Relation of early-stage renal insufficiency and cardiac structure and function in a large population of asymptomatic Asians: a cross-sectional cohort analysis.

Background: Few studies have addressed early-stage kidney disease and preclinical cardiac structural and functional abnormalities from a large-scale Asian population. Further, the extent to which measures of myocardial function and whether these associations may vary by testing various formulas of renal insufficiency remains largely unexplored. Objective: To explore the associations among renal function, proteinuria, and left ventricular (LV) structural and diastolic functional alterations. Design: A cross-sectional, retrospective cohort study. Setting: Registered data from a cardiovascular health screening program at MacKay Memorial Hospital from June 2009 to December 2012. Participants: Asymptomatic individuals. Measurements: Renal function was evaluated in terms of estimated glomerular filtration rate (eGFR) by both MDRD and CKD-EPI formulas and severity of proteinuria, which were further related to cardiac structure, diastolic function (including LV e' by tissue Doppler), and circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) level. Results: Among 4942 participants (65.8% men, mean age 49.4 ± 11.2 years), the mean CKD-EPI/MDRD eGFR was 90.6 ± 15.7 and 88.5 ± 16.9 ml/min/1.73m2, respectively. Lower eGFR, estimated either by the MDRD or CKD-EPI method, and higher proteinuria were significantly associated with lower LV e' and higher NT-proBNP (all p<0.05) even after adjusting for clinical covariates. In general, lower eGFR estimated by CKD-EPI and MDRD displayed similar impacts on worsening e' and NT-proBNP, rather than E/e', in multivariate models. Finally, lower LV e' or higher composite diastolic score, rather than E/e', demonstrated remarkable interaction with eGFR level estimated by either CKD-EPI or MDRD on circulating NT-proBNP level (p interaction <0.05). Limitations: Proteinuria was estimated using a urine dipstick rather than more accurately by the urine protein-to-creatinine ratio. Also, pertaining drug history and clinical hard outcomes were lacking. Conclusion: Both clinical estimate of renal insufficiency by eGFR or proteinuria, even in a relatively early clinical stage, were tightly linked to impaired cardiac diastolic relaxation and circulating NT-proBNP level. Elevation of NT-proBNP with worsening renal function may be influenced by impaired myocardial relaxation.

S-Nitrosylation of Tissue Transglutaminase in Modulating Glycolysis, Oxidative Stress, and Inflammatory Responses in Normal and Indoxyl-Sulfate-Induced Endothelial Cells.

Circulating uremic toxin indoxyl sulfate (IS), endothelial cell (EC) dysfunction, and decreased nitric oxide (NO) bioavailability are found in chronic kidney disease patients. NO nitrosylates/denitrosylates a specific protein's cysteine residue(s), forming S-nitrosothios (SNOs), and the decreased NO bioavailability could interfere with NO-mediated signaling events. We were interested in investigating the underlying mechanism(s) of the reduced NO and how it would regulate the S-nitrosylation of tissue transglutaminase (TG2) and its substrates on glycolytic, redox and inflammatory responses in normal and IS-induced EC injury. TG2, a therapeutic target for fibrosis, has a Ca2+-dependent transamidase (TGase) that is modulated by S-nitrosylation. We found IS increased oxidative stress, reduced NADPH and GSH levels, and uncoupled eNOS to generate NO. Immunoblot analysis demonstrated the upregulation of an angiotensin-converting enzyme (ACE) and significant downregulation of the beneficial ACE2 isoform that could contribute to oxidative stress in IS-induced injury. An in situ TGase assay demonstrated IS-activated TG2/TGase aminylated eNOS, NFkB, IkBα, PKM2, G6PD, GAPDH, and fibronectin (FN), leading to caspases activation. Except for FN, TGase substrates were all differentially S-nitrosylated either with or without IS but were denitrosylated in the presence of a specific, irreversible TG2/TGase inhibitor ZDON, suggesting ZDON-bound TG2 was not effectively transnitrosylating to TG2/TGase substrates. The data suggest novel roles of TG2 in the aminylation of its substrates and could also potentially function as a Cys-to-Cys S-nitrosylase to exert NO's bioactivity to its substrates and modulate glycolysis, redox, and inflammation in normal and IS-induced EC injury.

Effect of Low Protein Diet Supplemented with Ketoanalogs on Endothelial Function and Protein-Bound Uremic Toxins in Patients with Chronic Kidney Disease.

Studies have demonstrated that a low-protein diet supplemented with ketoanalogs (KAs) could significantly retard progression of renal function in patients with chronic kidney disease (CKD) stages 3-5. However, its effects on endothelial function and serum levels of protein-bound uremic toxins remain elusive. Therefore, this study explored whether a low-protein diet (LPD) supplemented with KAs affects kidney function, endothelial function, and serum uremic toxin levels in a CKD-based cohort. In this retrospective cohort, we enrolled 22 stable CKD stage 3b-4 patients on LPD (0.6-0.8 g/day). Patients were categorized into control (LPD only) and study groups (LPD + KAs 6 tab/day). Serum biochemistry, total/free indoxyl sulfate (TIS/FIS), total/free p-cresyl sulfate (TPCS/FPCS), and flow-mediated dilation (FMD) were measured before and after 6 months of KA supplementation. Before the trial, there were no significant differences in kidney function, FMD, or uremic toxin levels between the control and study groups. When compared with the control group, the paired t-test showed a significant decrease in TIS and FIS (all p < 0.05) and a significant increase in FMD, eGFR, and bicarbonate (all p < 0.05). In multivariate regression analysis, an increase in FMD (p < 0.001) and a decrease in FPCS (p = 0.012) and TIS (p < 0.001) remained persistent findings when adjusted for age, systolic blood pressure (SBP), sodium, albumin, and diastolic blood pressure (DBP). LPD supplemented with KAs significantly preserves kidney function and provides additional benefits on endothelial function and protein-bound uremic toxins in patients with CKD.

Prediction of Intradialytic Blood Pressure Variation Based on Big Data.

INTRODUCTION: Cardiovascular (CV) events are the major cause of morbidity and mortality associated with blood pressure (BP) in hemodialysis (HD) patients. BP varies significantly during HD treatment, and the dramatic variation in BP is a well-recognized risk factor for increased mortality. The development of an intelligent system capable of predicting BP profiles for real-time monitoring is important. Our aim was to build a web-based system to predict changes in systolic BP (SBP) during HD. METHODS: In this study, dialysis equipment connected to the Vital Info Portal gateway collected HD parameters that were linked to demographic data stored in the hospital information system. There were 3 types of patients: training, test, and new. A multiple linear regression model was built using the training group with SBP change as the dependent variable and dialysis parameters as the independent variables. We tested the model's performance on test and new patient groups using coverage rates with different thresholds. The model's performance was visualized using a web-based interactive system. RESULTS: A total of 542,424 BP records were used for model building. The accuracy was greater than 80% in the prediction error range of 15%, and 20 mm Hg of true SBP in the test and new patient groups for the model of SBP changes suggested the good performance of our prediction model. In the analysis of absolute SBP values (5, 10, 15, 20, and 25 mm Hg), the accuracy of the SBP prediction increased as the threshold value increased. DISCUSSION: This databae supported our prediction model in reducing the frequency of intradialytic SBP variability, which may help in clinical decision-making when a new patient receives HD treatment. Further investigations are needed to determine whether the introduction of the intelligent SBP prediction system decreases the incidence of CV events in HD patients.

Studying the Roles of the Renin-Angiotensin System in Accelerating the Disease of High-Fat-Diet-Induced Diabetic Nephropathy in a db/db and ACE2 Double-Gene-Knockout Mouse Model.

Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.

Transforming growth factor-ß1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells.

BACKGROUND: Renal erythropoietin (EPO)-producing (REP) cells produce EPO through hypoxia-inducible factor (HIF) 2α-activated gene transcription. Insufficient EPO production leads to anemia in patients with chronic kidney disease. Although recombinant EPO is effective to improve anemia, no reliable REP cell lines limit further progress of research and development of novel treatment. METHODS: We screened Epo mRNA expression in mouse fibroblast cell lines. Small interfering RNA specific for HIF1α or HIF2α was transfected to study Epo expression in C3H10T1/2 cells. The effect of transforming growth factor-ß1 (TGF-ß1) on HIF-EPO axis was studied in C3H10T1/2 cells and mice. RESULTS: Similar to mouse REP pericytes, C3H10T1/2 cells differentiated to α-smooth muscle actin+ myofibroblasts after exposure to TGF-ß1. Specific HIF knockdown demonstrated the role of HIF2α in hypoxia-induced Epo expression. Sustained TGF-ß1 exposure increased neither DNA methyltransferase nor methylation of Epas1 and Epo genes. However, TGF-ß1 repressed HIF2α-encoding Epas1 promptly through activating activin receptor-like kinase-5 (ALK5), thereby decreasing Epo induction by hypoxia and prolyl hydroxylase domain inhibitor roxadustat. In mice with pro-fibrotic injury induced by ureteral obstruction, upregulation of Tgfb1 was accompanied with downregulation of Epas1 and Epo in injured kidneys and myofibroblasts, which were reversed by ALK5 inhibitor SB431542. CONCLUSION: C3H10T1/2 cells possessed the property of HIF2α-dependent Epo expression in REP pericytes. TGF-ß1 induced not only the transition to myofibroblasts but also a repressive effect on Epas1-Epo axis in C3H10T1/2 cells. The repressive effect of TGF-ß1 on Epas1-Epo axis was confirmed in REP pericytes in vivo. Inhibition of TGF-ß1-ALK5 signaling might provide a novel treatment to rescue EPO expression in REP pericytes of injured kidney.

Association between regional economic status and renal recovery of dialysis-requiring acute kidney injury among critically ill patients.

The association between regional economic status and the probability of renal recovery among patients with dialysis-requiring AKI (AKI-D) is unknown. The nationwide prospective multicenter study enrolled critically ill adult patients with AKI-D in four sampled months (October 2014, along with January, April, and July 2015) in Taiwan. The regional economic status was defined by annual disposable income per capita (ADIPC) of the cities the hospitals located. Among the 1,322 enrolled patients (67.1 ± 15.5 years, 36.2% female), 833 patients (63.1%) died, and 306 (23.1%) experienced renal recovery within 90 days following discharge. We categorized all patients into high (n = 992) and low economic status groups (n = 330) by the best cut-point of ADIPC determined by the generalized additive model plot. By using the Fine and Gray competing risk regression model with mortality as a competing risk factor, we found that the independent association between regional economic status and renal recovery persisted from model 1 (no adjustment), model 2 (adjustment to basic variables), to model 3 (adjustment to basic and clinical variables; subdistribution hazard ratio, 1.422; 95% confidence interval, 1.022-1.977; p = 0.037). In conclusion, high regional economic status was an independent factor for renal recovery among critically ill patients with AKI-D.

CharXgen-Activated Bamboo Charcoal Encapsulated in Sodium Alginate Microsphere as the Absorbent of Uremic Toxins to Retard Kidney Function Deterioration.

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are two protein bound uraemic toxins accumulated in chronic kidney disease (CKD) and associated with adverse outcomes. The purpose of this study isto evaluate the effect of the new activated charcoal, CharXgen, on renal function protection and lowering serum uraemic toxins in CKD animal model. The physical character of CharXgen was analyzed before and after activation procedure by Scanning Electron Microscope (SEM) and X-ray diffractometer (XRD). The effect of CharXgen on biochemistry and lowering uremic toxins was evaluated by in vitro binding assay and CKD animal model. CharXgen have high interior surface area analyzed by SEM and XRD and have been produced from local bamboo after an activation process. CharXgen was able to effectively absorb IS, p-cresol and phosphate in an in vitro gastrointestinal tract simulation study. The animal study showed that CharXgen did not cause intestine blackening. Serum albuminand liver function did not change after feeding with CharXgen. Moreover, renal function was improved in CKD rats fed with CharXgen as compared to the CKD group, and there were no significant differences in the CKD and the CKD + AST-120 groups. Serum IS and PCS were higher in the CKD group and lower in rats treated with CharXgen and AST-120. In rats treated with CharXgen, Fibroblast growth factor 23 was significantly decreased as compared to the CKD group. This change cannot be found in rats fed with AST-120.It indicates that CharXgen is a new safe and non-toxic activated charcoal having potential in attenuating renal function deterioration and lowering protein-bound uraemic toxins. Whether the introduction of this new charcoal could further have renal protection in CKD patients will need to be investigated further.

Osteocalcin is an Independent Predictor for Hungry Bone Syndrome After Parathyroidectomy.

BACKGROUND: Hungry bone syndrome is characterized by prolonged and severe hypocalcemia following parathyroidectomy. Previously, we reported that preoperative alkaline phosphatase is a major factor predicting prolonged hospital stay. Nonetheless, some patients with low alkaline phosphatase levels presented with hungry bone syndrome, suggesting that additional factors may play a role. METHODS: From September 2010 to December 2017, consecutive dialysis patients who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Length of hospital stay was used as a surrogate marker for postoperative bone hunger. RESULTS: A total of 260 patients were included in the study. The median postoperative hospital stay was 3 days, and 69 (27%) patients had a stay longer than 3 days. Multivariate logistic regression analysis revealed that alkaline phosphatase (odds ratio [OR] = 1.005), osteocalcin (OR = 1.001), and subtotal parathyroidectomy (OR = 0.061) were associated with prolonged hospital stay. Multivariate linear regression analysis indicated that age (ß = - 0.170), alkaline phosphatase (ß = 0.430), and osteocalcin (ß = 0.166) were correlated with the length of stay. After surgery, the median osteocalcin level increased from 264 to 478 ng/mL (P < 0.001). CONCLUSIONS: Alkaline phosphatase is the main predictor of hungry bone syndrome after parathyroidectomy, and preoperative osteocalcin is an additional independent predictor. Patients with a high osteocalcin level may prone to have a higher demand for calcium supplementation.

Dataset supporting blood pressure prediction for the management of chronic hemodialysis.

Hemodialysis (HD) is a treatment given to patients with renal failure. Notable treatment-related complications include hypotension, cramps, insufficient blood flow, and arrhythmia. Most complications are associated with unstable blood pressure during HD. Physicians are devoted to seeking solutions to prevent or lower the incidence of possible complications. With advances in technology, big data have been obtained in various medical fields. The accumulated dialysis records in each HD session can be gathered to obtain big HD data with the potential to assist HD staff in increasing patient wellbeing. We generated a large stream of HD parameters collected from dialysis equipment associated with the Vital Info Portal gateway and correlated with the demographic data stored in the hospital information system from each HD session. We expect that the application of HD big data will greatly assist HD staff in treating intradialytic hypotension, setting optimal dialysate parameters, and even developing an intelligent early-warning system as well as providing individualized suggestions regarding dialysis settings in the future.

Increasing Age Hinders the Decline in B-Type Natriuretic Peptide Following Parathyroidectomy in Dialysis Patients.

BACKGROUND/AIM: Parathyroidectomy has beneficial effects on all-cause and cardiovascular mortality in patients with uncontrolled hyperparathyroidism. B-Type natriuretic peptide (BNP) correlates with the severity of heart failure. We aimed to investigate whether parathyroidectomy modulates the BNP levels in dialysis patients. PATIENTS AND METHODS: Patients who underwent surgical intervention for hyperparathyroidism were included. The serum BNP levels were determined before parathyroidectomy and during follow-up. RESULTS: The preoperative and postoperative BNP levels were 499±561 and 453±442 pg/ml, respectively (p=0.82). The baseline BNP level was positively correlated with weakness and headache, but not biochemical parameters. In multivariate analysis, age (odds ratio=0.837) and preoperative symptom score (odds ratio=0.935) were independent predictors for the postoperative decline in BNP levels Conclusion: The serum BNP levels may increase or decrease after parathyroidectomy. Younger age and lower symptom burden are associated with decline in BNP levels.

The Paradoxical Role of Uric Acid in Osteoporosis.

Because of its high prevalence worldwide, osteoporosis is considered a serious public health concern. Many known risk factors for developing osteoporosis have been identified and are crucial if planning health care needs. Recently, an association between uric acid (UA) and bone fractures had been explored. Extracellular UA exhibits antioxidant properties by effectively scavenging free radicals in human plasma, but this benefit might be disturbed by the hydrophobic lipid layer of the cell membrane. In contrast, intracellular free oxygen radicals are produced during UA degradation, and superoxide is further enhanced by interacting with NADPH oxidase. This intracellular oxidative stress, together with inflammatory cytokines induced by UA, stimulates osteoclast bone resorption and inhibits osteoblast bone formation. UA also inhibits vitamin D production and thereby results in hyper-parathyroidism, which causes less UA excretion in the intestines and renal proximal tubules by inhibiting the urate transporter ATP-binding cassette subfamily G member 2 (ABCG2). At normal or high levels, UA is associated with a reduction in bone mineral density and protects against bone fracture. However, in hyperuricemia or gout arthritis, UA increases bone fracture risk because oxidative stress and inflammatory cytokines can increase bone resorption and decrease bone formation. Vitamin D deficiency, and consequent secondary hyperparathyroidism, can further increase bone resorption and aggravated bone loss in UA-induced osteoporosis.

Correction: The role of indoxyl sulfate in renal anemia in patients with chronic kidney disease.

[This corrects the article DOI: 10.18632/oncotarget.18789.].

Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center.

BACKGROUND/AIMS: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. METHODS: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. RESULTS: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients' correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. CONCLUSION: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology.

Improvement in Mortality and End-Stage Renal Disease in Patients With Type 2 Diabetes After Acute Kidney Injury Who Are Prescribed Dipeptidyl Peptidase-4 Inhibitors.

OBJECTIVE: To focus on the potential beneficial effects of the pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP4is) on attenuating progression of diabetic kidney disease in reducing the long-term effect of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. PATIENTS AND METHODS: Data from the National Health Insurance Research Database from January 1, 1999, to July 31, 2011, were analyzed, and patients with diabetes weaning from dialysis-requiring AKI were identified. Cox proportional hazards models and inverse-weighted estimates of the probability of treatment were used to adjust for treatment selection bias. The outcomes were incident end-stage renal disease (ESRD) and mortality, major adverse cardiovascular events, and hospitalized heart failure. RESULTS: Of a total of 6165 patients with diabetes weaning from dialysis-requiring AKI identified, 5635 (91.4%) patients were DPP4i nonusers and 530 (8.6%) patients were DPP4i users. Compared with DPP4i nonusers, DPP4i users had a lower risk of ESRD (hazard ratio, 0.81; 95% CI, 0.70-0.94; P=.04) and all-cause mortality (hazard ratio, 0.28; 95% CI, 0.23-0.34; P<.001) after adjustments for CKD, advanced CKD, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. In contrast, the risk of major adverse cardiovascular events and hospitalized heart failure did not differ significantly between groups. CONCLUSION: Dipeptidyl peptidase-4 inhibitor users had a lower risk of ESRD and mortality than did nonusers among patients with diabetes after weaning from dialysis-requiring AKI. Therefore, a prospective study of AKI to CKD transitions after episodes of AKI is needed to optimally target DPP4i interventions.

Norepinephrine Administration Is Associated with Higher Mortality in Dialysis Requiring Acute Kidney Injury Patients with Septic Shock.

(1) Background: Norepinephrine (NE) is the first-line vasoactive agent used in septic shock patients; however, the effect of norepinephrine on dialysis-required septic acute kidney injury (AKI-D) patients is uncertain. (2) Methods: To evaluate the impact of NE on 90-day mortality and renal recovery in septic AKI-D patients, we enrolled patients in intensive care units from 30 hospitals in Taiwan. (3) Results: 372 patients were enrolled and were divided into norepinephrine users and non-users. After adjustment by Inverse probability of treatment weighted (IPTW), there was no significant difference of baseline comorbidities between the two groups. NE users had significantly higher 90-day mortality rate and using NE is a strong predictor of 90-day mortality in the multivariate Cox regression (HR = 1.497, p = 0.027) after adjustment. The generalized additive model disclosed norepinephrine alone exerted a dose⁻dependent effect on 90-day mortality, while other vasoactive agents were not. (4) Conclusion: Using norepinephrine in septic AKI-D patients is associated with higher 90-day mortality and the effect is dose-dependent. Further study to explore the potential mechanism is needed.

Intelligent system to predict intradialytic hypotension in chronic hemodialysis.

BACKGROUND: Intradialytic hypotension (IDH) is a serious complication and a major risk factor of increased mortality during hemodialysis (HD). However, predicting the occurrence of intradialytic blood pressure (BP) fluctuations clinically is difficult. This study aimed to develop an intelligent system with capability of predicting IDH. METHODS: In developing and training the prediction models in the intelligent system, we used a database of 653 HD outpatients who underwent 55,516 HD treatment sessions, resulting in 285,705 valid BP records. We built models to predict IDH at the next BP check by applying time-dependent logistic regression analyses. RESULTS: Our results showed the sensitivity of 86% and specificity of 81% for both nadir systolic BP (SBP) of <90 mmHg and <100 mmHg, suggesting good performance of our prediction models. We obtained similar results in validating via test data and data of newly enrolled patients (new-patient data), which is important for simulating prospective situations wherein dialysis staff are unfamiliar with new patients. This compensates for the retrospective nature of the BP records used in our study. CONCLUSION: The use of this validated intelligent system can identify patients who are at risk of IDH in advance, which may facilitate well-timed personalized management and intervention.

Physiology and pathophysiology of renal erythropoietin-producing cells.

Anemia is a common complication and contributes to increased morbidity and mortality in chronic kidney disease (CKD) patients. Whereas there has been a significant improvement of understanding the underlying mechanism of erythropoiesis, the treatment of renal anemia is still restricted to erythropoietin (EPO)-stimulating agents. The purpose of this article is to review the physiology of erythropoiesis, functional role of EPO and underlying molecular and cellular basis that regulate EPO production. Regulation of EPO production is at mRNA level. When anemia or hypoxia occurs, transcriptional factor, hypoxia-inducible factor (HIF), binds to EPO 5' hypoxic response element and EPO gene transcription increases. The renal EPO is mainly produced by pericytes. In CKD, pericytes transdifferentiate to myofibroblasts, and subsequently the ability of EPO production decreases, leading to renal anemia. Recent experimental and clinical studies show the promising efficacy of prolyl hydroxylase inhibitors in renal anemia through increasing EPO production by stabilizing HIF. Recent advances on epigenetics create a new field to study EPO gene expression at chromatin level. We will discuss the role of demethylating agent on restoring EPO expression, providing a novel approach to the treatment of renal anemia.

Parathyroidectomy decreases neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios.

BACKGROUND: Systemic inflammation has been implicated in complications and heightened mortality of patients with secondary hyperparathyroidism. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are widely available surrogate markers of inflammation. This study sought to delineate the changes in NLR and PLR after parathyroidectomy. METHODS: A total of 213 patients undergoing initial parathyroidectomy from 2010 to 2015 for secondary hyperparathyroidism were identified from a prospectively maintained clinical database. Among 183 patients free of persistent or recurrent disease, follow-up NLR and PLR were available for analysis in 85 patients. RESULTS: In the whole study population, the baseline NLR was positively correlated with male sex, total white blood cell count, height, serum phosphorus, and calcium-phosphorus product levels. The baseline PLR was positively correlated with platelet count, serum phosphorus, and calcium-phosphorus product levels and negatively associated with patient age. Postoperative parathyroid hormone levels were positively correlated with NLR and PLR at follow-up. For patients who had successful parathyroidectomy, there was a decrease in NLR (P = 0.0006), PLR (P = 0.0003), and platelet count (P = 0.033), whereas hemoglobin significantly increased (P = 0.0002) after surgery. Those with persistent or recurrent hyperparathyroidism had no change in NLR, PLR, hemoglobin, total white blood cell, or platelet count. CONCLUSIONS: Successful parathyroidectomy is associated with a decrease in NLR and PLR. The modulatory effects of parathyroidectomy on systemic inflammation may partially explain the benefits of surgery in secondary hyperparathyroidism.