Renal cell therapy is associated with dynamic and individualized responses in patients with acute renal failure

BACKGROUND: Renal cell therapy in conjunction with continuous hemofiltration techniques may provide important cellular metabolic activities to patients with acute renal failure (ARF) and may thereby change the natural history of this disorder. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) human renal proximal tubule cells provides an opportunity to evaluate this form of therapy in patients with ARF in the intensive care unit. METHODS: Nine patients with ARF and multi-organ systems failure (MOSF) have been treated so far with a tissue-engineered kidney in an FDA-approved Phase I/II clinical study currently underway. Acute physiologic parameters and serum cytokine levels were assessed before, during and after treatment with a bioartificial kidney. RESULTS: Use of the RAD in this clinical setting demonstrates maintenance of cell viability and functionality. Cardiovascular stability appears to be maintained during RAD treatment. Human tubule cells in the RAD demonstrated differentiated metabolic and endocrinologic activity. Acute physiologic and plasma cytokine data demonstrate that renal cell therapy is associated with rapid and variable responses in patients with ARF and MOSF. CONCLUSION: The initial clinical experience with the bioartificial kidney and the RAD suggests that renal tubule cell therapy may provide a dynamic and individualized treatment program as assessed by acute physiologic and biochemical indices.     

Blood leukocytes recapitulate diabetogenic peptide–MHC-II complexes displayed in the pancreatic islets

Assessing the self-peptides presented by susceptible major histocompatibility complex (MHC) molecules is crucial for evaluating the pathogenesis and therapeutics of tissue-specific autoimmune diseases. However, direct examination of such MHC-bound peptides displayed in the target organ remains largely impractical. Here, we demonstrate that the blood leukocytes from the nonobese diabetic (NOD) mice presented peptide epitopes to autoreactive CD4 T cells. These peptides were bound to the autoimmune class II MHC molecule (MHC-II) I-A^g7 and originated from insulin B-chain and C-peptide. The presentation required a glucose challenge, which stimulated the release of the insulin peptides from the pancreatic islets. The circulating leukocytes, especially the B cells, promptly captured and presented these peptides. Mass spectrometry analysis of the leukocyte MHC-II peptidome revealed a series of β cell–derived peptides, with identical sequences to those previously identified in the islet MHC-II peptidome. Thus, the blood leukocyte peptidome echoes that found in islets and serves to identify immunogenic peptides in an otherwise inaccessible tissue.     

Network remodeling of intramural coronary resistance arteries in the aged rat: A statistical analysis of geometry

AimsTo identify the geometrical alterations in the age-remodeled rat coronary artery network and to develop a useful technique to analyze network properties in the rat heart.Methods and resultsWe analyzed the networks of the left anterior descendent coronary arteries on in situ perfused hearts of young (3 months) and old (18 months) male rats. All segments and branching over >80 μm diameter were analyzed using 50 μm long cylindrical ring units of the networks. Arterial widening and paucity, increased tortuosity were typical features in the old network. In addition, axis angles deviated more from the mother branches in the old, whereas the diameters of daughter branches fit the Murray law in both groups. The detected changes in the old network resulted in a longer blood flow route for the same direct distance.ConclusionWe developed a useful method to investigate arterial network property changes in the rat heart. Ageing resulted in longer, more tortuous flow route in the LAD network that might be hemodynamically disadvantageous.     

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.METHODS. We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).RESULTS. Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.CONCLUSION. These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00990808","term_id":"NCT00990808"}}NCT00990808.FUNDING. Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).