Chronic Kidney Disease Subjects Research Articles

#2902 How does IGF-1 levels relate to different stages of chronic kidney disease

Abstract Background and Aims Insulin like growth factor-1 (IGF-I) influences glomerular filtration rate (GFR).Chronic kidney disease (CKD) influences the IGF/GH axis also. Serum IGF-I level is proposed to be a risk factor for renal and cardiovascular complications which is accentuated in CKD. This study is undertaken to observe the level of serum IGF-1 in different stages of chronic kidney disease and its association with cardio-metabolic risk factors Method This cross-sectional pilot study included consecutive 102 CKD patients of advanced renal failure (CKD3-5). Also 52 healthy subjects (free from any known disease) served as healthy referent for IGF-1 level. Stable CKD subjects ( < 15% deviation of eGFR in 3 months) from OPD of study center were included as cases. Information on socio-demographic and clinical characteristics with medical histories was collected from all in a predesigned data collection sheet Urine spot samples and fasting blood samples were collected and stored at −80°C for future analyses. The four-variable Modification of Diet in Renal Disease (MDRD) study equation was used for calculation of the eGFR using enzymatic creatinine. IGF-I was determined by ELISA method. Results Mean age was of CKD subjects was 50.45 ± 10.45 years with male-49% female-51%. Most common primary disease responsible for CKD was GN (53%) followed by DM (21%), HTN (13.0%) and rest others. The IGf-1 level was 297 ± 107 (range 79-588) in CKD patients and in healthy it was 246 ± 82 (114-529) ng/ml, (p < 0.004). The IGF-1 value at 25th percentile of healthy was only present in 12.7% of CKD and above 75th it was present in 42% of CKDs (p < 0.11). Study subjects in CKD 3 was 36%, in 4- 44% and in 5- 24%. The serum IGF-1 levels at CKD 3, 4 and 5 was 246 ± 82, 278 ± 95 and 328 ± 101 ng/ml, (p < 0.014); Hb% 11.1 ± 1.4, 11.3 ± 1.5 and 10.6 ± 1.5 g% (p < 0.001); calcium 9.5 ± 1.4, 9.6 ± 1.4 and 8.9 ± 1.0 mg% (P < 0.014); phosphate 3.6 ± 1.1, 3.6 ± 0.4 and 4.2 ± 1.0 mg%(p < 0.02); iPTH 24 ± 27, 22 ± 16 and 61 ± 82 pg/ml (p < 0.01) and albumin 4.5 ± 1.1, 4.56 ± 1.4 and 8.9 ± 1.0 mg%, (p < 0.04) respectively in 3 stages. The correlation study showed only a negative association of IGF-1 with eGFR (p < 0.01).The logistic regression analysis showed (taking in consideration of cardio-metabolic risk factors) only a significant association of eGFR with IGF-1. Conclusion The Serum IGF-1 level had an increasing value along with alterations in other biochemical parameters at advancing stage of CKD. This increase in IGF-1 value seems to be a reflection of progressing CKD rather than a causal relation to other cardio-metabolic risk markers.

#2898 Exposure response model describing hematologic changes with chronic treatment of CKD anemia with vadadustat

Abstract Background and Aims Vadadustat (VADA) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate endogenous erythropoietin production, increasing iron mobilization and red blood cell production. VADA is approved in 36 countries globally and is indicated in the European Union for the treatment of symptomatic anaemia associated with chronic kidney disease (CKD) in adults on chronic maintenance dialysis and is an alternative to treatment with erythropoiesis-stimulating agents (ESAs). The aim of this work was to develop a predictive, semi-mechanistic model to understand the effects of VADA and erythropoiesis-stimulating agents (ESAs) on hemoglobin response and to evaluate the impact of intrinsic and extrinsic patient characteristics on that response for non-dialysis dependent (NDD) and dialysis-dependent (DD) patient populations. Method A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. Results A predictive semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for VADA and ESA treatment was developed using nonlinear mixed effects methods. The model describes changes in reticulocyte count (RETICs), mature erythrocytes (RBCs) and hemoglobin (Hb) as a function of drug exposure and subject-specific characteristics. The dataset was based on data from 7 Phase 1 to Phase 3 studies (Table 1; N = 894 for VADA; N = 560 for ESA modeling) in healthy volunteers and subjects with NDD- or DD-CKD who were either ESA-naïve or ESA experienced but not receiving treatment at screening. Prior population PK modeling of VADA provided estimated drug exposures for VADA-treated subjects, while dose normalized to standard units (IU/kg/wk) was used as the exposure metric for subjects on ESA. Each of these exposure metrics could vary with time, as the dose was adjusted according to observed Hb response. This work evaluated alternative model structures, as well as covariate effects affecting Hb individual response. A similar model structure was found to describe early changes in RETICs and longer-term changes in Hb for both VADA and ESAs. In each case, the magnitude of response increases with increased drug exposure up to a maximum value (Emax), and the Emax values were similar between VADA and ESAs. Subject intrinsic predictors of response included eGFR, subject age, BMI, and serum albumin, while extrinsic factors affecting response included geographic region, limits on acceptable Hb values (which also differ by geographic region) and the presence of previous ESA treatment. Interestingly, Hb responses were also correlated with changes in serum hepcidin, a key regulator of iron homeostasis, following both VADA and ESA treatment. Differences between the response to VADA and ESA were also described, including differences in temporal changes in RETICs and Hb. Conclusion This model showed an exposure-response relationship between VADA or ESA treatment and changes in RETICs and Hb for ESA naïve or ESA-experienced CKD subjects. The model will be used to inform dosage recommendations for VADA based on patient characteristics.

Characterization of gut microbiota in patients with stage 3-4 chronic kidney disease: a retrospective cohort study.

Multiple factors, such as dietary patterns, pharmaceutical interventions, and exposure to harmful substances, possess the capacity to influence gut microbiota composition. Gut microbiota dysbiosis has emerged as a significant contributor to the progression of chronic kidney disease (CKD) and its associated complications. By comprehending the intricacies of the intestinal microbiota, this research endeavor holds the potential to offer novel perspectives on potential strategies for mitigating CKD progression. In this retrospective analysis, we assessed gut microbiota composition in CKD patients. Fecal samples were collected from a cohort of 44 patients with stage 3-4 CKD, alongside a control group consisting of 132 healthy volunteers. Subsequently, 16s rDNA sequencing was conducted to examine the composition of the gut microbiota. Our findings revealed significant alterations in the diversity of intestinal microbiota in fecal samples between patients with stage 3-4 CKD and healthy subjects. Among the 475 bacterial genera, 164 were shared, while 242 dominant genera were exclusive to healthy subjects and 69 to CKD stages 3-4 samples. Notably, healthy volunteers exhibited a prevalence of intestinal Firmicutes and Bacteroidetes, whereas stage 3-4 CKD patients displayed higher abundance of Proteobacteria and Actinobacteria. The presence of uncultured Coprobacillus sp. notably contributed to distinguishing between the two groups. ROC curve analysis identified distinct microbiota with superior diagnostic efficacy for discriminating stage 3-4 CKD patients from healthy individuals. Metabolic pathway analysis revealed differing dominant pathways between the two groups-the NADH dehydrogenase pathway in healthy individuals and the phosphate acetyltransferase pathway in stage 3-4 CKD patients. Moreover, the CKD cohort displayed a higher proportion of Gram-negative bacteria and facultative anaerobes. In conclusion, our study underscores the profound influence of gut microbiota dysbiosis on CKD progression. The distinct microbial profiles observed in CKD patients highlight the potential efficacy of microbiota-based interventions in mitigating CKD advancement.

FHL2 in arterial medial calcification in chronic kidney disease.

Arterial medial calcification (AMC) is a common complication in individuals with chronic kidney disease (CKD), which can lead to cardiovascular morbidity and mortality. The progression of AMC is controlled by a key transcription factor called runt-related transcription factor 2 (RUNX2), which induces vascular smooth muscle cells (VSMCs) transdifferentiation into a osteogenic phenotype. However, RUNX2 has not been targeted for therapy due to its essential role in bone development. The objective of our study was to discover a RUNX2 coactivator that is highly expressed in arterial VSMCs as a potential therapy for AMC. We employed transcriptomic analysis of human data and an animal reporter system to pinpoint FHL2 as a potential target. Subsequently, we investigated the mRNA and protein expression patterns of FHL2 in the aortas of both human and animal subjects with CKD. To examine the role of FHL2 in the RUNX2 transcription machinery, we conducted coimmunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) experiments. Next, we manipulated FHL2 expression in cultured VSMCs to examine its impact on high phosphate-induced transdifferentiation. Finally, we employed FHL2 null mice to confirm the role of FHL2 in the development of AMC in vivo. Among all the potential RUNX2 cofactor, FHL2 displays selective expression within the cardiovascular system. In the context of CKD subjects, FHL2 undergoes upregulation and translocation from the cytosol to the nucleus of arterial VSMCs. Once in the nucleus, FHL2 interacts structurally and functionally with RUNX2, acting as a coactivator of RUNX2. Notably, the inhibition of FHL2 expression averts transdifferentiation of VSMCs into an osteogenic phenotype and mitigates aortic calcification in uremic animals, without causing any detrimental effects on the skeletal system. These observations provide evidence that FHL2 is a promising target for treating arterial calcification in patients with CKD.

Plasma Fibrinogen Levels and Protein C Activity in Patients with Chronic Kidney Disease in a Nigerian Tertiary Hospital

Introduction: Haemostatic abnormalities have been observed in patients with chronic kidney disease (CKD). Hypercoagulability and thrombotic complications may contribute to the increased morbidity and mortality associated with CKD. Thrombotic tendency has not been fully evaluated in CKD subjects in our environment. This research was to assess the plasma fibrinogen and protein C activity levels in patients with CKD in a Nigerian tertiary hospital, with the view of deducing their associations with thromboembolic manifestations and providing possible therapeutic interventions.
 Material and Methods: A hospital based, cross-sectional survey conducted amongst CKD patients on renal replacement therapy (RRT), who were managed in the renal unit of the University of Benin Teaching Hospital (UBTH). Participants were appropriately matched with apparently healthy control subjects and these were interviewed with a structured questionnaire to obtain data on their clinical details as well as hospital records. Citrated plasma was obtained and analysed to determine the functional protein C activity as well as the fibrinogen levels of both subjects on RRT and apparently healthy control. Haematologic and biochemical parameters were also determined including complete blood count, urea and creatinine and liver function tests. Descriptive and Inferential statistics were performed using Statistical Package for Social Sciences (SPSS) version 20. Results were presented in tables and charts
 Results: A total of 222 subjects participated in this study, comprising 74 patients with CKD on conservative management, 74 subjects with CKD on RRT, and 74 apparently healthy control subjects. The mean age across the groups including subjects on conservative management, RRT, and controls were 54.70±14.42, 49.5±15.73, and 49.3±12.5 years respectively; with the median age of 56-, 52-, and 48.5- years f across the groups respectively. The mean plasma fibrinogen levels across the groups were 240.4±57.76, 241.8±54.87, 360.9±69.5mg/dl respectively. This was statistically significant. The mean protein C activity for the respective groups was 59.6 ± 24.20, 63.6 ± 28.89, 86.7.±2.6%. Protein C activity was significantly depleted in the CKD subjects (p = 0.002).
 Conclusion: The study showed a low protein C activity amongst patients with CKD and those with cardiovascular or thromboembolic events, suggestive of thromboembolic risk in these individuals. Contrary to existing literature, plasma fibrinogen levels were not significantly elevated in patients with CKD, and there was no association with thromboembolic events.

Identification of common and specific fibrosis-related genes in three common chronic kidney diseases

Background Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD. Methods Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes. Results Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis. Conclusions There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

LEFT VENTRICULAR GEOMETRY AMONG CHRONIC KIDNEY DISEASE PATIENTS: THE ROLE OF ANEMIA

BACKGROUND: Anaemia and abnormal left ventricular (LV) geometric pattern are common findings in Chronic Kidney disease (CKD) patients.
 OBJECTIVES: To assess LV geometric pattern and its relationship with anaemia among CKD patients.
 METHODS: A cross sectional study of 163 subjects (102 and 61 CKD subjects with and without anaemia respectively). Echocardiography determined the LV geometric pattern while packed cell volume (PCV) levels determined anaemia.
 RESULTS: The mean age of subjects with and without anaemia was 54.04 ± 14.47 and 54.92 ± 15.67 years respectively (p = 0.717) while the prevalence of LVH among the two groups was 68.8% and 57.9% respectively (p = 0.174). The most frequent LV geometry in both groups was concentric LVH (53.8% and 43.9% respectively). Prevalence of LV systolic dysfunction was 45%, higher among anaemic subjects (58(61.7%) vs 10(17.5%)) p < 0.001. There was a strong negative correlation between PCV and left ventricular mass index (r = -0.345, p = 0.001) among anaemic subjects, but weak positive correlation among patients without anaemia (r = 0.001, p = 0.993).
 CONCLUSION: Anaemic CKD patients had a high prevalence of abnormal LV geometry with significant contribution from anaemia. Early management of anaemia may thus improve cardiovascular outcomes.

The Association between Serum Adiponectin Levels and Endothelial Function in Non-Dialysis-Dependent Chronic Kidney Disease Patients.

Adiponectin is the richest human circulating adipokine with anti-inflammatory, antioxidant, and insulin-sensitizing effects. We evaluated the association between serum adiponectin levels and endothelial function in chronic kidney disease (CKD) patients, obtaining fasting blood samples from 130 non-dialysis CKD subjects. We measured the endothelial function-represented by the vascular reactivity index (VRI)-via non-invasive digital thermal monitoring, and serum adiponectin concentrations by enzyme immunoassay kits. A total of 22 (16.9%), 39 (30.0%), and 69 (53.1%) patients had poor (VRI < 1.0), intermediate (1.0 ≤ VRI < 2.0), and good (VRI ≥ 2.0) vascular reactivity. Elevated serum blood urea nitrogen (BUN) level was negatively correlated with VRI values, but serum adiponectin and estimated glomerular filtration rate were positively associated with VRI values by univariate linear regression analysis. After applying multivariate stepwise linear regression analysis adjustment, the significantly positive association of adiponectin (p < 0.001), and the significantly negative association of log-BUN (p = 0.021) with VRI values in CKD subjects remained. In an animal study using in vitro blood-vessel myography, treatment with adiponectin enhancing acetylcholine-mediated vasorelaxation in 5/6 nephrectomy CKD mice. Our study results indicated that adiponectin concentration was positively associated with VRI values and modulated endothelial function in non-dialysis CKD patients.

A retrospective view of the relationship of soluble Fas with anemia and outcomes in chronic kidney disease.

Anemia is common in chronic kidney disease (CKD) and is associated with outcomes. In addition, serum soluble Fas (sFas) levels are related to anemia and erythropoietin (EPO) resistance. Firstly, to compare clinical data and serum levels of sFas, EPO, and pro-inflammatory markers between patients with non-dialytic CKD (NDD-CKD) and healthy subjects. Subsequently, to compare and evaluate the relationship of serum EPO, sFas levels with anemia, and outcomes in patients with NDD-CKD over a long follow-up period. We performed a retrospective study in 58 NDD-CKD patients compared with 20 healthy subjects on complete blood count, kidney function, serum EPO, sFas, and inflammatory markers (CRP, IL- 6, and IFN-γ) at baseline. We then compared the same baseline data between patients with NDD-CKD who evolved to anemia and those who did not have anemia over the follow-up. We also evaluated the frequency of outcomes in patients with CKD with higher sFas levels. Finally, we performed a multivariate analysis of factors associated with CKD anemia. There were lower eGFR and Hb but higher serum inflammatory markers, sFas levels, sFas/eGFR, and EPO/Hb ratios in patients with NDD-CKD. Comparatively, on the other hand, NDD-CKD patients with anemia had lower eGFR but were older, had more diabetes, and had higher sFas/ eGFR, EPO/Hb ratios, and serum levels of IL-6 and sFas than NDD-CKD without anemia for an extended period. In addition, there was an association in a multivariate analysis of diabetes, age, and sFas levels with kidney anemia. Furthermore, there were higher frequencies of outcomes in increased serum sFas levels. As an elective risk factor, serum sFas levels, in addition to age and diabetes, were independently associated with kidney anemia for an extended period. Thus, more studies are necessary to analyze the proper relationship of sFas with kidney anemia and its outcomes and therapy in CKD.

ABSENT VASOREACTIVE RESPONSE TO HIGH SODIUM INTAKE COINCIDES WITH SALT SENSITIVITY IN CKD PATIENTS

Objective: Chronic kidney disease (CKD) patients are advised to limit salt intake, because of its detrimental effects on blood pressure (BP) and albuminuria. The salt-sensitive BP response in CKD is classically attributed to impaired renal ability to excrete sodium (Na+) resulting in fluid overload. Yet, BP sensitivity to salt is also linked to vasodysfuction, and may even be fluid independent. We aimed to investigate which factor contributes to BP sensitivity to salt in CKD. Design and method: In this randomized crossover study, CKD patients (KDIGO stage G2-3A, proteinuria &gt;0.5 g/d) and healthy controls (HC) followed a 7-day low sodium diet (LSD, &lt;50mmol/d) and high sodium diet (HSD, &gt;200mmol/d), respectively. After each diet, assessment of the hemodynamic profile included daytime BP (Mobil-O-Graph) and cardiac output (CO) measurements (using NexfinTM), by which SVR was calculated accordingly. Extracellular fluid volume (ECV) change was assessed with multi-frequency body impedance spectroscopy (FHCresenius). Results: We included 16 HC (median age 36.0 yrs) and 8 CKD patients (median age 49.5 yrs, and median (IQR) proteinuria 0.6 (0.5-1.1) g/d and plasma creatinine 144 (103 - 167) μmol/l. Dietary salt intervention was successful with median difference in urine Na+ excretion of 242.2 vs 224.6 mmol/day in HC and CKD respectively (p = 0.74). After HSD, the median (IQR) change in systolic BP of patients with CKD was 14 mmHg (4 - 18; p = 0.04), while systolic BP change (4 mmHg (-3 - 8)) in HC was not significant (Fig 1A). After HSD, we observed a significant ECV expansion in both CKD and HC subjects (Fig 1B), but no effect on CO. No associations between HSD-induced BP changes and both ECV and CO were found. Systolic BP increase was correlated with SVR decline in HC, but not in CKD patients (Fig 1C). Conclusions: In contrast to healthy persons, BP salt sensitivity in CKD does not associate with vasodilation. Regarding the absence of differences with ECV and CO between healthy and CKD persons, our data indicate that the incapacity for vasodilation might explain salt sensitivity in CKD.

Chronic Kidney Disease: Interaction of Adiponectin Gene Polymorphisms and Diabetes.

Adiponectin is an adipokine multipeptide hormone with insulin-sensitizing; anti-atherosclerotic; and anti-inflammatory properties. Chronic kidney disease (CKD) may be associated with low adiponectin. The adiponectin gene ADIPOQ is thought to be the only major gene responsible for plasma adiponectin levels; which are associated with diabetes and diabetic nephropathy. The purpose of this study was to investigate the association between ADIPOQ polymorphism and CKD. In addition; the combined effects of ADIPOQ polymorphism and diabetes and levels of total urinary arsenic and blood cadmium on CKD were also explored. This study included 215 CKD patients and 423 age-sex matched controls. The ADIPOQ polymorphisms were determined using the Agena Bioscience Mass ARRAY System. The levels of blood cadmium and urinary arsenic species were measured. The ADIPOQ rs182052 GA/AA genotype had a marginally lower odds ratio (OR) for CKD than the GG genotype. The OR (95% confidence interval; CI) was 16.33 (5.72-46.66) of CKD in subjects carrying the ADIPOQ rs182052 GG genotype and diabetes compared to non-diabetes subjects carrying the ADIPOQ rs182052 GA/AA genotype; the interaction term had p = 0.015; and the synergy index was 6.64 (1.81-24.36) after multivariate adjustment. A significant interaction of diabetes and ADIPOQ rs1501299 risk genotype increased the OR of CKD after multivariate adjustment with a synergy index of 0.31 (0.11-0.86) and a multiplicative interaction with p = 0.001. These results suggest that ADIPOQ rs182052 and rs1501299 risk genotypes may significantly modify the association between diabetes and CKD but not the association between total urinary arsenic and blood cadmium and CKD.

High Fructose Corn Syrup Accelerates Kidney Disease and Mortality in Obese Mice with Metabolic Syndrome.

The presence of obesity and metabolic syndrome is strongly linked with chronic kidney disease (CKD), but the mechanisms responsible for the association are poorly understood. Here, we tested the hypothesis that mice with obesity and metabolic syndrome might have increased susceptibility to CKD from liquid high fructose corn syrup (HFCS) by favoring the absorption and utilization of fructose. We evaluated the pound mouse model of metabolic syndrome to determine if it showed baseline differences in fructose transport and metabolism and whether it was more susceptible to chronic kidney disease when administered HFCS. Pound mice have increased expression of fructose transporter (Glut5) and fructokinase (the limiting enzyme driving fructose metabolism) associated with enhanced fructose absorption. Pound mice receiving HFCS rapidly develop CKD with increased mortality rates associated with intrarenal mitochondria loss and oxidative stress. In pound mice lacking fructokinase, the effect of HFCS to cause CKD and early mortality was aborted, associated with reductions in oxidative stress and fewer mitochondria loss. Obesity and metabolic syndrome show increased susceptibility to fructose-containing sugars and increased risk for CKD and mortality. Lowering added sugar intake may be beneficial in reducing the risk for CKD in subjects with metabolic syndrome.

Global coagulation assays in patients with chronic kidney disease and their role in predicting thrombotic risk

BackgroundDespite cardiovascular diseases and thrombosis being major causes of death in patients with chronic kidney disease (CKD), there remains no effective biomarker to predict thrombotic risk in this population. ObjectiveTo evaluate global coagulation assays in patients with CKD and correlate the biomarkers to clinical outcomes. Material and methodsPatients with eGFR<30 mL/min/1.73m2 were recruited (n = 90) in this prospective observational study. Blood samples were collected for global coagulation assays, including thromboelastography, calibrated automated thrombogram (CAT), overall hemostatic potential (OHP) and tissue factor pathway inhibitor (TFPI). ResultsFollowing adjustment for age and gender, CKD subjects (mean age 66 years, 36 % female) had increased maximum amplitude on thromboelastography (70.1 vs 60.2 mm, p < 0.001), higher peak thrombin (233.2 vs 219.7 mm, p = 0.030) and increased OHP (16.1 vs 6.4 units, p < 0.001) compared to healthy controls (n = 153). TFPI was also increased in CKD patients (36.4 vs 14.5 ng/mL, p < 0.001). Compared to hemodialysis patients (n = 43), peritoneal-dialysis patients (n = 25) had more hypercoagulable parameters. Thirty-five CKD patients reported thrombotic complications – key predictors included dialysis, higher fibrinogen, reduced endogenous thrombin potential, elevated D-dimer and increased TFPI. Using the dialysis cohort, the predictive risk model based on the key predictors performed better than Framingham heart score and number of cardiovascular risk factors (Harrell's C-stat 0.862 vs 0.585 vs 0.565). ConclusionCKD appears to confer a hypercoagulable state compared to healthy controls. Interestingly, reduced thrombin generation and raised TFPI was paradoxically associated with increased thrombotic risks, highlighting possible complex compensatory mechanisms within the coagulation system, which may be important in predicting clinical outcomes.

Blood Pressure Reducing Potential and Renoprotective Action of Cilnidipine Among Hypertensive Patients Suffering From Chronic Kidney Disease: A Meta-Analysis.

Hypertension is a risk factor for cardiovascular diseases which also causes progressive kidney damage leading to chronic kidney disease (CKD), so the rate of progression of CKD can be controlled by reducing blood pressure (BP). Many anti-hypertensive drugs are available. Cilnidipine is a new-generation calcium channel blocker (CCB). This meta-analysis is aimed to generate pooled evidence about the effectiveness of cilnidipine as an anti-hypertensive and to explore its reno-protective actions. Pubmed, Scopus, Cochrane Library, and Google Scholar were searched from January 2000 to December 2022 to include the studies. The pooled mean difference, along with 95% CI, was computed using Revman 5.4.1 software (Revman International, Inc., New York City, New York). The Cochrane risk-of-bias assessment tool was used for bias assessment. This meta-analysis was registered in PROSPERO with Reg. no. CRD42023395224. This meta-analysisincluded seven studies with 289 participants in the intervention groupand 269 in the comparator group, and were selected from Japan, India, and Korea. Systolic blood pressure (SBP) was significantly reduced in cilnidipine treated group among hypertensives with CKD subjects weighted mean difference (WMD) was 4.33, and the 95% confidence interval (CI) was 1.26 to 7.31as compared to the other group. Cilnidipine also shows a significant reduction in proteinuria with WMD 0.61 and 95% CI 0.42 to 0.80. Both groups were similar in adverse drug reactions (ADR). Cilnidipine is a more effective anti-hypertensive as compared to Amlodipine or other CCBs, mainly in reducing SBP. Besides this, cilnidipine also shows better reno-protective action because it also significantly reduces proteinuria in such patients.

A phase 2 study of oral difelikefalin in subjects with chronic kidney disease and moderate-to-severe pruritus

Chronic pruritus is burdensome for patients with chronic kidney disease (CKD). We evaluated difelikefalin efficacy and safety in reducing itch in subjects with non-dialysis-dependent CKD and those undergoing hemodialysis (HD). This phase 2, double-blind, randomized, placebo-controlled, dose-finding study enrolled non-dialysis-dependent CKD (stage 3-5) and HD subjects with moderate-to-severe pruritus. Subjects were equally randomized to oral difelikefalin (0.25, 0.5, or 1.0mg) or placebo once daily for 12weeks. The primary end point was the change in the weekly mean Worst Itching Intensity Numeric Rating Scale (WI-NRS) score at week 12. Two hundred sixty-nine subjects were randomized (mean [SD] baseline WI-NRS: 7.1 [1.2]). Difelikefalin 1.0mg significantly reduced weekly mean WI-NRS scores versus placebo at week 12 (P=.018), with numerical reductions observed with difelikefalin 0.25 and 0.5mg. At week 12, 38.6% of subjects receiving difelikefalin 1.0mg achieved a complete response (WI-NRS 0-1) versus 14.4% receiving placebo. Difelikefalin resulted in ∼20% improvement in itch-related quality-of-life measures. The most common treatment-emergent adverse events were dizziness, fall, constipation, diarrhea, gastroesophageal reflux disease, fatigue, hyperkalemia, hypertension, and urinary tract infection. Study duration was 12weeks. Oral difelikefalin significantly reduced itch intensity in stage 3-5 CKD subjects with moderate-to-severe pruritus, supporting continued development for this condition.

Urinary Markers of Tubular Injury and Renal Fibrosis in Patients with Type 2 Diabetes and Different Phenotypes of Chronic Kidney Disease

This study assessed the urinary excretion of markers and mediators of tubular injury and renal fibrosis in patients with type 2 diabetes (T2D) and non-albuminuric and albuminuric patterns of chronic kidney disease (CKD). One hundred and forty patients with long-term T2D and different patterns of CKD and twenty non-diabetic individuals were included. Urinary retinol-binding protein 4 (RBP-4), glutathione-S-transferase α1 and π (GST-α1 and GST-π), transforming growth factor β (TGF-β), type I and type IV collagen (Col1 and Col4), bone morphogenic protein 7 (BMP-7), and hepatocyte growth factor (HGF) were assessed by ELISA. Patients with T2D demonstrated increased urinary excretion of RBP-4, GST-π, Col4, BMP-7, and HGF (all p < 0.05 vs. control). The excretion of RBP-4, GST-π, Col1, and Col4 was increased in patients with elevated albumin-to-creatinine ratio (UACR; all p < 0.05 vs. control), while BMP-7 and HGF were increased innormoalbuminuric patients also (p < 0.05). Urinary RBP-4, GST-α1, Col1, Col4, and HGF correlated positively with UACR; meanwhile, no correlations with glomerular filtration rate were found. The results demonstrate that elevated urinary excretions of the markers of tubular injury (RBP-4, GST-π) and renal fibrosis (Col1, Col4), as well as HGF, an antifibrotic regulator, are associated with the albuminuric pattern of CKD in subjects with T2D.

Evaluation of Serum Lipoprotein (a) Levels and Novel Lipid Indices in Patients with Chronic Kidney DiseaseA Case-control Study

Introduction: Majority of Chronic Kidney Disease (CKD) patients are more likely to die of cardiovascular complications, before reaching End Stage Renal Disease (ESRD). Although there are many risk factors contributing to pathogenesis of cardiovascular disease in CKD subjects, dyslipidemia represents one of the modifiable risk factors. American Heart Association has recommended that CKD patients should be classified in the highest risk group for developing cardiovascular events. Kidney Disease: Improving Global Outcome (KDIGO) recommends, these patients should be evaluated for dyslipidemia and for treatment to reduce the risk of cardiovascular events. Aim: To evaluate serum Lipoprotein (a) {Lp(a)} levels and assess the significance of novel lipid indices in non dialysis patients of CKD. Materials and Methods: This analytical case-control study was conducted from January 2016 to June 2016 at Government Stanley Medical College and Hospital, Chennai, Tamil Nadu, India. It included 70 non dialysis CKD subjects and 70 healthy control subjects, adhering to inclusion and exclusion criteria. Fasting Blood Samples (FBS) were collected and analysed for: Fasting blood glucose, Fasting Lipid Profile, Serum Lp(a). Serum Lp(a) was estimated by immunoturbidimetry method and lipid profile by enzymatic method. Estimated Glomerular Filtration Rate (eGFR) was calculated using Modification of Diet in Renal Disease (MDRD) formula and staging of CKD subjects was done, based on KDIGO guidelines. Novel lipid indices were calculated using appropriate formula. Statistical analysis of the tabulated data was done using Social Sciences of the Statistical Package (SPSS) software. Results: There were significant differences in the levels of FBS, Triglycerides (TG), Lp(a) between controls and non dialysis CKD subjects (p&lt;0.001). Among Lipid Indices, Atherogenic Index of Plasma (AIP) and Lipid Tetrad Index (LTI) values were significantly higher in CKD subjects compared to controls (p&lt;0.001), but there was no significant difference was seen in Atherogenic Coefficient (AC), Castelli’s Risk Index-I (CRI-I) and CRI-II values. AIP and LTI showed significant positive correlation with Lp(a). LTI had the highest Positive Predictive Value (PPV) (77.8%) and Negative Predictive Value (NPV) (72.7%); AIP had PPV of 65.3% and NPV of 66.2%. Conclusion: The present study concludes that, among lipid indices, AIP and LTI are the most suitable for assessment of atherogenicity in non dialysis CKD. In developing countries like India, owing to high cost of tests like Serum Lp(a), novel lipid index AIP can serve as a cost-effective screening tool for monitoring cardiovascular disease risk in CKD patients.

A Toll‐like receptor‐4/NLRP3 inflammasome pathway promotes inflammation in skeletal muscle of chronic kidney disease patients

AbstractBackgroundAn emerging hypothesis is that the activation of innate immunity in the muscle of patients with chronic kidney disease (CKD) is implicated in the development and progression of wasting and cachexia. We previously observed that Toll‐like receptor‐4 (TLR4) and its downward NF‐κB‐dependent pro‐inflammatory pathways are activated in CKD muscle. It is however unknown if TLR4 can activate the TLR4/NOD, LRR, and pyrin domain‐containing protein 3 (NLRP3) inflammasome pathway, which is implicated in cardiovascular disease and frailty, clinical settings that are commonly observed in CKD patients.MethodsIn a case–control cohort study, we hypothesized that a TLR4/NLRP3 inflammasome pathway is activated in skeletal muscle in uraemia. First, we studied the regulation TLR4/NLRP3/caspase‐1 in skeletal muscle biopsies (20M/11F) obtained from 31 non‐diabetic CKD5 patients (eGFR 8 ± 1 mL/min 1.73 m2) scheduled for peritoneal dialysis catheter insertion and 15 controls (10M/5F, eGFR 99 ± 6 mL/min 1.73 m2). Second, the effects of uraemic serum on the TLR4/NLRP3 inflammasome pathway were studied in C2C12 cells.ResultsIn the muscle of CKD subjects, NLRP3 mRNA as well as its protein were overexpressed (by ~16‐fold, respectively, P &lt; 0.05 both vs. controls). Both IL‐1β and IL‐18 mRNA expressions were also up‐regulated (~11.8–3.2‐fold, respectively, P &lt; 0.05). Also, cleaved caspase‐1 was overexpressed in CKD muscle samples (P &lt; 0.001 vs. controls). Both muscle NLRP3 mRNA (n = 22, r = −0.606, P &lt; 0.01) and logIL‐1 β protein (n = 26, r = −0.460, P &lt; 0.02) were inversely associated with residual renal function, which suggests that the inflammasome is progressively activated in skeletal muscle of CKD patients as the residual renal function deteriorates. In addition, we observed that in C2C12 myotubes, uraemic serum up‐regulates NLRP3 mRNA (~11‐fold increase, P &lt; 0.05), cleaved caspase‐1 (by ~5‐fold, P &lt; 0.05), Il‐1β mRNA (~3‐fold increase, P &lt; 0.05) and oxidative stress markers respect to normal serum. These effects were prevented by TAK‐242, a selective TLR4 inhibitor.ConclusionsOverall, our data demonstrate the activation of TLR4/NLRP3/caspase‐1 inflammasome and its downward inflammatory cascade in the muscle of subjects with advanced‐stage CKD and suggest targeting TLR4/NLRP3 inflammasome as a new therapeutic strategy to blunt muscle inflammation in CKD.

Association of metabolic dysfunction-associated fatty liver disease with chronic kidney disease: a Chinese population-based study

Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a multisystem disorder, but its relationship with kidney injury remains controversial. This study aimed to evaluate MAFLD effects on the chronic kidney disease (CKD) prevalence in a general population in China. Methods In total, 15,010 individuals from the Health Management Center of West China Hospital from July 2020 to June 2021 were screened. Hepatic steatosis was defined as a median FibroScan controlled attenuation parameter (CAP)≥240 dB/m using liver ultrasound transient elastography. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and/or the presence of albuminuria. The association of MAFLD with CKD was examined using logistic regression. Risk factors for CKD in different MAFLD subgroups were also investigated. Results A total of 8226 individuals were finally included. Of them, 4406 (53.6%) had MAFLD, and 592 (7.2%) had CKD. After propensity score matching (PSM), 5530 eligible subjects were selected (n = 2765 in each group). There was a higher CKD prevalence in subjects with MAFLD than in those without MAFLD (8.9% vs. 5.4%, p < 0.001). MAFLD was significantly associated with a higher CKD prevalence (OR 1.715, 95% CI 1.389–2.117, p < 0.001), although it was not an independent risk factor. The results indicated that age, diabetes mellitus (DM), overweight/obesity, hypertension, hyperuricemia, hypertriglyceridemia, remnant cholesterol (RC), and C-reactive protein (CRP) were independently associated with a higher CKD prevalence. In the subgroup analysis, hypertension, hyperuricemia, RC, and the nonalcoholic fatty liver disease fibrosis score (NFS) were independent risk factors for the prevalence of CKD in individuals with DM or prediabetes and MAFLD. Furthermore, hypertension, hyperuricemia, and body fat percentage (BFP) were independently associated with CKD in subjects with MAFLD without DM. Conclusion Individuals with MAFLD had a higher prevalence of CKD, whereas it was not an independent risk factor for CKD.

The impact of senescence on muscle wasting in chronic kidney disease.

Muscle wasting is a common complication of chronic kidney disease (CKD) that is associated with higher mortality. Although the mechanisms of myofibre loss in CKD has been widely studied, the contribution of muscle precursor cell (MPC) senescence remains poorly understood. Senescent MPCs no longer proliferate and can produce proinflammatory factors or cytokines. In this study, we tested the hypothesis that the senescence associated secretory phenotype (SASP) of MPCs contributes to CKD-induced muscle atrophy and weakness. CKD was induced in mice by 5/6th nephrectomy. Kidney function, muscle size, and function were measured, and markers of atrophy, inflammation, and senescence were evaluated using immunohistochemistry, immunoblots, or qPCR. To study the impact of senescence, a senolytics cocktail of dasatinib+quercetin (D&Q) was given orally to mice for 8weeks. To investigate CKD-induced senescence at the cellular level, primary MPCs were incubated with serum from CKD or control subjects. The roles of specific proteins in MPC senescence were studied using adenoviral transduction, siRNA, and plasmid transfection. In the hindlimb muscles of CKD mice, (i) the senescence biomarker SA-β-gal was sharply increased (~30-fold); (ii) the DNA damage response marker γ-H2AX was increased 1.9-fold; and (iii) the senescence pathway markers p21 and p16INK4a were increased 1.99-fold and 2.82-fold, respectively (all values, P<0.05), whereas p53 was unchanged. γ-H2AX, p21, and p16INK4A were negatively correlated at P<0.05 with gastrocnemius weight, suggesting a causal relationship with muscle atrophy. Administration of the senolytics cocktail to CKD mice for 8weeks eliminated the disease-related elevation of p21, p16INK4a , and γ-H2AX, abolished positive SA-β-gal, and depressed the high levels of the SASP cytokines, TNF-α, IL-6, IL-1β, and IFN (all values, P<0.05). Skeletal muscle weight, myofibre cross-sectional area, and grip function were improved in CKD mice receiving D&Q. Markers of protein degradation, inflammation, and MPCs dysfunction were also attenuated by D&Q treatment compared with the vehicle treatment in 5/6th nephrectomy mice (all values, P<0.05). Uraemic serum induced senescence in cultured MPCs. Overexpression of FoxO1a in MPCs increased the number of p21+ senescent cells, and p21 siRNA prevented uraemic serum-induced senescence (P<0.05). Senescent MPCs are likely to contribute to the development of muscle wasting during CKD by producing inflammatory cytokines. Limiting senescence with senolytics ameliorated muscle wasting and improved muscle strength in vivo and restored cultured MPC functions. These results suggest potential new therapeutic targets to improve muscle health and function in CKD.