Dysfunction In Chronic Kidney Disease Research Articles

Urine-Derived Stem Cell-Secreted Klotho Plays a Crucial Role in the HK-2 Fibrosis Model by Inhibiting the TGF-β Signaling Pathway.

Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor against CKD. Urine-derived stem cells (UDSCs) have been identified as a novel stem cell source for kidney regeneration and CKD treatment because of their kidney tissue-specific origin. However, the relationship between UDSCs and Klotho in the kidneys is not yet known. In this study, we discovered that UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-inhibiting ability of UDSCs. Here, we suggest an alternative cell source that can overcome the limitations of MSCs through the synergetic effect of the origin specificity of UDSCs and the anti-fibrotic effect of Klotho.

Roxadustat Attenuates the Disruption of Epithelial Tight Junction in Caco2 Cells and a Rat Model of CKD Through MicroRNA-223.

IntroductionIncreasing evidence supports the idea that the disruption of epithelial tight junction proteins (TJPs) caused by accumulation of uremia toxins, such as homocysteine (Hcy), is one of the most important mechanisms underlying the damage of intestinal barrier function (IBF) in chronic kidney disease (CKD). Since the decrease of hypoxia inducible factor-1α (HIF-1α) is reported to be involved in Hcy-induced cell injury, and the upregulation of microRNA-223 (miR-223) plays a vital protective role in the impairment of IBF in the experimental colitis, we investigated the effect of HIF-1α stabilizer roxadustat on the disruption of TJPs induced by Hcy and CKD and the underlying mechanism.MethodsChronic kidney disease was induced in rats via 5/6 nephrectomy. In a series of experiments, the rats were treated orally with roxadustat of different doses. The expression of tight junction proteins, HIF-1α, and miR-223 was analyzed in different groups by western blotting analysis, RT-qPCR techniques and immunofluorescence. A series of experiments with cultured Caco2 cells was performed.ResultsThe results showed that the expression of TJPs (occludin, claudin-1, and ZO-1) decreased significantly, accompanied by the reduction of HIF-1α and miR-223 in Hcy-treated Caco2 cells and colonic mucosa of uremic rats. The reduction of HIF-1α and miR-223 was reversed by roxadustat and the decrease of TJPs expression was attenuated in both Caco2 cells induced by Hcy and colon tissue of CKD rats. Furthermore, transfection with miR-223 mimics increased the expression of TJPs, while transfection with miR-223 inhibitor decreased their expression in Caco2 cells. MiR-223 inhibitor applied before roxadustat treatment partly diminished the effect of roxadustat on TJPs expression in Caco2 cells.ConclusionThese results indicated that roxadustat attenuated the disruption of epithelial TJPs induced by Hcy in Caco2 cells and the damage of colonic epithelium in CKD rats through the upregulation of miR-223 induced by HIF-1α. A novel insight into the IBF dysfunction in CKD was provided, and it suggests a potential therapeutic use of roxadustat for the IBF dysfunction besides anemia in CKD.

Increase of Oxidative Stress by Deficiency of The ALDH2/UCP2/Nrf2 Axis Exacerbates Cardiac Dysfunction in Chronic Kidney Disease.

Both epidemiologic and experimental studies have evidenced that chronic kidney disease (CKD) could increase the incidence and risk of cardiac dysfunction, especially in aging patients. However, the underlying mechanisms are still not fully understood. In this study, we used 8 weeks old male wild-type (WT) C57BL/6 mice and ALDH2 knockout (ALDH2-/-) mice with C57BL/6 background. Here the 5/6 nephrectomy (NX) mouse model was constructed to study how CKD affects cardiac function and explored the related role of aldehyde dehydrogenase 2 (ALDH2), a well-established cardioprotective factor, in this process. Compensatory cardiac hypertrophy was found in wild type (WT) mice 12 weeks post 5/6 NX as shown by increased left ventricular wall thickness (LVWD), cross-sectional area (CSA) of cardiomyocytes, and preserved left ventricular ejection fraction (EF) and fractional shorten (FS). Deficiency of ALDH2 (ALDH2-/-) significantly reduced EF and FS as compared with WT mice 12 weeks post 5/6 NX, while left ventricular hypertrophy was similar between the two NX groups. ALDH2-/- CKD groups showed more severe nephritic damages and increased fibrosis deposition in hearts. Besides, levels of reactive oxygen species (ROS) and apoptosis were also significantly upregulated in hearts of ALDH2-/- NX mice. The above changes were related with decreased expressions of uncoupling protein 2 (UCP2) and nuclear factor like 2 (Nrf2), as well as the downstream effectors of Nrf2 (heme oxygenase-1, HO-1 and superoxide dismutase 2, SOD2). Our data indicated that ALDH2 deficiency did not affect NX-induced left ventricular hypertrophy, but could increase oxidative stress and exacerbate CKD-induced cardiac dysfunction, partly via downregulation of UCP2 and Nrf2/ARE (antioxidant response element) pathways.

Blood\u2013brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins

Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.

Uremic toxins activate CREB/ATF1 in endothelial cells related to chronic kidney disease

Uremic toxins, such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS), contribute to endothelial dysfunction in chronic kidney disease (CKD). This process is mediated by several cellular pathways, but it is unclear whether cAMP-responsive element-binding protein (CREB) and activating transcription factor 1 (ATF1) participate in endothelial dysfunction in uremic conditions despite playing roles in inflammatory modulation. This study aimed to evaluate the expression, activation, and transcriptional activity of CREB/ATF1 in endothelial cells exposed to PCS, IS, and uremic serum (US). In vitro, ATF1 protein levels were increased by PCS and IS, whereas CREB levels were enhanced only by IS. Activation through CREB-Ser133 and ATF1-Ser63 phosphorylation was induced by PCS, IS, and US. We evaluated the CREB/ATF1 transcriptional activity by analyzing the expression of their target genes, including ICAM1, PTGS2, NOX1, and SLC22A6, which are related to endothelial dysfunction through their roles in vascular inflammation, oxidative stress, and cellular uptake of PCS and IS. The expression of ICAM1, PTGS2 and NOX1 genes was increased by PCS, IS, and US, whereas that of SLC22A6 was induced only by IS. KG-501, a CREB inhibitor, restored the inductive effects of PCS on ICAM1, PTGS2, and NOX1 expression; IS on ICAM1, PTGS2 and SLC22A6 expression; and US on NOX1 expression. The presence of CREB and ATF1 was observed in healthy arteries and in arteries of patients with CKD, which were structurally damaged. These findings suggest that CREB/ATF1 is activated by uremic toxins and may play a relevant role in endothelial dysfunction in CKD.

Impact of Chronic Kidney Disease on Brain Structure and Function.

Chronic kidney disease (CKD) affects more than 37 million American adults. Adult-onset CKD is typically attributed to acquired comorbidities such as aging, type II diabetes, and cardiovascular disease. Conversely, congenital abnormalities of the kidney and urinary tract are the most common cause of CKD in children. Both adult and pediatric patients with CKD are at risk for neurocognitive dysfunction, particularly in the domain of executive function. The exact mechanism for neurocognitive dysfunction in CKD is not known; however, it is conceivable that the multisystemic effects of CKD—including hypertension, acidosis, anemia, proteinuria, and uremic milieu—exert a detrimental effect on the brain. Quantitative neuroimaging modalities, such as magnetic resonance imaging (MRI), provide a non-invasive way to understand the neurobiological underpinnings of cognitive dysfunction in CKD. Adult patients with CKD show differences in brain structure; however, much less is known about the impact of CKD on neurodevelopment in pediatric patients. Herein, this review will summarize current evidence of the impact of CKD on brain structure and function and will identify the critical areas for future research that are needed to better understand the modifiable risk factors for abnormal brain structure and function across both pediatric and adult CKD populations.

Immune dysfunction in chronic kidney disease

Chronic kidney disease is characterized by immune dysfunction that increases predisposition to infections, virus-associated cancers and impaired response to vaccination. The altered immune response is caused by impairment of both innate and adaptive immune systems, as well as other factors that are hallmarks of renal disease, such as uremia, malnutrition, chronic inflammation, mineral bone disease and anemia. The aim of this article is to review the causes and mechanisms that lead to immune dysfunction in patients with chronic kidney disease.

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review.

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

Neuropeptide Y as a risk factor for cardiorenal disease and cognitive dysfunction in chronic kidney disease: translational opportunities and challenges.

ABSTRACTNeuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut–brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.

Platelet glycogen synthase kinase 3β regulates plasma β amyloid and phosphorylated tau levels in chronic kidney disease patients with cognitive dysfunction; therapeutic role of erythropoietin

Introduction: Patients with chronic kidney disease (CKD) have increasingly been diagnosed with cognitive impairment. Glycogen synthase kinase 3β (GSK3β) is directly causing both phosphorylated tau (pTau) and amyloid β (Aβ) accumulation in Alzheimer’s disease (AD). GSK3β expression is more abundant in human platelets than in other blood cells. Recombinant human erythropoietin (rHuEPO) is a common medicine for treating anemia in patients with CKD, as well as a neuroprotective agent. Objectives: The goal of this research is to find out how platelet GSK3β regulates plasma Aβ, total Tau and tau phosphorylated at threonine 181 (p-tau181) levels in CKD patients with cognitive dysfunction and also the efficacy of rHuEPO treatment. Patients and Methods: The study included 60 participants, which consist of 30 CKD without cognitive dysfunction and 30 CKD with cognitive dysfunction based on the neuropsychological examination. The expression of GSK3β in platelets was evaluated using a western blot and plasma Aβ, total Tau, pTau 181 levels were quantified by ELISA. The data were compared statistically (P< 0.05) to AD, normocytic normochromic anemic and healthy patients. Results: In CKD with cognitive dysfunction subjects, platelet GSK3β expression and plasma Aβ, total Tau and pTau181 levels were significantly (P< 0.05) altered like AD when compared to normocytic normochromic anemic, healthy and CKD without cognitive dysfunction subjects. In post rHuEPO (100 IU/kg, weekly twice, six months) treatment, the altered protein abnormalities were retrieved significantly (P<0.05) compared to pre-treatment. Conclusion: This study established that platelet GSK3β expression and plasma Aβ, total Tau, pTau181 are the candidate biomarkers for cognitive dysfunction in CKD patients. The clinical utility of rHuEPO as a GSK3β inhibitor and therapeutic agent for cognitive dysfunction in CKD has been determined.

The Ratio of NT-proBNP to CysC1.53 Predicts Heart Failure in Patients With Chronic Kidney Disease.

Background: The N-terminal pro B type natriuretic peptide (NT-proBNP) is important for prognosis of heart failure in patients with chronic kidney disease (CKD). However, the NT-proBNP level is easily affected by renal insufficiency, which limits its clinical use.Methods: This study included 396 patients with CKD. Plasma levels of NT-proBNP and cystatin C (CysC) were measured during hospitalization. The echocardiographic parameters were also detected. Patients were divided into the heart failure group and control group according to the European Society of Cardiology Guideline on Chronic Heart Failure 2021. Multiple modeling analysis of the values of NT-proBNP and CysC, including NT-proBNP/Cyscn and NT-proBNP/nCysC was performed. The receiver operating characteristic (ROC) curve, combined with the cardiac function, was used to determine the formula with the best diagnostic efficiency. Then, the sensitivity and specificity of new predictors for cardiac insufficiency in CKD patients were calculated. Pearson correlation analysis was used to analyze the relationship between new predictors and the NT-proBNP level. The clinical data of CKD patients from another local hospital were used to validate the new predictors and the cut-off values.Results: An elevated NT-proBNP/CysC1.53 ratio was an independent risk factor for cardiac dysfunction in CKD and the best predictor derived from multiple modeling analysis. There was no correlation between the NT-proBNP/CysC1.53 ratio and the NT-proBNP level (r = 0.376, p = 6.909). The area under the ROC curve for the NT-proBNP/CysC1.53 ratio was 0.815 (95% confidence interval: 0.772–0.858), and for a cut-off point of 847.964, this ratio had a sensitivity of 78.24%, and a specificity of 69.44%. When applied to the data of CKD patients from another local hospital, the NT-proBNP to CysC1.53 ratio had a sensitivity of 70.27% and a specificity of 67.74%.Conclusion: The NT-proBNP to CysC1.53 ratio was superior to NT-proBNP alone for predicting cardiac dysfunction in patients with CKD.

Assessments of left ventricular systolic and diastolic functions with tissue Doppler imaging and myocardial performance index in children with chronic kidney disease.

This study aimed to document early left ventricular (LV) dysfunction in chronic kidney disease (CKD) using methods such as tissue Doppler imaging and the myocardial performance index (MPI). A total of 40 patients diagnosed with CKD (mean age, 10.1 ± 4.1 years) and 40 sex- and age-matched healthy controls (mean age, 9.6 ± 4.3 years) were examined. In the patient group, 20 patients had early stage (Stage 2-3) CKD and 20 patients had late-stage (stage 4-5) CKD, and 18 patients had hypertension. The pulmonary artery systolic pressure (PAPs) and LV mass index (LVMI) were significantly higher in the patient group (P < 0.05). The LV septal and lateral margins of the mitral annulus E'/A' ratio, E/E' ratio and MPI results were significantly different between the groups (P < 0.05). The MPI scores were higher in late-stage CKD than in early stage CKD (P < 0.05). The E'/A' ratio was lower and the MPI was higher in the hypertensive CKD group compared with the normotensive CKD group (P < 0.05). The E/E' ratio was correlated positively with the LVMI, and the PAPs, and negatively with glomerular filtration rate, S' value, E'/A' ratio. The MPI was correlated positively with blood pressure, LVMI, PAPs, and the S value, and negatively with the E'/A' ratio. The E'/A' ratio, the E/E' ratio, and the isovolumetric relaxation time measured by tissue Doppler imaging is highly accurate and easily applicable for detecting diastolic LV function, and the MPI is suitable for detecting both systolic and diastolic LV dysfunction. Their routine use may be useful in evaluating LV functions in children with CKD.

Effects of sevelamer carbonate versus calcium acetate on vascular calcification, inflammation, and endothelial dysfunction in chronic kidney disease.

Hyperphosphatemia is present in most patients with end‐stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium‐based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with chronic kidney disease (CKD) treated with sevelamer carbonate (SC) versus calcium acetate (CA). Fifty patients with CKD (stages 3 and 4) were enrolled and assigned to treatment with SC and CA for 12 weeks. At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. A significant increase in HDL‐cholesterol was observed with SC but not with CA in patients with CKD. Treatment with SC reduced serum phosphate, calcium phosphate, and FGF‐23 levels and there was no change with CA treatment. The inflammatory markers IL‐8, IFN‐γ, and TNFα decreased with response to both treatments. The levels of IL‐6 significantly increased with CA treatment and no change was observed in the SC treatment group. SC showed favorable effects on anti‐inflammatory and vascular calcification biomarkers compared to CA treatment in patients with CKD stages 3 and 4 with normal phosphorous values.

Abstract MP21: Circadian Cycle Exaggerates Sympathoexcitatory Responses To Activation Of Chemosensitive Renal Sensory Nerves

Renal sensory nerves contribute to hypertension and renal dysfunction in chronic kidney disease. Selective chemokines (e.g., bradykinin or capsaicin) activate renal sensory nerves and produce reflexive efferent sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses. SNA, ABP, and renal function exhibit circadian patterns; yet the impact of circadian cycle on chemosensitive responses is unknown. We hypothesized that SNA and hemodynamic responses would be greater during the active phrase or nighttime versus the inactive phase or daytime. In Inactin anesthetized rats, simultaneous renal and splanchnic SNA and ABP were measured during intrarenal arterial infusion of capsaicin or bradykinin (0.1 μM - 30.0 μM; 50 μl over 15 s) at nighttime (N; 20:00-04:00; n= 12M, 10F) versus daytime (D; 09:00-16:00; n= 8M, 8F). Baseline mean ABP was significantly elevated during nighttime (N: 104±2 mmHg; D: 97±2 mmHg, p=0.04). Intrarenal capsaicin infusion produced concentration-dependent increases in renal and splanchnic SNA. Renal SNA increased more at nighttime versus daytime at 10 μM (N: 723±136 vs D: 409±79 %; p=0.03) and 30 μM (N: 826±181 vs D: 509±80 %; p=0.03). Similarly, splanchnic SNA was greater during nighttime versus daytime at 10 μM (N: 501±117 vs D: 204±53 %, p=0.03) and 30 μM (N: 537±101 vs D: 295±68 %; p=0.03). However, ABP responses were similar between nighttime versus daytime (30uM: 7±1 vs 6±1 mmHg, respectively). Intrarenal infusion of bradykinin produced concentration-dependent increases in renal and splanchnic SNA. Renal SNA increased more at nighttime versus daytime at 10 μM (N: 1773±216 vs D: 1249±112 %; p=0.01) and 30 μM (N: 2605±263 vs D: 1783±163 %; p=0.001). Similarly, splanchnic SNA was exaggerated at nighttime versus daytime at 0.1 μM (N: 163±65 vs D: 0±0 %; p=0.02), 1.0 μM (N: 566±114 vs D: 184±52 %; p=0.005), 10 μM (N: 1110±193 vs D: 583±87 %; p=0.006) and 30 μM (N: 2008±193 vs D: 1044±162 %; p&lt;0.001). ABP response were similar between nighttime versus daytime at 30 μM (10±2 vs 6±1 mmHg, respectively). Circadian cycle exaggerates sympathoexcitatory responses produced by chemosensitive renal sensory nerve activation.

Impact of Physical Activity and Natural Bioactive Compounds on Endothelial Dysfunction in Chronic Kidney Disease.

Chronic kidney disease (CKD) represents a world-wide public health problem. Inflammation, endothelial dysfunction (ED) and vascular calcifications are clinical features of CKD patients that increase cardiovascular (CV) mortality. CKD-related CV disease pathogenic mechanisms are not only associated with traditional factors such as arterial hypertension and dyslipidemia, but also with ED, oxidative stress and low-grade inflammation. The typical comorbidities of CKD contribute to reduce the performance and the levels of the physical activity in nephropathic patients compared to healthy subjects. Currently, the effective role of physical activity on ED is still debated, but the available few literature data suggest its positive contribution. Another possible adjuvant treatment of ED in CKD patients is represented by natural bioactive compounds (NBCs). Among these, minor polar compounds of extra virgin olive oil (hydroxytyrosol, tyrosol and oleocanthal), polyphenols, and vitamin D seem to exert a beneficial role on ED in CKD patients. The objective of the review is to evaluate the effectiveness of physical exercise protocols and/or NBCs on ED in CKD patients.

Effect of diabetes mellitus on markers of left ventricular dysfunction in chronic kidney disease

ObjectivesTo identify markers of left ventricular dysfunction in chronic kidney disease (CKD) and the effects of diabetes mellitus on them. MethodsThis was a cross sectional study of 200 consecutive chronic kidney disease patients (stage III-V). Echocardiographic assessment of left ventricular function including left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left atrial volume, grade of diastolic dysfunction, E/E’, left and right ventricular myocardial performance indices (LVMPI, RVMPI) were compared between diabetic and non-diabetic CKD. ResultsLVMI significantly increased with increasing stage of CKD (p < 0.001) in both diabetics (158.82 ± 48.76 gm/m2 in stage III to 201.06 ± 63.62 gm/m2 in stage V) and non-diabetics (133.14 ± 43.06 gm/m2 stage III to 196.24 ± 58.75 gm/m2 in stage V). This was significantly higher among diabetics of similar CKD stage compared to non-diabetics (p = 0.001). The LVEF worsened with increasing stage of CKD (p = 0.002) and was significantly reduced in diabetic patients (LVEF 61.96 ± 8.48 % in stage III CKD to 51.62 ± 13.45 % in stage V CKD) (p < 0.001). Diastolic dysfunction (Grades ≥2) and LA volume increased significantly with stage of CKD (p < 0.001) and was higher among diabetics (p = 0.048). Pulmonary artery systolic pressure (PASP) increased with increasing stage of CKD (p < 0.001), and was higher among diabetics (p = 0.035). E/E’ worsened significantly with increasing stage of CKD and was also significantly higher in diabetics (p < 0.001). LVMPI (p < 0.001) and RVMPI (p < 0.001) were significantly reduced with worsening stage of CKD and in diabetics. ConclusionAdvancing CKD stage was linearly associated with progressive left ventricular dysfunction which was significantly greater in diabetics.

Εndothelial and microvascular function in CKD: Evaluation methods and associations with outcomes.

Cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). Endothelial dysfunction, the hallmark of atherosclerosis, is suggested to be involved pathogenetically in cardiovascular and renal disease progression in these patients. This is a narrative review presenting the techniques and markers used for assessment of microvascular and endothelial function in patients with CKD and discussing findings of the relevant studies on the associations of endothelial dysfunction with co-morbid conditions and outcomes in this population. Venous Occlusion Plethysmography was the first method to evaluate microvascular function; subsequently, several relevant techniques have been developed and used in patients with CKD, including brachial Flow-Mediated Dilatation, and more recently, Near-Infrared Spectroscopy and Laser Speckle Contrast Analysis. Furthermore, several circulating biomarkers are commonly used in clinical research. Studies assessing endothelial function using the above techniques and biomarkers suggest that endothelial dysfunction occurs early in CKD and contributes to the target organ damage, cardiovascular events, death and progression towards end-stage kidney disease. Older and newer functional methods and several biomarkers have assessed endothelial dysfunction in CKD; accumulated evidence supports an association of endothelial dysfunction with outcomes. Future research with new, non-invasive and easily applicable methods could further delineate the role of endothelial dysfunction on cardiovascular and renal disease progression in patients with CKD.

Особливості гормонального тестування тиреоїдної функції у пацієнтів із цукровим діабетом 1-го типу і хронічною хворобою нирок

Актуальність. Перебіг хронічної хвороби нирок (ХХН) може впливати на метаболізм тиреоїдних гормонів. Встановлено, що зниження ниркової функції може поєднуватися зі змінами функції щитоподібної залози (ЩЗ). Тиреоїдна дисфункція також має наслідки для ренального потоку крові, швидкості клубочкової фільтрації (ШКФ), канальцевого транспорту, електролітного гомеостазу та структури клубочків. Мета дослідження— визначити особливості функції ЩЗ у пацієнтів із цукровим діабетом (ЦД) 1-го типу та ХХН, на підставі чого розробити рекомендації щодо термінів гормонального тестування тиреоїдної патології. Матеріали та методи. З метою визначення оптимальних термінів гормонального тестування була проведена оцінка тиреоїдної функції у 121 пацієнта з ЦД 1-го типу та ХХН. Пацієнти з ЦД 1-го типу та ХХН були розділені на 3 групи: перша— 78 осіб із ШКФ ≤ 60 мл/хв/1,73 м2, група 2— 20 осіб, які отримують нирково-замісну терапію (НЗТ), група 3— 23 особи після трансплантації нирки (ТН) з адекватною функцією трансплантату (тривалість роботи ниркового трансплантату— 3,62 (1,47–4,28) року). Результати. У пацієнтів із ЦД 1-го типу та ХХН знижена діагностична цінність рівня тиреотропного гормону (ТТГ) у зв’язку з відсутністю відмінностей його значень при зниженні вільного тироксину (вТ4) і вільного трийодтироніну (вТ3). Найбільш чутливим маркером тиреоїдної дисфункції є вТ3. Генез тиреоїдних порушень у пацієнтів з ЦД 1-го типу та ХХН має неімунну природу. У пацієнтів із ЦД 1-го типу, які отримують НЗТ, після процедури гемодіалізу відбувається збільшення периферичних загальних вТ4 і вТ3, що обумовлює необхідність моніторингу функціональних порушень ЩЗ безпосередньо після проведення сеансу гемодіалізу. Після ТН відбувається відновлення нормальних значень індексу периферичної конверсії (ІПК) і вТ3 протягом 1–2 років залежно від тривалості отримання НЗТ. У пацієнтів із ЦД 1-го типу з тривалістю роботи ренотрансплантату більше трьох років відбувається збільшення ІПК, що характеризує дисбаланс периферичних тиреоїдних гормонів у бік зниження вТ3 при відносно стабільному вТ4. Висновки. Тиреоїдні дисфункції характерні для всіх стадій патологічного процесу при ХХН у пацієнтів із ЦД 1-го типу, включаючи пацієнтів на термінальній стадії і після успішної трансплантації нирки. Зміни тиреоїдних гормонів асоційовані з тривалістю НЗТ, тривалістю роботи ренотрансплантату, а також можуть потенційно впливати на виживання пацієнтів після ТН.

Study of the Prevalence of Echocardiographic Abnormalities and their Relation to Disease Progression in Chronic Kidney Disease

Context: Study of the prevalence of echocardiographic abnormalities and there relation to disease progression in chronic kidney disease (CKD). Aims: Study correlation of echocardiographic changes and CKD progression. Settings and Design: A prospective, cross-sectional, observational, analytical study, where we performed complete echocardiographic evaluation of patients with CKD stage II–V. We compared various echocardiographic parameters to predict the progression of CKD. Subjects and Methods: Ninety CKD patients stage II–V presenting to our hospital from November 2016 to December 2017 were included in the study. A complete echocardiographic evaluation was done. Left ventricular hypertrophy (LVH), systolic and diastolic dysfunction using Doppler indices at mitral inflow, left atrial volume, speckle tracking, and global longitudinal strain (GLS) were studied. Results: Patients were age and sex matched in all the groups with a male preponderance. Forty-one patients (45.56%) were diabetic and 74 (82.22%) were hypertensive. The prevalence of hypertension increased from 66.67% to 89.29% as CKD stage progressed from stage II to stage V. There were significant echocardiographic abnormalities seen in CKD patients. The severity increased with worsening of the stages of CKD. LVH and early diastolic mitral inflow to annular velocity ratio progression was statistically significant when stage V was compared to stage II. Left atrial volume, mitral early diastolic to late diastolic velocity ratio, maximum tricuspid regurgitation (TRmax) velocity, and diastolic dysfunction prevalence were significantly raised in stage IV and stage V compared to stage II. Only GLS showed statistical significance between stage II to stage III, stage IV and stage V and thus predicting progression of CKD. Conclusions: LVH, dilated left atrium, abnormal GLS, TRmax, diastolic dysfunction, and related tissue Doppler imaging parameters correlate with worsening renal function. GLS was the only parameter showing significant difference between stage II and stage III. This can be used as a novel modality for detection of subclinical cardiac dysfunction in CKD.

Preparation of Gold Nanoparticles and Its Effect on Autophagy and Oxidative Stress in Chronic Kidney Disease Cell Model.

Gold nanoparticles (GNPs) are widely used in life sciences and medicine due to their simple preparation, stable physical and chemical properties, controllable optical properties and no significant toxicity. However, in recent years, studies have found that there are still many uncertain factors in the application of gold nanoparticles in the field of biomedicine, and there are few studies on the main excretion organs and kidneys of the body, especially the toxicological effects under the disease state have not been reported. Obviously, carrying out relevant research is of great significance for accelerating the clinical application of GNPs. Chronic kidney disease (CKD) is a group of chronic progressive diseases that have high prevalence and high mortality and are serious threats to human life and health. Renal tubular injury and interstitial fibrosis are key factors in renal dysfunction in chronic kidney disease. Drug and toxic kidney damage mostly involve renal tubular epithelial cells; hypoxia is the most common pathological condition of cells. In renal lesions, renal tubular epithelial cells often have hypoxia. Based on this, we propose the hypothesis of this study: glomerular filtration membrane damage in kidney disease, GNPs increase in urine, followed by reabsorption of renal tubular epithelial cells, thereby causing damage to the latter; if accompanied by hypoxia, GNPs it will aggravate renal tubular epithelial cell damage and promote tubulointerstitial fibrosis. In order to verify the above hypothesis, this study used a mouse model of adriamycin nephropathy and tubular epithelial cells and macrophages in vitro, and observed the damage of GNPs on renal tubular epithelial cells by various means, and explored related mechanisms. The results show that under normal oxygen conditions, GNPs can induce autophagy after cell entry, which can damage damaged proteins and organelles to maintain cell survival. In the absence of oxygen, nanoparticles entering cells increase and induce excessive autophagy. In the absence of oxygen, GNPs also aggregate in macrophages, which can cause decreased cell proliferation activity and induce activation of macrophage inflammasome, which induces inflammatory response: GNPs-induced secretion of hypoxic macrophages can be promoted.