An international patient-centred study of retroperitoneal fibrosis.

BACKGROUND: The impact that rare chronic disorders, such as retroperitoneal fibrosis (RPF), can have on the physical and psychological aspects of a patient's health is poorly understood. Patient-related outcome measures and experiences provide a unique opportunity to understand the impact rare chronic disorders have on a patient's life as well as allowing healthcare providers to compare and improve performance. AIM: To understand the physical and psychosocial impact that RPF has upon peoples' lives. DESIGN: An international online questionnaire was therefore created to gain insights into how patients with RPF, a rare fibro-inflammatory condition, viewed their health and experiences. METHODS: An international online questionnaire comprising 62 questions/free text options, was designed in collaboration with two patient advocates and the multi-disciplinary Renal Association Rare Disease Registry (RaDaR) RPF Group the questionnaire was anonymous and freely accessible on a GOOGLE Form online platform for 6 months. RESULTS: A total of 229 patients from 30 countries across 5 continents responded. Four key issues were identified; (i) pain; (ii) therapy-related side effects; (iii) lack of informed doctors/information about their condition and its management; and (iv) psychological burden. Variations in diagnosis and management are highlighted with 55% undergoing a biopsy to reach a diagnosis of RPF; 75% of patients underwent a further interventional procedure with 60% concurrently treated medically. CONCLUSION: This study will guide further development of clinical and academic multi-disciplinary activity and shows the importance of trying to understand the impact of rare chronic disorders on the physical and psychological aspects of a patient's health.

Renal cytokines improve early after bariatric surgery.

BACKGROUND: Bariatric surgery has been suggested to improve arterial hypertension and renal function. This prospective controlled observational study aimed to investigate changes in renal inflammation, renal function and arterial blood pressure before and after bariatric surgery. METHODS: Blood pressure was measured, and urine and blood samples were collected from 34 morbidly obese patients before and 4 weeks after bariatric surgery. Serum levels of cystatin C, creatinine, albumin, cholesterol and C-reactive protein (CRP) were measured, along with urinary cytokine/creatinine ratios for macrophage migration inhibitory factor (MIF), monocyte chemotactic protein (MCP) 1, chemokine ligand (CCL) 18 and CCL-15. RESULTS: Mean(s.e.m.) bodyweight dropped from 124·1(2·6) to 114·8(2·4) kg (P < 0·001) and mean arterial blood pressure decreased from 105·7(1·8) to 95·5(1·2) mmHg (P < 0·001) in 4 weeks. Systemic and urinary inflammatory markers improved, with a reduction in serum CRP level (P < 0·001), and decreased urinary MIF/creatinine (P < 0·001), MCP-1/creatinine (P < 0·001) and CCL-18/creatinine (P = 0·003) ratios. In contrast, urinary CCL-15/creatinine ratios did not change and the glomerular filtration rate, measured by serum cystatin C, was unchanged (P = 0·615). CONCLUSION: Surgically induced weight loss contributed to a decrease in blood pressure and markers of renal inflammation. The reduced levels of CRP and urinary cytokines suggest that bariatric surgery attenuates systemic and renal inflammatory status.

IgG4-related disease in a multi-ethnic community: clinical characteristics and association with malignancy.

BACKGROUND: Immunoglobulin-G4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood. AIM: To describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy. DESIGN: Retrospective analysis of case-note and electronic data. METHODS: Cases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using 'IgG4' or 'inflammatory pseudotumour' as search terms. Electronic records, imaging and histopathology reports were reviewed. RESULTS: In total, 66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. Total of 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response; however, 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, seven patients subsequently relapsed after a mean duration of 11 months and four progressed despite treatment. CONCLUSIONS: We report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens.

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.

Interleukin-11 reduces renal injury and glomerular NF-kappa B activity in murine experimental glomerulonephritis.

BACKGROUND/AIMS: There is now considerable evidence implicating T cells and macrophages in glomerular injury in crescentic glomerulonephritis. Recently, it has been shown that interleukin-11 (IL-11) has an immune modulatory function through its effect on both macrophages and T cells. We, therefore, examined the therapeutic effect of IL-11 in a murine model of experimental glomerulonephritis. METHOD: Accelerated nephrotoxic nephritis was induced in C57BL/6 mice. IL-11 at a dose of 0.5 mg/kg/day (n = 10) in vehicle was given daily subcutaneously from the day of sensitization until day 14 after initiation of glomerulonephritis. Control mice (n = 10) received injection of vehicle alone with the same schedule. RESULTS: IL-11 treatment markedly decreased albuminuria (6.2 +/- 1.9 vs. 18.2 +/- 4.5 mg/day, p < 0.05), the number of glomerular macrophages (1.1 +/- 0.2 vs. 1.7 +/- 0.3 cells/glomerular cross-section, p < 0.05) and glomerular fibrin deposition (fibrin score 0.9 +/- 0.3 vs. 2 +/- 0.3, p < 0.05). There was no difference in the glomerular T cell numbers between the IL-11-treated and the vehicle group. Glomerular NF-kappaB activity was markedly suppressed by 75% in the treated group (p = 0.0015). CONCLUSION: In this study, we provide the first in vivo evidence that IL-11 treatment decreases glomerular NF-kappaB activity and reduces renal injury in experimental glomerulonephritis.

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child.

PURPOSE: To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. METHODS: A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre- and post-immunodepletion to remove complexed VEGF. RESULTS: Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. CONCLUSIONS: These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

Up-regulation of type 1 plasminogen activator inhibitor messenger RNA with thrombotic changes in renal grafts.

Small vessel thrombosis is a prominent feature in kidneys undergoing vascular rejection. Type I and type 2 plasminogen activator inhibitors (PAI-1 and PAI-2, respectively) are known to mediate thrombosis. To examine the potential role of PAI-1 and PAI-2 in the mediation of vascular injury, the relationship and the time course of gene expression of PAI-1 and PAI-2 with the thrombotic changes in renal grafts were investigated in an unmodified rejection model in rats. Orthotopic renal transplantation was performed from Lewis to dark agouti (DA) rats and from DA to DA isografts; untreated normal rat kidneys were used as controls. The rats were killed on days 1-9 posttransplantation (n=18 in each allograft and isograft group). The grafts were analyzed by histopathology, in situ mRNA hybridization and Northern blot methods. The results show that PAM mRNA was first detected at day 4, when the thrombotic changes in the grafts were first seen, and that this relationship persisted during the time course observed to day 9. There was no detectable PAI-1 mRNA in the control groups and no PAI-2 in either group. In situ hybridization showed that PAI-1 positive cells were predominantly located in the cortical interstitium, consistent with the distribution of interstitial microthrombi. These results provide experimental evidence that the thrombotic changes in rejecting allografts are associated with the up-regulation of PAI-1 in the donor tissue, whereas PAI-2, from our results, does not seem to influence these changes. The data are consistent with a role for PAI-1 in the pathogenesis of vascular rejection.

Aversive effects of subcutaneously injected vasopressin in the rat: independence of the ascending dorsal noradrenergic bundle.

The unconditioned stimulus properties of subcutaneously administered arginine vasopressin (AVP) were examined using place and taste conditioning paradigms. Evidence for an aversive effect of the peptide was found, in general agreement with a previous report, although a high dose of AVP (10 micrograms) was required. Also investigated was the possible role of the dorsal noradrenergic bundle (DNAB) in conditioned taste aversion established by AVP. Although the DNAB has been proposed as one of the central pathways through which AVP exerts a facilitatory effect on conditioned behaviour, destruction of this pontine-forebrain projection with 6-hydroxydopamine did not appear to alter the aversiveness of the drug in the present study. These results replicate the finding that AVP can serve as an aversive stimulus but also indicate that the aversive properties of the peptide may prove to be dissociable from its ability to enhance the retention of learned behaviour.

Urinary proteomic profiles distinguish between active and inactive lupus nephritis.

OBJECTIVES: Key aims of the treatment of lupus nephritis (LN) are to induce and maintain remission with minimal side effects. However, assessing ongoing renal inflammatory activity is poorly served by current diagnostic tests apart from renal biopsy, but frequent biopsies cannot be justified. Our long-term aim is to identify novel biomarkers from urinary protein profiles to improve diagnosis and monitoring of activity and response to therapy in LN. METHODS: We used surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to identify biomarkers able to discriminate between urine samples from patients with inactive (n= 49) and active (n= 26) LN. Discriminant function analysis was used to define the minimum number of proteins whose levels best distinguished between the two patient groups. Serial urines of six biopsied patients were studied prospectively, and multiple regression (MR) scores calculated. RESULTS: Proteins with masses of 3340 and 3980 distinguished active from inactive LN with 92% sensitivity and specificity of 92% each. The prospective study of the biopsied patients demonstrated that MR scores could predict both relapse and remission earlier than traditional clinical markers. CONCLUSIONS: SELDI-TOF MS identified potential biomarker profiles strongly associated with activity in LN. Identification of these proteins will allow us to devise specific assays to routinely monitor disease progression, and alter immunosuppressive drug regimens accordingly. These proteins may also play a critical role in the pathogenesis of glomerulonephritis, and could therefore provide targets for therapeutic intervention.

Modulation of antibody-mediated glomerular injury in vivo by interleukin-6.

We have shown previously that pretreatment with small doses of bacterial lipopolysaccharide (LPS), human recombinant interleukin-1 beta (hrIL-1 beta) and human recombinant tumor necrosis factor-alpha (hrTNF) increase injury in the heterologous phase of nephrotoxic nephritis (NTN). All three pretreatments induce synthesis of interleukin-6 (IL-6) which in some systems down-regulates synthesis of IL-1 and TNF. We have now investigated the influence of IL-6 on injury in both heterologous and autologous phases of NTN in rats. Injection of hrIL-6 in doses sufficient to induce hepatic synthesis of acute phase proteins (assessed by plasma alpha 2-macroglobulin concentration) had no effect on glomerular injury in the heterologous phase of NTN (albuminuria in NTAb alone 9 +/- 6; LPS/NTAb 34 +/- 10 and IL-6/NTAb 2 +/- 1 mg/24 hr, P < 0.001, Wilcoxon test). In contrast, IL-6 pretreatment partially abrogated the effect of LPS on albumin excretion (NTAb 4 +/- 2; LPS/NTAb 85 +/- 11 and IL-6/LPS/NTAb 32 +/- 6 mg/24 hr, P < 0.002), percentage of glomerular capillary thrombi (3 +/- 1%; 39 +/- 8%; and 6 +/- 1%, P < 0.001) and glomerular neutrophil infiltrate (29 +/- 3; 58 +/- 5; and 34 +/- 2 neutrophils/50 glomeruli in section, P < 0.001, respectively) at 24 hours. The effect of IL-6 was also evident four hours after induction of nephritis and was associated with a marked reduction in glomerular concentration of mRNA for IL-1 beta and TNF, without change in that of tubulin. Serum TNF concentrations were also significantly reduced at four hours in IL-6 treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Human mesangial cells synthesize interleukin 1 alpha but not interleukin 1 beta, interleukin 1 receptor antagonist, or tumour necrosis factor.

There is controversy over whether mesangial cells synthesize and release IL-1 and TNF, and many of the positive experiments were performed before specific reagents and molecular probes were available. Consequently we have stimulated human mesangial cells using protocols known to stimulate the synthesis of other cytokines. No mRNA for IL-1 beta or TNF could be detected in quiescent or proliferating mesangial cells irrespective of whether they had been exposed to cytokines or not. In contrast mRNA for IL-1 alpha was detected in cells stimulated with IL-1 beta 10 ng/ml or with TNF 500 ng/ml; IL-1 alpha was also detected in cell lysates from stimulated mesangial cells. We could not detect mRNA for IL-1 receptor antagonist in any of the cell preparations. These results suggest that mesangial cells are unlikely to be a major source of IL-1 beta or TNF.

Arginase activity is modulated by IL-4 and HOArg in nephritic glomeruli and mesangial cells.

Arginase shares a common substrate, L-arginine, with nitric oxide synthase (NOS). Both enzymes are active at inflammatory sites. To understand regulation of arginase and its relationship to nitric oxide (NO) production, we studied effects of NG-hydroxy-L-arginine (HOArg) and interleukin-4 (IL-4) on urea and NO2- synthesis by glomeruli during rat immune glomerulonephritis and compared these with macrophages and glomerular mesangial cells (MC). In nephritic glomeruli, elicited macrophages, and MC stimulated with IL-1 and adenosine 3',5'-cyclic monophosphate agonists, increased arginase and induced NOS activity was found. Urea production was inhibited by HOArg and increased by IL-4. NO inhibition [NG-monomethyl-L-arginine (L-NMMA)] increased arginase activity in nephritic glomeruli and macrophages but not MC. NO2- synthesis was inhibited by L-NMMA and IL-4. It was increased with HOArg under conditions of NO inhibition. In contrast, in normal glomeruli and basal MC, where there was no induced NO synthesis, IL-4 had no effect on arginase activity, whereas HOArg consistently reduced it in glomeruli only. Type II arginase (Arg II) mRNA was detected in normal glomeruli; nephritic glomeruli expressed both Arg I and Arg II mRNAs. This is the first demonstration of arginase modulation in glomeruli and MC and of the expression of arginase isoforms in glomeruli. The differential responses to two endogenous compounds generated by inflammation suggest this may be part of coordinated regulation of arginase and inducible NOS in immune injury, whereby arginase is inhibited during high-output NO production and stimulated with NO suppression. This, together with control of arginase and NOS isoforms, may be important in controlling the balance of inflammatory and repair mechanisms.

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.

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.

Rat mesangial cells have a selective role in macrophage recruitment and activation.

In proliferative glomerulonephritis glomeruli are the target of an inflammatory reaction involving macrophage recruitment and activation. We examined the role of mesangial cells in this process. Supernatants from basal, IL-1, IFN-tau or LPS-stimulated rat mesangial cells (MCS) were tested for chemotactic, colony-stimulating and activation effects on macrophages in vitro. IL-1-stimulated MCS produced a macrophage chemoattractant (p = 0.007 compared with basal MCS) and MCP-1 mRNA was detected in IL-1-stimulated mesangial cells. LPS or IL-1-stimulated MCS produced colony-stimulating activity (LPS p < 0.05, IL-1 p < 0.01, compared with basal MCS or control supernatant, CS). Macrophage activation, assessed by nitric oxide generation, was suppressed. This evidence from functional bioassays supports a selective role for mesangial cells in the control of macrophage-induced glomerular injury, whereby activated mesangial cells participate in the recruitment and proliferation of infiltrating macrophages, and suppresses at least one field of macrophage activation, namely nitric oxide generation.

Arginase AI is upregulated in acute immune complex-induced inflammation.

Previous studies have shown high arginase activity at inflammatory sites. Arginase converts L-arginine to L-ornithine, sharing a common substrate with nitric oxide synthase. It exists as two isoforms, AI and AII. While the function of liver arginase (AI) in ureagenesis has been defined, the role and isoform of arginase in cells without a complete urea cycle are unknown. We therefore determined arginase isoform mRNA expression in glomerular acute immune complex inflammation, and its cultured constituent cells. AI was induced in nephritic glomeruli, and in mesangial cells stimulated with IL-4 and cAMP, and was present in elicited neutrophils and macrophages. AII was constitutively expressed. Our data strongly suggest that AI, thought to be restricted to the liver, accounts for high arginase activity at inflammatory sites where it may limit high output nitric oxide production and generate polyamines and proline essential for cell proliferation and matrix production. This identification of AI in inflamed tissue is an important step for understanding the consequences of increased arginase activity.

Gummatous lesions in men infected with human immunodeficiency virus and syphilis.

Two HIV-infected men are reported who developed gummatous lesions more than 12 months after appropriate treatment of presumptive syphilis. In one patient the lesions developed without any change in the VDRL titre. The most likely explanation for these lesions is reactivation of syphilis in the context of HIV infection. As these lesions respond to penicillin, the possible reactivation of appropriately treated syphilis, or even yaws, should now be considered in any ulcerative lesion in HIV infected individuals at risk from treponemal infection.

Glomerular expression of interleukin-1 receptor antagonist and interleukin-1 beta genes in antibody-mediated glomerulonephritis.

Interleukin-1 (IL-1) is a powerful proinflammatory cytokine whose function is modulated by a natural IL-1 receptor antagonist (IL-1ra). There are few data about kinetics of in vivo synthesis of IL-1ra at tissue level, except in response to bacterial endotoxin. The purpose of this study was to examine the kinetics of local expression of IL-1ra gene in relation to IL-1 beta gene in a model of anti-glomerular basement membrane antibody-mediated glomerulonephritis. Rats were killed in groups of 5 or 6 at 0, 4, 6, 24, 48, and 96 hours after induction of glomerulonephritis. Messenger RNA for IL-1ra and IL-1 beta was undetectable by Northern blot in normal glomeruli but increased markedly 4 to 6 hours after induction of nephritis. The increase in IL-1ra mRNA was more sustained than that of IL-1 beta mRNA. In situ hybridization showed that IL-1 beta mRNA increased diffusely within glomeruli, while IL-1ra mRNA was expressed more discretely. Expression of these mRNA in noninflamed tissues, spleens and lungs, was different, particularly increase in IL-1ra mRNA was more substantial than that of IL-1 beta. These observations suggest that differential expression of IL-1ra and IL-1 beta might focus inflammation in glomeruli while protecting more distant sites. They also raise the possibility of reducing glomerular injury by therapeutic measures that upregulate glomerular synthesis of IL-1ra while reducing that of IL-1 beta.

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.

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.