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Biomedical subjects

R Waldherr

Publications and source records attributed to R Waldherr.

At least 37 records · Page 2Linked to original sources
PubMed1999

Kidney biopsy as a predictor for renal outcome in ANCA-associated necrotizing glomerulonephritis.

BACKGROUND: In kidney biopsies of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis, a variety of histopathological lesions occur, and their relationship to renal outcome is virtually unknown. This multicenter European study reports a clinicopathological analysis of biopsies from 157 patients with systemic vasculitis. METHODS: The biopsies were evaluated according to a previously standardized scoring protocol. Serum creatinine values were measured at the time of biopsy and one year later. In addition, the lowest creatinine level during follow-up was taken into account as the optimum level of renal function recovery. The clinical prognostic value of the histopathological parameters was analyzed with the Kruskal-Wallis one-way analysis of variance and the Mann-Whitney U-test. RESULTS: The percentage of normal glomeruli correlated most significantly with renal outcome at all points of measurement (all P < 0.001). Other lesions predicting for renal function were glomerular sclerosis (P < 0.0005 at one year after the biopsy), diffuse interstitial infiltrates (P < 0.0001 at entry, P < 0.0003 at one year), tubular necrosis (P < 0.0025 at entry), and tubular atrophy (P < 0.002 at entry, P < 0.0002 at one year). CONCLUSION: Traditionally, attention is focused on the extent of active lesions in the renal biopsy in order to determine the severity of renal disease and its implication for renal outcome. Because of their significant impact on renal function, combined with their easy recognition, we recommend the use of the percentage of normal glomeruli in an adequate biopsy in predicting renal function of patients with systemic vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1999

Clinical features and natural history of IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. It is characterized by recurrent gross hematuria, microhematuria and/or proteinuria and diffuse mesangial IgA deposits in glomeruli. It is predominantly a disease of young males. Apart from primary IgAN (Berger's disease), IgA deposits in the glomeruli are also seen in Henoch-Schönlein purpura and in association with various of other diseases, particularly liver cirrhosis. Originally it was thought that IgAN was a benign disease, but it is now known that approximately 20-40% of patients develop progressive renal disease 5 to 25 years after diagnosis and progress to end-stage renal disease. Clinical predictors of progressive disease are elevated serum creatinine concentration at presentation, increased systemic blood pressure, persistent protein excretion > 1.0 g/day and histological predictors are glomerulosclerosis, tubular atrophy/interstitial fibrosis, extension of immune deposits to the perivascular space and crescent formation. Progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions. These features of IgAN reported in literature were mostly, but not completely, confirmed by analysis of all consecutive patients with biopsy proven IgAN and follow-up > 12 months in the renal units of Heidelberg and Prague using univariate analysis, multiple range test and multiple regression analysis.

Adult↗
PubMed1999

Idiopathic myelofibrosis with extramedullary hematopoiesis in the kidneys.

Extramedullary hematopoiesis is a common finding in idiopathic myelofibrosis and is usually found in liver and spleen. We report on a patient with biopsy-proven myeloid metaplasia and fibrosis of the renal parenchyma as a rare cause of chronic renal failure. The renal biopsy specimen showed numerous infiltrates of hematopoietic cells expressing growth factors like M-CSF, GM-CSF, IL-1beta and PDGF while TGF-beta was not elevated. These findings suggest that hematopoietic growth factors play a key role in the pathogenesis of this condition causing proliferating fibrosis and enlargement of the kidneys.

Aged↗
PubMed1998

Molecular cloning of genes differentially regulated by TNF-alpha in bovine aortic endothelial cells, fibroblasts and smooth muscle cells.

OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic-cytokine binding to and thereby stimulating vascular cells. TNF-alpha mediated intermediate stimulation of vascular cells is believed to play a pivotal role in the development of arteriosclerosis. While extensive information has recently become available on gene induction by TNF-alpha, less is known about gene suppression by TNF-alpha in vascular cells. Endothelial cells are the first cell layer within the vessel wall interacting with circulating, cytokine releasing cells. Therefore, they were selected as target for these study. METHODS: A differential screening approach has been used to isolate cDNAs whose abundance was suppressed by incubating bovine aortic endothelial cells (BAEC) for 6 h with 1 nM TNF-alpha. The gene expression of 6 isolated cDNAs after TNF-alpha was investigated by dot blots and nuclear run-on analysis in BAEC. The investigated genes were partially or completely sequenced. Differential expression after TNF-alpha stimulation of BAEC, bovine fibroblasts and vascular smooth muscle cells (SMC) was studied by Northern blots. RNA transcripts of the clone C7 in aortic aneurysms were examined by in situ hybridization. RESULTS: 49 independent cDNAs were isolated by the differential screening approach and 6 clones were further analyzed. These genes were downregulated in a time and dose dependent manner in BAEC. Sequence analysis revealed that 3 cDNAs encoded previously unidentified genes (C1, C5, C7), while 3 encoded known genes: connective tissue growth factor (CTGF; A1), fibronectin (A8) and the mitochondrial genome (B1). A1 and B1 were suppressed in BAEC, fibroblasts and SMC, whereas A8, C1, C5 and C7 were not uniformly downregulated in the investigated cells. C7 RNA transcripts were exclusively induced in the endothelium of an uninflamed aortic aneurysm. The transcripts were undetectable in an inflamed aortic aneurysm and control vessels. CONCLUSIONS: Gene suppression is a prominent feature of the intermediate effect of TNF-alpha on endothelial cells. Differences in the expression of the tested genes in endothelial cells, fibroblasts and vascular smooth muscle cells open possibilities for the study of cellular interactions in the vascular wall in disease situations with high local TNF-alpha concentrations.

Animals↗
PubMed1998

Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations.

We investigated 17 children with nephrotic syndrome (NS) of early onset (14 aged < 1 year) and rapid progression to end-stage renal disease for the presence of mutations in the Wilms' tumor suppressor gene WT1 on chromosome 11. In eight children (7 genotypic males) an association with Wilms' tumor and/or ambiguous genitalia (Denys-Drash syndrome) was observed. In these eight and two additional female patients with NS only constitutional missense mutations in the WT1 gene were detected; four children presented the so-called hot spot mutation in exon 9 (R394N) and six had different mutations in exons 8 and 9 (4 not previously described). Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases. End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients. A unilateral Wilms' tumor was found before or concomitant with NS in four children (3 males, 1 female). From the seven genotypic males with WT1 mutations, five presented ambiguous genitalia and two a female phenotype. No mutation of the WT1 gene was found in seven other children with isolated congenital or infantile NS with or without DMS who appeared to have a slower progression than the first group. It is proposed that patients with early onset, rapidly progressive NS and diffuse mesangial or focal segmental sclerosis should be tested for WT1 mutations to identify those at risk for developing Wilms' tumor.

Base Sequence↗
PubMed1998

In situ upregulation of IL-10 reflects the activity of human glomerulonephritides.

A reciprocal regulation between the expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, demonstrated in monocytes and mesangial cells, provides a rationale for new therapeutic approaches in glomerulonephritis (GN). Administration of IL-10 to mice with antibody-mediated GN attenuated the severity of glomerular lesions. Recently, however, it has been shown that the genetically determined predominance of Th1 or Th2 cytokines results in different glomerular responses to the same planted antigen, but in an equally severe impairment of renal function. We looked for the expression of IL-10 and TNF-alpha in 111 renal biopsy specimens with proliferative and nonproliferative forms of GN and in 10 control kidneys, by means of immunocytochemistry, in situ hybridization, or reverse-transcriptase polymerase chain reaction (RT-PCR). Six patients had acute endocapillary GN (AGN), 10 patients had pauci-immune GN due to microscopic polyangiitis (MP), 48 patients had immunoglobulin-A (IgA)-GN, 18 patients had idiopathic membranous GN (IMGN), 12 patients had minimal change disease (MCD), and 13 patients had focal segmental glomerulosclerosis (FSGS) and four other forms of GN. Antibodies against monocytes (CD14) and macrophages (CD68) were applied to attribute the expression of TNF-alpha and IL-10 to resident renal or infiltrating cells. We show that mRNAs for TNF-alpha and IL-10 are detected by RT-PCR and in situ hybridization in the normal kidney. A constitutive expression of TNF-alpha protein is observed in mesangial cells, smooth muscle cells in renal arteries, and in the interstitium. A trace immunoreactivity for IL-10 is restricted to arterial smooth muscle cells, distal tubular epithelial cells, and some interstitial cells. Upregulation of both cytokines is found in glomerular diseases. The expression of TNF-alpha increases in mesangial areas in MCD, IMGN stages I/II, and IgA-GN with minor glomerular abnormalities, that is, under conditions with a generally well-preserved glomerular structure. Conversely, marked glomerular proliferation in IgA-GN and, particularly, acute vascular lesions in MP, are accompanied by a significant upregulation of IL-10 (at the mRNA and protein level). Patients with nephrotic-range proteinuria show a significant increase in tubulointerstitial expression of IL-10, whereas the immunoreactivity for TNF-alpha reflects the extent of interstitial fibrosis. Thus, our results confirm previous suggestions that proinflammatory and antiinflammatory cytokines are produced in situ by resident renal cells and contribute to the natural course of human GN.

Adult↗
PubMed1998

Diffuse mesangial sclerosis: association with unreported congenital anomalies and placental enlargement.

A case of diffuse mesangial sclerosis (DMS) associated with a number of undescribed congenital anomalies is reported. The occurrence of additional anomalies, especially ocular anomalies, is a common finding in DMS. However, neither megalocornea, Dandy-Walker malformation, postaxial hexadactyly, rocker-bottom feet, nor atrial septal defect, as observed in our patient, has been reported previously in association with DMS. This case might be considered an atypical manifestation of the Galloway-Mowat syndrome. In contrast to most cases of DMS, the patient revealed intrauterine proteinuria as the placenta was enlarged to 31% of birth weight. This case demonstrates that the large placenta, >25% of birth weight, is not only pathognomonic of the congenital nephrotic syndrome of the Finnish type but can also occur in DMS.

Abnormalities, Multiple↗
PubMed1998

Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney, and the inner ear of mice.

The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear. The primary cause of the disease is the loss of function of the Mpv17 protein, a peroxisomal gene product involved in reactive oxygen metabolism. In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression. This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals. When these cells were transfected with the human Mpv17 homolog, an inverse causal relationship between Mpv17 and MMP-2 expression was established. These results indicate that the Mpv17 protein plays a crucial role in the regulation of MMP-2 and suggest that enhanced MMP-2 expression might mediate the mechanisms leading to glomerulosclerosis, inner ear disease, and hypertension in this model.

Animals↗
PubMed1998

First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying.

BACKGROUND: Ethanol undergoes a first pass metabolism (FPM) in the stomach and liver. Gastric FPM of ethanol primarily depends on the activity of gastric alcohol dehydrogenase (ADH). In addition, the speed of gastric emptying (GE) may modulate both gastric and hepatic FPM of ethanol. AIMS: To study the effect of modulation of GE on FPM of ethanol in the stomach and liver. METHODS: Sixteen volunteers (eight men and eight women) received ethanol (0.225 g/kg body weight) orally and intravenously, and the areas under the ethanol concentration time curves were determined to calculate FPM of ethanol. In seven of these subjects, FPM of ethanol was measured after the intravenous administration of 10 mg metoclopramide (MCP) and 20 mg N-butylscopolamine (NBS) in separate experiments to either accelerate or delay GE. GE was monitored sonographically by integration of the antral area of the stomach every five minutes for 90 minutes after oral ethanol intake. In addition, gastric biopsy specimens were taken to determine ADH activity and phenotype, as well as to evaluate gastric histology. Blood was also drawn for ADH genotyping. RESULTS: GE time was significantly delayed by the administration of NBS as compared with controls (p<0.0001) and as compared with the administration of MCP (p<0.0001). This was associated with a significantly enhanced FPM of ethanol with NBS compared with MCP (p = 0.0004). A significant correlation was noted between GE time and FPM of ethanol (r = 0.43, p = 0.0407). Gastric ADH activity did not significantly correlate with FPM of ethanol. CONCLUSION: FPM of ethanol is strikingly modulated by the speed of GE. Delayed GE increases the time of exposure of ethanol to gastric ADH and may therefore increase gastric FPM of ethanol. In addition, hepatic FPM of ethanol may also be enhanced as the result of slower absorption of ethanol from the small intestine. Thus a knowledge of GE time is a major prerequisite for studying FPM of ethanol in humans.

Administration, Oral↗
PubMed1998

Percutaneous renal biopsy in children: a 27-year experience.

BACKGROUND: The introduction of automated biopsy devices and the localization of the kidney by ultrasound were aimed at optimizing efficacy and safety of the percutaneous renal biopsy procedure. We evaluated these technological advances in our renal biopsies performed in children. METHODS: We sequentially used the Silverman needle (1969-1974), the TruCut needle (1974-1990), and the automated Biopty device (1990-1996). Fluoroscopy was used to localize the kidney until 1985, ultrasound examination prior to biopsy from 1985 to 1992, and direct ultrasound guidance since 1992. A total of 962 native kidney biopsies and 119 allograft biopsies were performed. RESULTS: In the native kidney biopsies, the introduction of the Biopty device and ultrasound guidance were independently associated with fewer passes required to obtain adequate tissue and more glomeruli per specimen. The rate of biopsies yielding more than 9 glomeruli increased from 69 to 92% (p < 0.05). The number of glomeruli harvested per centimeter core length was inversely related to patient age (p < 0.01). More appropriate cortical tissue was retrieved in renal allograft biopsy specimens with the application of the new techniques. The occurrence of macroscopic hematuria (9. 6%) in the native kidney biopsies was not affected by the puncture or localization technique applied, but subcapsular hematomas were documented more often with the Biopty device (42%) than with the TruCut needle (16%), probably due to improved ultrasound equipment. In the whole series 2 patients died, and 3 others required renal surgery and 4 blood transfusions. CONCLUSIONS: The automated ultrasound-guided procedure is a feasible and reliable technique for percutaneous renal biopsy in children. It gives a greater yield of diagnostic tissue without increasing the rate of clinical complications.

Adolescent↗
PubMed1998

Cell proliferation and its evaluation in the colorectal mucosa: effect of ethanol.

Colorectal cell turn over is affected by numerous factors including diets, alcohol consumption, smoking or age and is also significantly changed in certain mucosal diseases including benign and malignant tumors. Mucosal hyperregeneration is associated with an increased cancer risk since it increases the susceptibility of the mucosa towards the action of carcinogens. The measurement of colorectal mucosal regenerativity can be used for risk assessment in carcinogenesis. For the evaluation of colorectal regeneration in vivo and in vitro methods exist. The most accurate and elegant in vivo method is the metaphase arrest technique which is a dynamic measurement of cell turn over using vincristine to arrest metaphase figures. This method is limited to animals. In man, colorectal biopsies can be incubated with tritiated thymidine or with bromodeoxyuridine and thereafter the incorporation of the two compounds into DNA can be visualized by autoradiography or by immunohistology. More recent developments include the use of antibodies against certain proteins which are closely related to certain phases of the cell cycle and which are expressed in dividing cells. The most frequently used proteins are proliferative cellular nuclear antigen (PCNA) and Ki-67 which are visualized by immunohistology in routinely fixed histological specimens. Finally, in situ hybridization of histone H3 mRNA which is almost exclusively expressed during S-phase, has been established as an excellent method for the determination of colorectal cell regeneration. In conclusion, chronic alcohol consumption both in animals and in man leads to mucosal cellular hyperregeneration, possibly secondary to mucosal injury, most likely due to acetaldehyde. The acetaldehyde is produced mainly by fecal bacteria and may exert its toxicity by mechanisms still unknown, possibly involving a direct effect on DNA. The ethanol-associated mucosal hyperregeneration is closely related to carcinogenesis since chronic ethanol ingestion leads to an increased risk of cancer in the colorectum.

Alcohol Drinking↗
PubMed1997

Role of NFkappaB in the mortality of sepsis.

Binding activity for nuclear factor kappa B (NFkappaB) consensus probes was studied in nuclear extracts from peripheral blood mononuclear cells of 15 septic patients (10 surviving and 5 not surviving). Nonsurvivors could be distinguished from survivors by an increase in NFkappaB binding activity during the observation period (P < 0.001). The increase in NFkappaB binding activity was comparable to the APACHE-II score as a predictor of outcome. Intravenous somatic gene transfer with an expression plasmid coding for IkappaBalpha was used to investigate the role of members of the NFkappaB family in a mouse model of endotoxemia. In this model, increased NFkappaB binding activity was present after injection of LPS. Intravenous somatic gene transfer with IkappaBalpha given before LPS attenuated renal NFkappaB binding activity and increased survival. Endothelial cells and monocytes/macrophages were the major target cells for somatic gene transfer, transfected with an average transfection efficiency of 20-35%. Tissue factor, a gene under regulatory control of NFkappaB, was induced by LPS. Somatic gene transfer with a reporter plasmid containing the functional tissue factor promoter demonstrated NFkappaB-dependent stimulation by LPS. Intravenous somatic gene transfer with IkappaBalpha reduced LPS-induced renal tissue factor expression, activation of the plasmatic coagulation system (decrease of thrombin-antithrombin III complexes) and renal fibrin/fibrinogen deposition. Somatic gene transfer with an expression plasmid with tissue factor cDNA in the antisense direction (in contrast to sense or vector alone) also increased survival. Furthermore, antisense tissue factor decreased renal tissue factor expression and the activation of the plasmatic coagulation system.

Adult↗
PubMed1997

Body growth in primary de Toni-Debré-Fanconi syndrome.

Body growth in nine children with primary de Toni-Debré-Fanconi syndrome was followed from birth to adolescence or adult life. At the time of diagnosis, corresponding to the start of treatment, the median age was 2.3 (range 0.4-13.9) years and height standard deviation score (SDS) was always decreased (median -3.5, range -6.8 to -2.1). Despite continuous electrolyte and bicarbonate supplementation only four patients showed a slight improvement in growth. At the time of the last observation at the age of 17.2 (4.5-20.1) years median height was -4.7 (-5.9 to -1.8) SDS. The median difference between height at last observation and target height was -4.5 SDS. Final height (n = 5) ranged between -1.8 and -5.5 (median -4.3) SDS. The pubertal growth spurt was absent in two children. Metabolic acidosis was identified as a significant growth-retarding factor. Mean serial blood bicarbonate levels and height SDS at the last observation were correlated (r = -0.87, P < 0.01). No correlation was observed between last height SDS and the degree of hypokalemia, hypophosphatemia, or hypercalciuria. In conclusion, patients with primary de Toni-Debré-Fanconi-syndrome present severe growth failure at the time of diagnosis which persists into adult life. Supportive therapy is frequently unable to prevent further loss of relative height.

Adolescent↗
PubMed1997

Demonstration of the proliferation marker Ki-67 in renal biopsies: correlation to clinical findings.

Assessment of cell proliferation in renal biopsy samples is a potentially promising analytical tool to evaluate disease activity. So far no information is available on the correlation between proliferative activity in different anatomic compartments of the kidney and clinical symptoms. To elucidate this issue, we examined renal biopsy specimens from 20 patients with systemic vasculitis (15 Wegener's granulomatosis, five microscopic polyangiitis), 20 patients with immunoglobulin (Ig) A nephropathy (IgAN), 13 patients with minimal-change disease (MCD), 11 patients with tubulointerstitial nephritis, and five patients with diabetes mellitus. The streptavidin-biotin-peroxidase complex technique was applied to autoclave-pretreated, formalin-fixed, paraffin-embedded tissue sections to label different cell types with the antibody MIB1 directed against the Ki-67 antigen. Proliferation index (PI) was estimated as the number of positively stained nuclei per glomerular cross-section or per square millimeter section area. The interstitial cells were discriminated by additional staining of Ki-67-processed samples with specific immune markers. In patients with vasculitis, PI was considerably elevated in the extracapillary glomerular compartment (0.86), in proximal tubules (6.24), and in the interstitium (8.62). High proliferative activity was also noted in interstitium (3.98) and proximal tubules (1.35) of patients with IgAN. Of particular interest was the increased interstitial proliferative activity (15.0) in diabetic patients. Resident renal cells, but not infiltrating cells, seemed to constitute the majority of the proliferating cell population in the interstitium. In systemic vasculitis, clinical disease activity was significantly correlated to endocapillary (r(s) = 0.58), extracapillary (r(s) = 0.67), proximal tubular (r(s) = 0.67), and interstitial PI (r(s) = 0.61). By multiple linear regression analysis, proximal tubular PI was correlated to the presence of hematuria (beta = 0.72) and to interstitial fibrosis score (beta = 0.59). Interstitial PI was independently correlated to antineutrophil cytoplasmic antibodies (ANCA) titer (beta = 0.7) and interstitial fibrosis score (beta = 0.55), and it was the only one PI correlated to serum creatinine concentration (beta = 0.53). The independent association between interstitial PI and serum creatinine (beta = 0.64) was also found in IgAN. Proximal tubular PI was correlated to interstitial fibrosis score (beta = 0.59) and proteinuria (beta = 0.54). In MCD, high PI values were noted in proximal tubular cells (1.42) but not in glomeruli and the interstitium. In conclusion, assessment of proliferation activity by immunohistology provides additional information beyond conventional pathological techniques to evaluate disease activity and prognosis in renal biopsies.

Adult↗
PubMed1997

Podocytes are the major source of IL-1 alpha and IL-1 beta in human glomerulonephritides.

To address the question of in situ production of IL-1 alpha and IL-1 beta in proliferative and non-proliferative forms of human glomerulonephritis (GN), we performed immunocytochemical and in situ hybridization studies on renal biopsies from patients with mesangial IgA-GN (N = 38), idiopathic membranous GN (MGN; N = 12), minimal change disease (MCD; N = 9), focal segmental glomerulosclerosis (FSGS; N = 5) and acute endocapillary GN (AGN; N = 3). Normal kidneys (N = 10) served as controls. Concomitantly, the expression of IL-1 receptor type I (IL-1 RI), IL-1 receptor type II (IL-1 RII) and of IL-1 receptor antagonist (IL-1 RA) was analyzed. Antibodies against antigens expressed on podocytes (PP-44), endothelial cells (CD31) and monocytes/macrophages (CD11b, CD14, CD68) were applied to attribute the expression of IL-1/IL-1 related peptides to intrinsic glomerular and/or blood-derived infiltrating cells. Our results demonstrate that IL-1 RII is constitutively expressed on endothelial cells, and its expression can be induced in proximal tubular cells and in the interstitium. In diseased glomeruli podocytes are capable of producing IL-1 alpha/beta. In MGN and MCD/FSGS, the expression of both IL-1 forms is particularly noted in early stages of the disease and is not only accompanied by a marked reactivity for IL-1 RI, but also for IL-1 RA. In segmental sclerosing lesions in FSGS and in IgA-GN with marked glomerular proliferation and/or sclerosis, a reduced expression of the PP-44 antigen and a diminished ability of podocytes to produce IL-1/IL-1 related peptides are noted. These results suggest that intrinsic glomerular production of IL-1 may be of relevance for the protection of glomeruli from continuing injury.

Acute Disease↗