Predicting hospital cost in CKD patients through blood chemistry values

<p>Abstract</p> <p>Background</p> <p>Controversy exists in predicting costly hospitalization in patients with chronic kidney disease and co-morbid conditions. We therefore tested associations between serum chemistry values and the occurrence of in-patient hospital costs over a thirteen month study period. Secondarily, we derived a linear combination of variables to estimate probability of such occurrences in any patient.</p> <p>Method</p> <p>We calculated parsimonious values for select variables associated with in-patient hospitalization and compared sensitivity and specificity of these models to ordinal staging of renal disease.</p> <p>Data from 1104 de-identified patients which included 18 blood chemistry observations along with complete claims data for all medical expenses.</p> <p>We employed multivariable logistic regression for serum chemistry values significantly associated with in-patient hospital costs exceeding $3,000 in any single month and contrasted those results to other models by ROC area curves.</p> <p>Results</p> <p>The linear combination of weighted Z scores for parathyroid hormone, phosphorus, and albumin correlated with in-patient hospital care at p < 0.005. ROC curves derived from weighted variables of age, eGFR, hemoglobin, albumin, creatinine, and alanine aminotransferase demonstrated significance over models based on non-weighted Z scores for those same variables or CKD stage alone. In contrast, the linear combination of weighted PTH, PO4 and albumin demonstrated better prediction, but not significance over non-weighted Z scores for PTH alone.</p> <p>Conclusion</p> <p>Further study is justified to explore indices that predict costly hospitalization. Such metrics could assist Accountable Care Organizations in evaluating risk adjusted compensation for providers.</p

Simple Shared Motifs (SSM) in conserved region of promoters: a new approach to identify co-regulation patterns

<p>Abstract</p> <p>Background</p> <p>Regulation of gene expression plays a pivotal role in cellular functions. However, understanding the dynamics of transcription remains a challenging task. A host of computational approaches have been developed to identify regulatory motifs, mainly based on the recognition of DNA sequences for transcription factor binding sites. Recent integration of additional data from genomic analyses or phylogenetic footprinting has significantly improved these methods.</p> <p>Results</p> <p>Here, we propose a different approach based on the compilation of Simple Shared Motifs (SSM), groups of sequences defined by their length and similarity and present in conserved sequences of gene promoters. We developed an original algorithm to search and count SSM in pairs of genes. An exceptional number of SSM is considered as a common regulatory pattern. The SSM approach is applied to a sample set of genes and validated using functional gene-set enrichment analyses. We demonstrate that the SSM approach selects genes that are over-represented in specific biological categories (Ontology and Pathways) and are enriched in co-expressed genes. Finally we show that genes co-expressed in the same tissue or involved in the same biological pathway have increased SSM values.</p> <p>Conclusions</p> <p>Using unbiased clustering of genes, Simple Shared Motifs analysis constitutes an original contribution to provide a clearer definition of expression networks.</p

INHIBITION OF PHOSPHOFRUCTOKINASE ACTIVITY IN PANCREATIC-ISLETS IN PHOSPHATE-DEPLETION

Phosphate depletion (PD) causes marked and significant reduction in glucose-induced insulin secretion by pancreatic islets. Certain data suggest that a defect in glucose metabolism, prior to the generation of glyceraldehyde-3-phosphate, by the islets is partly responsible for the impairment in insulin secretion. Phosphofructokinase-1 (PFK-1) is the enzyme that facilitates the conversion of fructose-6-phosphate to fructose-1,2-bisphosphate, a step in the glycolytic pathway that precedes the production of triose phosphates. It is, therefore, possible that PD impairs the activity of this enzyme and contributes to the defect in glucose metabolism by pancreatic islets. We studied the V(max) and K(m) of PFK-1 for fructose-6-phosphate in islets obtained from PD rats and pair-weighed (PW) animals fed the PD and normal diets, respectively, for 6 weeks. PD did not affect the V(max) of PFK-1 but the K(m) of the enzyme for fructose-6-phosphate was significantly (p < 0.01) higher in PD (0.364 +/- 0.056 mM) than in PW rats (0.244 +/- 0.019 mM). The data demonstrate that in PD (a) the affinity of PFK-1 for its substrate fructose-6-phosphate is reduced; (b) the combination of normal V(max) and high K(m) points toward the presence of a negative allosteric effector, and (c) the change in the activity of PFK-1 contributes to the defect in glucose metabolism by the pancreatic islets

MECHANISMS OF IMPAIRED INSULIN-SECRETION AFTER CHRONIC EXCESS OF PARATHYROID-HORMONE

Excess parathyroid hormone (PTH) in presence or absence of chronic renal failure impairs insulin release from pancreatic islets. This abnormality has been attributed to PTH-induced accumulation of Ca in the cytosol of the islets. Direct evidence for the latter phenomenon is lacking. This study examined the effect of chronic administration of PTH to rats with normal renal function on resting cytosolic Ca of the islets and evaluated the mechanisms through which a rise in resting cytosolic Ca may inhibit insulin secretion. After 42 days of PTH administration, glucose-induced insulin secretion was impaired, and this defect was corrected by the use of D-glyceraldehyde as secretagogue for insulin. Resting cytosolic Ca of islets from PTH-treated rats was markedly increased compared with that of islets from normal animals (288 ± 27.1 vs. 135 ± 3.7 nM, P < 0.01), and their content of ATP in the presence of both 2.8 and 16.7 mM D-glucose was reduced (2.8 mM D-glucose, 4.6 ± 0.17 vs. 6.0 ± 0.42 pmol/islet, P < 0.01; and 16.7 mM D-glucose, 6.9 ± 0.25 vs. 11.1 ± 0.95 pmol/islet, P < 0.01). D-Glyceraldehyde increased ATP content in islets of PTH-treated rats from 4.6 ± 0.17 to 8.8 ± 0.71 pmol/islet. Glucose uptake by the islets, their insulin content, and both the V(max) and the apparent K(m) for fructose 6-phosphate of phosphofructokinase 1 (EC 2.7.1.11) in PTH-treated rats were not different from normal. The two major cellular derangements in the islets of PTH-treated rats were a reduction in ATP content and a rise in resting cytosolic Ca. These two abnormalities may interfere with glucose metabolism by the islet and lead to impaired insulin secretion. Also, a reduced ATP content may cause impaired insulin release through its effect on ATP-dependent K channels

MECHANISM OF ORGAN DYSFUNCTION IN PHOSPHATE-DEPLETION - A CRITICAL ROLE FOR A RISE IN CYTOSOLIC CALCIUM

Phosphate depletion (PD) is associated with multiorgan dysfunction. it has been proposed that this phenomenon is due to two metabolic derangements: (a) there is a reduction in ATP content of cells and hence reduced availability of energy-rich phosphate compounds, and (b) there is a decrease in 2,3-diphosphoglycerate in red blood cells, a change that would increase the affinity of hemoglobin to oxygen resulting in tissue hypoxia. Recent studies have demonstrated that PD is associated with a significant elevation in basal levels of cytosolic calcium [Ca2+]i in many cells. This is due to an increased entry into and decreased extrusion of calcium out of cells. This rise in [Ca2+]i plays a major role in organ dysfunction in PD and in the genesis of decreased ATP content of cells

CHRONIC PARATHYROID-HORMONE EXCESS INVIVO INCREASES RESTING LEVELS OF CYTOSOLIC CALCIUM IN BRAIN SYNAPTOSOMES - STUDIES IN THE PRESENCE AND ABSENCE OF CHRONIC-RENAL-FAILURE

It has been suggested that excess parathyroid hormone (PTH) in chronic renal failure (CRF) or chronic administration of PTH to normal rats caused derangements in norepinephrine and phospholipid metabolism of brain synaptosomes, because of an increase in their resting levels of cytosolic calcium which may induce a decrease in synaptosomal content of ATP. In the study presented here, the resting levels of cytosolic calcium in brain synaptosomes were measured in six groups of rats including: (1) normal rats; (2) rats with CRF of 21-days duration; (3) normocalcemic parathyroidectomized rats with CRF of 21-days duration; (4) rats with CRF of 21-days duration treated with verapamil from day 1 of CRF; (5) normal rats treated with verapamil for 21 days; and (6) normal rats treated with PTH for 21 days. Resting levels of cytosolic calcium of brain synaptosomes of CRF rats (437 +/- 18.0 nM) and normal rats treated with PTH (428 +/- 5.6 nM) were significantly (P < 0.01) higher than those of normal rats (345 +/- 9.0 nM), normal rats treated with verapamil (354 +/- 8.7 nM), CRF rats treated with verapamil (361 +/- 12.9 nM), or CRF-parathyroidectomized rats (363 +/- 8.2 nM). There were no significant differences between the values of the last three groups of rats. The ATP content of brain synaptosomes of CRF rats (2.95 +/- 0.23 nmol/mg of protein) and normal rats treated with PTH (3.06 +/- 0.13 nmol/mg of protein) were significantly (P < 0.01) lower than that in normal rats (4.49 +/- 0.30 nmol/mg of protein), normal rats treated with verapamil (4.60 +/- 0.30 nmol/mg of protein), CRF rats treated with verapamil (4.05 +/- 0.25 nmol/mg of protein), or CRF-parathyroidectomized rats (4.03 +/- 0.22 nmol/mg of protein). There were no significant differences between the values of the last three groups of animals. The data demonstrate that chronic excess of PTH in the presence or absence of CRF is associated with significant elevations in the resting levels of cytosolic calcium of brain synaptosomes and significant reduction of their ATP content