Background: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclassify elderly persons in terms of their stage of chronic kidney disease. Objective: To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants. Design: Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation. Setting: Random community-based population of a large insurance company. Participants: 610 participants aged 70 years or older (mean age, 78.5 years). Intervention: lohexol plasma clearance measurement as gold standard. Measurements: GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine-and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy in the validation sample. Results:The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and CockcroftGault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m 2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). Limitation: There was no validation by an external data set. Conclusion: The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C is not available, the BIS1 equation is an acceptable alternative. Primary Funding Source: Kuratorium für Dialyse und Nierentransplatation (KfH) Foundation of Preventive Medicine.

Objective-Angiotensin peptides play a central role in cardiovascular physiology and pathology. Among these peptides, angiotensin II (Ang II) has been investigated most intensively. However, further angiotensin peptides such as Ang 1-7, Ang III, and Ang IV also contribute to vascular regulation, and may elicit additional, different, or even opposite effects to Ang II. Here, we describe a novel Ang II-related, strong vasoconstrictive substance in plasma from healthy humans and end-stage renal failure patients. ]-Ang II, in the following named Angiotensin A (Ang A), is most likely generated enzymatically. In the presence of mononuclear leukocytes, Ang II is converted to Ang A by decarboxylation of Asp 1 . Ang A has the same affinity to the AT 1 receptor as Ang II, but a higher affinity to the AT 2 receptor. In the isolated perfused rat kidney, Ang A revealed a smaller vasoconstrictive effect than Ang II, which was not modified in the presence of the AT2 receptor antagonist PD 123319, suggesting a lower intrinsic activity at the AT 1 receptor. Ang II and Ang A concentrations in plasma of healthy subjects and end-stage renal failure patients were determined by matrix-assisted laser desorption/ionisation mass-analysis, because conventional enzyme immunoassay for Ang II quantification did not distinguish between Ang II and Ang A. In healthy subjects, Ang A concentrations were less than 20% of the Ang II concentrations, but the ratio Ang A / Ang II was higher in end-stage renal failure patients. Conclusion-Ang

Objectives-High-density lipoprotein (HDL) levels are inversely proportional to the risk of atherosclerosis, but mechanisms of HDL atheroprotection remain unclear. Monocyte chemoatractant protein-1 (MCP-1) constitutes an early component of inflammatory response in atherosclerosis. Here we investigated the influence of HDL on MCP-1 production in vascular smooth muscle cells (VSMCs) and rat aortic explants. Methods and Results-HDL inhibited the thrombin-induced production of MCP-1 in a concentration-dependent manner.The HDL-dependent inhibition of MCP-1 production was accompanied by the suppression of reactive oxygen species (ROS), which regulate the MCP-1 production in VSMCs. HDL inhibited NAD(P)H oxidase, the preponderant source of ROS in the vasculature, and prevented the activation of Rac1, which precedes NAD(P)H-oxidase activation. The HDL capacity to inhibit MCP-1 production, ROS generation, and NAD(P)H-oxidase activation was emulated by sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), two lysosphingolipids present in HDL, but not by apolipoprotein A-I. HDL-, S1P-, and SPC-induced inhibition of MCP-1 production was attenuated in VSMCs pretreated with VPC23019, an antagonist of lysosphingolipid receptors S1P 1 and S1P 3 , but not by JTE013, an antagonist of S1P 2 . In addition, HDL, S1P, and SPC failed to inhibit MCP1 production and ROS generation in aortas from S1P 3 -and SR-B1-deficient mice. Conclusion-HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent ROS generation and MCP-1 production in a process that requires coordinate signaling through S1P 3 and SR-B1 receptors. (Arterioscler Thromb Vasc Biol. 2008;28:1542-1548)Key Words: HDL Ⅲ sphingosine-1-phosphate Ⅲ MCP-1 Ⅲ ROS Ⅲ NADPH-oxidase M onocyte infiltration into the vessel wall is an initial step in the formation of atherosclerotic lesion. 1,2 Monocyte chemoattractant protein-1 (MCP-1) is a key regulator of monocyte recruitment to sites of vascular inflammation. [2][3][4] In addition, MCP-1 induces several proinflammatory changes including secretion of cytokines and expression of adhesion molecules. 2-4 MCP-1 was detected in atherosclerotic lesion, and elevated levels of MCP-1 were encountered in acute coronary syndromes. 2-4 Animals genetically modified to lack MCP-1 or its receptor, CCR2, displayed reduced atherosclerotic lesions, whereas overexpression of MCP-1 in macrophages led to increased susceptibility to atherosclerosis. [2][3][4] Numerous studies documented an inverse relationship between high-density lipoprotein (HDL) levels and the progression of atherosclerosis and suggested that antiatherogenic effects of HDL are related to inflammation and its sequel. 5 For instance, HDL inhibits expression of adhesion molecules and reduces leukocyte homing to arterial endothelium. 5,6 Suppression of cytokine and chemokine production by HDL was observed after infusion of reconstituted HDL in animal models of inflammation. 7 The inverse relationship between HDL and acute phase proteins was repeatedly reported. 8 De...

These results suggest that SAA enrichment of HDL during disease conditions contributes to the decreased protective function. It is a novel finding that SAA acts as a pro-inflammatory molecule to reduce the anti-inflammatory properties of HDL.

Objective-The sphingosine-1-phosphate (S1P) analogue FTY720 is a potent immunosuppressive agent currently in Phase III clinical trials for kidney transplantation. FTY720 traps lymphocytes in secondary lymphoid organs thereby preventing their migration to inflammatory sites. Previously, we have identified FTY720 as a potent activator of eNOS.As both inhibition of immune responses and stimulation of eNOS may attenuate atherosclerosis, we administered FTY720 to apolipoprotein E Ϫ/Ϫ mice fed a high-cholesterol diet. Methods and Results-FTY720 dramatically reduced atherosclerotic lesion volume (62.5%), macrophage (41.8%), and collagen content (63.5%) after 20 weeks of high-cholesterol diet. In isolated aortic segments and cultured vascular smooth muscle cell, FTY720 potently inhibited thrombin-induced release of monocyte chemoattractant protein-1. This effect was mediated by the S1P 3 sphingolipid receptor as FTY720 had no effect on thrombin-induced monocyte chemoattractant protein-1 release in S1P 3 Ϫ/Ϫ mice. In contrast to S1P receptors on lymphocytes, FTY720 did not desensitize vascular S1P receptors as arteries from FTY720-treated mice retained their vasodilator response to FTY720-phosphate. Conclusions-We suggest that FTY720 inhibits atherosclerosis by suppressing the machinery involved in monocyte/macrophage emigration to atherosclerotic lesions. As vascular S1P receptors remained functional under FTY720 treatment, S1P agonists that selectively target the vasculature and not the immune system may be promising new drugs against atherosclerosis. Key Words:T he novel immunomodulator FTY720 has proven highly effective in Phase III clinical trials for prevention of kidney graft rejection. 1 FTY720 is a structural homologue of sphingosine-1-phosphate (S1P), a natural sphingolipid present at high nanomolar concentrations in serum. 2 After endogenous phosphorylation, FTY720 serves as a potent agonist of 4 of the 5 G protein-coupled sphingolipid receptors S1P 1 , -3 , -4 and -5 3 . These receptors mediate a multitude of physiological processes such as immunity, angiogenesis, cell migration, and inflammation. 4,5 The immunosuppressive effect of FTY720 has been attributed to downregulation of lymphocyte S1P 1 thus preventing effector T-cell recirculation from lymphoid organs to peripheral sites of inflammation, the prerequisite for the adaptive immune response in the T-cell compartment. 6,7 Atherosclerosis is a chronic inflammatory disease that strongly depends on T-lymphocyte-mediated immune responses for initiation and progression. 8 Atherosclerotic plaques contain activated CD4 ϩ T-cells of the T helper 1 (T H 1)-phenotype that induce the expression of numerous cytokines important in lesion progression and destabilisation. 8 Their genetic deletion has been shown to attenuate atherosclerosis implying a T H 1-cell-driven process. 8 Although systemic administration of immunosuppressive drugs is currently not an option for treating atherosclerosis, 8 their local application in drug-eluting stents (sirolimus) has proven ext...

No abstract

Background Arteriosclerosis is a pathological, structural (media vascular calcification) and physiological (modified vascular smooth vessel cells; increased arterial stiffness) alteration of the vessel wall. Through improved assessment methods (functional and imaging), it has become a well-known phenomenon in recent decades. However, its clinical importance was underestimated until recently.

The BIS is a very well-characterized, representative cohort of older adults. Participants with an ACR ≥30 had significantly higher odds for most cardiovascular risk factors compared with an ACR <30 mg/g. Kidney function declined and ACR rose with increasing age.