Argatroban pharmacokinetics and pharmacodynamics in critically ill cardiac surgical patients with suspected heparin-induced thrombocytopenia.

Only limited data are available on the pharmacokinetic and pharmacodynamic properties of argatroban in critically ill patients under clinical conditions. We determined plasma concentrations of argatroban, and its main metabolite M1, within a time period of 48 hours in 25 critically ill cardiac surgical patients, who were suspected of heparin-induced thrombocytopenia and had the clinical need for anticoagulation. Argatroban infusion was started at 0.5 µg/kg/minute, and adjusted in 0.1-0.25 µg/kg/minute increments when the activated partial thromboplastin time (aPTT) was not within the target range. Median argatroban plasma half-life was 2.7 hours (interquartile range 1.8 to 7.3). Linear regression analysis revealed that argatroban half-life was significantly related to the total bilirubin concentration (R² = 0.66, p< 0.001), as well as to the metabolism of argatroban, which was assessed by the ratio of the areas under the concentration time curves (AUC) of argatroban and M1 (R² = 0.60, p< 0.001). Continuous veno-venous haemodialysis did not significantly affect argatroban plasma half-life. The predictive property of argatroban plasma levels for aPTT was low (R² = 0.28, p< 0.001). Multiple linear regression analysis revealed significant contributions of age and serum albumin levels to the effect of argatroban on aPTT, expressed as the AUC ratio argatroban/aPTT (R² = 0.67, adjusted R² = 0.65, p< 0.001). In conclusion, argatroban plasma half-life is markedly increased in critically ill cardiac surgical patients, and further prolonged by hepatic dysfunction due to impaired metabolism. Patient age and serum albumin concentration significantly contribute to the variability in the anticoagulant activity of argatroban.

Methemoglobinemia in critically ill patients during extended hemodialysis and simultaneous disinfection of the hospital water supply.

INTRODUCTION: To evaluate the cause of methemoglobinemia in patients undergoing extended daily hemodialysis/hemodiafiltration we analyzed the relationship between methemoglobinemia and the water disinfection schedule of the hospital. METHODS: We reviewed all arterial blood gas analyses, obtained over a one-year period, in patients undergoing extended hemodialysis/hemodiafiltration, and compared the methemoglobin concentrations obtained on the days when the water supply was disinfected, using a hydrogen peroxide/silver ion preparation, with data measured on disinfection-free days. RESULTS: The evaluation of 706 measurements revealed a maximum methemoglobin fraction of 1.0 (0.8; 1.2) % (median and 25th; 75th percentiles) during hemodialysis/hemodiafiltration on the disinfection-free days. The methemoglobin fraction increased to 5.9 (1.3; 8.4) % with a maximal value of 12.2% on the days of water disinfection (P < 0.001 compared to disinfection-free days). Spot checks on hydrogen peroxide concentrations in the water supply, the permeate, and the dialysate, using a semi-quantitative test, demonstrated levels between 10 and 25 mg/l during water disinfection. CONCLUSIONS: Our results demonstrate that even a regular hospital water disinfection technique can be associated with significant methemoglobinemia during extended hemodialysis. Clinicians should be aware of this potential hazard.

Hypertension in mice lacking the CXCR3 chemokine receptor.

The CXC chemokine receptor 3 (CXCR3) has been linked to autoimmune and inflammatory disease, allograft rejection, and ischemic nephropathy. CXCR3 is expressed on endothelial and smooth muscle cells. Although a recent study posited that antagonizing of CXCR3 function may reduce atherosclerosis, the role of CXCR3 in controlling physiological vascular functions remains unclear. This study demonstrates that disruption of CXCR3 leads to elevated mean arterial pressures in anesthetized and conscious mice, respectively. Stimulation of isolated resistance vessels with various vasoconstrictors showed increased contractibility in CXCR3-/- mice in response to angiotensin II (ANG II) and a decreased vasodilatation in response to acetylcholine (ACh). The increased contractibility was related to higher ANG II type 1 receptor (AT1R) expression, whereas the decreased vasodilatation was related to lower M3-ACh receptor expression in the mesenteric arteries of CXCR3-/- mice compared with wild-type mice. The vasodilatatory response to ACh could be antagonized by the nonselective ACh receptor antagonist atropine and the selective M3 receptor antagonist 4-DAMP, but not by M1, M2, and M4 receptor antagonists. Additionally, EMSA studies revealed that transcription factors SP-1 and EGR-1 interact as a complex with the murine AT1R promoter region. Furthermore, we could show increased expression of SP-1 in CXCR3-/- mice indicating an imbalanced SP-1 and EGR-1 complex formation which causes increased AT1R expression and hypertension. The data indicate that CXCR3 receptor is important in vascular contractility and hypertension, possibly through upregulated AT1R expression.

Alpha/beta hydrolase 1 is upregulated in D5 dopamine receptor knockout mice and reduces O2- production of NADPH oxidase.

Renal dopamine receptors have been shown to play a critical role in ROS-dependent hypertension. D5 dopamine receptor deficient (D5-/-) mice are hypertensive and have increased systemic oxidative stress which is manifested in the kidney and the brain. To further investigate the underlying mechanisms of hypertension in D5-/- mice, we used RNA arrays to compare mRNA levels of kidneys from wildtype and D5-/- mice. Our data show, that the mRNA level of alpha/beta hydrolase 1 (ABHD1) is significantly upregulated in D5-/- mice. Additionally, overexpression of ABHD1 in a new established renal proximal tubule cell line reduced the amount of O(2)(-) produced by the NADPH oxidase. Therefore the upregulation of ABHD1 in D5-/- mice could be an answer to the increased oxidative stress. While oxidative stress is an important factor for the development of hypertension, ABHD1 could play a protective role in the pathogenesis of hypertension.

Upregulation of Id-1 via BMP-2 receptors induces reactive oxygen species in podocytes.

Bone morphogenetic proteins (BMPs) are secreted signaling molecules, which play a major role in kidney development and disease. Here, we show the existence of mRNA for BMP-2 and for the BMP receptors BMPR1A, BMPR1B, BMPRII, ACVR1A, ACVR2, and ACVR2B in differentiated mouse podocytes and the protein expression of BMPR1A in human glomerular podocytes. BMP-2 dose dependently increases the free cytosolic Ca(2+) concentration in podocytes proving the existence of a functional receptor in these cells. Recent data indicate that in a myoblastic cell line and in a breast cancer cell line, BMP-2 increases the expression of Id-1, a negative regulator of basic helix-loop-helix transcription factors, but the role of BMP-2 stimulated Id-1 expression in the kidney has not been further characterized. Here, we show that BMP-2 increases the expression of Id-1 in differentiated podocytes. To investigate a role of Id-1 for podocyte function, overexpression of Id-1 was induced in differentiated mouse podocytes. Id-1-overexpressing podocytes show an increased NADPH-dependent production of reactive oxygen species (ROS). This effect can be evoked by BMP-2 and can be antagonized by anti-Id-1 antisense oligonucleotides. The data indicate that BMP-2 may, via an increased expression of Id-1 and an increased generation of ROS, contribute to important cellular functions in podocytes. ROS supposedly play a major role in cell adhesion, cell injury, ion transport, fibrogenesis, angiogenesis and are involved in the pathogenesis of membranous nephropathy.