Maximilian von Eynatten

Retinol-binding protein-4 in experimental and clinical metabolic disease.

Retinol-binding protein-4 (RBP4), a 21-kDa protein synthesized in the liver and adipose tissue, has recently been described as a murine adipokine involved in the development of insulin resistance. The expression of the gene encoding RBP4 was increased in the adipose tissue, but not in the liver, of insulin-resistant adipose GLUT4-/- mice and five other mouse models of obesity and insulin resistance. In addition, intraperitoneal injection or transgenic overexpression of RBP4 in mice induced insulin resistance. While experimental clinical approaches (mostly applying clamp techniques) in humans confirmed correlations of RBP4 with insulin resistance, studies in larger groups out of clinical routine failed to demonstrate a connection with alternative measures of insulin sensitivity. Yet, significant associations of RBP4 with atherogenic lipids were found and a focus of future studies should be the influence on atherosclerosis and related complications. Based on current data, the function of RBP4 as an adipokine exerting metabolic effects in glucose metabolism in humans remains uncertain and might be restricted to rodent models.

Serum Fetuin-A, Cardiovascular Risk Factors, and Six-Year Follow-up Outcome in Patients With Coronary Heart Disease

High circulating fetuin-A has recently been linked to risk of primary cardiovascular disease (CVD). The clinical importance of fetuin-A in patients at markedly increased cardiovascular risk, however, has not been fully elucidated. We studied the association between serum fetuin-A and future cardiovascular outcome in patients with prevalent coronary heart disease (CHD). Fetuin-A levels were measured in 1,049 patients with CHD. Associations with traditional cardiovascular risk factors and with secondary CVD events during 6 years of follow-up (median 73.4 months, interquartile range 57.4 to 74.3) were analyzed. Serum fetuin-A levels were significantly increased in patients with prevalent hypertriglyceridemia (0.71 vs 0.69 g/L, p = 0.013). No association with baseline metabolic syndrome was found (odds ratio 0.95 for highest vs lowest fetuin-A quintile, 95% confidence interval 0.59 to 1.53, p = 0.82). In Cox proportional hazards analyses, serum fetuin-A levels were not significantly associated with secondary CVD events (hazard ratio 0.67 for highest vs lowest fetuin-A quintile, 95% confidence interval 0.37 to 1.21, p = 0.18). In conclusion, fetuin-A is significantly associated hypertriglyceridemia but not with other traditional cardiovascular risk factors or metabolic syndrome in patients with manifest CHD. Measurement of serum fetuin-A levels may not emerge as a valuable tool for evaluating future CVD risk in patients aggressively treated for advanced atherosclerosis.

Fetuin-A and arterial stiffness in patients with normal kidney function

AIMnTo evaluate the association between fetuin-A level (AHSG), its encoding gene (Thr256Ser) and arterial function in subjects with normal kidney function.nnnINTRODUCTIONnThe aortic pulse wave velocity (aPWV) is a predictor for cardiovascular mortality. Fetuin-A is a calcification inhibitor and correlates negatively with increased vascular stiffness in dialysis patients. The fetuin-A polymorphism (Thr256Ser) is associated with reduced fetuin levels and accelerated vascular calcification in dialysis patients. Little is known about the role of fetuin-A as an independent predictor for the development of arterial stiffness in healthy subjects.nnnMATERIALS AND METHODSnWe studied 116 subjects with normal kidney function (age 47+/-12 years, 50 females and 66 males) of the FLEMENGHO study. Calcium measurements, plasma fetuin-A, its encoding gene (Thr256Ser) and indexes of arterial stiffness, such as aPWV and arterial distensibility, were determined.nnnRESULTSnFetuin-A levels were negatively correlated with aPWV (r=-0.21, p=0.029). After an adjustment for multiple covariables, fetuin-A levels were independently associated with aPWV (r=-0.30, p=0.022) in males but not in females. Male fetuin-A SerSer carrier had lower fetuin-A levels and higher aPWV (fetuin-A: 61.9+/-29.0 microg/ml; aPWV: 14.3+/-0.9 m/s) as compared to ThrThr (fetuin-A: 109.9+/-54.9 microg/ml; aPWV: 6.4+/-1.3 m/s) and ThrSer carrier (fetuin-A: 100.8+/-52.5 microg/ml; aPWV: 6.6+/-1.3 m/s). Other calcium variables were not significantly associated with arterial stiffness.nnnCONCLUSIONnWith respect to common calcium variables, only fetuin-A level showed an inverse relation with aPWV in men with normal renal function. Male fetuin-A SerSer carriers demonstrate particularly high aortic stiffness, possibly implying a status of increased cardiovascular risk.

Altered Molecular Weight Forms of Adiponectin in Hypertension

An important link between adiponectin and hypertension has been proposed in clinical studies. In the circulation, adiponectin is predominantly present in multimeric complexes, of which high–molecular weight (HMW) adiponectin is thought to represent the biological active form. The authors investigated which role the different multimeric adiponectin isoforms play in context with hypertension as compared to total adiponectin levels. Fifty (19 normotensive/31 hypertensive) patients were included in the study. Total adiponectin and adiponectin multimers were determined by enzyme‐linked immunosorbent assay and western blot. The authors analyzed associations between adiponectin multimer levels and blood pressure. Total adiponectin concentrations were not significantly different between hypertensive and normotensive patients (6.8±2.3 vs 7.5±4.2 μg/mL). HMW adiponectin was significantly lower (P<.05) and low–molecular weight adiponectin was significantly higher (P<.01) in hypertensive than in normotensive persons (3.8±1.7 vs 5.2±3.0 μg/mL and 0.9±0.5 vs 1.8±0.9, respectively). Low molecular weight was an independent predictor for the presence of hypertension (effect coefficient: 0.160–0.445; P<.001) in multivariate analyses. These results suggest that the composition of the molecular weight forms of adiponectin in hypertension are characterized by reduced HMW adiponectin, the proposed major active form of adiponectin, and increased low–molecular weight adiponectin. Moreover, the latter represents an independent predictor of prevalent hypertension, suggesting an association between adiponectin multimer composition and hypertension.

MRP8/14 is associated with systemic inflammation in stable coronary atherosclerosis in men

Eur J Clin Invest 2011; 41 (12): 1261–1267

Pulsatile stress correlates with (micro-)albuminuria in renal transplant recipients.

Pulsatile stress is defined as product of pulse pressure (PP) and heart rate (HR) and is largely regulated by arterial stiffness in general and specifically with reference to patients with renal insufficiency by sympathetic nerve activity. Direct effects of the pulsatile stress on heart, coronary system and ultimately cardiovascular survival have been documented whereas no data exist relating to renal transplant patients. We analysed the relation of macrocirculatory disturbance to microcirculatory defects in 92 renal transplant recipients. Therefore, we investigated aortic stiffness by carotid‐femoral pulse wave velocity (PWV), pulsatile stress and albuminuria. Pulsatile stress, not PWV was associated with the extent of albuminuria (ru2003=u20030.29; Pu2003<u20030.01 and ru2003=u20030.06; Pu2003=u20030.6 respectively), which was confirmed in multivariate stepwise regression analysis (Pu2003=u20030.008). Dividing the data in tertiles of pulsatile stress revealed an eightfold increased risk for microalbuminuria and 12.2‐fold increased risk for macroalbuminuria comparing upper with lower tertile of pulsatile stress. Pulsatile stress, not PWV correlates with albuminuria and predicts the degree of albuminuria in renal transplant recipients. Therefore, pulsatile stress reflects an easy and cost‐effective marker for renal microcirculatory defects in renal transplant patients.

Low pre-transplant adiponectin multimers are associated with adverse allograft outcomes in kidney transplant recipients a 3-year prospective study.

BACKGROUNDnIn kidney transplant recipients endothelial dysfunction is almost a universal risk factor for allograft failure. Adiponectin, an adipocyte derived hormone, has endothelial-protective properties and the high-molecular weight (HMW) multimer is the major active form, exerting anti-inflammatory and anti-apoptotic effects on endothelial cells. This study evaluated, whether pre-transplant total and HMW multimer adiponectin levels are associated with markers of endothelial dysfunction and arteriosclerosis and predict long-term graft survival in patients after kidney transplantation.nnnMETHODSnIn 206 renal transplant recipients pre-transplant total and HMW adiponectin levels were measured in serum by ELISA and Western blot, respectively. During the 36 months active follow up (median [interquartile range] 1249 [1020; 1445] days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival).nnnRESULTSnPre-transplant total and HMW adiponectin levels were significantly associated with lipid and glucose parameters at baseline. After 3 years follow-up pre-transplant total and HMW adiponectin levels were significantly inversely associated with the incidence of allograft failure (adiponectin: r=-0.216; p=0.002: HMW: r=-0.218; p=0.002). In multivariable adjusted Cox proportional hazard regression models patients in the lowest total and HMW adiponectin quartile had a significantly increased risk for allograft failure within 3 years post-transplantation: odds ratio [95%CI]: total adiponectin: 4.25 [1.27-14.24; p=0.019], and HMW multimers: 3.35 [1.04-10.76; p=0.042], respectively.nnnCONCLUSIONnLow pre-transplant levels of total and HMW adiponectin reflect a pro-atherogenic endothelial milieu and independently predict an increased risk of allograft failure in kidney-transplant recipients. Measurement of adiponectin levels may identify patients at risk for adverse allograft outcomes after kidney transplantation.

Retinol-binding protein 4 & atherosclerosis: risk factor or innocent bystander?

The discovery of leptin in 1995, the first bioactive serum protein hat was identified to be released exclusively from fat cells, has draatically changed the understanding of adipose tissue [1]. Research ver the last decade has focussed attention on the endocrine funcion of adipocytes as source of circulating molecules collectively ermed ‘adipokines’, since they have been shown to contribute to he pathogenesis of obesity-related diseases, such as insulin resisance, type 2 diabetes, and cardiovascular disease (CVD) [2]. Besides he classical adipokines that are specifically expressed in adipose issue, there are growing numbers of well-known factors, newly dentified as being secreted by adipocytes. An interesting example for this is retinol-binding protein-4 RBP4). RBP4, a 21 kDa protein of the ‘lipocalin superfamily’ and hought to be expressed mainly in the liver, is the sole transporter rotein for retinol (vitamin A) [3]. Although RBP4 was isolated from uman serum back in 1968, Kahn et al. only recently identified onsiderable proportions of circulating RBP4 to be released from dipocytes [4]. Using microarrays, they described RBP4 as a facor influencing systemic insulin sensitivity in experimental mouse odels. It was found that transgenic overexpression of human RBP4 nd injection of recombinant RBP4 decreased insulin sensitivity in ormal mice, and deletion of the RBP4 gene or normalization of BP4 concentrations in obese mice improved insulin sensitivity. lthough these studies confirmed that elevation of serum RBP4 oes in fact cause insulin resistance and hyperglycemia in expermental mouse models, subsequent findings in humans have been nconsistent and revealed that the mechanisms defined in genetcally altered mice do not translate easily to the clinical situation 5–8]. Hence, the role of RBP4 as a mediator of insulin resistance n humans is yet not clarified, and further studies are clearly waranted.

Comparing aortic stiffness in kidney transplant recipients, hemodialysis patients, and patients with chronic renal failure.

Pan CR, Schmaderer C, Roos M, von Eynatten M, Sollinger D, Lutz J, Heemann U, Baumann M. Comparing aortic stiffness in kidney transplant recipients, hemodialysis patients, and patients with chronic renal failure.u2028Clin Transplant 2011: 25: E463–E468.