Retraction: Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids.
Explore the source record for details and available documents.
Retraction Notice↗
Biomedical subjects
Gerhard A Müller
Publications and source records attributed to Gerhard A Müller.
Osmoregulation of aldose reductase and sorbitol dehydrogenase in cultivated interstitial cells of rat renal inner medulla.
BACKGROUND: Little is known about sorbitol metabolism in renal papillary interstitial cells. For characterization we studied regulation of sorbitol synthesis by aldose reductase (AR) and degradation by sorbitol dehydrogenase (SDH) in papillary interstitial cells. METHODS: Interstitial cells were isolated from rat renal inner medulla to a pure cell fraction. mRNA was isolated from cultivated cells and sorbitol, AR and SDH activity were determined enzymatically in homogenates. RESULTS: Sorbitol concentration in these cells at 300 mosmol/l was 4.4+/-0.3 vs 78+/-3.6 micro mol/g protein at 600 mosmol/l. At steady-state conditions at 300 mosmol/l, AR activity was nearly the same as SDH activity (15.1+/-1.6 vs 16.6+/-2.0 U/g protein). At 600 mosmol/l, AR activity increased to 82.5+/-11.4 U/g protein and SDH activity to 31.5+/-6.0 U/g protein. Studying the time course of enzyme activity after changing osmolarity from 300 to 600 mosmol/l, we found half maximal stimulation after 2-3 (AR) or 3 (SDH) days. The amount of AR-mRNA preceded the rise of enzyme activity, whereas SDH-mRNA was not significantly influenced. Lowering osmolarity from 600 to 300 mosmol/l, enzyme activity decreased to less than half within 2 (AR) or 1 (SDH) day(s). CONCLUSIONS: The results suggest that sorbitol metabolism contributes to handling of osmotic stress in rat renal papillary interstitial cells.
Aldehyde Reductase↗
Classification of rheumatoid joint inflammation based on laser imaging.
We describe a classification system for a novel imaging method for arthritic finger joints. The basis of this system is a laser imaging technique which is sensitive to the optical characteristics of finger joint tissue. From the laser images acquired at baseline and follow-up, finger joints can automatically be classified according to whether the inflammatory status has improved or worsened. To perform the classification task, various linear and kernel-based systems were implemented and their performances were compared. Based on the results presented in this paper, we conclude that the laser-based imaging permits a reliable classification of pathological finger joints, making it a sensitive method for detecting arthritic changes.
Algorithms↗
Proinflammatory role of fractalkine (CX3CL1) in rheumatoid arthritis.
OBJECTIVE: Fractalkine (CX3CL1) represents the sole member of the so-called CX3C chemokines. In rheumatoid arthritis (RA), functional studies suggest a role for this chemokine in monocyte chemotaxis and angiogenesis in the rheumatoid synovium. We analyzed the expression of fractalkine within different T cell subsets of the peripheral blood and expression of its receptor CX3CR1 within the rheumatoid synovium to further characterize its pathogenic role in RA. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 17 patients with RA and analyzed by flow cytometry in comparison to healthy blood donors. To identify the T helper cell cytokine profile of fractalkine-expressing cells, flow cytometric analysis of PBMC was performed after stimulation with PMA and ionomycin. Expression of fractalkine and its receptor was characterized in RA synovium by immunohistochemistry and laser capture microdissection microscopy. RESULTS: Flow cytometric analysis of fractalkine-expressing T cell subsets revealed a low proportion of fractalkine-expressing CD4+ and CD8+ T cells in both RA patients and controls. In addition, fractalkine was predominantly expressed in CD4+ T cells with a Th1-type cytokine expression profile. In RA synovium, fractalkine was detected in synovial macrophages, dendritic cells, endothelial cells, and a small proportion of T cells. The fractalkine receptor CX3CR1 was found in synovial macrophages, dendritic cells, and T cells as well as in synovial fibroblasts. Fractalkine stimulation of cultured synovial fibroblasts resulted in a marked upregulation of matrix metalloproteinase-2 (MMP-2) production. CONCLUSION: The results suggest that fractalkine may represent a Th1-type chemokine. Upregulation of MMP-2 production in synovial fibroblasts upon fractalkine stimulation in vitro supports the hypothesis of a proinflammatory role of this chemokine in RA.
Adult↗
[Metformin-associated lactic acidosis with acute renal failure in type 2 diabetes mellitus].
CASE REPORT: An 83-year-old patient was admitted to our hospital because of gastrointestinal symptoms, mental confusion and dysarthria. The patient suffered from type 2 diabetes mellitus and was taking metformin. A mild renal insufficiency was known. On admission, we found impaired consciousness, Kussmaul breathing, a body temperature of 32.1 degrees C, and hemodynamic instability. Laboratory testing revealed lactic acidosis (pH 6.71, base excess--30, standard bicarbonate 4.0 mmol/l, lactate 24.4 mmol/l) and acute renal failure with a creatinine of 10.6 mg/dl and blood urea nitrogen of 134 mg/dl. Electrolytes were not altered; the blood glucose was elevated (147 mg/dl). According to history, physical examination, and laboratory testing the diagnosis metformin-induced lactic acidosis with acute renal failure was made. This diagnosis was confirmed by an elevated level of metformin. As soon as possible a bicarbonate hemodialysis was initiated. After 8 hours of hemodialysis the acid-base metabolism was almost balanced and the vigilance of the patient normalized. No further sessions of hemodialysis were needed and insulin therapy was started. CONCLUSIONS: Metformin-induced lactic acidosis is a common side effect in patients with renal insufficiency. For an early diagnosis, clinical symptoms of intoxication should be well known by physicians and patients. First-line therapy for correction of lactic acidosis and effective elimination of metformin is bicarbonate hemodialysis. Sodium bicarbonate infusions are not able to correct the acid-base metabolism sufficiently. For prevention the renal function should be monitored closely and metaformin therapy should be stopped, if a deterioration of renal function is observed.
Acidosis, Lactic↗
Assessment of proximal finger joint inflammation in patients with rheumatoid arthritis, using a novel laser-based imaging technique.
OBJECTIVE: To evaluate a newly developed laser-based imaging technique for the study of soft tissue changes and acute inflammatory processes of the proximal interphalangeal (PIP) joints in patients with rheumatoid arthritis (RA). METHODS: A novel imaging device was developed which allows the transillumination of PIP joints using laser light in the near-infrared wavelength range. In a first clinical followup study, a total of 72 PIP joints of 22 patients with RA and 64 PIP joints of 8 healthy controls were examined both clinically and with the new laser device. At baseline and at followup after a mean of 6 weeks, clinical signs of synovitis, the joint circumference, and the degree of pain were assessed for each PIP joint in order to determine the clinical degree of inflammation. Different features were extracted from the laser images and evaluated by a neural network. RESULTS: At baseline, 72 PIP joints in the RA patients showed clinical signs of inflammation. At followup, 45 PIP joints showed clinical improvement, 13 showed steady active inflammation, and 14 showed deterioration compared with the first visit. None of the 64 PIP joints in the healthy individuals showed any signs of synovitis. The inflammatory status of 60 of the 72 RA joints examined was classified correctly by laser examination and joint circumference determination, giving a sensitivity of 80%, a specificity of 89%, and an accuracy of 83% in detecting inflammatory changes in affected joints. Laser data and joint circumference determination of healthy joints at followup resulted in an accuracy of 85% in reproducing the image. CONCLUSION: The new laser-based imaging technique allows the transillumination of PIP joints and gives information about the inflammatory status of the joint after processing through a neural network. Our data indicate that laser imaging may provide additional information in the early diagnosis of an inflammatory joint process and may prove particularly useful in assessing acute joint inflammation at followup.
Adult↗
Human alpha-defensins HNPs-1, -2, and -3 in renal cell carcinoma: influences on tumor cell proliferation.
The alpha-defensins human neutrophil peptides (HNPs)-1, -2, and -3 have been described as cytotoxic peptides with restricted expression in neutrophils and in some lymphocytes. In this study we report that HNPs-1, -2, and -3 are also expressed in renal cell carcinomas (RCCs). Several RCC lines were found to express mRNA as well as the specific peptides of HNP-1, -2, and -3 demonstrated by reverse transcriptase-polymerase chain reaction, mass spectrometric, and flow cytometric analyses. At physiological concentrations HNPs-1, -2, and -3 stimulated cell proliferation of selected RCC lines in vitro but at high concentrations were cytotoxic for all RCC lines tested. As in RCC lines, alpha-defensins were also detected in vivo in malignant epithelial cells of 31 RCC tissues in addition to their expected presence in neutrophils. In most RCC cases randomly, patchy immunostaining of alpha-defensins on epithelial cells surrounding neutrophils was seen, but in six tumors of higher grade malignancy all tumor cells were diffusely stained. Cellular necrosis observed in RCC tissues in association with extensive patches of HNP-1, -2, and -3, seemed to be related to high concentrations of alpha-defensins. The in vitro and in vivo findings suggest that alpha-defensins are frequent peptide constituents of malignant epithelial cells in RCC with a possible direct influence on tumor proliferation.
Antigen Presentation↗
Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation.
BACKGROUND: Epithelial-mesenchymal transformation (EMT) plays an important role in embryonic development and tumorigenesis and has been described in organ remodeling during fibrogenesis. In the kidney, EMT can be induced efficiently in cultured proximal tubular epithelium by coincubation of transforming growth factor (TGF)-beta1 and epidermal growth factor (EGF). Recently, we also have observed overexpression of basic fibroblast growth factor-2 (FGF-2) protein and mRNA in human kidneys with marked interstitial fibrosis. The aims of the present study were to compare the effects of FGF-2 as a facilitator of EMT in tubular epithelial cells with EGF and TGF-beta1. We analyzed the morphogenic effects of the three cytokines on four different aspects of EMT: cell motility, expression and regulation of cellular markers, synthesis and secretion of extracellular matrix (ECM) proteins as well as matrix degradation. METHODS: Cell motility was studied by a migration assay and cell differentiation markers were analyzed by immunofluorescence and immunoblots. In addition, regulation of the epithelial adhesion molecule E-cadherin and fibroblast-specific protein 1 (FSP1) were analyzed by luciferase reporter constructs and stable transfections. ELISAs for collagen types I and IV and fibronectin were used for ECM synthesis, and zymograms were utilized for analysis of matrix degradation. RESULTS: FGF-2 induced cell motility across a tubular basement membrane in two tubular cell lines. All three cytokines induced the expression of vimentin and FSP1, but only FGF-2 and TGF-beta1 reduced cytokeratin expression by immunofluorescence. These effects were most demonstrable in the distal tubular epithelial cell line and were confirmed by immunoblot analyses. Expression of E-cadherin was reduced by 61.5 +/- 3.3% and expression of cytokeratin by 91 +/- 0.5% by TGF-beta1 plus FGF-2. Conversely, the mesenchymal markers alpha-smooth muscle actin (SMA) and FSP1 were induced with FGF-2 by 2.2 +/- 0.1-fold and 6.8 +/- 0.9-fold, respectively. Interestingly, de novo expression of the mesenchymal marker OB-cadherin was induced only by FGF-2 and EGF but not by TGF-beta1. All three cytokines stimulated FSP1 and decreased E-cadherin promoter activity. FGF-2 also induced intracellular fibronectin synthesis but not secretion, the latter of which was stimulated exclusively by TGF-beta1. Finally, zymographic analyses demonstrated that FGF-2 induced MMP-2 activity by 2.6 +/- 0.5-fold and MMP-9 activity by 2.4 +/- 0.1-fold, providing a mechanism for basement membrane disintegration and migratory access of transforming epithelium to the interstitium. CONCLUSIONS: FGF-2 makes an important contribution to the mechanisms of EMT by stimulating microenvironmental proteases essential for disaggregation of organ-based epithelial units. Furthermore, the expression of epithelial and mesenchymal marker proteins seems to be affected at the promoter level.
Animals↗
Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies.
BACKGROUND: In recent studies performed on cultured cells and experimental nephropathies, it has been hypothesized that tubular epithelial cells (TEC), via epithelial-mesenchymal transformation (EMT), can become collagen-producing cells. According to this theory, they should proceed through several activating steps, such as proliferation and phenotype changes, to eventually synthesize extracellular matrix (ECM). METHODS: To evaluate whether EMT operates in human TECs, 133 renal biopsies of different renal diseases were studied, analyzing by immunohistochemistry and in situ hybridization the possible expression of markers of proliferation (PCNA, Mib-1), cellular phenotype (vimentin, alpha-SMA, cytokeratin, ZO-1) and ECM production (prolyl 4-hydroxylase, HSP47, interstitial collagens). RESULTS: Independently of histological diagnosis, variable degrees of TEC positivity for PCNA (2.7 +/- 2.4 cells/field) and Mib-1 (1.9 +/- 2.3) were present. TECs expressing vimentin (1.4 +/- 4.7) and alpha-smooth muscle actin (alpha-SMA; 0.04 +/- 0.4) also were detected. It was possible to observe loss of epithelial antigens from 8 to 10% of the tubular cross sections. Moreover, TECs were stained by prolyl 4-hydroxylase (3.6 +/- 4.3), heat shock protein-47 (HSP47; 2.9 +/- 5.4), collagen type I (0.2 +/- 2.7) and type III (0.3 +/- 2.0). Collagen types I and III mRNAs were found in 0.8 to 1.4 cells/field. The number of TEC with EMT features were associated with serum creatinine and the degree of interstitial damage (P< or = 0.03), and even considering the 45 cases with mild interstitial lesions, the tubular expression of all markers remained strictly associated with renal function (P< or = 0.01). CONCLUSIONS: Our results suggest that, via transition to a mesenchymal phenotype, TEC can produce ECM proteins in human disease and directly intervene in the fibrotic processes. Moreover, the association of EMT features with serum creatinine supports the value of these markers in the assessment of disease severity.
Actins↗
A case of late-onset primary hyperoxaluria type 1.
Primary hyperoxaluria type 1 (PH1) is an inherited metabolic disorder characterized by recurrent urolithiasis and nephrocalcinosis frequently leading to progressive renal insufficiency during the second decade of life. Systemic organ involvement as a result of the accumulation of calcium oxalate crystal deposits in vessel walls often is observed. We report a case of a 56-year-old woman with late-onset of PH1 who developed rapidly progressive renal failure and severe systemic oxalosis with skin and eye involvement despite intensified hemodialytic therapy during the waiting period for combined liver and kidney transplantation. This case illustrates the difficulties in treatment of PH1-induced end-stage renal disease. Combined liver and kidney transplantation should be offered to these patients as soon as possible to reverse the underlying metabolic defect and to restore renal function.
Female↗
Lectin staining for urine cytologic monitoring after kidney transplantation.
BACKGROUND: Urine cytology, although considered a valuable diagnostic tool in the monitoring of kidney graft function, is hampered by difficulty in differentiating the nucleated non-squamous cells in urine using conventional techniques. We have now developed a method for the simple identification of urinary cell types by lectin staining. METHODS: Acetone-fixed cytopreparations of urinary sediments were incubated with the lectin combination Sophora Japonica agglutinin (SJA; rhodamine-labelled) and Erythrina cristagalli agglutinin (ECA; fluorescein isothiocyanate (FITC)-labelled) for 15 min, followed by staining of the nuclei with 4',6-diamidino-2-phenylindole (DAPI). The courses of 38 patients were serially monitored after kidney transplantation during the period in hospital. RESULTS: Nucleated urinary cell types could be easily identified from one specimen by their characteristic lectin-binding pattern using triple-immunofluorescence microscopy (FITC/rhodamine/ultra violet), permitting a differentiation between proximal (SJA+/ECA+) and distal tubules (SJA-/ECA+), collecting ducts (SJA+/ECA-) and lymphocytes (SJA-/ECA-). Stable graft function was characterized by low numbers of lymphocytes, tubular cells and urothelia. During rejection episodes, but not graft dysfunction unrelated to rejection, urinary excretion of lymphocytes as well as of distal tubular cells (from 1.0 to 6.0 and from 1.4 to 4.0 per 10 high-power fields, respectively) increased significantly up to 3 days prior to clinical diagnosis. CONCLUSIONS: Lectin staining facilitates unambiguous differentiation of the urinary cell types, in particular the various tubular epithelial cells, which are otherwise difficult to identify. This technique provides a rapid and easily applicable tool to evaluate the significance of the respective cell types in the monitoring of kidney graft function.
Adult↗
Apolipoprotein A-IV serum concentrations are elevated in patients with mild and moderate renal failure.
Cell culture studies and investigations in mice that overexpress either human or mouse apolipoprotein A-IV (apoA-IV) revealed anti-atherogenic properties of apoA-IV. An association between low apoA-IV concentrations and coronary artery disease in humans was demonstrated; therefore, apoA-IV may also play an antiatherogenic role in humans. Because apoA-IV is markedly elevated in dialysis patients, patients with the earliest and modest stages of renal impairment were studied to assess the association of apoA-IV with GFR and atherosclerotic complications. GFR was measured by the use of iohexol in 227 non-nephrotic patients with different degrees of renal impairment. ApoA-IV increased significantly with decreasing GFR and was already elevated in earliest stages of renal disease (GFR > 90 ml/min per 1.73 m2). Multiple linear regression analysis identified renal function parameters (GFR, creatinine, and urea) as the most important determinants of apoA-IV levels in serum of these patients. Twenty-six patients had already experienced 36 atherosclerotic events. Logistic regression analysis identified three variables associated with atherosclerotic complications: age, apoA-IV, and gender. Each 1 mg/dl increase of apoA-IV decreased the odds ratio for an atherosclerotic complication by 8% (P = 0.011). The data clearly show that the anti-atherogenic apoA-IV starts to increase during the earliest phases of renal insufficiency, which makes apoA-IV an early marker of renal impairment.
Adult↗
Role of mast cell tryptase in renal interstitial fibrosis.
Renal interstitial fibrosis is characterized by increased proliferation of fibroblasts and excessive accumulation of extracellular matrix. Mast cell tryptase has been implicated in the development of tissue fibrosis in skin and lungs. However, the significance of mast cell tryptase in human renal diseases has not been investigated. The potential role of mast cell-derived tryptase in the development of renal fibrosis was studied using immunohistochemical techniques and cultured human renal fibroblast cell lines. Semiquantitative immunostaining analysis of samples from 70 patients with several renal diseases, including IgA glomerulonephritis (GN) (n = 30), non-IgA GN (n = 5), membranous GN (n = 5), focal segmental glomerulosclerosis (n = 4), minor glomerular abnormalities (n = 5), lupus nephritis (n = 3), and acute or chronic tubulointerstitial nephritis (n = 18), revealed that the degree of renal interstitial fibrosis was well correlated with the number of infiltrating tryptase-positive mast cells (P < 0.01). Mast cells could not be detected in damaged glomeruli in any form of renal disease. [(3)H]Thymidine uptake experiments demonstrated that DNA synthesis by cultured renal fibroblasts was increased with the concentration of tryptase (0.5 to 5 nM) coincubated with heparin and was suppressed by coincubation with the protease inhibitors leupeptin and benzamidine hydrochloride. Tryptase alone also increased DNA synthesis by fibroblasts but exhibited less effectiveness, compared with the combination of tryptase and heparin. Conversely, heparin alone suppressed DNA synthesis by fibroblasts. Metabolic [(35)S]methionine-labeling experiments with cultured renal fibroblasts indicated that tryptase increased the synthesis of fibronectin and collagen type I, in a dose-dependent manner. These findings suggest that mast cell tryptase plays a role in the proliferation and extracellular matrix protein production of renal interstitial fibroblasts and thus contributes to the development of renal interstitial fibrosis.
Cell Division↗
Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
High lipoprotein(a) (Lp(a)) serum concentrations and the underlying apolipoprotein(a) (apo(a)) phenotypes are risk factors for cardiovascular disease in the general population as well as in patients with renal disease. Lp(a) concentrations are markedly elevated in patients with end-stage renal disease. However, nothing is known about the changes of Lp(a) depending on apo(a) size polymorphism in the earliest stages of renal impairment. In this study, GFR was measured by iohexol technique in 227 non-nephrotic patients with different degrees of renal impairment and was then correlated with Lp(a) serum concentrations stratified according to low (LMW) and high (HMW) molecular weight apo(a) phenotypes. Lp(a) increased significantly with decreasing GFR. Such an increase was dependent on apo(a) phenotype. Only renal patients with HMW apo(a) phenotypes expressed higher median Lp(a) concentrations, i.e., 6.2 mg/dl at GFR >90 ml/min per 1.73 m2, 14.2 at GFR 45 to 90 ml/min per 1.73 m2, and 18.0 mg/dl at GFR <45 ml/min per 1.73 m2. These values were markedly different when compared with apo(a) phenotype-matched control subjects who had a median level of 4.4 mg/dl (ANOVA, linear relationship, P < 0.001). In contrast, no significant differences were observed at different stages of renal function in patients with LMW apo(a) phenotypes when compared with phenotype-matched control subjects. The elevation of Lp(a) was independent of the type of primary renal disease and was not related to the concentration of C-reactive protein. Multiple linear regression analysis found that the apo(a) phenotype and GFR were significantly associated with Lp(a) levels. Non-nephrotic-range proteinuria modified the association between GFR and Lp(a) levels. In summary, an increase of Lp(a) concentrations, compared with apo(a) phenotype-matched control subjects, is seen in non-nephrotic patients with primary renal disease even in the earliest stage when GFR is not yet subnormal. This change is found only in subjects with HMW apo(a) phenotypes, however.
Adult↗
[Expression of Fas and Fas-L in renal cell carcinoma].
INTRODUCTION: The previous investigations revealed that Fas-L expression on tumor cells can be one of the reasons of tumor growth, or tumor regression, with or without activation of the immune response. OBJECTIVE: The objective of our study was to investigate the expression of Fas and Fas-L in situ in normal human renal tissue as well as in different types of renal cell carcinoma (RCC) according to tumor grading. METHOD: Expression of Fas and Fas-L was examined in 25 RCCs classified according to nuclear grades: G1-G3 and to cell type: 17 clear cells, 3 chromophilics (2 eosinophilics, 1 basophilic), 2 chromophobes and 3 spindle cells. Ten normal human kidneys were analyzed, too. Indirect immunoperoxidase technique was applied. Spread and intensity of staining of Fas and Fas-L molecules expression were scored semiquantitatively. RESULTS: Distribution of Fas expression in these RCC was typically diffuse. However, Fas-L was almost completely absent in clear cell RCC. In 3 clear cell RCC, some tumor stromal cells exhibited strong expression of Fas-L. On the contrary, chromophilic, chromophobe and spindle cell RCCs grading from G2-G3, manifested variable combinations of Fas and Fas-L expression. CONCLUSION: The most of clear cell type low grade RCCs manifested intensive and extensive expression of Fas and completely absence of Fas-L. However, RCCs of high grade malignancy belonging to the clear cell, eosinophilic, chromophobe or spindle cell types can have various combinations of Fas and Fas-L expression. It may probably lead to development of different mechanisms of avoidance of immune response to RCC.
Carcinoma, Renal Cell↗
Tuberculous meningitis in a renal transplant recipient.
Tuberculous meningitis is a very rare, but serious extrapulmonary complication of mycobacterial infections in immunocompromised patients, such as organ transplant recipients. We describe here a 66-year-old Turkish woman without any history of tuberculosis, who received a renal allograft transplant in 1994. After a pilgrimage to an endemic area for tuberculosis, she presented with fever and headache in August 1998. Clinical examination revealed positive meningism and hyperreflexia. Lymphocytosis was noted in her cerebrospinal fluid (CSF) and Mycobacterium tuberculosis infection was detected by PCR within the CSF. Despite immediate triple antituberculosis therapy, the patient's clinical condition deteriorated rapidly, with the development of septic shock syndrome, and she died three weeks after admission due to cardiovascular and respiratory failure. Mycobacterial infections, including extrapulmonary manifestations, should thus be considered in all renal transplant recipients presenting with unexplained fever. Preventive therapy, i.e. isoniazid prophylaxis, may also be recommended for patients risking exposure in areas endemic for tuberculosis.
Aged↗