scholarly journals Shedding of Klotho: Functional Implications in Chronic Kidney Disease and Associated Vascular Disease

2021 ◽  
Vol 7 ◽  
Author(s):  
Valeria Saar-Kovrov ◽  
Marjo M. P. C. Donners ◽  
Emiel P. C. van der Vorst
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Function ◽  
Transmembrane Protein ◽  
Protein A ◽  
Cardiovascular Complications ◽  
Soluble Form ◽  
Functional Implications ◽  
Membrane Bound ◽  
Underlying Mechanisms

α-Klotho (Klotho) exists in two different forms, a membrane-bound and soluble form, which are highly expressed in the kidney. Both forms play an important role in various physiological and pathophysiological processes. Recently, it has been identified that soluble Klotho arises exclusively from shedding or proteolytic cleavage. In this review, we will highlight the mechanisms underlying the shedding of Klotho and the functional effects of soluble Klotho, especially in CKD and the associated cardiovascular complications. Klotho can be cleaved by a process called shedding, releasing the ectodomain of the transmembrane protein. A disintegrin and metalloproteases ADAM10 and ADAM17 have been demonstrated to be mainly responsible for this shedding, resulting in either full-length fragments or sub-fragments called KL1 and KL2. Reduced levels of soluble Klotho have been associated with kidney disease, especially chronic kidney disease (CKD). In line with a protective effect of soluble Klotho in vascular function and calcification, CKD and the reduced levels of soluble Klotho herein are associated with cardiovascular complications. Interestingly, although it has been demonstrated that soluble Klotho has a multitude of effects its direct impact on vascular cells and the exact underlying mechanisms remain largely unknown and should therefore be a major focus of further research. Moreover, functional implications of the cleavage process resulting in KL1 and KL2 fragments remain to be elucidated.

Does Vitamin K Intake Influence High Phosphate Induced Vascular Pseudo-ossification: An Underappreciated Therapeutic Prospect in General Population?

2019 ◽  
Vol 20 (4) ◽  
pp. 421-430
Author(s):  
Zar Chi Thent ◽  
Gabriele R.A. Froemming ◽  
Suhaila Abd Muid
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Prolonged Exposure ◽  
Vascular Complication ◽  
Key Factors ◽  
The Matrix ◽  
Underlying Mechanisms ◽  
High Phosphate

Increasing interest in vascular pseudo-ossification has alarmed the modern atherosclerotic society. High phosphate is one of the key factors in vascular pseudo ossification, also known as vascular calcification. The active process of deposition of the phosphate crystals in vascular tissues results in arterial stiffness. High phosphate condition is mainly observed in chronic kidney disease patients. However, prolonged exposure with high phosphate enriched foods such as canned drinks, dietary foods, etc. can be considered as modifiable risk factors for vascular complication in a population regardless of chronic kidney disease. High intake of vitamin K regulates the vascular calcification by exerting its anti-calcification effect. The changes in serum phosphate and vitamin K levels in a normal individual with high phosphate intake are not well investigated. This review summarised the underlying mechanisms of high phosphate induced vascular pseudo ossification such as vascular transdifferentiation, vascular apoptosis and phosphate uptake by sodium-dependent co-transporters. Pubmed, Science Direct, Scopus, ISI Web of Knowledge and Google Scholar were searched using the terms ‘vitamin K’, ‘vascular calcification, ‘phosphate’, ‘transdifferentiation’ and ‘vascular pseudoossification’. Vitamin K certainly activates the matrix GIA protein and inhibits vascular transition and apoptosis in vascular pseudo-ossification. The present view highlighted the possible therapeutic linkage between vitamin K and the disease. Understanding the role of vitamin K will be considered as potent prophylaxis agent against the vascular disease in near future.

scholarly journals New Pathogenic Concepts and Therapeutic Approaches to Oxidative Stress in Chronic Kidney Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-21 ◽  
Author(s):  
José Pedraza-Chaverri ◽  
Laura G. Sánchez-Lozada ◽  
Horacio Osorio-Alonso ◽  
Edilia Tapia ◽  
Alexandra Scholze
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Cardiovascular Complications ◽  
Vitamin D Metabolism ◽  
Therapy Options ◽  
Mitochondrial Alterations ◽  
Inflammatory Processes ◽  
The Impact

In chronic kidney disease inflammatory processes and stimulation of immune cells result in overproduction of free radicals. In combination with a reduced antioxidant capacity this causes oxidative stress. This review focuses on current pathogenic concepts of oxidative stress for the decline of kidney function and development of cardiovascular complications. We discuss the impact of mitochondrial alterations and dysfunction, a pathogenic role for hyperuricemia, and disturbances of vitamin D metabolism and signal transduction. Recent antioxidant therapy options including the use of vitamin D and pharmacologic therapies for hyperuricemia are discussed. Finally, we review some new therapy options in diabetic nephropathy including antidiabetic agents (noninsulin dependent), plant antioxidants, and food components as alternative antioxidant therapies.

scholarly journals Endothelium-Dependent and -Independent Vascular Function in Advanced Chronic Kidney Disease

2017 ◽  
Vol 12 (10) ◽  
pp. 1588-1594 ◽  
Author(s):  
Tal Kopel ◽  
James S. Kaufman ◽  
Naomi Hamburg ◽  
John S. Sampalis ◽  
Joseph A. Vita ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Vascular Function ◽  
Advanced Chronic Kidney Disease

scholarly journals THU0300 RISK FACTORS FOR COMPLICATIONS AND REFRACTORY COURSE IN PATIENTS WITH ANCA-ASSOCIATED SYSTEMIC VASCULITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 378.2-378
Author(s):  
A. Chudinov ◽  
I. Belyaeva ◽  
M. Pervakova ◽  
V. Mazurov ◽  
O. Inamova ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Induction Therapy ◽  
Granulomatosis With Polyangiitis ◽  
Disease Risk ◽  
Systemic Vasculitis ◽  
Cardiovascular Complications ◽  
Infectious Complications ◽  
Eosinophilic Granulomatosis With Polyangiitis

Background:ANCA-associated systemic vasculitis (AAV) is characterized by a high incidence of complications and high mortality. The most significant complications during the first 3 years of the disease are infectious and cardiovascular. Development of chronic kidney disease also impairs the prognosis of AAV. Refractory to induction therapy can significantly increase the severity of organ lesions in patients with AAV.Objectives:The aim of this study was to determine risk factors for complications and refractory course in patients with AAV.Methods:Patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) were observed during the first 3 years of the disease and included in this study between 2010 and 2018. Most common infectious complications requiring inpatient treatment were pneumonia, mycosis, sepsis, purulent arthritis, purulent otitis media. Cardiovascular complications included pulmonary thromboembolism, myocardial infarction, ischemic stroke, venous thrombosis.Results:In total 209 (165 [79%] female and mean age 51.8 ± 13.2 years) AAV patients (94 GPA; 46 MPA; and 69 EGPA) were included in the analysis. Risk factors for infectious complications were BVAS level at the beginning of induction therapy > 25 (OR – 2.92, 95% CI (1.53;5.45) p<0.001), usage of prednisone in doses more than 60 mg / day at the induction of remission (OR – 2.76, 95% CI (1.45;5.29) p=0.003), usage of prednisone in doses ≥ 10 mg / day after 6 months of induction therapy (OR – 2.60, 95% CI (1.38;4.93) p=0.003), ANCA-PR3 positivity (OR – 2.25, 95% CI (1.13;4.46) p=0.017) and presence of diabetes mellitus in the AAV onset (OR – 1.77, 95% CI (1.14;3.45) p=0.038). Patients with AAV had following risk factors for cardiovascular complications: male (OR – 2.28, 95% CI (1.33;3.88) p=0.002), BVAS level > 25 (OR – 2.1, 95% CI (1.11;3.16) p=0.008) and presence of coronary artery disease in the AAV onset (OR – 2.2, 95% CI (1.18;4.10) p=0.015). ANCA positivity (OR – 5.62, 95% CI (2.1;14.9) p<0.001), presence of rapidly progressive glomerulonephritis in the first 3 months from onset AAV (OR – 5.02, 95% CI (3.42;7.35) p<0.001) and over 60 years of age (OR – 2.17, 95% CI (1.38;3.44) p=0.001) were risk factors of development of chronic kidney disease. Risk factors for refractory to induction therapy in patients with AAV were ANCA-PR3 positivity (OR – 3.13, 95% CI (1.63;6.02) p<0.001), BVAS level > 25 (OR – 2.63, 95% CI (1.74;4.34) p<0.001), initiation of therapy after 4 months from the onset of clinical manifestations (OR – 2.17, 95% CI (1.26;3.91) p=0.005). We additionally defined that identification of pathological phenotypes of alpha-1-antitrypsin was risk factors for refractory course in patients with GPA manifestations (OR – 2.66, 95% CI (1.12;6.33) p=0.048).Conclusion:Our study has shown that high disease activity, ANCA positivity and comorbid pathology increase risk of serious complications. Early administration of immunosuppressive therapy, adequate steroid dosing and use of risk factors for complications and refractory course in clinical practice can significantly improve the prognosis of AAV.Disclosure of Interests:None declared

Abstract 109: Gamma-adducin Effects on Microvascular Function- a Common Link of Hypertension Induced Chronic Kidney Disease and Cognitive Impairments

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Shaoxun Wang ◽  
Paige N Mims ◽  
Chao Zhang ◽  
Richard J Roman
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Genetic Model ◽  
Cognitive Impairments ◽  
Microvascular Dysfunction ◽  
Small Region ◽  
Glomerular Injury ◽  
Flow Pressure ◽  
Underlying Mechanisms ◽  
Stop Flow

Chronic kidney disease (CKD) and cognitive impairments are common complications of hypertension. Increasing evidence suggests that the cognitive impairments associated with CKD may be related to microvascular dysfunction, however, the underlying mechanisms remain to be elucidated. FHH is a genetic model of hypertension-induced nephropathy. We found that the myogenic response and autoregulation of the renal and cerebral circulation is impaired in FHH rats, and was restored in a FHH.1 BN congenic strain in which a small region of Chr. 1 containing 15 genes, including Add3, from BN rats was transferred into the FHH background. The present study examined whether Add3 contributes to hypertension related CKD, and is associated with the development of cognitive impairments due to microvascular dysfunction. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1 BN rats. Pgc estimated from the stop flow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in FHH.1 BN . FHH rats developed severe renal injury, and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1 BN and FHH.Add3 rats. Glomerular injury scores were 3.31 ± 0.01, 2.54 ± 0.01 and 2.50 ± 0.03, and areas of fibrosis in renal cortex were 23.57 ± 1.04%, 8.28 ± 0.33 and 4.71 ± 0.3 in DOCA/salt induced hypertensive FHH, FHH.1 BN and FHH.Add3 rats, respectively. CBF rose by 99 ± 7%, 64 ± 5% and 42 ± 4% in FHH, FHH.1 BN and FHH.Add3 rats, respectively, when MAP was increased from 100 to 190 mmHg, demonstrating impaired autoregulation of CBF in FHH rats was partially rescued with the replacement of wildtype Add3. BBB leakage was greater in FHH rats than in FHH.1 BN and FHH.Add3 rats, and hypertensive FHH rats exhibited marked neurodegeneration and vascular remodeling of the neocortex and hippocampus. The hypertensive FHH rats took 2.5 times longer time to escape from an eight-arm water maze in comparison to FHH.1 BN rats suggesting cognitive deficit. These results indicate that Add3 may play a role in the development of hypertension related CKD and cognitive impairments in FHH rats associated with microvascular dysfunction.

Abstract 16926: The Effects of a Mitochondrial Targeted Ubiquinone (MitoQ) on Vascular Function in Chronic Kidney Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Danielle L Kirkman ◽  
Ninette Shenouda ◽  
Joseph M Stock ◽  
Bryce J Muth ◽  
Nicholas Chouramanis ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Brachial Artery ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Aortic Pressure ◽  
Double Blind ◽  
Reflected Waves ◽  
Arterial Hemodynamics ◽  
Artery Flow

Introduction: Aberrant vascular function contributes to the substantially high cardiovascular burden of chronic kidney disease (CKD). Mitochondrial derived oxidative stress is a potential therapeutic target to ameliorate CKD related vascular dysfunction. Hypothesis: We hypothesized that a mitochondrial targeted antioxidant (MitoQ) would improve vascular function in Stage 3-5 CKD patients without overt cardiovascular disease. Methods: In this controlled, double-blind trial, 18 CKD patients (Mean±SEM: Age, 62±3 years; eGFR, 45±3 ml•min•1.73 2 ) were randomized to receive an oral dose of MitoQ (20mg/day; MTQ) or a Placebo (PLB) for 4 weeks. Outcome measures were assessed at week 0 and week 4. Aortic pressure waves were synthesized from brachial artery waveforms acquired by oscillometry and the use of a generalized transfer function. The central pressure waveform was separated into forward and reflected waves using a triangular flow waveform. Conduit artery vascular function was assessed via brachial artery flow mediated dilation (FMD). Results: MitoQ was well tolerated and patient compliance was high (MTQ, 99.6±0.4%; PLB, 97.8±2.2%). Independent of peripheral (Baseline vs. Follow Up: MTQ, 140±6 vs. 137±6 mmHg; PLB, 136±4 vs. 134±6 mmHg; interaction p=0.7) and central (MTQ, 128±5 vs. 123±6 mmHg; PLB, 124±3 vs. 123±5 mmHg; interaction p=0.8) systolic blood pressures, MitoQ maintained forward wave amplitudes (MTQ, 31±3 vs. 29±1 mmHg; PLB, 29±3 vs. 36±3 mmHg; interaction p=0.05) and tended to reduce reflected wave amplitudes (MTQ, 18±2 vs. 16±1 mmHg; PLB, 19±2 vs. 21±2 mmHg; interaction p=0.04). MitoQ administration favored improvements in FMD (MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; interaction p=0.04). Conclusions: These results suggest that targeting mitochondrial derived reactive oxygen species holds promise as a potential therapeutic strategy to improve CKD related vascular dysfunction. Whether MitoQ related improvements in arterial hemodynamics are a result of augmented cardiac function or a reduction in vascular resistance warrants future investigation in larger studies.

Pediatric problems of stratification of the severity of stages, cardiovascular complications and renal forecast of chronic kidney disease by NKF-K / DOQI (2002) and KDIGO (2012) classifications

2021 ◽  
Vol 25 (3) ◽  
pp. 9-19
Author(s):  
N. D. Savenkova ◽  
O. P. Grigoreva
Keyword(s):  
Chronic Kidney Disease ◽  
High Risk ◽  
Kidney Disease ◽  
Pediatric Patients ◽  
Cardiovascular Complications ◽  
High Risk Group ◽  
Cardiovascular Pathology ◽  
Cardiovascular Prognosis ◽  
Renal Prognosis

Chronic kidney disease (CKD) in children is a global problem worldwide. The article discusses the problem of stratification of CKD severity according to the classifications of the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K / DOQI) (2002) and Kidney Disease Improving Global Outcomes (KDIGO) (2012) in pediatric patients. There are limitations in assessing severity of CKD stages C1-5 according to NKF-K / DOQI (2002) and KDIGO (2012) in children under 2 years of age who have a low glomerular filtration rate in contrast to adults. The stratification of the severity of stages 1-5 of CKD, cardiovascular complications and renal prognosis in children and adolescents according to the classifications NKF-K / DOQI (2002) [3] and KDIGO (2012) [14] are discussed. In adult patients with CKD, there is a compelling case for identifying of C3a and C3b sub stages in 3 stages of CKD according to KDIGO (2012) was that renal and cardiovascular prognosis are different with GFR 45-59 ml/min/1.73 m 2and GFR 30-44 ml/min/1.73 m 2 . The prognosis of the risk of developing cardiovascular diseases and complications for stages C2-5 in accordance with the KDIGO classification (2012) in children and adults differ. As follows from the publications, children with CKD in the pre-dialysis stages C2-4 form a high-risk group, with C4-5 on dialysis a group of very high risk of complications associated with cardiovascular pathology. Cardiovascular complications account for more than 30 % of all deaths of pediatric patients with CKD C4-5 on dialysis. The arguments justifying the allocation of CKD stages C1-5 in children under 2 years of age in accordance with the classification of NKF-K/DOQI (2002) are presented.

scholarly journals Oxidative Balance and Inflammation in Hemodialysis Patients: Biomarkers of Cardiovascular Risk?

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Daniele La Russa ◽  
Daniela Pellegrino ◽  
Alberto Montesanto ◽  
Paolo Gigliotti ◽  
Anna Perri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Renal Function ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Cardiovascular Events ◽  
Cardiovascular Complications ◽  
Hemodialysis Patients ◽  
Healthy Population ◽  
Oxidative Balance

During chronic kidney disease, the progressive deterioration of renal function induces several biological/clinical dysfunctions, including enhancement of synthesis of inflammation/oxidative stress mediators. Impaired renal function is an independent cardiovascular risk factor; indeed, cardiovascular complications dominate the landscape of both chronic kidney disease and end-stage renal disease. The aim of this study is to explore the correlation between the global oxidative balance in hemodialysis patients and both inflammatory markers and cardiovascular events. Using photometric tests, this study explored plasmatic oxidative balance in 97 hemodialysis patients compared to a healthy population. In the hemodialysis patients, we showed that oxidative stress values were significantly lower than in controls while effectiveness in the antioxidant barrier was significantly increased in the hemodialysis group. Furthermore, we highlighted a strong correlation between oxidative index and blood levels of C-reactive protein. When patients were divided into two groups based on previous cardiovascular events, we found that subjects with previous cardiovascular events had higher values of both oxidative stress and antioxidant barrier than patients without cardiovascular events. Our results indicated that in hemodialysis patients, the clinical and prognostic significance of oxidative status is very different from general population. As cardiovascular complications represent a strong negative factor for survival of hemodialysis patients, the research of new cardiovascular risk biomarkers in these patients takes on particular importance in order to translate them into clinical practice/primary care.

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