Interleukin 6 production by human proximal tubular epithelial cells in vitro: analysis of the effects of interleukin-1{alpha} (IL-1{alpha}) and other cytokines

Proximal tubular epithelial cells (PTEC) from human renal tissueobtained from biopsy or nephrectomy were grown in monocultureand evaluated in vitro at passage 2–4 for interleukin6 (IL-6) production in response to medium alone or to interleukin1 alpha (IL-1), tumour necrosis factor alpha (TNF), interleukin2 (IL-2), interferon gamma (INF) or lipopolysaccharide (LPS).IL-6 bioactivity was quantitated using the IL-6-dependent murinehybridoma cell line (B9) and expressed as IL-6 units/ml/10⁵PTEC. PTEC cell lines exposed to medium alone produced intermediateamounts of IL-6 with substantial variability between cell lines.Introduction of IL-1 resulted in a dose- and time-dependentincrease in IL-6 production by PTEC that was maximal at 1 ng/mlIL-1 at 24 h. All PTEC cell lines showed an increased IL-6 productionon exposure to IL-1 varying from 1.3- to 24-fold increase overbaseline production. This response was completely blocked byanti-rIL-1. No significant IL-6 production by PTEC could beinduced by TNF, IL-2, IFN, or LPS over a broad dosage range.Cycloheximide inhibited IL-6 production without irreversiblecell toxicity, indicating de-novo synthesis. IL-6 produced byPTEC had a molecular weight of 26-29 kDa as demonstrated byWestern blot analysis. Using PCR analysis we could demonstrateupregulation by IL-1 of IL-6 mRNA in a dose-response fashion,indicating that IL-1 regulates IL-6 production at a pretranslationalvalue of protein synthesis. These results show that human culturedPTEC produce IL-6 under both normal and IL-1-stimulated conditions,and suggest that they may have a regulatory function in responseto cytokines in the setting of inflammation in the renal cortex.     

Expression and function of fibronectin receptors on peripheral mononuclear cells in IgA nephropathy

The ß1 integrin family, major adhesive receptors forthe extracellular matrix (ECM), have been reported to be presentin normal and diseased kidneys. Attachment of glomerular cellsto ECM is mediated by ß1 integrins. Several membersof the ß1 integrins are referred to as VLA (very lateactivation) antigens. Peripheral mononuclear cells also expressVLA antigens in both resting and activated states. We examinedthe expression and function of VLA antigens on peripheral lymphocytesand monocytes in patients with IgA nephropathy using monoclonalantibodies (mAbs) specific for VLA -chains. Peripheral lymphocytesfrom patients with IgA nephropathy expressed VLA-4 and 5, butnot VLA-1 2 or 3. Peripheral monocytes from patients with IgAnephropathy expressed VLA-2 4 and 5, but not VLA-1 or 3. Theexpression of VLA adhesive receptors was observed in healthyindividuals. Adhesion assay to fibronectin revealed augmentedadhesion of mononuclear cells in IgA nephropathy (P<0.05),and this increased adhesion was inhibited by mAbs to VLA-4 and5. The expression of ß1 integrins in IgA nephropathywas similar to that of healthy individuals, but the functionof these molecules in terms of adhesion to fibronectin thoughVLA-4 and VLA-5 is increased in these patients. These findingssuggest that the activation of fibronectin receptors on peripheralmononuclear cells plays an important role in the pathogenicprocess of IgA nephropathy.     

Interleukin-8 in chronic renal failure and dialysis patients

A total of 105 patients participated in this study, including10 with chronic glomerulonephritis with normal renal function(CGN patients), 36 uraemic patients (CRF patients), 19 continuousambulatory peritoneal dialysis patients (CAPD) without peritonitis,three CAPD patients with peritonitis, 37 patients undergoingchronic haemodialysis (HD) divided into short-term HD, 15 patients;medium-term HD, 12 patients; and long-term HD, 10 patients.IL-8 and two other proinflammatory cytokines, IL-6 and TNFweretested using a specific immunoassay. IL-8, IL-6, and TNFc serumlevels were significantly increased in patients with chronicrenal failure compared to their levels in normal individuals(P<0.000l, P<0.05 and P<0.000l respectively). The mostpronounced incre ment in IL-8, IL-6 and TNF serum levels wasobserved in CAPD patients (P<0.000l). CAPD patients withoutperitonitis showed relatively low levels of IL-8 or IL-6 inperitoneal dialysate effluents (PDE), whereas PDE-TNF were notdetectable in almost all patients tested. Patients with peritonitisshowed very high serum and PDE levels of IL-8, IL-6 and TNF.The clinical recovery from peritonitis was characterized bya rapid fall in IL-8, IL-6 and TNF in serum and dialysate. HDpatients showed a significant increase in serum levels of IL-8and also IL-6 and TNFcompared to normal individuals (P<0.05,P<0.05 and P<0.01 respectively). HD duration influencedserum levels of IL-8 and TNF since they were significantly higherin short-term HD patients than medium- or long-term HD patients(respectively P<0.05, P<0.00l for IL-8, and P<0.01,P<0.001 for TNF Pre-HD IL-6 levels were not influenced byHD duration. No major modification of IL-8 serum levels couldbe evinced after and before HD sessions in the short-term group,but concentrations of this cytokine were significantly higherafter HD in medium- and long-term HD patients (P<0.05, P<0.0lrespectively). In contrast, HD session did not influence IL-6and TNF levels. We conclude that the cytokine profile is perturbedin uraemia and during dialysis, and that this should be consideredas an inflammatory status.     

Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy

Background. We have previously documented that human mesangialcell (HMC)-derived tumour necrosis factor- (TNF-) is an importantmediator involved in the glomerulo-tubular communication inthe development of interstitial damage in IgA nephropathy (IgAN).With the strategic position of podocytes, we further examinedthe function of podocytes in IgAN. Methods. Podocyte markers were examined in renal tissues byimmunofluorescence. In vitro experiments were conducted withpodocytes cultured with polymeric IgA (pIgA) or conditionedmedium prepared from HMC incubated with pIgA (IgA–HMCconditioned medium). Results. Glomerular immunostaining for nephrin or ezrin wassignificantly weaker in patients with IgAN. The immunostainingof IgA and nephrin was distinctly separate with no co-localization.In vitro experiments revealed no effect of pIgA on the expressionof these podocyte proteins as IgA from IgAN patients did notbind to podocytes. In contrast, IgA conditioned medium preparedfrom IgAN patients down-regulated the expression of these podocyteproteins as well as other podocyte markers (podocin and synaptopodin)in cultured podocytes. The mRNA expression of nephrin, erzin,podocin but not synaptopodin correlated with the degree of proteinuriaand creatinine clearance. The down-regulation was reproduciblein podocytes cultured with TNF- or transforming growth factor-β(TGF-β) at concentration comparable to that in the IgA–HMCconditioned medium. The expression of these podocyte proteinswas restored partially with a neutralizing antibody againstTNF- or TGF-β and fully with combination of both antibodies. Conclusion. Our finding suggests podocyte markers are reducedin IgAN. An in vitro study implicates that humoral factors (predominantlyTNF- and TGF-β) released from mesangial cells are likelyto alter the glomerular permeability in the event of proteinuriaand tubulointerstitial injury in IgAN.     

Serum {alpha}2-macroglobulin in haemodialysis patients: baseline and kinetic studies

The pathogenesis of dialysis related amyloidosis remains unresolveddespite the identification of ß₂-microglobulin (ß₂M)as the major protein constituent, as well as other proteinsbeing present in the deposits. Among the latter we have assessedthe serum concentrations of ₂-macroglobulin (₂M) both in thebaseline stage and during the haemodialysis (HD) procedure.We have also assessed the influence of the membrane on ₂M kinetics. Fifteen HD patients with histologically proven dialysis-relatedamyloidosis (DRA group) and 15 HD patients clinically and radiologicallyconsidered dialysis-related amyloidosis free (control group)were included in the baseline study. Blood was sampled the daybefore the second dialysis of the week and ₂M, ß₂Mand ₁, antitrypsin were determined along with the routine biologicalanalysis of these patients. Serum ₂M was greater in dialysis-relatedamyloidosis than in control patients (t = 2.35; P<0.026).Serum ß₂M was similar in both groups. The serum ₂Mand ß₂M correlated in patients with dialysis-relatedamyloidosis (r = 0.64; P<0.01), while no correlation wasfound in controls (r = 0.17; NS). Stepwise analysis taking thepresence of dialysis-related amyloidosis as the dependent variableretained the serum ₂M concentration as the first variable inthe model (F = 4.4; partial r = 0.38; P<0.046). The sameproteins were determined in another group of seven patients,before and hourly during HD as well as 2 and 8 h after the endof HD during nine consecutive dialyses (3 cycles of 3 HD eachusing AN69 and cuprophane membranes in a crossover design).Serum ₂M significantly increased from hour 3 and continued toincrease 2 hours post-HD (+11% and +9% with AN69 and cuprophanerespectively; P<0.001). Total proteins peaked at hour 4 (+4% and +3% P<0.01) and decreased after HD. Serum ß₂Msignificantly decreased with AN69 HD ( – 29% P<0.001)and remained unchanged during cuprophane HD. In conclusion, significant increases in serum ₂M are observedimmediately after and during the early post-dialysis periods,regardless of the membrane used. Further, serum ₂M correlateswith ß₂M only in patients with dialysis-related amyloidosis,and this variable was retained in the multivariate regressionanalysis to predict dialysis-related amyloidosis. Although thebaseline results require confirmation with larger studies, wepostulate that the present results are of relevance for dialysis-relatedamyloidosis pathogenesis since ₂M, previously identified indialysis related amyloid deposits, is closely related to acute-phasereactant proteins, and interacts with the main infiltratingcells of the deposits (macrophages). ₂M modifications couldrepresent a new manifestation of the inflammatory response tothe haemodialysis procedure.     

Non-endotoxinic tumour necrosis factor-{alpha}-inducing factors in haemodialysis

A transmembrane passage of endotoxins may account for the dysfunctionof cytokine production which has been often reported in haemodialysis.We developed an assay based on the ability of patient serumto stimulate tumour necrosis factor (TNF) secretion in normalperipheral blood mononuclear cells. Three groups of subjectswere investigated: normal controls (n=14), patients with chronicrenal failure, CRF (n=15), and patients dialysed with poly-acrylonitrile(n=7), polysulphone (n=8), and cellulose acetate (n=7). Serafrom dialysed patients displayed a significantly higher TNF-inducingactivity than those of controls and CRF patients. The abilityof serum to elicit TNF secretion was neither modified duringthe dialysis session nor influenced by the type of haemodialysismembrane. TNF-inducing activity in serum was not inhibited bypolymyxin B, known to impair endotoxin-dependent cell responses,thus suggesting that it was not related to circulating endotoxins.We conclude that non-endotoxinic factors are present in serumfrom dialysed patients and are able to induce cytokine secretion.     

Endotoxins modulate chronically tumour necrosis factor {alpha} and interleukin 6 release by uraemic monocytes

We examined in vivo the release of tumour necrosis factor alpha(TNF) and interleukin 6 (IL-6) by uraemic monocytes upon stimulationwith endotoxin-contaminated bicarbonate concentrate. Twelveuraemic patients underwent 1-month-subsequent periods of standardhaemodialysis (SHD) with cuprophane (CU), a high-complement-activatingmembrane (6 patients), or haemodiafiltration (HDF) with polyacrylonitrile(PAN), a low-complement-activating membrane (6 patients), byusing a dialysate prepared with either non-sterile bicarbonateconcentrate tanks (phase 1) or sterile bicarbonate concentratebags (phase 2). TNF and IL-6 concentrations were determinedin monocyte supernatants by ELISA; endotoxin levels in bicarbonateconcentrates were measured by a chromogenic limulus amoebocytelysate (LAL) assay. A significant increase in LAL reactivity was found in bicarbonateconcentrate tanks compared to sterile bags (P<0.001). Non-steriledialysate caused a significant (P<0.001) predialytic increasein monocyte TNF release as compared to controls and nondialyseduraemic patients. One month treatment with sterile bicarbonatesignificantly decreased TNF predialytic activity in monocytesupernatants (P<0.001) to levels closer to those of non-dialyseduraemic patients. A similar decrease was observed for IL-6 production.Dialytic treatment induced a further increase in both TNF andIL-6 production, particularly in phase 1. When uraemic patientswere examined separately according to the different dialyticprocedures (SHD-CU or HDF-PAN), the use of sterile dialysate(phase 2) caused a significant decrease of predialysis TNF releasein both SHD CU patients (24.1±8.4 pg/ml versus 55.3±5.7pg/ml, P<0.001) and HDF PAN-treated patients (16.6±5.3pg/ml versus 29.1±5.4pg/ml, P<0.005), so that thedifferences between the dialytic procedures were completelyabolished. In conclusion, TNF and IL-6 release may be induced by endotoxin-contaminateddialysate during haemodialysis. The use of sterile bicarbonatecan ameliorate the bioincompatibility of CU membranes and probablyinfluences the biocompatibility of PAN membranes. Therefore,regardless of the type of dialyser used, all attempts to obtainan ultrapure dialysate are important to optimize dialytic treatment,in order to attenuate the chronic monocyte activation whichoccurs during haemodialysis.     

{beta}1 and {beta}3 integrin upregulation in rapidly progressive glomerulonephritis

The expression and distribution pattern of ß₁ (₁–₆)and _vß₃ integrins and ICAM-1 and VCAM-1 counter receptorswere evaluated by an immunohistochemical technique on eightrenal samples from patients affected by rapidly progressiveglomerulonephritis (RPGN) of different aetiologies. In all casesintegrins and counterreceptors displayed similar patterns. Ontubular cells of renal cortex, a marked upregulation of ₂ß₁,₃ß₁, ₅ß₁, _vß₃ integrins and VCAM-1was observed with as many as 60–90% of tubular cross-sectionslabelled, while a strong ICAM-1 reactivity was limited to theluminal surface. The same adhesion molecules were also uniformlyexpressed on crescentic cells. In glomeruli, integrin upregulationoccurred only on apparently preserved capillary tufts, i.e.in an early stage of lesion, while collapsed and sclerotic tuftsshowed a reduced integrin expression. In addition a morphometricstudy of extracellular matrix (EM) proteins cellular fibronectinand tenascin showed a 9.56±1.9-fold and 3.35±0.6-foldincrease respectively in these proteins, as compared to normalkidney (P<0.001). The upregulation of _vß₃. on podocytesmight play a role in the adhesion of crescentic cells. An increasedproduction of cytokines, in particular transforming growth factor-ß,might induce augmented deposition of EM proteins and upregulationof ß₁ and ß₃ integrins in RPGN.     

Adriamycin-induced proteinuria in nude mice: an immune-system-mediated toxic effect

BACKGROUND.: The renal minimal lesion disease induced in rats by adriamycin(ADR) is generally thought to be consequent to a direct cytotoxiceffect of this drug on glomerular epithelial cells. Only recentlyan altered synthesis of mediators, including reactive oxygenspecies and monocyte-macrophage cytokines, has been hypothesized. METHODS.: A mouse strain (nude) bearing a congenital thymic aplasia isa suitable experimental animal to evaluate the role of immunereactions in the development of ADR nephropathy, provided mousesusceptibility to its toxic effect. Therefore, experimentalmice were divided into three groups (G) each receiving adriamycin7.5 mg/kg b.w.: GA (15 heterozygous nu/O mice with normal immunesystem); GB (15 homozygous nu/nu athymic mice); GC (15 homozygousnu/nu mice which were also splenectomized, irradiated, and treatedwith anti-asialo Gml antibody to abolish NK and decrease macrophageactivity). All animals were maintained under pathogen-free conditions.Urinary proteins, albumin and TNF- excretion were measured. RESULTS.: After 14 days the proteinuria was 43.8± 1.7 µg/minin GA, 30.2±2.9 µg/min in GB (P<0.05) and 12.2±2.8µg/min in GC (GA vs GC, P<0.0001; GB vs GC, P<0.05).Albuminuria gave a similar profile. TNF- urinary excretion wassignificantly higher in GA (17.3±3.2 mU/min) than inGB (5±0.6 mU/min, P<0.001) and GC (3.2±0.9mU/min, P<0.001). A significant correlation was found inGA between urinary TNF- and protein losses (r²=0.63 P<0.0001).Kidney tissue homogenates failed to show in each experimentalgroup any evidence of mRNA encoding for TNF-, which was detectablein peripheral mononuclear cells from GA and GB, but undetectablein GC mice. Segmental effacements of glomerular epithelial cellfoot process were observed by electron-microscopy in GA only,while they were minimal in GB and absent in GC. Iron colloidalstaining for anionic sites on frozen sections always showeda normal pattern. CONCLUSIONS.: Nude mice bearing cellular immunity deficiency are protectedfrom proteinuria following ADR toxicity. An impaired synthesisand release of lymphomonocyte mediators including TNF- couldbe envisaged.     

Myofibroblasts, predictors of progression of mesangial IgA nephropathy?

The limited knowledge of the cellular mediators of renal scarringhampers progress in the management of progressive chronic renalfailure (CRF). We have studied 38 patients with biopsy-provenmesangial IgA nephropathy with emphasis on attempting to definethe role of myofibroblasts(-smooth muscle actin/SMA-positivecells) in renal scarring. In 18 untreated patients, correlationswere undertaken between known histological parameters of progressionas well as the presence of myofibroblasts in tissues and theclinical outcome. -SMA staining by an avidin-biotin-peroxidasemethod was confined to a large extent to the vascular smoothmuscle cells of normal kidneys but extended to the tubulointerstitiumand periglomerular space in scarred kidneys. Mild glomerularstaining was also noted. The interstitial immunostain followeda similar distribution to that of interstitial type III collagen.Morphometric analysis showed the interstitial SMA staining tobe a reliable histological predictor of outcome as it discriminatedbetween progressors and non-progressors (²=4.923, P=0.026).The intensity of the interstitial -SMA staining correlated withrenal functional outcome; inversely with the reciprocal of serumcreatinine slopes (r=-0.466, P<0.025) and positively withthe serum creatinine value at the end of the observation period(r=0.704, P<0.00l). Other histological parameters that correlatedwith outcome included the degree of tubulointerstitial (TI)inflammatory infiltrate (r=-0.425, P<0.05 with 1/Cr slopeand r=0.760, P< with serum creatinine) and the intensityof the TI staining for collagen IV (r=-0.567 and 0.667 respectively).In 20 patients treated with prednisolone and azathioprine, asecond renal biopsy showed the persistence of interstitial myofibroblastsin the absence of progressive fibrosis. In conclusion, stainingof renal biopsies of patients with mesangial IgA for -SMA-positivecells may identify the myofibroblasts as important mediatorsof TI scarring and have useful prognostic implications.     

Acute effect of oral, intraperitoneal, and intravenous 1{alpha}-hydroxycholecalciferol on markers of bone metabolism

OBJECTIVE: To study the acute effect of 1-hydoxycholecalciferol (1-OHD₃)on serum levels of alkaline phosphatase, Ca²⁺, osteocalcin,parathyroid hormone (PTH), phosphate and type I and III procollagens(PICP and PIIINP respectively) in patients undergoing peritonealdialysis. Also, 1,25-(OH)₂D₃ was measured. DESIGN: Single doses of 1-OHD₃ (80 ng/kg body wt) were given in randomizedcross-over fashion, orally, intraperitoneally (i.p.) and intravenously(i.v.) on three occasions. Blood was sampled at 0, 1, 6, 12,and 24 h after administration of 1-OHD₃. MAIN RESULTS: Following oral administration of 1-OHD₃, a decrease in serumalkaline phosphatase was seen when levels at 1 and 6 h werecompared to baseline (P<0.05). Oral and i.v. drug administrationsresulted in an increasing trend in serum Ca²⁺ throughout thestudy (P<0.05). Moreover, a difference in serum Ca²⁺ wasfound when 24-h levels after oral 1-OHD₃ dose was compared tobaseline (P<0.05). Serum osteocalcin at 12 and 24 h afteroral 1-OHD₃ compared to baseline were increased (P<0.05).Intact PTH followed a circadian rhythm after all three routesof drug delivery. After 24 h, significant decreases of intactPTH were observed in the oral and i.v. group. No changes inserum phosphate and serum PICP levels were observed over timeafter oral, i.p., and i.v. delivery of 1-OHD₃However, serumPIIINP following oral and i.p. administration of 1-OHD₃ decreasedat 1 and 6 h (P<0.05). CONCLUSION: Oral and iv. administration of 1-OHD₃ does influence serum levelsof osteocalcin, PTH, and PIINP. Noticeable is the significantincrease in serum osteocalcin after oral administration of 1-OHD₃,the remarkable increase (22.6%) in osteocalcin 24 h after i.v.1-OHD₃, though not statistically significant, the increase inserum PTH levels 12 h following oral and i.v. doses of 1-OHD₃and the moderate effect on serum Ca²⁺ levels.     

Effect of calcium-channel blocker on tumour necrosis factor alpha (TNF{alpha}) production in cyclosporin-treated renal transplant recipients

PURPOSE OF THE STUDY.: The influence of calcium-channel blocker treatment on in-vitroTNF production by peripheral blood mononuclear cells (PBMC)from renal transplant recipients treated with cyclosporin wasstudied. DESIGN.: We compared spontaneous and OKT3-induced TNF production of 12renal transplant recipients treated with calcium-channel blockertherapy with that of 18 renal transplant recipients who werenever treated with a calcium antagonist. RESULTS.: The two groups were similar with regards to age, time aftertransplantation, dosage of immunosuppressive drugs, and bloodcyclosporin levels. Spontaneous (481±161 versus 319±74pg/ml, n.s.) and OKT3-induced (745±182 versus 632±112pg/ml, n.s.) TNF production were similar in both groups. CONCLUSIONS.: The results indicate that in cyclosporintreated renal transplantrecipients calcium-channel blockers do not affect TNF production.     

De novo expression of transforming growth factor-{alpha} in parathyroid gland tissue of patients with primary or secondary uraemic hyperparathyroidism

BACKGROUND.: The factors involved in abnormal parathyroid cell secretoryfunction and growth in patients with primary and secondary hyperparathyroidismare still incompletely understood. PATIENTS AND METHODS.: We studied the expression of transforming growth factor- (TGF-),epidermal growth factor (EGF) and EGF receptor (EGF-R) at thegene message and the protein level in parathyroid tissue obtainedfrom six patients with primary hyperparathyroidism, 15 patientswith secondary uraemic hyperparathyroidism and five subjectswith normal parathyroid tissue, using in situ hybridizationand/or immunostaining technique. RESULTS.: We found a consistent expression of TGF- mRNA and protein inparathyroid endocrine cells of all six cases of primary parathyroidadenoma and in nearly all cases of secondary hyperplasia, incontrast to the absence of expression in normal parathyroidtissue. A marked expression of EGF-R mRNA and protein was alsofound in four of five tissue samples of primary parathyroidadenoma, in 13 of 15 tissue samples of secondary parathyroidhyperplasia and in most samples of normal parathyroid glandtissue. EGF mRNA and protein expression was undetectable inthe majority of parathyroid tissue samples examined. CONCLUSION.: Since TGF- is known to bind to the EGF-R, the finding of anincreased expression of TGF- at the gene message and the proteinlevel, together with a strong expression of EGF-R, in hyperplasticand adenomatous parathyroid glands suggests that this growthfactor interacts with its receptor to promote parathyroid cellproliferation, perhaps by an autocrine mechanism.     

Sera from patients with anti-GBM nephritis including Goodpasture syndrome show heterogenous reactivity to recombinant NC1 domain of type IV collagen {alpha} chains

BACKGROUND.: Goodpasture (GP) syndrome is defined by the clinical associationof pulmonary haemorrhage with rapidly progressive glomerulonephritis.The disease is caused by pathogenic autoantibodies directedagainst type IV collagen, which is a major structural componentof glomerular basement membranes (GBM). METHODS.: The non-collagenous domains (NC1) of all six human type IV collagenchains was produced in E. coli as recombinant fusion proteinswith glutathione-S transferase. Sera from 10 patients with differenttypes of anti-GBM nephritis, including GP syndrome, were testedfor reactivity with the six proteins using immunoblotting ofdenatured and reduced proteins and ELISA without reduction. RESULTS.: All 10 sera reacted with the 3(IV) collagen chain by immunoblottingand ELISA. One serum also recognized the 2(IV) 4(IV), 5(IV)and 6(IV) chains by immunoblotting. ELISA measurements revealedreactivity of several other sera with 2(IV), 4(IV) or 6(IV)but not with 5(IV) collagen chains. No reactivity was observedwith the 1(IV) chain. CONCLUSION.: Autoantibodies in anti-GBM nephritis may not be directed onlyagainst the 3(IV) collagen chain and they frequently recognizeconformational epitopes.     

Urinary excretion of cytokines and complement SC5b-9 in idiopathic membranous glomerulonephritis

Idiopathic membranous glomerulonephritis (iMGN) has previouslybeen shown to be associated with urinary excretion of terminalcomplement complexes while increased urinary levels of cytokineshave been reported in mesangial proliferative glomerulonephritis.In the present cross-sectional study urinary excretion of IL-1ßTNF-, IL-6;, and soluble C5b-9 (SC5b-9) was examined for 23patients with iMGN, 16 patients with diabetic nephropathy (DNP),and 17 healthy subjects. IL-1ß excretion (pg/mg crea)was significantly higher in iMGN patients (375, range 162–11000) than in DNP patients (39, range 22–59, P<0.001)or healthy controls (151, range 23–481, P<0.00l). TNF-excretion rate (pg/mg crea) was clearly higher (38, range 21–700)in iMGN patients than in DNP patients (14, range 8–52,P< 0.001) or healthy subjects (11, range 7–26, P<0.001).Median IL-6 excretion (pg/mg crea) was only marginally higherin iMGN patients (73, range 0–850) than in healthy subjects(64, range 3–158, P=0.02) but significantly higher thanin DNP patients (29, range 17–47, P<0.001). No significantcorrelation with corresponding serum values was observed forurinary IL-6 or TNF- excretion. Urinary IL-1/ß andTNF- correlated with decreased renal function. Five of 23 patientsshowed progression of iMGN over a follow-up of 6 months. Theexcretion of all cytokines, TNF- in particular, was significantlyhigher in patients with a progressive disease than in the otherpatients. High TNF- excretion (>57 pg/mg crea) was detectedin 4/5 patients with progression but in none of the stable patients(P<0.001). Seventy-seven per cent of the iMGN patients and94% of DNP patients, but none of the healthy subjects had detectableSC5b-9 excretion. In DNP patients the urinary SC5b-9 levelscorrelated with proteinuria whereas in iMGN the SC5b-9 excretioncould not be accounted for by proteinuria alone. Urinary excretionof SC5b-9 correlated with decreased renal function and had arelationship to urinary IL-1/ß and TNF- excretionin iMGN patients. Moreover the median excretion rate of SC5b-9was higher in patients with than in those without progressionof iMGN. The results suggest that increased urinary IL-1ß,TNF-, and SC5b-9 excretion are detected in patients having iMGN.They may be indicators of a progressive renal disease in iMGN.     

Once-weekly erythropoietic therapy: is there a difference between the available preparations?

Sir, Iain Macdougall provided, in general, a comprehensive reviewof once-weekly administrations of epoetin , epoetin ßand darbepoetin [1]. However, additional mention could havebeen made of the differences between epoetin and epoetin ß,as well as further analysis of the data from studies of subcutaneous(s.c.) administration. With regard to the differences between epoetin and epoetin     

Light Chain Nephropathy: Histological and Clinical Aspects in 15 Cases

Fifteen patients aged 31–74 years (five male, ten female)on renal biopsy showed intense linear deposits of light chainsalong tubular basement membranes (TBM) by immunofluorescence.and/or granular dense deposits on electronmicroscopy. Multiplemyeloma was diagnosed in ten patients. The onset of myelomaand nephropathy was simultaneous in six patients; nephropathypreceded or followed the diagnosis of myeloma in three and onepatients respectively. The mode of onset of nephropathy wasacute or rapidly progressive renal failure in five cases, chronicrenal failure in seven, and heavy proteinuria in three. Onlytwo patients had normal renal function at biopsy. Serum monoclonalcomponent was in five patients, IgG in three, IgD in one. IgGin one, IgA in one, absent in three, and not detected in one.On light microscopy eight cases had nodular glomerulosclerosis,three cast nephropathy and 14TBM thickening. Immunofluorescencefor monoclonal light chain(s) was positive in 11 of 13 cases.Electron microscopy showed finely granular deposits in the innerside of glomerular basement membranes(GBM) and the outer sideof TBM in 11 of 11 tesied cases. The evolution was towards chronicrenal failure in 12 patients (six of whom required dialysis),death in two. unknown in one. Four patients died after a periodof dialysis, from infections or cardiovascular complications.     

Interferon-{alpha}2b treatment of chronic hepatitis C in haemodialysis patients

Nineteen haemodialysis (HD) patients with chronic hepatitisC were treated with interferonalpha2b (IFN-) at a dose of 3or 1 MU thrice weekly for 6 months and were followed-up foranother 14 months without treatment. Six patients discontinuedtreatment because they either presented severe side-effectsto IFN- or had complications of their primary disease. Levelsof AST and ALT were within normal limits on the 2nd month oftreatment and remained so throughout the treatment and the follow-upperiod in all patients except one who showed an elevation oftransaminase levels 2 months after the end of treatment. SerumHCVRNA became negative in 10/13 patients at the end of treatmentand was negative in all patients on the 6th month and in 12/13patients on the 14th month during the follow-up period. Levelsof 2'5' oligosynthetase were increased significantly on the2nd and 4th month of treatment and returned to pretreatmentvalues the 2nd month after treatment. These findings demonstratethat haemodialysis patients with chronic hepatitis C respondwell to interferon treatment and that a long-term response isachieved in a high proportion of patients.     

Increased renal expression of cytokines and growth factors induced by DOCA-NaCl treatment in Heymann nephritis

DOCA-NaCl treatment causes hypertension, accelerates developmentof proteinuria, and leads to glomerulosclerosis in rats withautoimmune Heymann nephritis. To study the mechanisms of kidneyinjury induced by renal haemodynamic load in chronic nephritis,we studied by immunohistochemistry the local expression of variouscytokines, growth factors and adhesion molecules in the kidneysof Heymann nephritic rats with or without DOCA-NaCl-inducedhypertension. The DOCA-NaCl-nephritis group developed hypertensionand marked renal enlargement as compared with the nephritisgroup, the DOCA-NaCl group, and the controls. Albuminuria appearedearlier and was heavier in the DOCA-NaCl-nephritis group comparedwith the nephritic rats without DOCA-NaCl. Expression of IL-6,TNF-, GM-CSF, b-FGF, NGF, TGF-ß, and ICAM-1 was enhancedin the kidneys of the DOCA-NaCl-nephritis group as comparedwith other groups, localized mainly in the glomerular mesangium(IL-6, GM-CSF, TGF-ß), glomerular and peritubularendothelium (ICAM-1), and collecting ducts (TNF-, b-FGF, NGF,TGF-ß), possibly associated with the observed tubulointerstitialmononuclear cellular infiltration. Thus in autoimmune Heymannnephritis, DOCA-NaCl treatment causes hypertension and increasedrenal mass together with upregulation of local cytokine andgrowth factor production, which may further aggravate hypertensionand accelerate progression of renal damage.