The relevance of geriatric assessments on the association between chronic kidney disease stages and mortality among older people: a secondary analysis of a multicenter cohort study

Background: age-adapted definition of chronic kidney disease (CKD) does not take individual risk factors into account. We aimed at investigating whether functional impairments influence CKD stage at which mortality increases among older people. Methods: our series consisted of 2,372 outpatients aged 75 years or more enrolled in a multicentre international prospective cohort study. The study outcome was 24-month mortality. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Geriatric assessments included handgrip strength, short physical performance battery (SPPB), cognitive impairment, dependency in basic activities of daily living (BADL) and risk of malnutrition. Analysis was carried out by Cox regression, before and after stratification by individual functional impairments. Survival trees including kidney function and functional impairments were also investigated, and their predictivity assessed by C-index. Results: overall, mortality was found to increase starting from eGFR = 30-44.9 ml/min/1.73 m2 (hazard ratio [HR] = 3.28, 95% confidence interval [CI] = 1.81-5.95) to ACR = 30-300 mg/g (HR = 1.96, 95%CI = 1.23-3.10). However, in survival trees, an increased risk of mortality was observed among patients with impaired handgrip and eGFR = 45-59.9 ml/min/1.73 m2, as well as patients with ACR < 30 mg/g and impaired handgrip and SPPB. Survival tree leaf node membership had greater predictive accuracy (C-index = 0.81, 95%CI = 0.78-0.84 for the eGFR survival tree and C-index = 0.77, 95%CI = 0.71-0.81 for the ACR survival tree) in comparison with that of individual measures of kidney function. Conclusions: physical performance helps to identify a proportion of patients at an increased risk of mortality despite a mild-moderate impairment in kidney function and improves predictive accuracy of individual measures of kidney function

Biomarkers of Sarcopenia in Clinical Trials—Recommendations from the International Working Group on Sarcopenia

Sarcopenia, the age-related skeletal muscle decline, is associated with relevant clinical and socioeconomic negative outcomes in older persons. The study of this phenomenon and the development of preventive/therapeutic strategies represent public health priorities. The present document reports the results of a recent meeting of the International Working Group on Sarcopenia (a task force consisting of geriatricians and scientists from academia and industry) held on June 7–8, 2011 in Toulouse (France). The meeting was specifically focused at gaining knowledge on the currently available biomarkers (functional, biological, or imaging-related) that could be utilized in clinical trials of sarcopenia and considered the most reliable and promising to evaluate age-related modifications of skeletal muscle. Specific recommendations about the assessment of aging skeletal muscle in older people and the optimal methodological design of studies on sarcopenia were also discussed and finalized. Although the study of skeletal muscle decline is still in a very preliminary phase, the potential great benefits derived from a better understanding and treatment of this condition should encourage research on sarcopenia. However, the reasonable uncertainties (derived from exploring a novel field and the exponential acceleration of scientific progress) require the adoption of a cautious and comprehensive approach to the subject

Structural basis of multivalent binding to wheat germ agglutinin.

The inhibition of carbohydrate-protein interactions by tailored multivalent ligands is a powerful strategy for the treatment of many human diseases. Crucial for the success of this approach is an understanding of the molecular mechanisms as to how a binding enhancement of a multivalent ligand is achieved. We have synthesized a series of multivalent N-acetylglucosamine (GlcNAc) derivatives and studied their interaction with the plant lectin wheat germ agglutinin (WGA) by an enzyme-linked lectin assay (ELLA) and X-ray crystallography. The solution conformation of one ligand was determined by NMR spectroscopy. Employing a GlcNAc carbamate motif with alpha-configuration and by systematic variation of the spacer length, we were able to identify divalent ligands with unprecedented high WGA binding potency. The best divalent ligand has an IC(50) value of 9.8 microM (ELLA) corresponding to a relative potency of 2350 (1170 on a valency-corrected basis, i.e., per mol sugar contained) compared to free GlcNAc. X-ray crystallography of the complex of WGA and the second best, closely related divalent ligand explains this activity. Four divalent molecules simultaneously bind to WGA with each ligand bridging adjacent binding sites. This shows for the first time that all eight sugar binding sites of the WGA dimer are simultaneously functional. We also report a tetravalent neoglycopeptide with an IC(50) value of 0.9 microM being 25,500 times higher than that of GlcNAc (6400 times per contained sugar) and the X-ray structure analysis of its complex with glutaraldehyde-cross-linked WGA. Comparison of the crystal structure and the solution NMR structure of the neoglycopeptide as well as results from the ELLA suggest that the conformation of the glycopeptide in solution is already preorganized in a way supporting multivalent binding to the protein. Our findings show that bridging adjacent protein binding sites by multivalent ligands is a valid strategy to find high-affinity protein ligands and that even subtle changes of the linker structure can have a significant impact on the binding affinity