Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD. METHODS: AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHRmKO (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD. RESULTS: PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared with either muscle from the PAD condition with normal renal function (P<0.05 for all 3 genes) or nonischemic controls. AHRmKO significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. CONCLUSIONS: These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.

Single-cell RNA sequencing reveals transdifferentiation of parathyroid chief cells into oxyphil cells in patients with uremic secondary hyperparathyroidism.

The parathyroid gland is one of the main organs that regulate calcium and phosphorus metabolism. It is mainly composed of chief cells and oxyphil cells. Oxyphil cell counts are low in the parathyroid glands of healthy adults but are dramatically increased in patients with uremia and secondary hyperparathyroidism (SHPT). Increased oxyphil cell counts are related to drug treatment resistance, but the origin of oxyphil cells and the mechanism of proliferation remain unknown. Herein, three types of parathyroid nodules (chief cell nodules, oxyphil cell nodules and mixed nodules, respectively) excised from parathyroid glands of uremic SHPT patients were used for single-cell RNA sequencing (scRNA-seq), other molecular biology studies, and transplantation into nude mice. Through scRNA-seq of parathyroid mixed nodules from three patients with uremic SHPT, we established the first transcriptomic map of the human parathyroid and found a chief-to-oxyphil cell transdifferentiation characterized by gradual mitochondrial enrichment associated with the uremic milieu. Notably, the mitochondrial enrichment and cellular proliferation of chief cell and oxyphil cell nodules decreased significantly after leaving the uremic milieu via transplantation into nude mice. Remarkably, the phenotype of oxyphil cell nodules improved significantly in the nude mice as characterized by decreased mitochondrial content and the proportion of oxyphil cells to chief cells. Thus, our study provides a comprehensive single-cell transcriptome atlas of the human parathyroid and elucidates the origin of parathyroid oxyphil cells and their underlying transdifferentiating mechanism. These findings enhance our understanding of parathyroid disease and may open new treatment perspectives for patients with chronic kidney disease.

Deletion of the aryl hydrocarbon receptor in endothelial cells improves ischemic angiogenesis in chronic kidney disease.

Chronic kidney disease (CKD) is a strong risk factor for peripheral artery disease (PAD) that is associated with worsened clinical outcomes. CKD leads to the accumulation of tryptophan metabolites that are associated with adverse limb events in PAD and are ligands of the aryl hydrocarbon receptor (AHR), which may regulate ischemic angiogenesis. To test if endothelial cell-specific deletion of the AHR (AHRecKO) alters ischemic angiogenesis and limb function in mice with CKD subjected to femoral artery ligation. Male AHRecKO mice with CKD displayed better limb perfusion recovery and enhanced ischemic angiogenesis compared with wild-type mice with CKD. However, the improved limb perfusion did not result in better muscle performance. In contrast to male mice, deletion of the AHR in female mice with CKD had no impact on perfusion recovery or angiogenesis. With the use of primary endothelial cells from male and female mice, treatment with indoxyl sulfate uncovered sex-dependent differences in AHR activating potential and RNA sequencing revealed wide-ranging sex differences in angiogenic signaling pathways. Endothelium-specific deletion of the AHR improved ischemic angiogenesis in male, but not female, mice with CKD. There are sex-dependent differences in Ahr activating potential within endothelial cells that are independent of sex hormones.NEW & NOTEWORTHY This study provides novel insights into the mechanisms by which chronic kidney disease worsens ischemic limb outcomes in an experimental model of peripheral artery disease. Deletion of the aryl hydrocarbon receptor (AHR) in the endothelium improved ischemic angiogenesis suggesting that AHR inhibition could be a viable therapeutic target; however, this effect was only observed in male mice. Subsequent analysis in primary endothelial cells reveals sex differences in Ahr activating potential independent of sex hormones.

Coupling capillary electrophoresis with mass spectrometry for the analysis of oxidized phospholipids in human high-density lipoproteins.

The oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) products in human high-density lipoproteins (HDLs) were investigated by low-flow capillary electrophoresis-mass spectrometry (low-flow CE-MS). To accelerate the optimization, native PAPC (n-PAPC) standard was first analyzed by a commercial CE instrument with a photodiode array detector. The optimal separation buffer contained 60% (v/v) acetonitrile, 40% (v/v) methanol, 20 mM ammonium acetate, 0.5% (v/v) formic acid, and 0.1% (v/v) water. The selected separation voltage and capillary temperature were 20 kV and 23°C. The optimal CE separation buffer was then used for the low-flow CE-MS analysis. The selected MS conditions contained heated capillary temperature (250°C), capillary voltage (10 V), and injection time (1 s). No sheath gas was used for MS. The linear range for n-PAPC was 2.5-100.0 µg/mL. The coefficient of determination (R2 ) was 0.9918. The concentration limit of detection was 1.52 µg/mL, and the concentration limit of quantitation was 4.60 µg/mL. The optimal low-flow CE-MS method showed good repeatability and sensitivity. The ox-PAPC products in human HDLs were determined based on the in vitro ox-PAPC products of n-PAPC standard. Twenty-one ox-PAPC products have been analyzed in human HDLs. Uremic patients showed significantly higher levels of 15 ox-PAPC products than healthy subjects.

The serum levels of gasdermin D in uremic patients and its relationship with the prognosis: a prospective observational cohort study.

OBJECTIVE: This study aimed to explore the serum levels of gasdermin D (GSDMD) in uremic (end-stage kidney disease, ESKD) patients and their correlation with vascular calcification (VC) and clinical results. METHODS: This prospective observational cohort study enrolled 213 ESKD patients who were undergoing regular maintenance hemodialysis (MHD) for > 3 months in our hospital from August 2019 to July 2022. The abdominal aortic calcification score (AACS) was used to assess the VC condition of patients with ESKD. Serum GSDMD, caspase-1, interleukin (IL)-6, IL-1ß, IL-18 and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay (ELISA). Demographic and clinical data were obtained. All patients were followed up for 1 year, and patients with major adverse cardiovascular events (MACE) were defined as having a poor prognosis. All data used SPSS 26.0 to statistical analyses. RESULTS: The serum total cholesterol (TC) levels of patients in the AACS > 4 group were significantly elevated compared with those in the AACS ≤ 4 group. In addition, ESKD patients with an AACS > 4 had significantly higher serum levels of GSDMD, caspase-1, IL-6, IL-18 and IL-1ß. Moreover, Pearson's analysis supported a positive correlation between GSDMD and caspase-1, IL-6, and IL-1ß. In addition, we found that GSDMD levels were positively correlated with the clinical data (AACS scores and serum TC levels) of patients with ERSD. Additionally, ROC curves showed that the serum levels of GSDMD could be a potential predictive biomarker of moderate/severe VC and prognosis in patients with ESKD. Finally, the results of logistic regression indicated that GSDMD and AACS scores were risk factors for poor prognosis in patients with ESKD. CONCLUSION: Serum GSDMD levels were remarkably elevated in patients with ESKD with moderate/severe calcification. In addition, serum levels of GSDMD could be a potential predictive biomarker of moderate/severe VC and prognosis in patients with ESKD.

Muscle plasticity is influenced by renal function and caloric intake through the FGF23-vitamin D axis.

Skeletal muscle, the main metabolic engine in the body of vertebrates, is endowed with great plasticity. The association between skeletal muscle plasticity and two highly prevalent health problems: renal dysfunction and obesity, which share etiologic links as well as many comorbidities, is a subject of great relevance. It is important to know how these alterations impact on the structure and function of skeletal muscle because the changes in muscle phenotype have a major influence on the quality of life of the patients. This literature review aims to discuss the influence of a nontraditional axis involving kidney, bone, and muscle on skeletal muscle plasticity. In this axis, the kidneys play a role as the main site for vitamin D activation. Renal disease leads to a direct decrease in 1,25(OH)2-vitamin D, secondary to reduction in renal functional mass, and has an indirect effect, through phosphate retention, that contributes to stimulate fibroblast growth factor 23 (FGF23) secretion by bone cells. FGF23 downregulates the renal synthesis of 1,25(OH)2-vitamin D and upregulates its metabolism. Skeletal production of FGF23 is also regulated by caloric intake: it is increased in obesity and decreased by caloric restriction, and these changes impact on 1,25(OH)2-vitamin D concentrations, which are decreased in obesity and increased after caloric restriction. Thus, both phosphate retention, that develops secondary to renal failure, and caloric intake influence 1,25(OH)2-vitamin D that in turn plays a key role in muscle anabolism.

Circulating Osteocalcin Fractions are Associated with Vascular Calcification and Mortality in Chronic Hemodialysis Patients.

BACKGROUND: Vascular calcification, a component of chronic kidney disease-mineral and bone disorder (CKD-MBD), is prevalent in patients with end-stage kidney disease (ESKD) and contributes to high mortality. However, the association between the blood level of total osteocalcin (OC) and vascular calcification and mortality remains inconclusive. We, therefore, investigated whether different OC fractions can serve as biomarkers of vascular calcification and mortality in the ESKD population. METHODS: This observational cohort study enrolled patients on maintenance hemodialysis. Plasma carboxylated OC (cOC), uncarboxylated OC (ucOC), and intact parathyroid hormone (PTH) were measured. The percentage of carboxylated OC (%cOC) was calculated as dividing cOC by total OC. The vascular calcification severity was defined by an aortic calcification grade. The patients were followed for three years and one month. RESULTS: A total of 184 patients were enrolled. In the multivariable logistic regression, plasma %cOC, but not cOC or ucOC, was independently associated with the severity of vascular calcification (OR 1.019, p = 0.036). A significant U-shaped correlation was found between plasma %cOC and PTH (p = 0.002). In the multivariable Cox regression, patients with higher plasma %cOC had a higher risk of mortality (quartiles Q4 versus Q1-Q3, HR 1.991 [95% CI: 1.036-3.824], p = 0.039). CONCLUSIONS: In patients undergoing chronic hemodialysis, plasma %cOC positively correlated with vascular calcification and exhibited a U-shaped correlation with PTH. Furthermore, a higher plasma %cOC was associated with increased mortality. These findings suggest that plasma %cOC may serve as a biomarker for CKD-MBD and a predictor of clinical outcomes in chronic hemodialysis patients.

Acute kidney injury in neurocritical care.

Approximately 20% of patients with acute brain injury (ABI) also experience acute kidney injury (AKI), which worsens their outcomes. The metabolic and inflammatory changes associated with AKI likely contribute to prolonged brain injury and edema. As a result, recognizing its presence is important for effectively managing ABI and its sequelae. This review discusses the occurrence and effects of AKI in critically ill adults with neurological conditions, outlines potential mechanisms connecting AKI and ABI progression, and highlights AKI management principles. Tailored approaches include optimizing blood pressure, managing intracranial pressure, adjusting medication dosages, and assessing the type of administered fluids. Preventive measures include avoiding nephrotoxic drugs, improving hemodynamic and fluid balance, and addressing coexisting AKI syndromes. ABI patients undergoing renal replacement therapy (RRT) are more susceptible to neurological complications. RRT can negatively impact cerebral blood flow, intracranial pressure, and brain tissue oxygenation, with effects tied to specific RRT methods. Continuous RRT is favored for better hemodynamic stability and lower risk of dialysis disequilibrium syndrome. Potential RRT modifications for ABI patients include adjusted dialysate and blood flow rates, osmotherapy, and alternate anticoagulation methods. Future research should explore whether these strategies enhance outcomes and if using novel AKI biomarkers can mitigate AKI-related complications in ABI patients.

Early clinical observation of supra-hemodiafiltration with endogenous reinfusion in the treatment of uremic pruritus.

BACKGROUND: To evaluate the clinical efficacy of supra-hemodiafiltration with endogenous reinfusion (Supra-HFR) for pruritus in uremic maintenance hemodialysis (HD) patients and explore the possible mechanism. METHODS: This study prospectively included 60 patients with uremia who underwent maintenance hemodialysis and developed pruritus. Patients were randomly divided into a study group (30 cases) and a control group (30 cases). Patients in the study group underwent dialysis once a week with Supra-HFR and twice a week with HD. The group received HD dialysis 3 times a week. Visual analog scales (VAS) scores, 5-D itch scale scores, and 12-Item Pruritus Severity Scale (12-PSS) were used to evaluate the itching degree of patients. Quality of life was assessed using KDTA and SF-36 scores. Blood levels of hypersensitive C-reactive protein, calcium ion (Ca2+), phosphorus ion (P3+ ), free parathyroid hormone (iPTH), and ß2-microglobulin (ß2-MG) were compared between the two groups before treatment and at follow-up 24 weeks after treatment. RESULTS: Before treatment, there was no significant difference in VAS, 5-D itch scale, and 12-PSS score between the study group and the control group (all p > 0.05). After 24 weeks of treatment, the VAS score of the study group (2.82 ± 0.91) was significantly lower than that of the control group (7.47 ± 1.32, p < 0.001), the 5-D itch scale score of the study group (9.47 ± 2.34) was significantly lower than that of the control group (18.53 ± 4.02, p < 0.001), the 12-PSS score of the study group (11.20 ± 1.81) was significantly lower than that of the control group (16.47 ± 2.09, p < 0.001). KDTA of the study group (64.17 ± 8.07 vs. 47.83 ± 13.46, p < 0.001) and SF-36 scores (65.37 ± 6.28 vs. 55.90 ± 14.28, p = 0.002) were significantly higher than that in the control group. The levels of hs-CRP, P3+ , iPTH, and ß2-MG in the study group after treatment were lower than those before treatment, and lower than those in the control group after treatment (all p < 0.05). CONCLUSIONS: The Supra-HFR can effectively reduce the itching symptoms of uremia patients and improve their quality of life.

Critical Appraisal of Limitations in the Current Definition/Classification of Uremic Toxins.

Progress in the identification and characterization of uremic retention solutes has refined our understanding of the pathophysiology of the uremic syndrome. Furthermore, the evolution of dialysis and other techniques designed to remove uremic retention solutes offers opportunities to provide a more personalized and targeted treatment for patients with chronic kidney disease (CKD) with an aim to improve outcomes. Considering these developments, a consensus report was recently published that readdressed the 2003 definition and classification of uremic toxins and formulated recommendations for future research to enhance the understanding of uremic retention solutes. In the present work, the authors of a work group that contributed to the consensus report provide a more detailed rationale for the recommendations related to their theme "Critical appraisal of limitations in the current definition/classification of uremic toxins." In summary, the authors propose that the current definition of uremic toxins should remain organized on hemodialysis strategies, membranes, and removal patterns since hemodialysis is the most frequently applied therapeutic strategy to reduce their concentration in advanced CKD. Nevertheless, the work group also acknowledges that any classification based on cutoff values and/or molecular spatial configurations is arbitrary and will likely need to be changed with therapeutic advancements. Furthermore, the current physicochemical classification might be extended to reflect the degree of toxicity of a specific toxin that is likely to support more personalized and targeted dialysis prescriptions and improve the outcomes for patients with CKD.

Induction of Vesicular Trafficking and JNK-Mediated Apoptotic Signaling in Mononuclear Leukocytes Marks the Immuno-Proteostasis Response to Uremic Proteins.

INTRODUCTION: Uremic retention solutes have been alleged to induce the apoptotic program of different cell types, including peripheral blood mononuclear leukocytes (PBL), which may contribute to uremic leukopenia and immune dysfunction. METHODS: The molecular effects of these solutes were investigated in uremic PBL (u-PBL) and mononuclear cell lines (THP-1 and K562) exposed to the high molecular weight fraction of uremic plasma (u-HMW) prepared by in vitro ultrafiltration with 50 kDa cut-off microconcentrators. RESULTS: u-PBL show reduced cell viability and increased apoptotic death compared to healthy control PBL (c-PBL). u-HMW induce apoptosis both in u-PBL and c-PBL, as well as in mononuclear cell lines, also stimulating cellular H2O2 formation and secretion, IRE1-α-mediated endoplasmic reticulum stress signaling, and JNK/cJun pathway activation. Also, u-HMW induce autophagy in THP-1 monocytes. u-PBL were characterized by the presence in their cellular proteome of the main proteins and carbonylation targets of u-HMW, namely albumin, transferrin, and fibrinogen, and by the increased expression of receptor for advanced glycation end-products, a scavenger receptor with promiscuous ligand binding properties involved in leukocyte activation and endocytosis. CONCLUSIONS: Large uremic solutes induce abnormal endocytosis and terminal alteration of cellular proteostasis mechanisms in PBL, including UPR/ER stress response and autophagy, ultimately activating the JNK-mediated apoptotic signaling of these cells. These findings describe the suicidal role of immune cells in facing systemic proteostasis alterations of kidney disease patients, a process that we define as the immuno-proteostasis response of uremia.

Implication of changes in xanthine oxidase activity following hemodialysis.

BACKGROUND: Xanthine oxidase activity has a key role in the development of oxidative stress and progression of cardiovascular diseases. However, the change of xanthine oxidase activity following hemodialysis and its prognostic impact remain uncertain. METHODS: We prospectively included hemodialysis patients who did not take any anti-hyperuricemic agents and measured their xanthine oxidase activity before and after the index hemodialysis. The impact of change in xanthine oxidase activity during hemodialysis on cardiovascular death were investigated. RESULTS: A total of 46 patients (median 72 years old, 29 men) were included. During hemodialysis, a common logarithm of xanthine oxidase activity decreased significantly from 1.16 (0.94, 1.27) to 1.03 (0.80, 1.20) (p < 0.01). Of them, xanthine oxidase activity remained unchanged or increased in 16 patients, who had a greater decrease in blood pressure and more hemoconcentration compared with others. Two-year survival from cardiovascular death was not significantly stratified by the changes in xanthine oxidase activity (p = 0.43). CONCLUSIONS: During hemodialysis, xanthine oxidase activity decreased among the overall cohort, whereas some patients experienced its increases, which might be associated with hypotension and hemoconcentration during hemodialysis. Further larger-scale studies are required to validate our findings and find clinical implication of change in xanthine oxidase activity during hemodialysis.

Knowledge, attitude, and practice of patients receiving maintenance hemodialysis regarding hemodialysis and its complications: a single-center, cross-sectional study in Nanjing.

BACKGROUND: Good knowledge of and attitudes toward hemodialysis and its complications might be expected to promote good practices and improve adherence. This study investigated, the knowledge, attitude, and practice of patients receiving hemodialysis regarding hemodialysis and its complications. METHODS: This cross-sectional study enrolled patients with uremia who were receiving hemodialysis at the Second Affiliated Hospital of Nanjing Medical University (China) between January 9, 2023, and January 16, 2023. A questionnaire was designed that included the following dimensions: demographic/clinical information, knowledge, attitude, and practice. Correlations between knowledge, attitude, and practice scores were evaluated by Pearson correlation analysis. RESULTS: The analysis included 493 patients (305 males, 61.87%). The average knowledge, attitude, and practice score was 19.33 ± 7.07 (possible range, 0-31), 28.77 ± 3.58 (possible range, 8-40), and 43.57 ± 6.53 (possible range, 11-55) points, respectively. A higher knowledge score was associated with younger age (P < 0.001), a higher education level (P < 0.001), and not living alone (P < 0.001), while a higher practice score was associated with a shorter history of hemodialysis (P < 0.001). There were positive correlations between the knowledge and practice scores (r = 0.220, P < 0.001) and between the attitude and practice scores (r = 0.453, P < 0.001), although the knowledge and attitude scores were not significantly correlated. CONCLUSIONS: The results provide important insights into the knowledge, attitudes, and practices of patients with uremia in Nanjing (China) regarding hemodialysis and its complications. These findings may facilitate education programs to improve self-care practices in patients receiving maintenance hemodialysis in Nanjing (China).

Association of Proximal Tubular Secretory Clearance with Long-Term Decline in Cognitive Function.

BACKGROUND: People with chronic kidney disease (CKD) are at high risk for cognitive impairment and progressive cognitive decline. Retention of protein-bound organic solutes that are normally removed by tubular secretion is hypothesized to contribute to cognitive impairment in CKD. METHODS: We followed 2362 participants who were initially free of cognitive impairment and stroke in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study. We estimated tubular secretory clearance by the 24-hour kidney clearances of eight endogenous solutes that are primarily eliminated by tubular secretion. CRIC study investigators assessed participants' cognitive function annually using the Modified Mini-Mental State (3MS) Examination. Cognitive decline was defined as a sustained decrease of more than five points in the 3MS score from baseline. Using Cox regression models adjusted for potential confounders, we analyzed associations between secretory solute clearances, serum solute concentrations, and cognitive decline. RESULTS: The median number of follow-up 3MS examinations was six per participant. There were 247 incident cognitive decline events over a median of 9.1 years of follow-up. Lower kidney clearances of five of the eight secretory solutes (cinnamoylglycine, isovalerylglycine, kynurenic acid, pyridoxic acid, and tiglylglycine) were associated with cognitive decline after adjustment for baseline eGFR, proteinuria, and other confounding variables. Effect sizes ranged from a 17% to a 34% higher risk of cognitive decline per 50% lower clearance. In contrast, serum concentrations of the solutes were not associated with cognitive decline. CONCLUSIONS: Lower kidney clearances of secreted solutes are associated with incident global cognitive decline in a prospective study of CKD, independent of eGFR. Further work is needed to determine the domains of cognition most affected by decreased secretory clearance and the mechanisms of these associations.

Carbamylation of Integrin α IIb ß 3: The Mechanistic Link to Platelet Dysfunction in ESKD.

BACKGROUND: Bleeding diatheses, common among patients with ESKD, can lead to serious complications, particularly during invasive procedures. Chronic urea overload significantly increases cyanate concentrations in patients with ESKD, leading to carbamylation, an irreversible modification of proteins and peptides. METHODS: To investigate carbamylation as a potential mechanistic link between uremia and platelet dysfunction in ESKD, we used liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to quantify total homocitrulline, and biotin-conjugated phenylglyoxal labeling and Western blot to detect carbamylated integrin α IIb ß 3 (a receptor required for platelet aggregation). Flow cytometry was used to study activation of isolated platelets and platelet-rich plasma. In a transient transfection system, we tested activity and fibrinogen binding of different mutated forms of the receptor. We assessed platelet adhesion and aggregation in microplate assays. RESULTS: Carbamylation inhibited platelet activation, adhesion, and aggregation. Patients on hemodialysis exhibited significantly reduced activation of α IIb ß 3 compared with healthy controls. We found significant carbamylation of both subunits of α IIb ß 3 on platelets from patients receiving hemodialysis versus only minor modification in controls. In the transient transfection system, modification of lysine 185 in the ß 3 subunit was associated with loss of receptor activity and fibrinogen binding. Supplementation of free amino acids, which was shown to protect plasma proteins from carbamylation-induced damage in patients on hemodialysis, prevented loss of α IIb ß 3 activity in vitro. CONCLUSIONS: Carbamylation of α IIb ß 3-specifically modification of the K185 residue-might represent a mechanistic link between uremia and dysfunctional primary hemostasis in patients on hemodialysis. The observation that free amino acids prevented the carbamylation-induced loss of α IIb ß 3 activity suggests amino acid administration during dialysis may help to normalize platelet function.

Beta Blockade Prevents Cardiac Morphological and Molecular Remodelling in Experimental Uremia.

Heart failure and chronic kidney disease (CKD) share several mediators of cardiac pathological remodelling. Akin to heart failure, this remodelling sets in motion a vicious cycle of progressive pathological hypertrophy and myocardial dysfunction in CKD. Several decades of heart failure research have shown that beta blockade is a powerful tool in preventing cardiac remodelling and breaking this vicious cycle. This phenomenon remains hitherto untested in CKD. Therefore, we set out to test the hypothesis that beta blockade prevents cardiac pathological remodelling in experimental uremia. Wistar rats had subtotal nephrectomy or sham surgery and were followed up for 10 weeks. The animals were randomly allocated to the beta blocker metoprolol (10 mg/kg/day) or vehicle. In vivo and in vitro cardiac assessments were performed. Cardiac tissue was extracted, and protein expression was quantified using immunoblotting. Histological analyses were performed to quantify myocardial fibrosis. Beta blockade attenuated cardiac pathological remodelling in nephrectomised animals. The echocardiographic left ventricular mass and the heart weight to tibial length ratio were significantly lower in nephrectomised animals treated with metoprolol. Furthermore, beta blockade attenuated myocardial fibrosis associated with subtotal nephrectomy. In addition, the Ca++- calmodulin-dependent kinase II (CAMKII) pathway was shown to be activated in uremia and attenuated by beta blockade, offering a potential mechanism of action. In conclusion, beta blockade attenuated hypertrophic signalling pathways and ameliorated cardiac pathological remodelling in experimental uremia. The study provides a strong scientific rationale for repurposing beta blockers, a tried and tested treatment in heart failure, for the benefit of patients with CKD.

A metabolomics approach identified toxins associated with uremic symptoms in advanced chronic kidney disease.

Uremic symptoms are common in patients with advanced chronic kidney disease, but the toxins that cause these symptoms are unknown. To evaluate this, we performed a cross-sectional study of the 12 month post-randomization follow-up visit of Modification of Diet in Renal Disease (MDRD) participants reporting uremic symptoms who also had available stored serum. We quantified 1,163 metabolites by liquid chromatography-tandem mass spectrometry. For each uremic symptom, we calculated a score as the severity multiplied by the number of days the symptom was experienced. We analyzed the associations of the individual symptom scores with metabolites using linear models with empirical Bayesian inference, adjusted for multiple comparisons. Among 695 participants, the mean measured glomerular filtration rate (mGFR) was 28 mL/min/1.73 m2. Uremic symptoms were more common in the subgroup of 214 patients with an mGFR under 20 mL/min/1.73 m2 (mGFR under 20 subgroup) than in the full group. For all metabolites with significant associations, the direction of the association was concordant in the full group and the subgroup. For gastrointestinal symptoms (bad taste, loss of appetite, nausea, and vomiting), eleven metabolites were associated with symptoms. For neurologic symptoms (decreased alertness, falling asleep during the day, forgetfulness, lack of pep and energy, and tiring easily/weakness), seven metabolites were associated with symptoms. Associations were consistent across sensitivity analyses. Thus, our proof-of-principle study demonstrates the potential for metabolomics to understand metabolic pathways associated with uremic symptoms. Larger, prospective studies with external validation are needed.

Uremic encephalopathy.

Uremic encephalopathy encompasses a wide range of central nervous system abnormalities associated with poor kidney function occurring with either progressive chronic kidney disease or acute kidney injury. The syndrome is likely caused by retention of uremic solutes, alterations in hormonal metabolism, changes in electrolyte and acid-base homeostasis, as well as changes in vascular reactivity, blood-brain barrier transport, and inflammation. There are no defining clinical, laboratory, or imaging findings, and the diagnosis is often made retrospectively when symptoms improve after dialysis or transplantation. The diagnosis is also made difficult because of the many confounding and overlapping conditions seen in patients with chronic kidney disease and acute kidney injury. Thus, institution of kidney replacement therapy should be considered as a trial to improve symptoms in the right clinical context. Neurological symptoms that do not improve after improvement in clearance should prompt a search for other explanations. Further knowledge linking possible uremic retention solutes with neurological symptoms is needed to better understand this syndrome as well as to develop more tailored treatments that aim to improve cognitive function.

Calciphylaxis: Part I. Diagnosis and pathology.

Calciphylaxis is an uncommon but devastating disorder characterized by vascular calcification and subsequent cutaneous tissue necrosis. This results in exquisitely painful and slow healing wounds that portend exceptionally high morbidity and mortality. The diagnosis of this condition can be complicated because there are no conclusive serologic, radiographic or visual signs that this disease is manifesting. The differential of tissue necrosis is broad, and identifying calciphylaxis requires an adroit understanding of the risk factors and physical signs that should raise suspicion of this condition. Reviews on this subject are uncommon and lack directed commentary from disease experts on the best diagnostic approach for patients suffering from this disease. The goal of this article is to update practicing dermatologists on the current standard of care for calciphylaxis.

Non-invasive myocardial work index contributes to early identification of impaired left ventricular myocardial function in uremic patients with preserved left ventricular ejection fraction.

BACKGROUND: Cardiac damage is the leading cause of death in uremic patients. This study aimed to evaluate the application of non-invasive myocardial work index (NIMWI) by echocardiography in assessing the left ventricular (LV) systolic function in uremic patients. METHODS: Twenty-six uremic patients and 27 age- and sex-matched healthy volunteers were enrolled in the study. Except for the conventional echocardiographic parameters, the LV myocardial work (MW) parameters including GWI (myocardial global work index), GCW (global constructive work), GWW (global wasted work), and GWE (global work efficiency) were calculated in study participants. Differences in MW parameters between the uremic and normal groups were compared by independent-sample t-test. Receiver operating characteristic (ROC) curves were constructed for MW parameters to detect abnormal LV systolic function in uremic patients. RESULTS: Compared with the normal group, GWW was significantly increased and GWE decreased in the uremic group (P < 0.05). Area under the curve (AUC) for GWE by the ROC analysis was 0.966. The best threshold, sensitivity and specificity values of GWE to detect abnormality of LV systolic function in uremic patients were 92.5%, 0.89 and 0.96, respectively. CONCLUSIONS: NIMWI may be applied to assess the global MW of uremic patients. The presence of reduced GWE can help identify impaired left ventricular myocardial function in uremic patients with preserved LV ejection fraction with a high sensitivity and specificity.