Gastrointestinal symptoms, inflammation and hypoalbuminemia in chronic kidney disease patients: a cross-sectional study

BACKGROUND: Few studies have focused on investigating hypoalbuminemia in patients during earlier stages of chronic kidney disease (CKD). In particular, little is known about the role of gastrointestinal (GI) symptoms. Our goal in this paper is to study how GI symptoms relate to serum albumin levels in CKD, especially in the context of and compared with inflammation. METHODS: We performed a cross-sectional study of 3599 patients with chronic kidney disease enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. All subjects were asked to complete the Modification of Diet in Renal Disease (MDRD) study patient symptom form. Our main predictor is GI symptom score. Serum level of C-reactive protein (CRP) was measured as well. Main outcome measures are serum albumin levels and prevalence of hypoalbuminemia. RESULTS: Of the participants assessed, mean serum albumin was 3.95 ± 0.46 g/dL; 12.7 % had hypoalbuminemia. Patients with lower estimated glomerular filtration rate (eGFR) were likely to have more GI symptoms (apparent at an eGFR <45 ml/min/1.73 m(2)). Patients with worse GI symptoms had lower dietary protein intake. GI symptoms, like inflammation, were risk factors for lower serum albumin levels. However, adding GI symptom score or CRP into the multivariable regression analysis, did not attenuate the association between lower eGFR and lower albumin or hypoalbuminemia. CONCLUSIONS: Increased prevalence of GI symptoms become apparent among CKD patients at relatively high eGFR levels (45 ml/min/1.73 m(2)), long before ESRD. Patients with more severe GI symptoms scores are more likely to have hypoalbuminemia. But our data do not support GI symptoms/decreased protein intake or inflammation as being the main determinants of serum albumin level in CKD patients. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12882-015-0209-z) contains supplementary material, which is available to authorized users

Deletion of PDK1 causes cardiac sodium current reduction in mice.

The AGC protein kinase family regulates multiple cellular functions. 3-phosphoinositide-dependent protein kinase-1 (PDK1) is involved in the pathogenesis of arrhythmia, and its downstream factor, Forkhead box O1 (Foxo1), negatively regulates the expression of the cardiac sodium channel, Nav1.5. Mice are known to die suddenly after PDK1 deletion within 11 weeks, but the underlying electrophysiological bases are unclear. Thus, the aim of this study was to investigate the potential mechanisms between PDK1 signaling pathway and cardiac sodium current.Using patch clamp and western blotting techniques, we investigated the role of the PDK1-Foxo1 pathway in PDK1 knockout mice and cultured cardiomyocytes. We found that PDK1 knockout mice undergo slower heart rate, prolonged QRS and QTc intervals and abnormal conduction within the first few weeks of birth. Furthermore, the peak sodium current is decreased by 33% in cells lacking PDK1. The phosphorylation of Akt (308T) and Foxo1 (24T) and the expression of Nav1.5 in the myocardium of PDK1-knockout mice are decreased, while the nuclear localization of Foxo1 is increased. The role of the PDK1-Foxo1 pathway in regulating Nav1.5 levels and sodium current density was verified using selective PDK1, Akt and Foxo1 inhibitors and isolated neonatal rat cardiomyocytes.These results indicate that PDK1 participates in the dysregulation of electrophysiological basis by regulating the PDK1-Foxo1 pathway, which in turn regulates the expression of Nav1.5 and cardiac sodium channel function

Western blot analysis of the <i>PDK1</i> signaling pathway.

<p>A) Western blot analysis was performed to assess levels of the indicated of proteins and phosphoproteins in <i>PDK1</i>^F/F control and <i>PDK1</i>^F/F αMHC-Cre knockout mice. B) Expression of total and phosphorylated Akt and Foxo1 was assessed after treatment of cardiomyocytes from neonatal rats with vehicle control (DMSO) or <i>PDK</i> inhibitor (GSK 234470). C) The expression of Nav1.5 in rat cardiomyocytes was assessed after treatment with DMSO, GSK 234470 (GSK), the Foxo1 inhibitor AS 1842856 (AS) or a combination of the two drugs. D-E) Nuclear Foxo1 expression was assessed for cardiomyocytes isolated from control and <i>PDK</i> deletion mice (D) or neonatal rat cardiomyocytes before and after treatment with <i>PDK</i> inhibitor (E). β-actin was tested as a loading control for total cellular protein levels, and histone H3 was tested as a loading control for nuclear protein levels. The mean +SD values from each group were normalized to 1.0 in the control mice. All drugs were dissolved in DMSO and added into cell culture media for 48h before the experiments. In each group, three bands of proteins represented three different hearts. *<i>P <0</i>.<i>05</i>.</p

Electrocardiography of <i>PDK1</i> deletion mice.

<p>A) ECGs in lead II Representative ECG traces are shown for a control <i>PDK1</i>^<i>F/F</i> mouse (top) at 8 weeks and a <i>PDK1</i>^<i>F/F</i> αMHC-Cre knockout mouse (bottom) at 8 weeks. B) Slower heart rate and prolongation of QRS and QTc intervals in <i>PDK1</i>^<i>F/F</i> αMHC-Cre mice at 8 weeks (n = 6). *<i>P</i> <0.05. C) Abnormal conduction in mice at 11 weeks. The trace is representative of results from 3 out of 4 <i>PDK1</i>>^<i>F/F</i> αMHC-Cre knockout mice.</p

Patch clamping in cardiomyocytes from mice lacking <i>PDK1</i>.

<p>(A-D) Sodium current recording in <i>PDK1</i>^<i>F/F</i> control and <i>PDK1</i>^<i>F/F</i>αMHC-Cre knockout mice at 8 and 11 weeks. E) Current-voltage relationship for mice at different weeks. F) Suppression of sodium current in mice lacking <i>PDK1</i>. G) Voltage dependence of activation. H) Voltage dependence of inactivation. I) Time-dependent recovery for sodium channel. (For cardiomyocytes, n = 13 to 32; for cells from mice, n = 2 to 3 for each group) *<i>P</i> <0.05</p

Tauopathy-associated PERK alleles are functional hypomorphs that increase neuronal vulnerability to ER stress.

Tauopathies are neurodegenerative diseases characterized by tau protein pathology in the nervous system. EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), also known as PERK (protein kinase R-like endoplasmic reticulum kinase), was identified by genome-wide association study as a genetic risk factor in several tauopathies. PERK is a key regulator of the Unfolded Protein Response (UPR), an intracellular signal transduction mechanism that protects cells from endoplasmic reticulum (ER) stress. PERK variants had previously been identified in Wolcott-Rallison Syndrome, a rare autosomal recessive metabolic disorder, and these variants completely abrogated the function of PERK's kinase domain or prevented PERK expression. In contrast, the PERK tauopathy risk variants were distinct from the Wolcott-Rallison variants and introduced missense alterations throughout the PERK protein. The function of PERK tauopathy variants and their effects on neurodegeneration are unknown. Here, we discovered that tauopathy-associated PERK alleles showed reduced signaling activity and increased PERK protein turnover compared to protective PERK alleles. We found that iPSC-derived neurons carrying PERK risk alleles were highly vulnerable to ER stress-induced injury with increased tau pathology. We found that chemical inhibition of PERK in human iPSC-derived neurons also increased neuronal cell death in response to ER stress. Our results indicate that tauopathy-associated PERK alleles are functional hypomorphs during the UPR. We propose that reduced PERK function leads to neurodegeneration by increasing neuronal vulnerability to ER stress-associated damage. In this view, therapies to enhance PERK signaling would benefit at-risk carriers of hypomorphic alleles