Membranous nephropathy in a patient with hereditary complete complement C4 deficiency.
Explore the source record for details and available documents.
Adolescent↗
Biomedical subjects
Gert Mayer
Publications and source records attributed to Gert Mayer.
Evaluation of the living kidney donor.
Living donor renal transplantation is the preferred treatment for end-stage renal failure as the risk-benefit ratio for the recipient usually very much favours this approach. However, the benefit for the donor is much harder to define and probably very small if pure medical criteria are considered. Nonetheless 'non-medical' issues (mostly socio-psychological) may outweigh the small medical risk. The medical pre-transplant evaluation of the potential donor must identify absolute contraindications and abnormalities, which would increase the peri-operative risk. Difficulties may arise, if during the process, minor abnormalities are detected that marginally increase the acute or especially the long-term risk or whose implications are not well defined. In this situation two options are available. If the transplant team assumes that donation per se is of no benefit for the donor, transplantation should not be performed. If, however, the supposed 'non-medical' benefit is large enough, this approach will be against the principle of 'doing no harm' because the individual is denied the possibility to help somebody and might suffer from the consequences. In these complicated cases the final decision should be with the potential donor after an intense discussion with everybody involved in the transplantation process. Such an approach, however, necessitates a post-donation follow-up programme to be offered.
Creatinine↗
Apoptosis of human polymorphonuclear neutrophils accelerated by dialysis membranes via the activation of the complement system.
BACKGROUND: Haemodialysis (HD) with bioincompatible cellulosic membranes like Cuprophan (CU) is considered to influence negatively the clinical outcome of acute and chronic renal failure. In this effect, apart from the disturbance of phagocytosis or oxygen species production by leukocytes, increased apoptosis also has been implicated recently. The objective of this study was to study the effect of HD membranes on apoptosis induction in polymorphonuclear neutrophils (PMN). METHODS: PMN from healthy donors and uraemic patients were isolated and apoptosis was induced by co-incubation with CU, Hemophan or polyamide hollow fibres in the presence of serum from healthy or uraemic humans. Apoptosis was quantified by flow cytometry using Annexin V-FITC and propidium iodide staining and was confirmed by the detection of DNA fragmentation on gel electrophoresis. The deposition of immunoglobulins (Ig) and complement factors on hollow fibres was detected by direct immunofluorescence. RESULTS: Heat inactivation or the depletion of complement components or Ig significantly reduced apoptosis, indicating its dependence on classical complement activation. The detection of IgG on hollow CU fibres and the restored acceleration of apoptosis by the appropriate replenishment of Ig-deficient sera additionally confirmed these findings. Inhibition experiments revealed that caspases were necessary mainly, but not exclusively, for apoptosis to occur after complement activation. Uraemia led to increased PMN apoptosis in the presence of bioincompatible, but not biocompatible, membranes. CONCLUSIONS: Our results suggest that the acceleration of PMN apoptosis in the presence of CU is mediated via an antibody-dependent activation of the classical complement pathway mobilizing both caspase-dependent and -independent pathways.
Apoptosis↗
Alterations in gene expression in cadaveric vs. live donor kidneys suggest impaired tubular counterbalance of oxidative stress at implantation.
Recipients of live donor transplant kidneys (LIV) exhibit a significantly longer allograft half-life compared with cadaveric donor organs (CADs). The reasons are incompletely understood. Therefore this study sought to elucidate the genome-wide gene expression profiles in microdissected transplant kidney biopsies obtained from five cadaveric and five matched live donors before transplantation. cDNA microarrays were used to determine the transcripts in isolated glomeruli (G) and the tubulointerstitial (TI) compartment. Data were subjected to hierarchical clustering, maxT adjustment and a jackknife procedure to ensure robustness of reported findings; validation was performed by independent analysis of split biopsies and TaqMan-PCR. One hundred and thirteen sequences representing 62 unique genes (17 redundant features), and 34 ESTs separated G from TI. No difference in gene expression was found in G between LIV and CAD kidneys, but nine genes (two represented twice) and three ESTs were abundantly expressed in the CAD TI compared with LIV. The main biological function of these genes is counter regulation of oxidative stress. Promoter analysis of significant features suggested coregulated gene groups. These data suggest that CAD kidneys exhibit a distinctly different set of transcripts in the TI compartment but not in the G compartment when compared with LIV kidneys.
Cadaver↗
Role of thrombospondin-1 in the autologous phase of an accelerated model of anti-glomerular basement membrane glomerulonephritis.
BACKGROUND: Thrombospondin-1 (TSP1), a multifunctional, extracellular matrix protein, regulates cellular attachment, proliferation, migration, and differentiation in vitro, and is expressed de novo in many inflammatory diseases, including glomerulonephritis (GN). METHODS: We investigated the role of TSP1 in the autologous phase of an accelerated model of anti-glomerular basement membrane (GBM) GN in mice deficient in TSP1. The model, induced by the injection of rabbit anti-mouse GBM antibody, is characterized by the development of proteinuria and glomerular damage over a 21-day observation period in wild-type mice. RESULTS: Mice deficient in TSP1 developed significantly less proteinuria than their wild-type controls 21 days after induction of disease (5,793 +/- 5,456 vs. 24,293 +/- 15,336 microg albumin/mg creatinine; p = 0.002). Serum creatinine levels were significantly higher in the wild-type mice than in the TSP1 deficient animals (29.03 +/- 2.34 vs. 16.39 +/- 2.87 micromol/l; p = 0.005). Other disease indices as crescent formation, fibrin deposition and macrophage influx, were also diminished in the TSP1 knockout animals. The numbers of interstitial CD4+ and CD8+ T cells were generally less in TSP1-deficient mice and reached statistical significance in CD4+ (p = 0.01) and CD8+ T cells (p = 0.02). The difference in outcome of the disease was not due to the difference in deposition/production of heterologous and autologous antibodies in the two groups of animals. CONCLUSION: This study suggests a proinflammatory role of TSP1 in an experimental model of GN.
Animals↗
Neutrophil transmigration in renal proximal tubular LLC-PK1 cells.
BACKGROUND/AIMS: Adhesion of intratubular leukocytes to proximal tubules in biopsies of patients with rapidly progressive glomerulonephritis and the appearance of leukocytes in the urine in interstitial nephritis suggest interactions between leukocytes and tubular epithelia in renal disease. The present study was performed to investigate whether incubation of tubular epithelia with cytokines or endotoxin (LPS) does stimulate adhesion and migration of leukocytes through these epithelia in vitro. METHODS: Experiments determined adhesion of PMN to LLC-PK cells cultured on tissue culture plates and transepithelial migration (TEM) through LLC-PK monolayers cultured on microporous membranes. Measurements of transepithelial electrical resistance (TER), cytokine release into apical or basolateral compartments and chemotactic activities of apical and basolateral supernatants were performed. RESULTS: Preincubation of LLC-PK cells with either TNFalpha or LPS resulted in stimulation of PMN adhesion and consequently PMN migration through LLC-PK monolayers in both apical-to-basolateral and basolateral-to-apical direction. TEM was not associated with a reduction of TER. Although largely apical IL-8 secretion by LLC-PK cells was found, apical-to-basolateral migration occurred against a concentration gradient of IL-8 and could not be inhibited by IL-8 antibodies. Chemotactic activities of supernatants were slightly increased by TEM but did not show any significant differences between apical and basolateral compartments independent of the direction of PMN migration. TEM in basolateral-to-apical direction was about twice as efficient as in apical-to-basolateral direction (Transmigration Index = 3,92 +/- 0,55 and 2,28 +/-,21, respectively). Only basolateral-to-apical TEM could be partly inhibited by preincubation of basolateral membrane with IL-8 antibodies. CONCLUSION: Inflammatory mediators stimulate PMN adherence to LLC-PK cells and subsequently TEM. The mechanisms involved in TEM stimulated by cytokines or endotoxin appear to be rather changes in surface receptor properties of LLC-PK cells than chemotactic stimuli. Basolateral-to-apical TEM appears to be the favored direction most likely augmented by IL-8 associated haptotactic PMN stimulation.
Animals↗
Reliability of t7-based mRNA linear amplification validated by gene expression analysis of human kidney cells using cDNA microarrays.
Genome wide gene expression analysis by cDNA microarrays is often limited by minute amounts of starting RNA. We therefore tested an optimized linear RNA amplification protocol using the RiboAmp amplification kit in the setting of cDNA microarrays. We isolated mRNA from a human kidney cell line (HK-2; ATCC) and from Universal Human Reference RNA (STR; Stratagene). After performing one and two rounds of linear RNA amplification, respectively, the amplified RNAs were co-hybridized to cDNA microarrays. Linearity and reproducibility of the individual experiments were then assessed by calculating the Pearson correlation. The intra-amplification consistency showed a correlation of 0.968 for the first round, 0.907 for the second round and 0.912 for two successive rounds of amplification. If the first round was compared to unamplified material, r was 0.925. The second round amplification yielded a correlation of 0.897 if compared to unamplified mRNA. Two rounds of amplification starting from 200 pg of mRNA compared to unamplified material resulted in a correlation of 0.868. These results indicate that linear amplification using RiboAmp kit yields amplified RNA with a high degree of linearity and reproducibility.
Cell Line↗
[Remission of chronic kidney diseases. A realistic goal?].
Explore the source record for details and available documents.
Adult↗
Detrimental effects of controlled reperfusion on renal function after porcine autotransplantation are fully compensated by the use of Carolina rinse solution.
Despite extensive efforts in the fields of donor selection and management, standardisation of organ retrieval procedures, storage solutions, and novel immunosuppressive protocols, the rates of delayed graft function (DGF) after renal transplantation have been stagnating between 30% and 50%. As DGF exerts negative influences on acute rejection episodes and long-term organ function, the early phase of transplantation immediately following reperfusion deserves special interest. Several studies on machine-controlled reperfusion showed promising results in various organs, in experimental and clinical settings. Moreover, the flushing of organs with Carolina rinse solution (CR) immediately prior to reperfusion has been proven beneficial and is being clinically applied in human liver transplantation in recognised departments. In our study, we set up an autogenic porcine kidney transplantation model and assessed the normal values (control group) for creatinine clearance (ClCr) and urine output per hour (U/h) after "standard" reperfusion similar to clinical transplantation. Subsequently, kidneys of the experimental group 1 were reperfused at a blood pressure (RR) under the systemic level by means of a roller pump. Group 2 kidneys were rinsed with CR before controlled reperfusion, analogous to group 1. Both groups were compared with each other and with the assessed normal values. Our findings for Group 1 are that pressure-reduced reperfusion negatively affected immediate graft function. ClCr was reduced from 9.9 (control group) to 3.4 ml/min, U/h from 233 to 132 ml ( P<0.05). Group 2 showed that rinsing the kidneys with CR before reperfusion improved functional parameters highly significantly, compared with group 1 (ClCr: 13.5 vs 3.4 ml/min, U/h: 384 vs 132 ml; P<0.05) and even showed a positive trend compared with the control group (ClCr: 13.5 vs 9.9 ml/min, U/h: 384 vs 233 ml; P=0.0546). We can conclude that in a model of porcine renal autotransplantation, pressure-reduced reperfusion via a roller pump is detrimental to early kidney graft function. The flushing of organs with CR prior to controlled reperfusion significantly improves ClCr as well as urine output.
Animals↗
Effect of iron treatment on circulating cytokine levels in ESRD patients receiving recombinant human erythropoietin.
BACKGROUND: Anemia in patients with end-stage renal disease (ESRD) is treated with recombinant human erythropoietin (rhEPO) often in combination with iron. However, iron catalyzes the formation of toxic radicals, which might promote vascular damage, is a nutrient for microorganisms, and negatively affects immune pathways, thus increasing the risk for severe infections. METHODS: We investigated 28 patients on chronic hemodialysis who were randomized to receive either rhEPO alone (N = 15) or rhEPO in combination with intravenous iron (N = 13) for a period of 12 weeks. We analyzed iron therapy associated changes in cytokine patterns and endogenous radical formation. RESULTS: Tumor necrosis factor-alpha (TNF-alpha) levels were increased in ESRD patients at study entry and then decreased significantly over time in subjects receiving additional iron, while they increased with rhEPO alone. In contrast, we found serum concentrations of the anti-inflammatory cytokine interleukin (IL)-4 to increase with iron therapy. A significant negative correlation between iron availability, as determined by transferrin saturation, and TNF-alpha levels (P = 0.008) and a positive one between transferring saturation and IL-4 (P = 0.02) pointed to the potential role of iron to induce immunologic changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF-alpha concentrations since peroxide concentrations were positively correlated to TNF-alpha levels (P = 0.046) and negatively to transferrin saturation (P = 0.02). CONCLUSION: Iron supplementation in ESRD patients down-regulates proinflammatory immune effector pathways and stimulates the expression of the anti-inflammatory cytokine IL-4. Such a condition is detrimental for host response toward invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition due to impaired TNF-alpha formation.
Aged↗
Age and renal transplantation: an interim analysis.
Explore the source record for details and available documents.
Adolescent↗
Regional variability in the incidence of end-stage renal disease: an epidemiological approach.
BACKGROUND: Regional variability in the incidence of end-stage renal disease (ESRD) in Austria is reported. Our aim was to investigate the reason for low rates in the state of Tyrol. METHODS: ESRD incidence data were obtained from the Austrian Dialysis and Transplantation Registry. Additional sources were two health interview surveys, the Hospital Discharge Registry, the Mortality Registry and the Drug Wholesale Registry. RESULTS: Between 1995 and 1999, 4811 new cases of ESRD were recorded; the state of Tyrol (T) had a mean annual, age-adjusted incidence of 97.9/1 000 000 population [95% confidence interval (CI) 86.9-109.1], a number significantly lower than that for the rest of Austria [(RA), 120.9 (95% CI 116.9-124.5); P < 0.001]. This was due mainly to a difference in the incidence of ESRD patients with type 2 diabetes mellitus [(DM-2) T = 12.2 (95% CI 8.2-16.2) vs RA = 28.9 (95% CI 27.2-30.6); P < 0.001]. When these patients were excluded, the difference in the overall ESRD incidence disappeared. When data from various registries were analysed for the prevalence of DM, a highly significant correlation was found between ESRD incidence and DM. CONCLUSION: We conclude that the variability in the ESRD incidence in Austria is explained mainly by regional differences in DM-2. Data from similar studies might be useful for predictions concerning resource allocation for ESRD programmes in the future.
Adolescent↗
One-year growth hormone therapy improves granulocyte function without major effects on nutritional and anthropometric parameters in malnourished hemodialysis patients.
BACKGROUND/AIMS: Growth hormone (GH) resistance leads to enhanced protein catabolism and contributes to the malnutrition of patients with chronic renal failure (CRF). In short-term trials anabolic effects of rhGH therapy have been demonstrated in patients on chronic hemodialysis. METHODS: This study was initiated to determine the effects of 12 months of rhGH therapy on polymorphonuclear leukocyte (PMNL) function as well as on nutritional and anthropometric parameters. 0.125 IU/kg rhGH was given 3 times a week during the first 4 weeks and 0.25 IU/kg thereafter to 19 malnourished hemodialysis patients with a mean age of 59.3 +/- 13.4 years. RESULTS: Insulin-like growth factor I (IGF-I) concentrations rose significantly from 169.2 +/- 95.6 to 262.9 +/- 144.4 ng/ml (p < 0.01) in the first 3 months, but declined thereafter. Phagocytic activity of PMNLs also increased significantly in response to rhGH therapy and this activation remained stable over the whole 12-month period. Other parameters of PMNL function were not influenced by rhGH therapy. In addition, nutritional parameters such as albumin, prealbumin, transferrin, cholesterol, HDL-cholesterol, cholinesterase, predialytic creatinine and blood urea nitrogen were not affected by rhGH therapy. A decline of total body fat (TBF) was observed after 3 and 9 months of rhGH therapy (17.5 +/- 10 vs. 16.7 +/- 10% after 3 months, p < 0.017 and 16.8 +/- 8.7% after 9 months, p < 0.049), whereas lean body mass remained stable. CONCLUSIONS: Twelve months of rhGH therapy caused a significant increase in IGF-I levels, stimulated phagocytic activity of PMNLs and induced a decline of TBF. Other anthropometric and nutritional parameters were not affected, which might be related to the persistence of GH resistance.
Anthropometry↗
Effects of AT1 and AT2 receptor blockade on angiotensin II induced apoptosis of human renal proximal tubular epithelial cells.
BACKGROUND: Tubular atrophy is a common histological feature of chronic renal failure, and epithelial cell death by apoptosis might play an important role in its pathogenesis. Angiotensin II contributes to the progressive nature of many kidney diseases and treatment with angiotensin converting enzyme inhibitors preserves the structure of the tubulointerstitial compartment in human and experimental renal diseases. METHODS: Primary cultures of human renal proximal tubular epithelial cells were co-incubated with angiotensin II alone or in combination with the angiotensin II AT1 receptor antagonist losartan or/and the AT2 antagonist PD123319. Apoptosis was determined after 20 hours by TUNEL staining and flow cytometry. RESULTS: Angiotensin II at concentrations of 10(-9) M induced apoptosis (control vs. angiotensin II 4 +/- 3% vs. 73 +/- 11%; p < 0.05). This effect was completely offset by co-incubation with the angiotensin II AT2 receptor blocker at concentrations 10(-7) M (control vs. PD123319 4 +/- 3% vs. 8 +/- 3%; p < 0.05); AT1 blockade was ineffective in apoptosis inhibition. When both angiotensin receptors were blocked, no additional effect on apoptosis inhibition could be detected. CONCLUSION: We provided evidence, that physiological concentrations of angiotensin II can induce apoptosis of human renal proximal tubule epithelial cells. This effect is mediated via AT2 receptors.
Angiotensin II↗
Antioxidant therapy in glomerular disease.
Explore the source record for details and available documents.
Animals↗
Antioxidant treatment of therapy-resistant idiopathic membranous nephropathy with probucol: a pilot study.
BACKGROUND: Proteinuria in Heymann's nephritis, an experimental rat model disease corresponding to membranous nephropathy, has been shown to be due to lipid peroxidation. Since the pathophysiology might be similar to idiopathic membranous nephropathy in humans, we performed a prospective multicenter trial to investigate the efficacy of the lipid peroxidation scavenger, probucol. METHODS: Fifteen patients with biopsy-proven idiopathic membranous nephropathy resistant to conventional immunosuppressive therapy (n = 7) and/or ACEI treatment (n = 12) were recruited. Probucol (1 g/d orally) was administered for three months, followed by a washout period of four weeks, whereon lovastatin (10-20 mg/d orally) was administered for additional three months. RESULTS: A significant reduction in proteinuria was seen during the probucol treatment (median (range): 6.4 (3.8-9.1) g/d vs. 4.7 (1.3-16) g/d; P < 0.05), with partial remission achieved in four patients. Three of these patients had previously been resistant to immunosuppressive therapy. Median protein excretion increased to pretreatment values during the washout period (6.2 (1.9-15) g/d; P < 0.05) and was not significantly different after the intake of lovastatin (4.9 (1.8-19) g/d; P = NS). None of the patients achieved partial remission during lovastatin therapy (P < 0.05 vs. probucol). CONCLUSION: The present study led us to conclude that proteinuria can be reduced by probucol in some patients with idiopathic membranous nephropathy. A randomized multicenter study to further elucidate the influence of lipid peroxidation scavengers on membranous nephropathy is warranted.
Adult↗
Regular physical exercise improves endothelial function in heart transplant recipients.
BACKGROUND: Impaired endothelial function is detectable in heart transplant (HTX) recipients and regarded as risk factor for coronary artery disease. We have studied whether endothelial function can be improved in HTX patients participating in a regular physical training program as demonstrated in patients with chronic heart failure, hypertension and coronary artery disease. METHODS: Male HTX patients and healthy, age-matched controls were studied. Seven HTX patients (age: 60 +/- 6 yr; 6 +/- 2 yr of HTX) participated in an outpatient training program, six HTX patients (age: 63 +/- 8 yr; 7 +/- 1 yr of HTX) maintained a sedentary lifestyle without regular physical exercise since transplantation. A healthy control group comprised six subjects (age: 62 +/- 6 yr). Vascular function was assessed by flow-mediated dilation of the brachial artery (FMD). Systemic haemodynamic responses to intravenous infusion of the endothelium independent vasodilator sodium nitroprusside (SNP) and to NG-monomethyl-L-arginine (L-NMMA), an inhibitor of constitutive nitric oxide synthase, were also measured. RESULTS: Resting heart rate was significantly lower (p < 0.05) in healthy controls (66 +/- 13) than in the HTX training group (83 +/- 11) and in non-training HTX patients (91 +/- 9), baseline blood pressure also tended to be lower in healthy subjects and in the training HTX patients. FMD was significantly higher (p < 0.05) in the control group (8.4 +/- 2.2%) and in the training group (7.1 +/- 2.4%), compared with non-training HTX patients (1.4 +/- 0.8%). The response of systolic blood pressure (p = 0.08) and heart rate (p < 0.05) to L-NMMA was reduced in sedentary HTX patients compared with healthy controls and heart rate response to SNP was also impaired in sedentary HTX patients. DISCUSSION: Regular aerobic physical training restores vascular function in HTX patients, who are at considerable risk for developing vascular complications. This effect is demonstrable in conduit and systemic resistance arteries.
Blood Pressure↗
Cigarette smoking and vascular pathology in renal biopsies.
BACKGROUND: In recent years cigarette smoking has been identified as a progression factor in chronic nephropathies such as glomerulonephritis or diabetic nephropathy. The exact pathomechanism of nicotine-induced renal damage is, however, unknown. Autopsy studies and functional investigations suggest that the renal vasculature is primarily affected by smoking. METHODS: Renal vascular pathology, that is, glomerulosclerosis, hyalinosis of arterioles and myointimal hyperplasia of small arteries, was determined in 135 biopsies of patients over thirty years of age. A questionnaire about smoking habits was returned by 107 of the patients. For glomerular sclerosis the percentage of sclerotic glomeruli was determined, whereas arteriolar hyalinosis and myointimal hyperplasia of small arteries were described as present or absent without further quantification. A univariate analysis was performed for existence of vascular changes and ever-smoking status. In addition, a multivariate analysis for glomerular sclerosis and logistic regression analysis for arteriolar hyalinosis and myointimal hyperplasia and the variables ever-smoking, age, body mass index, creatinine clearance, blood pressure and lipids were performed. RESULTS: Creatinine clearance was comparable for nonsmokers, ex-smokers and smokers. Frequency of myointimal hyperplasia of small arteries was twice as high in ever-smokers as compared to nonsmokers (50% vs. 25.5%, P < 0.01). Arteriolar hyalinosis was detected in 23.5% of nonsmokers and in 35.7% of smokers, showing a trend toward hyalinosis in ever-smokers (P=0.20). Glomerular sclerosis was found in 62.7% of nonsmokers and in 69.6% of ever-smokers. Logistic regression analysis confirmed an association between ever-smoking and myointimal hyperplasia (P < 0.01). This association also was present in males and patients over fifty years of age, but not in younger patients and females. CONCLUSION: In patients with renal, especially glomerular disease, cigarette smoking exhibits its deleterious effect on the kidneys primarily through damage of small interlobular arteries.
Adult↗