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.

HDL is a major atheroprotective factor, but the mechanisms underlying this effect are still obscure. HDL binding to scavenger receptor-BI has been shown to activate eNOS, although the responsible HDL entities and signaling pathways have remained enigmatic. Here we show that HDL stimulates NO release in human endothelial cells and induces vasodilation in isolated aortae via intracellular Ca2+ mobilization and Akt-mediated eNOS phosphorylation. The vasoactive effects of HDL could be mimicked by three lysophospholipids present in HDL: sphingosylphosphorylcholine (SPC), sphingosine-1-phosphate (S1P), and lysosulfatide (LSF). All three elevated intracellular Ca2+ concentration and activated Akt and eNOS, which resulted in NO release and vasodilation. Deficiency of the lysophospholipid receptor S1P3 (also known as LPB3 and EDG3) abolished the vasodilatory effects of SPC, S1P, and LSF and reduced the effect of HDL by approximately 60%. In endothelial cells from S1P3-deficient mice, Akt phosphorylation and Ca2+ increase in response to HDL and lysophospholipids were severely reduced. In vivo, intra-arterial administration of HDL or lysophospholipids lowered mean arterial blood pressure in rats. In conclusion, we identify HDL as a carrier of bioactive lysophospholipids that regulate vascular tone via S1P3-mediated NO release. This mechanism may contribute to the vasoactive effect of HDL and represent a novel aspect of its antiatherogenic function

In the European Society of Cardiology–European Society of Hypertension guidelines of the year 2007, the consequences of arterial stiffness and wave reflection on cardiovascular mortality have a major role. But the investigators claimed the poor availability of devices/methods providing easy and widely suitable measuring of arterial wall stiffness or their surrogates like augmentation index (AIx) or aortic systolic blood pressure (aSBP). The aim of this study was the validation of a novel method determining AIx and aSBP based on an oscillometric method using a common cuff (ARCSolver) against a validated tonometric system (SphygmoCor). aSBP and AIx measured with the SphygmoCor and ARCSolver method were compared for 302 subjects. The mean age was 56 years with an s.d. of 20 years. At least two iterations were performed in each session. This resulted in 749 measurements. For aSBP the mean difference was −0.1 mm Hg with an s.d. of 3.1 mm Hg. The mean difference for AIx was 1.2% with an s.d. of 7.9%. There was no significant difference in reproducibility of AIx for both methods. The variation estimate of inter- and intraobserver measurements was 6.3% for ARCSolver and 7.5% for SphygmoCor. The ARCSolver method is a novel method determining AIx and aSBP based on an oscillometric system with a cuff. The results agree with common accepted tonometric measurements. Its application is easy and for widespread use.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2. This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2. Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Beyond serving as a mechanical barrier, the endothelium has important regulatory functions. The discovery of nitric oxide revolutionized our understanding of vasoregulation. In contrast, the identity of endothelium-derived vasoconstrictive factors (EDCFs) remains unclear. The supernatant obtained from mechanically stimulated human endothelial cells obtained from dermal vessels elicited a vasoconstrictive response in an isolated perfused rat kidney. A purinoceptor blocker had a greater effect than an endothelin receptor blocker in decreasing endothelially derived vasoconstriction in the isolated perfused rat kidney. The nucleotide uridine adenosine tetraphosphate (Up(4)A) was isolated from the supernatant of stimulated human endothelium and identified by mass spectrometry. Up(4)A is likely to exert vasoconstriction predominantly through P2X1 receptors, and probably also through P2Y2 and P2Y4 receptors. Plasma concentrations of Up(4)A that cause vasoconstriction are found in healthy subjects. Stimulation with adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress releases Up(4)A from endothelium, suggesting that Up(4)A contributes to vascular autoregulation. To our knowledge, Up(4)A is the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties. We conclude that Up(4)A is a novel potent nonpeptidic EDCF. Its vasoactive effects, plasma concentrations and its release upon endothelial stimulation strongly suggest that Up(4)A has a functional vasoregulatory role.

Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and a-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia.

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

Background Sub-Saharan Africa faces a rapid spread of diabetes mellitus type 2 (DM2) but its potentially specific characteristics are inadequately defined. In this hospital-based study in Kumasi, Ghana, we aimed at characterizing clinical, anthropometric, socio-economic, nutritional and behavioural parameters of DM2 patients and at identifying associated factors. Methods Between August 2007 and June 2008, 1466 individuals were recruited from diabetes and hypertension clinics, outpatients, community, and hospital staff. Fasting plasma glucose (FPG), serum lipids and urinary albumin were measured. Physical examination, anthropometry, and interviews on medical history, socio-economic status (SES), physical activity and nutritional behaviour were performed. Results The majority of the 675 DM2 patients (mean FPG, 8.31 mmol/L) was female (75%) and aged 40-60 years (mean, 55 years). DM2 was known in 97% of patients, almost all were on medication. Many had hypertension (63%) and microalbuminuria (43%); diabetic complications occurred in 20%. Overweight (body mass index > 25 kg/m 2 ), increased body fat (> 20% (male), > 33% (female)), and central adiposity (waist-to-hip ratio > 0.90 (male), > 0.85 (female)) were frequent occurring in 53%, 56%, and 75%, respectively. Triglycerides were increased (≥ 1.695 mmol/L) in 31% and cholesterol (≥ 5.17 mmol/L) in 65%. Illiteracy (46%) was high and SES indicators generally low. Factors independently associated with DM2 included a diabetes family history (adjusted odds ratio (aOR), 3.8; 95% confidence interval (95%CI), 2.6-5.5), abdominal adiposity (aOR, 2.6; 95%CI, 1.8-3.9), increased triglycerides (aOR, 1.8; 95%CI, 1.1-3.0), and also several indicators of low SES. Conclusions In this study from urban Ghana, DM2 affects predominantly obese patients of rather low socio-economic status and frequently is accompanied by hypertension and hyperlipidaemia. Prevention and management need to account for a specific risk profile in this population.