M. van der Giet

Sphingosine-1-phosphate and FTY720 as anti-atherosclerotic lipid compounds

All stages of atherosclerosis have been identified as a chronic vascular inflammatory disease. In the last few years there is increasing evidence that endogenous lysophospholipids such as sphingosine‐1‐phosphate (S1P) have potent anti‐inflammatory properties. The S1P analogue FTY720 that has been developed as a potent, orally active, immunosuppressant in the field of transplantation and autoimmune disease has interesting effects on inflammatory processes in the arterial vessel wall. S1P targets five specific S1P receptors (S1P1−5), which are ubiquitously expressed. S1P1−3 receptor expression is identified in arterial vessels. S1P and FTY720 show potent silencing effects on some vascular proinflammatory mechanisms in endothelial and vascular smooth muscle cells. In addition, the interaction of monocytes with the vessel wall is inhibited. As shown recently, FTY720 can effectively reduce the progression of atherosclerosis in apolipoprotein E‐deficient mice having a high‐cholesterol diet. It is not entirely clear which S1P receptor subtype is mainly involved in this process. However, it is currently speculated that the S1P3 and probably the S1P1 is involved in the anti‐atherosclerotic effects of FTY720. This review summarizes the current knowledge about S1P‐ and FTY720‐effects on mechanisms of vascular inflammatory disease. In addition S1P receptor subtypes are identified which might be interesting for molecular drug targeting.

Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine.

BACKGROUND Recurrent urinary tract infections (UTIs) increase mortality and reduce graft survival after renal transplantation. Strategies to prevent recurrent UTIs include L-methionine, cranberry juice, and antibiotics. Data on the efficacy of cranberry and L-methionine, however, are controversial in the general population; there are few data in renal transplant recipients. METHODS We performed a retrospective analysis of 82 transplant recipients with recurrent UTIs, who underwent prophylaxis with cranberry juice (2 × 50 mL/d, n = 39, 47.6%), or L-methionine (3 × 500 mg/d, n = 25, 30.5%), or both modalities (n = 18, 21.9%). Thirty patients without prophylaxis served as controls. We analyzed symptoms, pyuria/nitrituria, and incidence of UTI events during 1 year before versus after initiation of prophylaxis. RESULTS Prophylaxis highly significantly decreased the annual UTI incidence by 58.3% (P < .001) in the study population with no change in the control group (P = .85); in addition, 53.7% of symptomatic patients reported relief of symptoms and pyuria/nitrituria disappeared in 42.4% of the dipstick-positive patients (P < .001 each). Cranberry reduced the annual number of UTI episodes by 63.9% from 3.6 ± 1.4 to 1.3 ± 1.3/year (P < .001) and L-methionine by 48.7% from 3.9 ± 1.8 to 2.0 ± 1.3/year (P < .001). CONCLUSION Cranberry juice and L-methionine successfully reduced the incidence of UTI after renal transplantation.

Intraoperative Assessment of Kidney Allograft Perfusion by Laser-Assisted Indocyanine Green Fluorescence Videography

BACKGROUND Kidney allograft function crucially depends on the quality of organ perfusion. Duplex sonography, however, frequently reveals hypoperfused segments that remained undetectable to visual inspection intraoperatively. To date, no imaging system supplementing the surgeons experience has achieved clinical acceptance. The present work examines whether laser-assisted indocyanine green (ICG) fluorescence-videography can be used as a safe and sensitive technique for the intraoperative assessment of renal allograft perfusion. METHODS Intraoperative assessment of organ perfusion by laser-assisted ICG fluorescence videography (IC-VIEW) was performed in 10 consecutive de novo renal transplantations. The IC-VIEW system allows the visualization of graft perfusion by the fluorescein dye ICG that emits infrared light after exposure to laser light. RESULTS Perfusion measurements were successful in all 10 transplant recipients. Fluorescence videography produced brilliant, sharply contrasted images of the organs, allowing the detection of even small perfusion deficits. Remarkably, this technique detected 1 large perfusion defect that had remained imperceptible to visual inspection. Repositioning of the graft led to a homogeneous overall perfusion. There were no complications with the ICG injection or the imaging device. CONCLUSION Laser-assisted ICG fluorescence videography is a feasible and safe technique for the intraoperative assessment of renal allograft perfusion.

Renal Denervation for Refractory Hypertension – Technical Aspects, Complications and Radiation Exposure

PURPOSE To analyze procedural details, complications and radiation exposure in renal denervation (RDN) using the Medtronic Symplicity® device in the treatment of refractory hypertension. MATERIALS AND METHODS Fifty three consecutive patients underwent RDN. The number of ablations per artery, peri-procedural complications, procedure time (PT), fluoroscopy time (FT), dose-area product (DAP) and procedure-related complications were documented. Additionally, the radiation dose was compared between obese (body mass index ≥ 30 kg/m(2)) and non-obese patients. RESULTS Bilateral RDN was performed in 50/53 (94 %) cases and with a minimum of 4 ablations per artery in 33/50 (66 %), the mean count being 5.4 (range R: 2 - 13) on the right and 4.3 (R: 1 - 10) on the left. The FT and DAP decreased significantly over the first 12 procedures, reaching a steady state with a median FT of 11.2 min (R: 7.5 - 27) and a median DAP of 4796 cGy × cm(2) (R: 1076 - 21 371), resulting in an effective dose of 15.7 mSv. The median PT was 57 min (R: 40 - 70). Obese patients had a 3.3-fold higher radiation dose (p < 0.001). We observed one severe spasm and one imminent respiratory depression, both resolved without sequelae. CONCLUSION For an experienced interventionalist, RDN has a short learning curve with a low risk profile. The radiation dose does not exceed that of other renal artery interventions, but is explicitly higher in obese patients, who account for a large portion of patients with refractory hypertension.

Regulation of endothelial nitric oxide synthase activation in endothelial cells by S1P1 and S1P3.

Endothelial nitric oxide synthase (eNOS) plays a crucial role in vascular homeostasis. Lysophospholipid interaction with sphingosine 1-phosphat (S1P) receptors results in eNOS activation in different cells. In endothelial cells, eNOS activation via S1P1 or S1P3 was shown controversially. The aim of this study is to investigate the meaning of both S1P receptors for eNOS activation in human endothelial cells. Therefore, several S1P1 and S1P3 agonists in combination with antagonists and specific RNAi approach were used. eNOS activation was measured in human umbilical vein endothelial cells (HUVEC) via DAF2-DA-based fluorescence microscopy. For investigation of the signaling pathway, agonists/antagonist studies, RNAi approach, Luminex™ multiplex, and Western Blot were used. In HUVEC, both the S1P1 agonist AUY954 as well as the S1P1,3 agonist FTY720P induced eNOS activation in a time- and dose-dependent manner. Other S1P1 agonists activated eNOS to a lesser extent. The AUY954-induced eNOS activation was blocked by the S1P1 antagonist W146, the combination of W146 and the S1P3 antagonist CAY10444 and the S1P1,3 antagonist VPC23019, but not by CAY10444 indicating the meaning of S1P1 for the AUY954-induced eNOS activation. The FTY720P-induced eNOS activation was blocked only by the combination of W146 and CAY10444 and the combined S1P1,3 antagonist VPC23019, but not by W146 or CAY10444 indicating the importance of both S1P1 and S1P3 for FTY720-induced eNOS activation. These results were confirmed using specific siRNA against S1P1 and S1P3. The S1P1,3 activation results in Akt phosphorylation and subsequent activation of eNOS via phosphorylation at serine(1177) and dephosphorylation at threonine(495). Beside former investigations with rather unspecific S1P receptor activation these data show potent selective S1P1 activation by using AUY954 and with selective S1P receptor inhibition evidence was provided that both S1P1 and S1P3 lead to downstream activation of eNOS in HUVEC in the same experimental setting. Inhibition or knockdown of one of these receptor subtypes did not abolish the eNOS activation and subsequent NO production.

Why HDL cholesterol is 'good cholesterol'.

Patients who seek an answer to this question may be inclined to have a look on the internet pages of the American Heart Association. There we learn: ‘Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver, where it’s passed from the body. Some experts believe that HDL removes excess cholesterol from plaque in arteries, thus slowing buildup’ (www.americanheart.org/presenter). First put forward in 1968 [1], now this concept has considerably aged, and there is increasing evidence that reverse cholesterol transport may be only one facet of the beneficial cholesterol actions [2], but may not be the only or even the most important cause. Going deeper into the problem why HDL cholesterol is protective, we find that several mechanisms have been proposed, such as beneficial HDL effects on endothelial function, leukocyte adhesion and antioxidative effects [3]. When entering into the subject of direct HDL effects on vascular function, we are faced with two principal questions: first, how does HDL affect vascular function, and second, if these direct vascular effects are relevant, do we have to redefine the relevance of HDL as a lipid transporter? Is cholesterol transport indeed the main function of HDL, or could ‘HDL cholesterol’ be a misnomer in that HDL has much more important functions than transporting cholesterol? In a recent issue of The Journal of Clinical Investigation Nofer et al . [4] opened the door towards a new understanding of HDL function: they showed that HDL should no longer be regarded just as a cholesterol transporter, but as a carrier of messengers most relevant for vascular structure and function. The authors demonstrated that HDL beneficially affects vascular function by releasing several agonists stimulating vascular Edg receptors, namely sphingosine-1phosphate (S1P), sphingosylphosphorylcholine (SPC) and lysosulphatidic acid (LSF) [4]. Yuhanna and coworkers [5] demonstrated earlier that release of these beneficial substances from HDL is dependent on the presence of endothelial SR-BI-receptors [for mechanism (see Fig. 1)]. Edg 1 and Edg 3 receptors may play a central role in vascular biology [6]. The lipid mediators stimulating Edg receptors have recently attracted much attention [7]. S1P might be an important cytoprotective factor for endothelial cells [8]. These cytoprotective actions on endothelial cells are mediated by Edg-1 receptors [9]: Edg-5 inhibits the migration of VSMCs, thereby adding atheroprotective effects [10]. However, S1P/Edg-1 potentially mediates pro-atherogenic effects by increasing the migration and proliferation of VSMCs [11]. Intracellular S1P is a mediator of VCAM-1 and ICAM-1 expression on endothelial cells and mitogenesis of VSMCs, and they could also be proatherogenic [12]. S1P thus seems to be Janus-faced with respect to atherogenesis, depending on whether it acts intracellularly or extracellularly and on receptor subtypes. Moreover, the data by Nofer et al . suggest that HDLderived lipid mediators may induce a wide variety of effects depending on the ratios of HDL-bound SP1-SPC and LSF [4]. Given this diversity of actions, first of all S1P, SPC and LSF are potent activators of eNOS, leading to an endotheliumdependent vasodilation [4]. Furthermore, the lysophospholipid content of HDL relevantly determines vasodilatory potential in vivo . If HDL indeed is a carrier of important lipid mediators affecting vascular function, obviously the HDL content of these mediators should be subject to variation, and logically the next question should be whether ‘good cholesterol’ is equally good in any case. Given the wellknown excess cardiovascular mortality in males, the authors compared the male and female HDL as to its vasoactivity. Female HDL is a more potent vasodilator than the male one (van der Giet, unpublished observation), and accordingly, the S1P content of female HDL exceeds that of male HDL [4]. These findings principally show that the vasodilatory potency of HDL may vary considerably among the population depending on age, sex and concomitant disease. An important message from these findings is that we should not equate the amount and the quality of HDL. Nofer et al . only carried out the first step to assess the functional quality of HDL independent from its quantity, and the paper might Charite – Campus Benjamin Franklin, Nephrology, Berlin, Germany (M. van der Giet , M. Tölle).

Hauttumoren nach Organtransplantation

ZusammenfassungEine der größten Herausforderung der Transplantationsmedizin war und ist die Kontrolle von Abstoßungsreaktionen. Die medikamentöse Inhibition der zellulären Immunüberwachung führt jedoch besonders an der Haut zu einer signifikanten Zunahme von Neoplasien. Invasive Plattenepithelkarzinome sind die am häufigsten diagnostizierten Malignome bei Organtransplantierten und können durch ihr multifokales Auftreten sowie das aggressive Wachstum eine Bedrohung für immunsupprimierte Patienten darstellen. Interdisziplinäre Nachsorgeprogramme basieren auf den epidemiologischen Analysen individueller dermatologischer Risikofaktoren für die Hauttumorgenese wie Alter, Hauttyp, Sonnenexposition sowie Art und Dauer der Immunsuppression. Neben Aufklärungsprogrammen und einer kausal orientierten Primärprophylaxe (Sonnenschutz) sowie der Verwendung einer risikoadaptierten Immunsuppression hat sich das proaktive Management präinvasiver Hauttumoren durch moderne Flächentherapien bewährt. Die am Beispiel der Organtransplantierten etablierten interdisziplinären Konzepte und Versorgungsstrukturen stehen hierbei exemplarisch für die ideale Nachsorge auch anderer immunsupprimierter Risikogruppen.AbstractOne of the most significant challenges in transplantation medicine was and still is sufficient control of graft rejection. The drug-induced inhibition of cellular immune response, however, induces a significant increase of neoplasms, especially skin cancer. Invasive squamous cell carcinomas are the most frequently diagnosed malignomas in organ transplant recipients and due to the multifocal development and aggressive growth can represent a threat to immunocompromised patients. Interdisciplinary aftercare programs are based on epidemiological analyses of individual dermatological risk factors for skin cancer development, such as age, skin type, sun exposure, type and dosing of immunosuppression. Patient education programs, primary preventive measures (UV protection), individual risk-adapted immunosuppression protocols as well as proactive management even of early stages of skin cancer have been shown to be successful. Interdisciplinary surveillance concepts and treatment algorithms have been shown to serve as a model for all kinds of immunocompromised patients with an increased risk of skin cancer.