BACKGROUND: Activation of nuclear factor-kappa B (NF-κB) signalling is key in the pathogenesis of chronic kidney disease (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: The relationship between activated and inactivated NF-κB signaling and the pathogenesis of CKD was investigated using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of interleukin 6, Tumor necrosis factor receptor associated factor 1 and Nef-associated factor 1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by periodic acid-Schiff, Masson trichrome and Sirius Red staining, as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine ratio are markedly increased in NF-κB-activated and -inactivated mice compared with controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared with wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.
- MeSH
- chronická renální insuficience metabolismus patologie etiologie MeSH
- fibróza MeSH
- hypertenze * metabolismus etiologie MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- NF-kappa B * metabolismus MeSH
- signální transdukce * MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient's prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. METHODS: CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. RESULTS: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. CONCLUSIONS: Our results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.
- MeSH
- antagonisté endotelinového receptoru A * farmakologie terapeutické užití MeSH
- chronická renální insuficience * komplikace farmakoterapie metabolismus MeSH
- endotelin-1 metabolismus MeSH
- inhibitory ACE farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- ledviny MeSH
- píštěle * metabolismus MeSH
- potkani transgenní MeSH
- receptor endotelinu A metabolismus MeSH
- renin-angiotensin systém MeSH
- srdeční selhání * farmakoterapie etiologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Data on the anti-Xa efficacy of fondaparinux in dialysis-dependent chronic kidney disease (DD-CKD) patients are scarce. This study characterizes the pharmacokinetics (PK) and pharmacodynamics (PD) of fondaparinux in DD-CKD patients undergoing renal replacement therapy (RRT), to assess dosing strategies. METHODS: A retrospective, observational study was conducted using data on anti-Xa activity (112 samples) from 12 (3 male and 9 female) DD-CKD patients (median (IQR) age 71 years (63-88), weight 73 kg (59-98.5)). Eleven patients underwent high-flux or low-flux hemodialysis (HD) and one patient underwent peritoneal dialysis. Three patients were also treated with therapeutic plasma exchange (TPE). A non-linear mixed effects analysis was performed using NONMEM 7.3.0. RESULTS: The lab-specific slope of the relationship between fondaparinux concentration and anti-Xa levels was 1.18 IU/μg. In a one-compartment model, clearance (CL) and volume of distribution (Vd) were 0.05289 L/h and 5.55 L, respectively. High-flux HD was found to increase the CL of fondaparinux 2.26 times. TPE also considerably increased CL, but the fold-change could not be accurately estimated. Low-flux HD and peritoneal dialysis did not impact PK parameters. CONCLUSIONS: Model-based simulations showed that standard dosing (2.5 mg three times weekly before HD) results in a median anti-Xa activity of 0.55 IU/mL and 0.98 IU/mL, pre- and post-low-flux HD, respectively. In patients undergoing high-flux HD, these values are approximately 27% lower. Additional caution is warranted with TPE, as this treatment can reduce anti-Xa activity even further.
- MeSH
- chronická renální insuficience metabolismus terapie MeSH
- fondaparinux farmakokinetika farmakologie MeSH
- inhibitory faktoru Xa farmakokinetika farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- náhrada funkce ledvin * MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- tělesná hmotnost MeSH
- věkové faktory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
It is generally accepted that angiotensin II plays an important role in high blood pressure (BP) development in both 2-kidney-1-clip (2K1C) Goldblatt hypertension and in partial nephrectomy (NX) model of chronic kidney disease (CKD). The contribution of sympathetic nervous system and nitric oxide to BP control in these models is less clear. Partial nephrectomy or stenosis of the renal artery was performed in adult (10-week-old) male hypertensive heterozygous Ren-2 transgenic rats (TGR) and normotensive control Hannover Sprague Dawley (HanSD) rats and in Wistar rats. One and four weeks after the surgery, basal blood pressure (BP) and acute BP responses to the consecutive blockade of renin-angiotensin (RAS), sympathetic nervous (SNS), and nitric oxide (NO) systems were determined in conscious rats. Both surgical procedures increased plasma urea, a marker of renal damage; the effect being more pronounced following partial nephrectomy in hypertensive TGR than in normotensive HanSD rats with a substantially smaller effect in Wistar rats after renal artery stenosis. We demonstrated that the renin-angiotensin system does not play so fundamental role in blood pressure maintenance during hypertension development in either CKD model. By contrast, a more important role is exerted by the sympathetic nervous system, the activity of which is increased in hypertensive TGR-NX in the developmental phase of hypertension, while in HanSD-NX or Wistar-2K1C it is postponed to the established phase. The contribution of the vasoconstrictor systems (RAS and SNS) was increased following hypertension induction. The role of NO-dependent vasodilation was unchanged in 5/6 NX HanSD and in 2K1C Wistar rats, while it gradually decreased in 5/6 NX TGR rats.
- MeSH
- chronická renální insuficience komplikace metabolismus patofyziologie MeSH
- hypertenze komplikace metabolismus patofyziologie MeSH
- krevní tlak fyziologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- potkani Sprague-Dawley MeSH
- potkani transgenní MeSH
- potkani Wistar MeSH
- renin-angiotensin systém * MeSH
- sympatický nervový systém patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney disease (CKD). Information on the activity of cardiac sympathetic innervation is non-homogeneous and incomplete. The aim of our study was to evaluate the tonic effect of SNS on heart rate, norepinephrine turnover and direct and indirect effects of norepinephrine in left ventricles of subtotally nephrectomized rats (SNX) in comparison with sham-operated animals (SHAM). Renal failure was verified by measuring serum creatinine and urea levels. SNX rats developed increased heart rates and blood pressure (BP). The increase in heart rate was not caused by sympathetic overactivity as the negative chronotropic effect of metipranolol did not differ between the SNX and SHAM animals. The positive inotropic effects of norepinephrine and tyramine on papillary muscle were not significantly different. Norepinephrine turnover was measured after the administration of tyrosine hydroxylase inhibitor, pargyline, tyramine, desipramine, and KCl induced depolarization. The absolute amount of released norepinephrine was comparable in both groups despite a significantly decreased norepinephrine concentration in the cardiac tissue of the SNX rats. We conclude that CKD associated with renal denervation in rats led to adaptive changes characterized by an increased reuptake and intracellular norepinephrine turnover which maintained normal reactivity of the heart to sympathetic stimulation.
- MeSH
- chronická renální insuficience komplikace metabolismus patofyziologie MeSH
- kardiovaskulární nemoci etiologie MeSH
- ledviny metabolismus MeSH
- modely nemocí na zvířatech MeSH
- nefrektomie MeSH
- neuropeptid Y metabolismus MeSH
- noradrenalin krev MeSH
- peptid spojený s genem pro kalcitonin metabolismus MeSH
- potkani Wistar MeSH
- srdeční frekvence MeSH
- srdeční komory metabolismus patofyziologie MeSH
- sympatický nervový systém patofyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- veverimer,
- MeSH
- acidóza * etiologie farmakoterapie metabolismus MeSH
- chronická renální insuficience * farmakoterapie komplikace metabolismus MeSH
- hydrogenuhličitany metabolismus MeSH
- lidé MeSH
- polymery aplikace a dávkování terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
AIM: Pentose phosphate pathway (PPP) with key enzyme transketolase (TKT), represents a potentially 'protective' mechanism in hyperglycaemia. Diabetic kidney disease (DKD), a common complication of both type 1 and type 2 diabetes associated with significant morbidity and mortality, represents the most common cause of chronic kidney disease (CKD). We hypothesized that protective PPP action in diabetes and eventually even more severely in concomitant DKD might be compromised by limited intracellular availability of an active TKT cofactor thiamine diphosphate (TDP). METHODS: Effect of hyperglycaemia on gene expression and protein levels of key PPP loci was studied in vitro using human cell lines relevant to diabetes (HUVEC and HRGEC) and (together with measurement of TKT activity, plasma thiamine and erythrocyte TDP concentration) in vivo in diabetic vs. non-diabetic subjects with comparable renal function (n=83 in total). RESULTS: Hyperglycaemia significantly decreased protein levels of RFC-1, THTR1, THTR2 and TKT (P<0.05) in vitro. Analysis of blood samples from CKD patients with and without diabetes and from controls did not reveal any difference in gene expression and protein levels of thiamine transporters while TKT activity and TDP in erythrocytes gradually increased with decreasing kidney function being highest in patients with CKD3-4 of both diabetic and non-diabetic aetiology. Hyperglycaemia and uremic serum mimicking CKD in diabetes did not affect TKT activity in vitro (P<0.05). CONCLUSION: Both in vitro and human experiments showed decrease or unchanged expression, respectively, of thiamine transporters induced by hyperglycaemia while TKT activity in parallel with intracellular TDP was increased in CKD patients with or without diabetes. Therefore, lack of adaptive increase of thiamine transmembrane transport allowing further increase of TKT activity might contribute to compromised PPP function in diabetes and CKD and to the development of glycotoxic injury.
- MeSH
- biologický transport MeSH
- chronická renální insuficience metabolismus MeSH
- diabetes mellitus 2. typu metabolismus MeSH
- diabetické nefropatie metabolismus MeSH
- dospělí MeSH
- erytrocyty metabolismus MeSH
- hyperglykemie metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- thiamin metabolismus MeSH
- transketolasa metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- chronická renální insuficience * komplikace metabolismus MeSH
- fosfor krev MeSH
- kalcitriol terapeutické užití MeSH
- kosti a kostní tkáň anatomie a histologie metabolismus patofyziologie MeSH
- lidé MeSH
- minerálová a kostní nemoc při chronickém onemocnění ledvin diagnóza MeSH
- poruchy metabolismu fosforu * diagnóza patologie MeSH
- poruchy metabolismu vápníku * diagnóza patologie MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- vápník krev MeSH
- vaskulární kalcifikace etiologie metabolismus MeSH
- vitamin D analogy a deriváty terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
- práce podpořená grantem MeSH
- MeSH
- albuminurie MeSH
- alopurinol aplikace a dávkování metabolismus MeSH
- antihypertenziva aplikace a dávkování metabolismus MeSH
- chronická renální insuficience farmakoterapie klasifikace metabolismus MeSH
- diabetes mellitus 2. typu farmakoterapie MeSH
- dyslipidemie farmakoterapie MeSH
- hodnoty glomerulární filtrace MeSH
- hyperurikemie farmakoterapie MeSH
- hypoglykemika aplikace a dávkování metabolismus MeSH
- hypolipidemika aplikace a dávkování metabolismus MeSH
- inhibitory agregace trombocytů aplikace a dávkování metabolismus MeSH
- kardiovaskulární nemoci farmakoterapie MeSH
- léková kontraindikace MeSH
- lidé MeSH
- multimorbidita MeSH
- náhrada funkce ledvin metody MeSH
- nežádoucí účinky léčiv MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- lidé MeSH
- MeSH
- anemie etiologie farmakoterapie komplikace MeSH
- chronická renální insuficience komplikace metabolismus patologie MeSH
- kardiovaskulární systém metabolismus patologie MeSH
- lidé MeSH
- náhrada funkce ledvin MeSH
- podvýživa etiologie komplikace MeSH
- poruchy acidobazické rovnováhy dietoterapie etiologie komplikace MeSH
- poruchy metabolismu fosforu etiologie farmakoterapie komplikace MeSH
- poruchy metabolismu lipidů etiologie farmakoterapie komplikace MeSH
- poruchy metabolismu vápníku etiologie farmakoterapie komplikace MeSH
- Check Tag
- lidé MeSH
