and residues that may be functionally important are identified. Alpha3(IV)NC1 sequences were found to be less closely conserved across species than alpha1 and alpha2(IV)NC1, 91 to 99% in comparison to a minimum of 97% for alpha1, but these differences were unevenly distributed along the molecule. There was a particularly striking homology between rodent and human sequences in the carboxyl-terminal region. Binding of Goodpasture autoantibodies to rat alpha3(IV)NC1 was poor in comparison with other species. CONCLUSIONS: Comparison of sequences and binding casts doubt on the importance of the carboxyl-terminal region for antibody binding, a region identified as a potential major epitope in previous studies. Sequence comparisons suggest possible reasons for the nephritogenicity of alpha3(IV)NC1 in active models of anti-GBM disease.
Amino Acid Sequence↗
Recurrent glomerulonephritis following renal transplantation.
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Glomerulonephritis↗
Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes.
Anti-glomerular basement membrane (anti-GBM) disease is caused by autoimmunity to a component of glomerular basement membrane. The major autoantigen has been identified as the NC1 domain of the alpha 3 chain of type IV collagen, and patients are characterized by the presence of specific autoantibodies to this molecule. In common with other autoimmune disorders, there is a strong association with HLA genes, with up to 80% of patients inheriting an HLA-DR2 haplotype. To examine the genetic basis of susceptibility to anti-GBM disease in more detail, the HLA-DRB and DQB alleles inherited by 82 patients were analyzed using sequence specific oligonucleotides. This identified a hierachy of association of DRB1 genes with anti-GBM disease, including susceptibility (DRB1*15, DRB1*04), neutral (DRB1*03) and protective (DRB1*07) alleles. Analysis of inherited haplotypes, particularly DRB1*04 and DRB1*07 carrying haplotypes, provided further evidence that the primary association was with genes at the DRB1 locus. Comparison of the sequences of the positively and negatively associated alleles showed that polymorphic residues in the second peptide binding region of the HLA Class II antigen binding groove segregated with disease. This work supports the hypothesis that the HLA associations in anti-GBM disease reflect the ability of certain Class II molecules to bind and present peptides derived from the autoantigen to T helper cells.
Alleles↗
Interleukin-4 ameliorates experimental glomerulonephritis and up-regulates glomerular gene expression of IL-1 decoy receptor.
Monocytes/macrophages and pro-inflammatory cytokines such as interleukin (IL)-1 are important in the pathogenesis of acute glomerulonephritis. The aim of this study was to examine whether IL-4, a cytokine with anti-inflammatory activity, could modulate glomerular inflammation and reduce injury in vivo. Treatment with recombinant rat IL-4 in a model of anti-glomerular basement membrane (GBM) antibody mediated glomerulonephritis in rats reduced glomerular injury. Albuminuria was less (73% less at day 4) and a lower proportion of glomeruli had capillary thrombi (79% less at day 4). In IL-4 treated rats, there was a moderate reduction in the number of macrophages in the glomeruli and also suppression of pro-inflammatory activities of the macrophages. Northern blot analysis of glomerular RNA showed that treatment with IL-4 up-regulated mRNA levels of type II IL-1 receptor (IL-1RTII). IL-1RTII, also known as IL-1 decoy receptor, may act as a decoy molecule to inhibit the effect of IL-1 beta. To our knowledge, this is the first demonstration of (i) recombinant IL-4 reducing glomerular inflammation in vivo and (ii) a treatment that increases IL-1RTII expression in association with reduction of tissue injury in vivo.
Animals↗
Abrogation of glomerular injury in nephrotoxic nephritis by continuous infusion of interleukin-6.
Interleukin-6 (IL-6) has been reported to have pro- and anti-inflammatory effects. It has also been shown to cause mesangial cell proliferation in vitro and has been suggested as a mediator of injury in proliferative nephritis. We have assessed the effects of continuous infusion of human recombinant (hr) IL-6, by osmotic minipump, on the degree of glomerular injury, and on glomerular and interstitial cell proliferation, in the accelerated autologous phase of nephrotoxic nephritis. Two groups of rats were pre-immunized with 1 mg of normal rabbit IgG in Freund's complete adjuvant. One week later, nephritis was induced by an intravenous injection of 1 ml of rabbit nephrotoxic serum. One day before the induction of nephritis, group 1 (N = 9) was subcutaneously implanted with osmotic minipumps filled with 50 micrograms (200 microliters) of IL-6 (equivalent to a dose of 6 micrograms/day), while in group 2 (N = 11) the minipumps were filled with 200 microliters of normal saline. In group 3 (N = 6) normal rats were infused with 50 micrograms of IL-6 alone. The rats were killed seven days after implantation of minipumps. The administered hrIL-6 was detectable in the circulation within the pathophysiological range, and induced a hepatic acute phase response, as assessed by alpha 2-macroglobulin levels. Continuous treatment with IL-6 resulted in a significant reduction in albuminuria (from 195 +/- 37 mg/20 hr to 60 +/- 15 mg/20 hr on day 1, and from 494 +/- 52 mg/20 hr to 238 +/- 30 mg/20 hr on day 7, P < 0.002) and in the prevalence of glomerular capillary thrombosis (from 19 +/- 3% to 5 +/- 1%, P < 0.002). There was also a reduction in macrophage infiltration (ED1 + ve cells from 524 +/- 34 to 466 +/- 14 per 50 glomeruli, P < 0.02) and activation (ED3 + ve cells from 106 +/- 13 to 42 +/- 5 per 50 glomeruli, P < 0.002). Immunohistology showed fewer interstitial Ia + ve cells (OX3 and OX4) in the IL-6 treated group. Similar results were obtained in a second set of experiments in which the IL-6 treatment was extended until day 14. Kidney sections taken from nephritic rats infused with IL-6 showed no increase in glomerular or interstitial cell proliferation when stained with antibodies to proliferating cell nuclear antigen. There was no difference in the deposition of rabbit IgG or rat IgG along the glomerular basement membrane (GBM), and the titer of rat anti-rabbit IgG was similar in the IL-6 and control treated rats. Infusion of IL-6 alone in normal rats had no functional or pathological effects. In conclusion, these results show that IL-6 has powerful anti-inflammatory effects in a rat model of anti-GBM nephritis, and does not induce mesangial cell proliferation in vivo.
Animals↗
Plasma immunoreactive leptin concentration in end-stage renal disease.
1. Leptin is thought to be an inhibitor of appetite. As the kidney helps clear several polypeptide hormones, plasma leptin may accumulate in end-stage renal disease. 2. Plasma immunoreactive leptin was measured in four groups of subjects: haemodialysis, continuous ambulatory peritoneal dialysis and renal transplant patients and a group of healthy controls. Leptin was also measured before and after a single dialysis session. 3. There was a strong correlation between plasma immunoreactive leptin and body mass index in all groups except female haemodialysis patients. Leptin was higher in females than in males in all groups when controlled for body mass index. Mean plasma leptin [mean (SD)] was significantly higher in all renal groups [haemodialysis, 15.1 (3.6) ng/ml; continuous ambulatory peritoneal dialysis, 25.4 (4.3) ng/ml; transplants, 11.6 (2.6) ng/ml] compared with controls [5.3 (2.3) ng/ml]. There was a significant difference in the regression equations relating leptin and body mass index (dialysis > transplants > controls), even when controlled for gender. Leptin correlated modestly with serum creatinine in non-dialysis subjects. Plasma leptin immunoreactivity was slightly reduced by haemodialysis, but post-dialysis leptin was still significantly higher than that found in controls. 4. Chromatographic characterization of the high level of leptin immunoreactivity found in haemodialysis subjects showed a single elution peak corresponding to that of the highly purified human leptin standard. 5. In conclusion, leptin is higher than expected for body mass index in end-stage renal disease. Hyperleptinaemia could contribute to the anorexia and poor nutritional status commonly seen in renal failure.
Adult↗