Thomas Weinreich

Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 +/- 0.6 h (Genius dialysis) to 2.4 +/- 0.9 h (hemodialysis) and 2.0 +/- 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.

Several experimental studies point to a potential role of angiotensin II (Ang II) in the progression of glomerulosclerosis even in the absence of glomerular hypertension. We tested the hypothesis that Ang II acts as a growth factor for adult human mesangial cells (AHMC). AHMC were isolated from noninvolved parts of tumor nephrectomy specimens and grown in RPMI medium with the addition of fetal calf serum (FCS). All studies were performed with growth-arrested cells. Proliferation studies were done in serum-free standard growth medium (SF) with the addition of either various concentrations of insulin, plasma-derived serum, or FCS. Ang II (10(-10) to 10(-6) M) dose dependently increased the 3H-thymidine uptake of AHMC up to 57 +/- 13% over solvent controls (p < 0.01). In parallel, the DNA content was 36 +/- 10% higher (p < 0.05) than in solvent controls after 2 days of culture. The cell numbers were higher up to 47 +/- 8% in Ang II (10(-6) M) stimulated cultures after 4 days of incubation (p < 0.01). The effect of Ang II was specific, since it was almost completely obliterated by the AT1 receptor antagonist DuP753. The effect of Ang II was particularly marked when cultures were incubated with SF plus high concentrations (1.7 x 10(-6) M) of insulin or SF plus 10% plasma-derived serum. In contrast, the effect was not significant when cultures were incubated with SF plus 10% FCS. Ang II, when added to platelet-derived growth factor at various concentrations, did not further increase the proliferation. The effect on protein synthesis was assessed in growth-arrested AHMC by 3H-methionine uptake and protein/DNA ratio in cell lysates. Ang II (10(-10) to 10(-6) M) dose dependently increased the 3H-methionine uptake of AHMC up to 47 +/- 10% over solvent controls (p < 0.01). In parallel Ang II (10(-8) to 10(-6) M) dose dependently increased the 3H-methionine uptake of the protein/DNA ratio by 24 +/- 6% after 48 h of incubation. DuP753 obliterated the stimulatory effect of Ang II. Ang II (10(-6) M) also increased the mRNA of the immediate-early growth-related gene Egr-1. We conclude that Ang II induces hypertrophy and proliferation in adult human mesangial cells. This result is of interest with respect to a potential role of Ang II in the pathogenesis of glomerulosclerosis in humans.

Patienten mit fortgeschrittener Herzinsuffizienz weisen oftmals auch eine begleitende Niereninsuffizienz auf. Diese enge pathophysiologische Interaktion wird als kardio-renales Syndrom (KRS) bezeichnet. Die hydropische Dekompensation ist bei diesen Patienten einer der häufigsten Hospitalisierungsgründe. Wenn trotz Optimierung der Therapie eine hydropische Dekompensation bzw. eine Diuretikaresistenz eintritt, kann eine Ultrafiltrationstherapie notwendig sein. In der akuten Dekompensation wird bei den oftmals intensivstationspflichtigen Patienten eine extrakorporale Nierenersatztherapie bevorzugt durchgeführt. Bei der chronischen Dekompensation, insbesondere wenn diese mit Aszitesbildung einhergeht, bietet eine peritoneale Ultrafiltration verfahrensspezifische Vorteile. Eine enge Kooperation zwischen Intensivmedizinern, Kardiologen und Nephrologen ist Voraussetzung für die optimale Behandlung des Patienten mit KRS.