Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat

Activity and functional significance of the renal kallikrein-kinin-system in polycystic kidney disease of the rat.BackgroundThe kallikrein-kinin-system is a complex multienzymatic system that has been implicated in the control of systemic blood pressure, glomerular filtration rate, and proteinuria. The present study investigated its functional role in rat polycystic kidney disease (PKD), which is characterized by progressive renal failure and proteinuria in the absence of systemic hypertension and stimulated renin-angiotensin-system.MethodsKallikrein and bradykinin levels were measured in plasma and urine of rats with polycystic kidneys and compared to non-affected controls (SD) and rats with reduced renal mass. The functional relevance of the kallikrein-kinin system (KKS) was assessed by the effects of a short-term treatment with either a selective bradykinin (BK) B1-receptor antagonist (des-Arg9-[Leu8]-BK), a B2-receptor antagonist (HOE 140), an angiotensin converting enzyme inhibitor (ramipril), or an angiotensin II-receptor blocker (HR 720) on systemic and renal parameters.ResultsUrine levels of kallikrein were increased threefold in 9-month-old PKD, and BK excretion was increased tenfold in 3-month and 30-fold in 9-month-old PKD compared to age-matched SD rats. Blood pressure in 9-month-old PKD rats was decreased to the same degree by ramipril and HR 720. In contrast, only ramipril and HOE 140 significantly reduced proteinuria and albuminuria, independent from creatinine clearance. This effect was accompanied by an increased excretion of bradykinin. The B1 receptor antagonist had no influence on functional renal parameters.ConclusionsThe present study demonstrates an age-dependent activation of the renal KKS in rats with polycystic kidney disease. The bradykinin B2-receptor is involved in the pathogenesis of proteinuria, independent from systemic blood pressure or creatinine clearance. The antiproteinuric effect of ramipril in this model is angiotensin II-independent and related to its influence on the renal KKS

Colocalization of ANCA-antigens and fibrinoid necrosis in ANCA-associated vasculitis

Colocalization of ANCA-antigens and fibrinoid necrosis in ANCA-associated vasculitis. A variety of antineutrophil cytoplasmic auto-antibodies (ANCAs) are known to be associated with small vessel vasculitides such as Wegener's granulomatosis and microscopic polyangiitis. To visualize colocalization patterns of the fibrinoid necrotic lesions and ANCA-antigens more accurately, we have developed a double staining technique in which an immunohistochemical staining is followed by a histological staining. Instead of using sequential biopsy slides of histologically and immunohistochemically stained sections, which may lead to an underestimation of the number and size of the lesions, our technique permits the visualization of the colocalized patterns of fibrinoid necrosis with an ANCA-antigen in a single slide. The double staining procedure is presented in this Technical Note

CsA, FK506, corticosteroids and rapamycin inhibit TNFα production by cultured PTEC

CsA, FK506, corticosteroids and rapamycin inhibit TNFα production by PTEC. In this study we investigated the effect of immunosuppressive drugs on the interleukin-1 alpha (IL-1α) enhanced tumor necrosis factor alpha (TNFα) production by proximal tubular epithelial cells (PTEC). Under basal conditions cultured PTEC produce between 0 to 390 pg/ml/105 cells of TNFα. Upon stimulation with IL-1α an enhancement of TNFα production was seen in each cell line tested, ranging from 230 to 2424 pg/ml/105 cells. The presence of cyclosporin A (CsA) during stimulation with IL-1α inhibited the enhanced TNFα production in a dose dependent fashion, with a maximal inhibition of 90% at a concentration of 250 ng/ml. Inhibition was at the level of mRNA as could be demonstrated by Northern blot analysis. FK506, corticosteroids and rapamycin also inhibited TNFa production in a dose dependent fashion, although not as effectively as CsA. Two corticosteroids were tested for their inhibitory effect on TNFa production. It was found that dexamethasone at a concentration of 10 ng/ml inhibited TNFα production for almost 40%. A 100-fold higher concentration of hydrocortisone was necessary to yield similar inhibition. The effect of rapamycin on the IL-1α enhanced TNFα production differed from the effect of CsA. While CsA induced a maximal inhibition of 90%, rapamycin only induced a maximal inhibition of 37%, and even less inhibition at higher concentrations of the drug. The presence of the various drugs was essential for their inhibitory effect, because removal of the drug from the PTEC by washing immediately resulted in loss of inhibition. Combinations of CsA and FK506 or rapamycin were not additive. However, combinations of rapamycin and FK506 were antagonistic when low concentrations of rapamycin and FK506 were used. Low concentrations of rapamycin with high concentrations of FK506 were synergistic. Since TNFα is likely to be an important mediator in renal allograft rejection, these data suggest that the beneficial effect of immunosuppressive drugs after renal transplantation may partly be due to the effect on TNFα production by renal parenchymal cells

Life-threatening intoxication with methylene bis(thiocyanate): clinical picture and pitfalls. A case report

BACKGROUND: Methylene bis(thiocyanate) (MBT) is a microbiocidal agent mainly used in industrial water cooling systems and paper mills as an inhibitor of algae, fungi, and bacteria. CASE PRESENTATION: We describe the first case of severe intoxication following inhalation of powder in an industrial worker. Profound cyanosis and respiratory failure caused by severe methemoglobinemia developed within several minutes. Despite immediate admission to the intensive care unit, where mechanical ventilation and hemodialysis for toxin elimination were initiated, multi-organ failure involving liver, kidneys, and lungs developed. While liver failure was leading, the patient was successfully treated with the MARS (molecular adsorbent recirculating system) procedure. CONCLUSION: Intoxication with MBT is a potentially life-threatening intoxication causing severe methemoglobinemia and multi-organ failure. Extracorporeal liver albumin dialysis (MARS) appears to be an effective treatment to allow recovery of hepatic function

N-Glycosylation of Carnosinase Influences Protein Secretion and Enzyme Activity: Implications for Hyperglycemia

OBJECTIVE-The (CTG)(n) polymorphism in the serum carnosinase (CN-1) gene affects CN-1 secretion Since CN-1 is heavily glycosylated and glycosylation might influence protein secretion as well, we tested the role of N-glycosylation for CN-1 secretion and enzyme activity. We also tested whether CN-1 secretion is changed under hyperglycemic conditions. RESULTS-N-glycosylation of CN-1 was either inhibited by tunicamycin in pCSII-CN-1-transfected Cos-7 cells or by stepwise deletion of its three putative N-glycosylation sites. CN-1 protein expression, N-glycosylation, and enzyme activity were assessed in cell extracts and supernatants. The influence of hyperglycemia on CN-1 enzyme activity in human serum was tested in homozygous (CTG)(5) diabetic patients and healthy control subjects Tunicamycin completely inhibited CN-1 secretion Deletion of all N-glycosylation sites was required to reduce CN-1 secretion efficiency. Enzyme activity was already diminished when two sites were deleted. In pCSII-CN-1-transfected Cos-7 cells cultured in medium containing 25 mmol/l D-glucose, the immature 61 kilodaltons (kDa) CN-1 immune reactive band was not detected. This was paralleled by an increased GlcNAc expression in cell lysates and CN-1 expression in the supernatants. Homozygous (CTG)(5) diabetic patients had significantly higher serum CN-1 activity compared with genotype-matched, healthy control subjects CONCLUSIONS-We conclude that apart from the (CTG)(n) polymorphism in the signal peptide of CN-1, N-glycosylation is essential for appropriate secretion and enzyme activity. Since hyperglycemia enhances CN-1 secretion and enzyme activity, our data suggest that poor blood glucose control in diabetic patients might result in an increased CN-1 secretion even in the presence of the (CTG)(5) allele Diabetes 59:1984-1990, 201

Isolation and Identification of the Amines Resulting From Chemical and Catalytic Reduction of 20‐Hydroxyimino‐Steroids (Restatement)

Sodium‐propanol reduction of 3β‐hydroxy‐5‐pregnen‐20‐one oxime affords the two 20‐amino epimers in a ratio 20 α to 20 β equal to 1.3, while hydrogenation with platinum in acetic acid gives a mixture of the two corresponding saturated amines in the ratio of 2:1. Quantitative separation of 20‐amino epimers is conveniently achieved by chromatography on silica gel. Thin layer chromatography, optical rotatory dispersion, infrared absorption, nuclear magnetic resonance data are joined. Copyright © 1967 Wiley‐VCH Verlag GmbH & Co. KGaA, WeinheimSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Acetylcysteine for prevention of contrast nephropathy: meta-analysis

Background Contrast nephropathy is associated with increased in-hospital morbidity and mortality and leads to extension of hospital stay in patients with chronic renal insufficiency. Acetylcysteine seems to be a safe and inexpensive way to reduce contrast nephropathy. We aimed to assess the efficacy of acetylcysteine to prevent contrast nephropathy after administration of radiocontrast media in patients with chronic renal insufficiency. Methods We did a meta-analysis of randomised controlled trials comparing acetylcysteine and hydration with hydration alone for preventing contrast nephropathy in patients with chronic renal insufficiency. The trials were identified through a combined search of the BIOSIS+/RRM, MEDLINE, Web of Science, Current Contents Medizin, and The Cochrane Library Databases. We used incidence of contrast nephropathy 48 h after administration of radiocontrast media as an outcome measure. Findings Seven trials including 805 patients were eligible according to our inclusion criteria and were analysed. Overall incidence of contrast nephropathy varied between 8% and 28%. Since significant heterogeneity was indicated by the Q statistics (p=0·016) we used a random-effects model to combine the data. Compared with periprocedural hydration alone, administration of acetylcysteine and hydration significantly reduced the relative risk of contrast nephropathy by 56% (0·435 [95% CI 0·215–0·879], P=0·02) in patients with chronic renal insufficiency. Meta-regression revealed no significant relation between the relative risk of contrast nephropathy and the volume of radiocontrast media administered or the degree of chronic renal insufficiency before the procedure. Interpretation Compared with periprocedural hydration alone, acetylcysteine with hydration significantly reduces the risk of contrast nephropathy in patients with chronic renal insufficiency. The relative risk of contrast nephropathy was not related to the amount of radiocontrast media given or to the degree of chronic renal insufficiency before the procedure