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Biomedical subjects

H Haller

Publications and source records attributed to H Haller.

At least 19 recordsLinked to original sources
PubMed2006

Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo.

Albuminuria in diabetic nephropathy is due to endothelial dysfunction, a loss of negative charges in the basement membrane, and changes a of the slit-membrane diaphragm composition. We have recently shown that protein kinase C alpha (PKCalpha)-deficient mice are protected against the development of albuminuria under diabetic conditions. We here tested the hypothesis that PKCalpha mediates the hyperglycemia-induced downregulation of the slit-diaphragm protein nephrin. After 8 weeks of streptozotocin (STZ)-induced hyperglycemia the expression of glomerular nephrin was significantly reduced. In contrast, other slit-diaphragm proteins such as podocin and CD2AP were unaltered in diabetic state. In PKCalpha-/- mice, hyperglycemia-induced downregulation of nephrin was prevented. Podocin and CD2AP remained unchanged. In addition, the nephrin messenger RNA expression was also reduced in hyperglycemic wild-type mice but remained unaltered in PKCalpha-/- mice. We postulate that the underlying mechanism of the hyperglycemia-induced regulation of various proteins of the glomerular filtration barrier is a PKCalpha-dependent regulation of the Wilms' Tumor Suppressor (WT1) which previously has been shown to act as a direct transcription factor on the nephrin promoter. Our data suggest that PKCalpha activation may be an important intracellular signaling pathway in the regulation of nephrin expression and glomerular albumin permeability in the diabetic state.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Side effects of sirolimus.

The mTOR inhibitor sirolimus improves renal transplant function compared with the nephrotoxic calcineurin inhibitors. We evaluated retrospectively the adverse events in 119 of 134 patients getting sirolimus which seemed to be caused by sirolimus. Patients were converted to sirolimus because of malignancies (n = 47), a creeping creatinine (n = 33), or hypertension (n = 26). One cohort had started sirolimus from the time of transplantation (n = 28). A rise in serum lipids and a decrease in hemoglobin were seen relatively regularly, while arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, electrolyte disturbances, and infections occurred only occasionally. Interestingly, 31% of patients developed doubling or more proteinuria. Among renal biopsies, 9/13 showed a glomerulopathy which in 6 cases was de novo and in 3 cases, a presumed recurrence of the primary kidney disease. Thus, we think that caution is required, particularly in connection with preexisting glomerular disease.

Biopsy↗
PubMed2006

Pivotal role of xanthine oxidase in the initiation of tubulointerstitial renal injury in rats with hyperlipidemia.

Hyperlipidemia can induce or aggravate renal tubulointerstitial injury. Experiments in a complex rat model with chronic glomerulonephritis and long-standing, coexisting hyperlipidemia suggested that induction of xanthine oxidase (XO), with increased oxygen radical generation, is involved in aggravation of tubulointerstitial injury. To separate the role of XO in the initial events of lipid-mediated tubulointerstitial injury, short-term experiments with diet-induced hyperlipidemia over 21 and 35 days were performed in otherwise healthy rats. XO expression in relation to the antioxidant enzymes was examined in the cortical tubulointerstitium (TIS) and proximal tubules (PT). Subsequent experiments with XO inhibition were performed, examining tubulointerstitial infiltration with ED1-positive cells and expression of adhesion molecules and monocyte chemoattractant protein-1 (MCP-1) as indicators of early injurious events. Hyperlipidemia increased XO activity in TIS by 40 and 86%, and in PT by 28 and 90% at days 21 and 35, compared with controls on regular diet. This increased activity was associated with increased reactive oxygen species. Among the antioxidant enzymes, glutathione peroxidase activity increased in TIS by 40% and in PT by 90%. Histological evaluation showed a three-fold increase in ED1-positive cells and increased MCP-1 and vascular cell adhesion molecule-1 (VCAM-1) expression at day 35 in the TIS. Inhibition of XO prevented tubulointerstitial ED1 cell infiltration, together with a decreased expression of MCP-1 and VCAM-1. These results point to an important role for XO in the early stage of hyperlipidemia-associated renal injury, mediating macrophage infiltration by a putatively redox-dependent upregulation of MCP-1 and VCAM-1.

Animals↗
PubMed2005

Circulating endothelial cells in relapse and limited granulomatous disease due to ANCA associated vasculitis.

OBJECTIVES: To evaluate numbers of circulating endothelial cells (CECs) in ANCA associated vasculitis and compare vasculitic relapse with limited granulomatous disease. METHODS: Sixteen patients with vasculitic relapse of ANCA associated vasculitis and 12 patients with limited granulomatous disease due to Wegener's granulomatosis (WG) were studied. Six patients with newly diagnosed vasculitic disease and six patients with vasculitis with infectious complications were also studied. Twenty two patients in remission were studied, as were 20 healthy controls. Counting of CECs was performed with anti-CD146 driven immunomagnetic isolation and staining with Ulex Europaeus lectin 1(UEA-1). RESULTS: Patients with vasculitic relapse had markedly increased numbers of circulating endothelial cells (12-800 cells/ml, median 88 cells/ml) as did patients with newly diagnosed systemic vasculitis (20-216 cells/ml, median 56 cells/ml). Patients with limited granulomatous disease due to WG had only slightly increased cell numbers (4-44 cells/ml, median 20 cells/ml), which were similar to those of patients in remission (4-36 cells/ml, median 16 cells/ml). Numbers of CECs in patients with granulomatous disease were significantly lower than in those patients with relapse or new onset vasculitis (p<0.001). Cell numbers in patients with relapse and new onset vasculitis declined with immunosuppressive treatment. Patients with infection had 4-36 cells/ml (median 10 cells/ml). A cut off value of 20 cells/ml for a positive result yielded 64% specificity and 95% sensitivity for active systemic vasculitis; the positive predictive value was 63% and the negative predictive value 95%. CONCLUSION: Markedly increased numbers of CECs discriminate active vasculitis from limited granulomatous disease and remission. These findings add further proof to the concept of CECs as a marker of ANCA associated small vessel vasculitis.

Acute Disease↗
PubMed2005

Biocompatibility parameters of different dialysis membranes assessed during systemic inflammation.

BACKGROUND: We explored whether biocompatible dialyzer membranes modulate the inflammatory response during blood contact in patients with systemic inflammation. METHODS: 15 patients with end-stage renal disease and systemic inflammation (mean serum C-reactive protein 86 +/- 4 mg/l) were randomly treated with Cuprophan (CU), polyamide (PA) and vitamin-E coated (VEC) membrane-based dialyzers. RESULTS: Changes in blood pressure, capillary blood oxygen saturation and differential blood counts during the hemodialysis session were not significantly different between the three dialyzers. Baseline blood levels of activated circulating complement (C3a) were more than 100 times above normal, and unlike expected they decreased during hemodialysis treatments (CU: from 7,389 +/- 783 to 5,423 +/- 761 ng/ml; PA: from 7,379 +/- 980 to 5,690 +/- 714 ng/ml; VEC: from 7.377 +/- 714 to 5,360 +/- 1,005 ng/ml; all n.s.). No significant differences between treatments were found with respect to changes in blood concentrations of TNF-alpha, interleukin-6 and interleukin-1 receptor antagonist as well as ICAM-1 (CU: from 451 +/- 41 to 477 +/- 41 ng/ml; PA: from 437 +/- 42 to 449 +/- 40 ng/ml; VEC: from 461 +/- 43 to 460 +/- 47 ng/ml). Furthermore, generation of reactive oxygen species by mononuclear blood cells was comparable during hemodialysis with the CU, PA and VEC dialyzer. CONCLUSION: The choice of dialyzer membrane material does not affect most aspects of biocompatibility when patients have significant systemic inflammation. This confounding variable should be taken into account in studies exploring the effects of biocompatible dialyzer membranes.

Female↗
PubMed2005

[New guidelines for treatment of hypertension].

Treatment of high blood pressure is a central element in prevention of cardiovascular diseases. The new classification of hypertension takes into consideration the close association between blood pressure level and cardiovascular risk and designates blood pressure between 140/90 and 130/80 mmHg as high-normal so that blood pressure <140/90 mmHg should always be the goal. The targeted blood pressure levels are also defined by the extent of end-organ damage already present. The therapeutic objective in patients with diabetes mellitus is a blood pressure level of 130/80 mmHg and in patients with kidney disease and proteinuria 125/75 mmHg. The five substance groups of diuretics, beta-blockers, calcium antagonists, ACE inhibitors, and angiotensin receptor blockers are recommended for primary treatment. In addition to the antihypertensive properties, substance-specific effects of ACE inhibitors and angiotensin receptor blockers have been described. Primarily, instead of monotherapy low-dose combination therapy can also be judicious.

Antihypertensive Agents↗
PubMed2005

Cyclosporine-based immunosuppressive strategies for kidney recipients: interim analysis of German data from the Multinational Observational Study (MOST).

INTRODUCTION: We collected data from kidney recipients with a functioning graft at German kidney transplant centers in order to analyze the efficacy of various cyclosporine (CsA)-based immunosuppressive strategies, the effects of different perioperative and maintenance regimens, and the impact of donor source on clinical outcome. METHODS: As part of the ongoing prospective Multinational Observational Study in Transplantation (MOST), data for both prospective and retrospective analysis were collected from kidney recipients over 18 years bearing a functioning graft that was transplanted at 21 German kidney transplant centers between 1987 and 2002. RESULTS: Data from 1223 renal graft recipients, including their CsA-based immunosuppressive regimens, were stratified as: 402 de novo patients (median 6.8 months posttransplant) and 821 patients on maintenance therapy (median 71 months posttransplant). Triple regimens with CsA + mycophenolate mofetil (MMF) + steroids (Ste) currently comprise the major perioperative immunosuppressive strategies in Germany (de novo 65%). IL-2 receptor antagonist (IL-2Ra) use is increasing (de novo 18%, maintenance 4%), while mono and dual regimen use de novo is declining (de novo 4%, maintenance 20%). Among 689 patients transplanted between 1987 and 2002 with outcome data, the mean incidence of acute rejection during the first posttransplant year was 21.6%. Rejection rates on initial therapy with CsA + MMF + Ste +/- antibodies (n = 517) averaged 17.8%. CONCLUSIONS: Between 1987 and 2002, CsA-based immunosuppression combined with MMF and Ste became the most commonly used strategy for both initial and maintenance therapy after kidney transplantation in Germany, yielding the low acute rejection rates particularly when combined with IL-2Ra.

Adult↗
PubMed2005

Smoking habits in patients diagnosed with ANCA associated small vessel vasculitis.

OBJECTIVES: To study the prevalence of smoking at onset of symptoms in patients with small vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA). METHODS: A retrospective study, in 197 patients with ANCA associated vasculitis, of the history of cigarette smoking at onset of symptoms. Prevalence of smoking in patients with ANCA associated vasculitis was compared with age-specific values for the general population in Germany. RESULTS: 27 (14%) patients were smokers at the time of first disease manifestation (p < 0.001, compared with the entire population); 54 (27%) had smoked previously with 1-110 pack-years (median 18) but had stopped > or = 2 years before onset of vasculitis; 116 (59%) patients were lifelong non-smokers. At onset of symptoms, active smokers were younger (median age 42 years) than patients with vasculitis (median 54 years, p < 0.01, Mann-Whitney U test) with a lower percentage of women (15%, p < 0.005, Fisher's exact test) than in the entire group (47%). Smokers, non-smokers, or ex-smokers did not differ in organ manifestation, mortality, and development of end stage renal disease and relapse rate. CONCLUSIONS: The proportion of active smokers in the group of patients with ANCA associated vasculitis is significantly lower than in the entire population. Cigarette smoking may be associated with a reduced risk of ANCA associated vasculitis.

Adolescent↗
PubMed2005

Life-threatening complications of extracorporeal treatment in patients with severe eosinophilia.

We report three patients with massive eosinophilia of different etiology who developed bronchoconstriction, hypotension, and shock shortly after dialysis or leukapheresis had been begun. In two cases, ethylene oxide-free materials had been used ruling out an allergic reaction related to this compound. Degranulation of eosinophils with release of eosinophil peroxidase may have caused the observed adverse reactions, as suggested by in vitro experiments with blood from the three patients. Our observations draw attention to the fact that extracorporeal therapies may initiate life-threatening complications in patients with severe eosinophilia.

Acute Kidney Injury↗
PubMed2005

Compartment-specific quantitative gene expression analysis after laser microdissection from archival renal allograft biopsies.

BACKGROUND: Various immunological and non-immunological pathomechanisms are responsible for the cellular damage in renal allografts. Since the kidney is an anatomically complex organ with functional and morphological heterogeneous compartments (interstitium, tubuli, vessels, glomeruli), the local response to injury maybe variable, therefore, the identification of local pathomechanisms is important. AIM: To elucidate any discrepancies in quantitative mRNA expression profiles between a total specimen analysis and a cell-specific evaluation after laser microdissection. METHODS: Real-time RT-PCR was performed for complement component C3 and heme oxygenase-1 (HO-1) genes compared to the housekeeping gene beta-actin using whole section RNA extracted from formalin-fixed and paraffin-embedded archival material of 16 explanted, rejected renal allografts. Ten non-transplant nephrectomies served as controls. For five cases from each group, five different compartments of the organs (interstitium, proximal tubuli, distal tubuli, vessels, glomeruli) were microdissected and quantitative analysis for C3 and HO-1 was performed identically. RESULTS: Whole section mRNA expression analysis: the data showed a constant expression of the housekeeping gene beta-actin, a 7-fold increased expression of C3 and a 3-fold decreased expression of HO-1 in the allograft group as compared to the control group. mRNA expression results from microdissected compartments: in the control group, C3 and HO-1 expression could only be detected in the proximal tubuli of all cases whereas all five compartments analyzed from the rejecting kidneys showed expression of the two genes. In the allografts, expression levels of the investigated genes varied considerably not only among the different compartments but between individual cases as well. CONCLUSION: Laser microdissection combined with real-time RT-PCR is a feasible approach for retrospective quantitative gene expression analysis in formalin-fixed and paraffin-embedded renal allograft specimens. As shown for C3 and HO-1, cell-specific expression patterns ofpathogenetically relevant genes vary considerably between individual cases. A close correlation of morphology and cell-specific gene expression analysis will contribute to the elucidation of the complex pathogenesis of chronic renal allograft nephropathy.

Actins↗
PubMed2005

Endometrial stromal sarcoma arising in extrauterine endometriosis: a case report.

We report a rare case of a 46-year-old woman developing endometrial stromal sarcoma (ESS) on the grounds of extrauterine endometriosis. The patient presented with symptoms of stenosis of the rectosygmoid colon. The tissue samples were submitted to histological and immunohistochemical analyses using antibodies for indirect staining. The trial showed multiple foci of endometriosis and mesenchymal malignant tissue described as ESS in the bowel wall, mesentery and in the remnants of the left adnexae. According to our findings, we suspect that ESS might have arisen in colon endometriosis.

Colonic Diseases↗
PubMed2004

Subpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition.

Increased blood concentrations of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to high blood pressure and to cardiovascular mortality. We evaluated the effects of a subpressor ADMA dose on NO production, renal hemodynamics, sodium handling and active renin and noradrenalin plasma concentrations in 12 healthy subjects (age 26 +/- 1 year) using a double-blind placebo-controlled study design. Infusion of ADMA caused a significant decrease in plasma cyclic guanosine monophosphate (cGMP) levels, i.e. the second messenger of NO (from 6.1 +/- 0.4 to 4.3 +/- 0.3 pmol/l; p < 0.05). In parallel, effective renal plasma flow (ERPF) decreased while renovascular resistance (RVR) increased significantly (ERPF from 667 +/- 9 to 603 +/- 10 ml/min/1.73 m2; RVR from 79 +/- 2 to 91 +/- 2 ml/min/mm Hg; both p < 0.05 vs. baseline). Infusion of placebo did not cause significant changes in plasma cGMP levels, ERPF and RVR (cGMP from 5.7 +/- 0.5 to 5.9 +/- 0.6 pmol/l; ERPF from 665 +/- 12 to 662 +/- 11 ml/min/1.73 m2; RVR from 79 +/- 2 to 78 +/- 2 ml/min/mm Hg; all non-significant). Moreover, urinary sodium excretion was significantly lower with infusion of ADMA as compared with placebo infusion (128 +/- 8 vs. 152 +/- 7 micromol/min; p < 0.05). In contrast, blood pressure, active renin and noradrenalin plasma concentrations did not change significantly with either infusion protocol. Acute infusion of a subpressor ADMA dose modulates several aspects of renal function in humans without affecting the activity of the renin-angiotensin and sympathetic system. Whether chronic (intrarenal) NO synthase inhibition in individuals with increased ADMA blood levels may cause persistent renal vasoconstriction and sodium retention must be evaluated.

Adult↗
PubMed2004

An improved assay for enumeration of circulating endothelial cells.

Circulating endothelial cells have been established as markers of vascular disease, such as small vessel vasculitis, acute vascular rejection in renal transplant recipients, and cyclosporine-induced endothelial damage. Enumeration of these cells by immunomagnetic isolation and acridine staining remains the gold standard but necessitates considerable experience and expenditure. A simpler test would therefore be of great utility. Hence, our aim was to develop an improved simple assay to enumerate endothelial cells in peripheral blood. We had already used various surface markers to corroborate the endothelial origin of cells. Here, we studied the enumeration of cell numbers with immunomagnetic isolation and a variety of subsequent stains, such as CD31, von Willebrand's factor (vWF) immunocytochemistry, and Ulex europaeus lectin-1 (UEA-1). Eventually, we devised a simple protocol for enumeration using immunomagnetic isolation and a subsequent UEA-1 lectin stain. We evaluated the use of this protocol in parallel to immunomagnetic isolation and acridine counting alone in 92 renal transplant recipients who underwent renal biopsy. Recovery of various concentrations of human umbilical vein endothelial cells from blood was also studied. Immunomagnetic isolation and subsequent UEA-1 staining permits easier enumeration of circulating endothelial cells in peripheral blood. The assay is simple and easy to use, thus allowing for a more widespread use of circulating endothelial cells as a marker of vascular damage.

Blood Cell Count↗