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1.
Arch Endocrinol Metab ; 63(4): 427-437, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365625

RESUMO

OBJECTIVE: Chronic kidney disease (CKD) risk is inconsistent in the normal-weight, overweight, and obese individuals due to the heterogeneity of metabolic status. This meta-analysis aimed to examine the combined effects of body mass index (BMI) and metabolic status on CKD risk. MATERIALS AND METHODS: The MEDLINE, EMBASE, and Web of Knowledge databases were systematically searched up to March 2019 to identify all eligible studies investigating the CKD risk (defined as GFR < 60 mL/min per 1.73 m2 and/or microalbuminuria or proteinuria) associated with the body size phenotypes which are known as metabolically unhealthy normal-weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight, metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO). The classification of subjects in included studies as metabolically unhealthy was based on the presence of three components of metabolic syndrome. BMI categorization was based on the criteria of included studies. The risk estimates and 95% confidence intervals (CIs) were extracted and pooled using random effects analysis. RESULTS: A total of 9 prospective cohort studies with 128773 participants and 4797 incident cases were included in the meta-analysis. Compared with healthy normal-weight individuals as reference, MUNW and MHO subjects showed an increased risk for CKD events with a pooled RR of 1.58 (95% CI = 1.28-1.96) in MUNW and 1.55 (95% CI = 1.34-1.79) in MHO persons. Also, MHOW was at increased risk for CKD (RR = 1.34, 95% CI = 1.20-1.51). MUHO individuals were at the highest risk for the development of CKD (RR = 2.13, 95% CI = 1.66-2.72). CONCLUSIONS: Individuals with metabolic abnormality, although at normal-weight, have an increased risk for CKD. Healthy overweight and obese individuals had higher risk; refuting the notion that metabolically healthy overweight and obese phenotypes are benign conditions.


Assuntos
Peso Corporal/genética , Síndrome Metabólica/genética , Fenótipo , Insuficiência Renal Crônica/genética , Índice de Massa Corporal , Humanos , Síndrome Metabólica/metabolismo , Estudos Observacionais como Assunto , Insuficiência Renal Crônica/metabolismo , Risco
2.
Life Sci ; 232: 116604, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260684

RESUMO

Chronic kidney disease (CKD) patients present L-arginine (L-arg) deficiency and L-arg supplementation has been used as a treatment. In addition, sarcopenia is another common problem in CKD population, resistance training (RT) is one of the conservative strategies developed to prevent CKD progression, and however there are no evidences of a combination of these two strategies to treat CKD outcomes. The aim of this study was to evaluate the effects of oral L-arg supplementation combined with RT in an experimental model of CKD. Twenty-five Munich-Wistar male rats, 8-week-old were divided in 5 groups: Sham (sedentary control), Nx (CKD sedentary), Nx L-arg (CKD sedentary supplemented with 2% of L-arg), Nx RT (CKD exercised) Nx RT + L-arg (CKD exercised and supplemented with 2% of L-arg). CKD model was obtained by a subtotal 5/6 nephrectomy. RT was performed on a ladder climbing, three weekly sessions on non-consecutive days, with an intensity of 70% maximum carrying capacity. They were submitted to RT and/or L-arg supplementation for 10 weeks. There was a significant improvement in muscle strength, renal function, anti-inflammatory cytokines, arginase metabolism and renal fibrosis after RT. However, the combination of RT and L-arg impaired all the improvements promoted by RT alone. The L-arg supplementation alone did not impair renal fibrosis and renal function. In conclusion, RT improved inflammatory balance, muscle strength, renal function and consequently decreased renal fibrosis. Nevertheless, the association with L-arg supplementation prevented all these effects promoted by RT.


Assuntos
Arginina/farmacologia , Condicionamento Físico Animal/fisiologia , Insuficiência Renal Crônica/dietoterapia , Animais , Arginina/metabolismo , Citocinas/metabolismo , Suplementos Nutricionais , Progressão da Doença , Fibrose/metabolismo , Rim/metabolismo , Masculino , Força Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal/métodos , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Treinamento de Resistência/métodos
3.
Cell Mol Life Sci ; 76(23): 4705-4724, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31350618

RESUMO

Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23-αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Nefropatias/patologia , Animais , Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/genética , Glucuronidase/química , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Nefropatias/metabolismo , Domínios Proteicos , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais
4.
Lancet ; 394(10196): 396-406, 2019 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-31248662

RESUMO

BACKGROUND: Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. METHODS: We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate 12-20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. FINDINGS: Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0·001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life-Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12·1 points (SE 3·3; p<0·0001). Time to do the repeat chair stand test improved by 4·3 s (1·2) on veverimer versus 1·4 s (1·2) on placebo (p<0·0001). INTERPRETATION: In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. FUNDING: Tricida.


Assuntos
Acidose/tratamento farmacológico , Polímeros/administração & dosagem , Insuficiência Renal Crônica/complicações , Acidose/etiologia , Acidose/metabolismo , Administração Oral , Idoso , Bicarbonatos/metabolismo , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polímeros/efeitos adversos , Insuficiência Renal Crônica/metabolismo , Resultado do Tratamento
5.
Mol Immunol ; 112: 247-255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31202101

RESUMO

Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-ß (TGF-ß) plays a pivotal role in progression of renal fibrosis. TGF-ß transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-ß, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-ß, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.


Assuntos
Fibrose/tratamento farmacológico , Limoninas/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Obstrução Ureteral/fisiopatologia , Animais , Transição Epitelial-Mesenquimal , Fibrose/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/metabolismo
6.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071929

RESUMO

(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-ß-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.


Assuntos
Alanina/análogos & derivados , Cálcio/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Sulfetos/farmacologia , Uremia/tratamento farmacológico , Alanina/química , Alanina/farmacologia , Aminoácidos Sulfúricos/efeitos dos fármacos , Aminoácidos Sulfúricos/metabolismo , Linhagem Celular , Cistationina beta-Sintase/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Oxirredução , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Sulfetos/química , Uremia/genética , Uremia/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
7.
Endokrynol Pol ; 70(2): 171-189, 2019.
Artigo em Polonês | MEDLINE | ID: mdl-31070771

RESUMO

Adipose tissue is currently considered not only as an energy store but also as an organ of internal secretion. Numerous adipocytokines regulating a number of human body processes are important in many disease processes, including chronic kidney disease (CKD). Nowadays, the role of zinc α2-glycoprotein (ZAG) is being sought as a potential link between these two organs. ZAG, through its lipolytic effect, contributes to progressive malnutrition in patients undergoing dialysis, and this significantly increases their mortality. It seems that ZAG may be a new potential biomarker of kidney damage, and the specific pharmacotherapy will significantly reduce the progressive process of cachexia.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Desnutrição/metabolismo , Insuficiência Renal Crônica/metabolismo , Proteínas de Plasma Seminal/metabolismo , Biomarcadores/sangue , Humanos , Metabolismo dos Lipídeos , Comunicação Parácrina
8.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052201

RESUMO

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease.


Assuntos
Hipertensão/complicações , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Angiotensinas/metabolismo , Animais , Humanos , Hipertensão/metabolismo , Fator 1 Induzível por Hipóxia/metabolismo , Insuficiência Renal Crônica/etiologia
9.
J Trace Elem Med Biol ; 54: 206-213, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31109613

RESUMO

Chronic kidney disease of uncertain etiology (CKDu) in areas in and around Sri Lanka's North Central Province has been identified as a major non-communicable disease due to its high prevalence and the burden on the public health system. Controversial evidence relating to the etiology and risk factors of CKDu has been reported. The most debated is the role of trace elements such as Cd and As in the pathogenesis of CKDu. Urine and hair samples collected from CKDu patients and healthy controls were measured for the concentration of different elements including Cd and As. To assess the possible environmental exposures, drinking water and rice samples collected from the affected areas as well as unaffected areas in the country were analyzed. Transmission electronic microscopic analysis of renal biopsies from CKDu patients was also performed. Analysis of drinking water and rice samples indicated that the levels of all minerals and trace elements analyzed including Cd and As were within the levels recommended by World Health Organization and Sri Lanka drinking water guidelines and did not suggest any form of contamination. Analysis of biological samples, including urine, hair and renal tissue, did not provide evidence to support Cd or As toxicity in CKDu patients. Overall, the observations of this integrated, comprehensive study, which included biological, environmental and pathological investigations, strongly support our previous reports on the absence of Cd and As toxicity in areas with high prevalence of CKDu. Further, these observations do not provide evidence on the involvement of Cd and As in pathogenesis of CKDu in Sri Lanka.


Assuntos
Água Potável/química , Minerais/análise , Oligoelementos/análise , Arsênico/análise , Cádmio/análise , Exposição Ambiental , Humanos , Oryza/química , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/urina , Sri Lanka
10.
Int J Mol Sci ; 20(10)2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109090

RESUMO

Chronic kidney disease (CKD) is associated with atherogenic dyslipidemia. Our aim was firstly to investigate patterns of fatty acids (FA) composition through various stages of CKD, and secondly, to evaluate the effect of CKD-specific FA disturbances on the expression of genes related to lipid metabolism at a cellular level. Serum FA composition was analyzed in 191 patients with consecutive severity stages of CKD, and 30 healthy controls free from CKD. Next, HepG2 human hepatic cells were treated with major representatives of various FA groups, as well as with FA extracted from a mix of serums of controls and of CKD stage 5 patients. Across worsening stages of CKD severity, there was an increasing monounsaturated FA (MUFA) content. It was associated with a concomitant decrease in n-3 and n-6 polyunsaturated FA. The incubation of hepatocytes with FA from CKD patients (compared to that of healthy subjects), resulted in significantly higher mRNA levels of genes involved in FA synthesis (fatty acid synthase (FASN) increased 13.7 ± 3.5 times, stearoyl-CoA desaturase 1 (SCD1) increased 4.26 ± 0.36 times), and very low density lipoprotein (VLDL) formation (apolipoprotein B (ApoB) increased 7.35 ± 1.5 times, microsomal triacylglycerol transfer protein (MTTP) increased 2.74 ± 0.43 times). In conclusion, there were progressive alterations in serum FA composition of patients with CKD. These alterations may partly contribute to CKD hypertriglyceridemia by influencing hepatocyte expression of genes of lipid synthesis and release.


Assuntos
Dislipidemias/etiologia , Dislipidemias/metabolismo , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/metabolismo , Biomarcadores , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Humanos , Testes de Função Renal , Metabolismo dos Lipídeos , Lipogênese , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética , Transcriptoma
11.
BMC Complement Altern Med ; 19(1): 107, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118021

RESUMO

BACKGROUND: Excessive activation of NLRP3 inflammasome and down-regulation of Sirt1/Smad3 deacetylation pathway play a significant role in the evolution of renal fibrosis. In China, it has been well known that Chinese herbal medicine is markedly effective in treating chronic kidney disease (CKD). Shen Shuai IIRecipe (SSR) has been used clinically for more than 20 years and has been confirmed to be effective in improvements of renal function and fibrosis. However, the specific mechanisms under the efficacy require further research. The purpose of this study was to evaluate whether SSR could alleviate renal injury and fibrosis by regulating NLRP3 inflammasome and Sirt1/Smad3 deacetylation pathway. METHODS: Four weeks after 5/6 ablation/infarction (A/I) surgery, Sprague-Dawley rats were randomly divided into the following groups: sham operation group, 5/6 (A/I) group, 5/6 (A/I) + SSR group, and 5/6 (A/I) + Losartan group (5/6 (A/I) + Los). After 8 weeks intervention,we mainly assessed the severity of renal injury and fibrosis along with the activation of NLRP3 inflammasome and Sirt1/Smad3 deacetylation pathway. RESULTS: SSR significantly attenuated renal injury and fibrosis in the remnant kidneys. In addition, we found that SSR effectively inhibited activation of NLRP3/ASC/Caspase-1/IL-1ßcascade, decreased inflammatory infiltration and up-regulated Sirt1/Smad3 deacetylation pathway. CONCLUSIONS: SSR could contribute to renal protection by inhibiting the activation of NLRP3 inflammasome and, furthermore, strengthen the antifibrotic effects by up-regulating Sirt1/Smad3 deacetylation pathway in 5/6 renal (A/I) model.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteína Smad3/metabolismo , Acetilação/efeitos dos fármacos , Animais , Fibrose/metabolismo , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
12.
Int J Mol Sci ; 20(7)2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30959940

RESUMO

Fatty acid (FA) profiles in the plasma of patients with metabolic syndrome and chronic kidney disease (CKD) seem to be identical despite their different etiology (dietary mistakes vs. cachexia). The aim of this study was to compare both profiles and to highlight the differences that could influence the improvement of the treatment of patients in both groups. The study involved 73 women, including 24 patients with chronic kidney disease treated with haemodialysis, 19 patients with metabolic syndrome (MetS), and 30 healthy women in the control group. A total of 35 fatty acids and derivatives were identified and quantified by gas chromatography. Intensified elongation processes from acid C10:0 to C16:0 were noted in both groups (more intense in MetS), as well as an increased synthesis of arachidonic acid (C20:4n6), which was more intense in CKD. Significant correlations of oleic acid (C18:1n9), gamma linoleic acid (C18:3n6), and docosatetraenoate acid (C22:4n6) with parameters of CKD patients were observed. In the MetS group, auxiliary metabolic pathways of oleic acid were activated, which simultaneously inhibited the synthesis of eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) from alpha lipoic acid (ALA). On the other hand, in the group of female patients with CKD, the synthesis of EPA and DHA was intensified. Activation of the synthesis of oleic acid (C18: 1n9 ct) and trans-vaccinic acid (C18:1) is a protective mechanism in kidney diseases and especially in MetS due to the increased concentration of saturated fatty acid (SFA) in plasma. The cause of the increased amount of all FAs in plasma in the CKD group, especially in the case of palmitic (C16:0) and derivatives stearic (C18:0) acids, may be the decomposition of adipose tissue and the progressing devastation of the organism, whereas, in the MetS group, dietary intake seems to be the main reason for the increase in SFA. Moreover, in MetS, auxiliary metabolic pathways are activated for oleic acid, which cause the simultaneous inhibition of EPA and DHA synthesis from ALA, whereas, in the CKD group, we observe an increased synthesis of EPA and DHA. The higher increase of nervonic acid (C24:1) in CKD suggests a higher degree of demyelination and loss of axons.


Assuntos
Ácidos Graxos/metabolismo , Síndrome Metabólica/metabolismo , Insuficiência Renal Crônica/metabolismo , Ácido Araquidônico/metabolismo , Cromatografia Gasosa , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Feminino , Humanos , Ácido Oleico/metabolismo
13.
Contrib Nephrol ; 198: 103-111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30991401

RESUMO

BACKGROUND: Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and occurs due to diminished renal function. The main cause of such anemia is decreased erythropoietin (EPO) production and secretion from the kidney and a lower erythropoietic response to EPO. Treatment therefore involves erythropoiesis-stimulating agents (ESAs). Optimal erythropoietic response to ESA therapy also requires adequate iron management. However, iron metabolism is also dysregulated in CKD patients. SUMMARY: During erythropoiesis, biomarkers of iron metabolism are dramatically altered by ESA therapy. Hepcidin 25 is a key hormone of iron metabolism that regulates iron absorption from the gut and the release of stored iron out of reticuloendothelial system cells. Recently, erythroferrone has been identified as an erythroid suppressor of hepcidin 25 production. Because erythroferrone levels are significantly increased by ESA treatment in CKD patients, it may be a key factor in facilitating the release of stored iron into the circulation during erythropoiesis in these patients. In this review, we discuss the characteristics of the important biomarkers of iron metabolism in CKD patients and the changes in these biomarkers after ESA administration. Key Messages: In CKD patients, the management of anemia with ESA therapy requires comprehensive assessment of the levels of various biomarkers, with consideration of their optimal and physiological levels during erythropoiesis.


Assuntos
Anemia/tratamento farmacológico , Ferro/metabolismo , Insuficiência Renal Crônica/metabolismo , Anemia/etiologia , Biomarcadores/sangue , Eritropoese , Eritropoetina/biossíntese , Eritropoetina/sangue , Hematínicos/farmacologia , Hematínicos/uso terapêutico , Humanos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico
14.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010001

RESUMO

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Masculino , Miocárdio/patologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
15.
Artigo em Inglês | MEDLINE | ID: mdl-30999273

RESUMO

Changes in metabolites composition can reflect currently present pathological processes in a living organism and constitute a basis for diagnosis and treatment improvements. Thus, the multiplatform metabolomics approach was applied for the investigation of molecular mechanisms of chronic kidney disease (CKD) progression. The high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-TOF-MS) and gas chromatography coupled with triple quadrupole mass spectrometry (GC-QqQ/MS) serum metabolic fingerprinting followed by uni- and multivariate statistical analysis was carried out to determine metabolic pattern differentiating CKD patients and healthy controls. Furthermore, metabolites changes between stage 3 and 4 of the disease, as well as health status were investigated. The progression of the disease was found to be related to alterations in acylcarnitine, amino acid, lysophospholipid and carbohydrate metabolism. Elevated levels of serum acylcarnitines, sugar alcohols, and organic acids, as well as decreased levels of lysophospholipids, and amino acids, were found to be statistically significant for CKD progression. The obtained results confirm the utility of metabolomics approach as a tool for an explanation of molecular processes underlying CKD development.


Assuntos
Metaboloma/fisiologia , Metabolômica/métodos , Insuficiência Renal Crônica , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Carnitina/análogos & derivados , Carnitina/sangue , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão/métodos , Análise por Conglomerados , Progressão da Doença , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/metabolismo
16.
Nat Commun ; 10(1): 1476, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931940

RESUMO

Early detection and accurate monitoring of chronic kidney disease (CKD) could improve care and retard progression to end-stage renal disease. Here, using untargeted metabolomics in 2155 participants including patients with stage 1-5 CKD and healthy controls, we identify five metabolites, including 5-methoxytryptophan (5-MTP), whose levels strongly correlate with clinical markers of kidney disease. 5-MTP levels decrease with progression of CKD, and in mouse kidneys after unilateral ureteral obstruction (UUO). Treatment with 5-MTP ameliorates renal interstitial fibrosis, inhibits IκB/NF-κB signaling, and enhances Keap1/Nrf2 signaling in mice with UUO or ischemia/reperfusion injury, as well as in cultured human kidney cells. Overexpression of tryptophan hydroxylase-1 (TPH-1), an enzyme involved in 5-MTP synthesis, reduces renal injury by attenuating renal inflammation and fibrosis, whereas TPH-1 deficiency exacerbates renal injury and fibrosis by activating NF-κB and inhibiting Nrf2 pathways. Together, our results suggest that TPH-1 may serve as a target in the treatment of CKD.


Assuntos
Fibrose/metabolismo , Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Insuficiência Renal Crônica/metabolismo , Triptofano Hidroxilase/genética , Triptofano/análogos & derivados , Acetilcarnitina/metabolismo , Animais , Canavanina/análogos & derivados , Canavanina/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Estudos de Casos e Controles , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Introdução de Genes , Técnicas de Silenciamento de Genes , Humanos , Inflamação/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Rim/citologia , Rim/efeitos dos fármacos , Rim/patologia , Metabolômica , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Taurina/metabolismo , Triptofano/metabolismo , Triptofano/farmacologia , Obstrução Ureteral
17.
Med Sci Monit ; 25: 2445-2451, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30944297

RESUMO

BACKGROUND The aim of this study was to determine the risk factors for early chronic kidney disease (CKD) (GFR 60-89 ml/min/1.73 m²; CKD stage 2) in asymptomatic Chinese individuals undergoing routine health examination. MATERIAL AND METHODS This cross-sectional study enrolled 9100 individuals who received voluntary medical examinations between 10/01/2011 and 09/30/2017. Demographic data, clinical history, clinical examination, medication, smoking, alcohol, blood biochemistry, urinalysis, and carotid ultrasound were extracted from the medical records. All laboratory analyses were performed routinely. Multivariable logistic regression for factors predicting CKD stage 2 was performed. RESULTS A total of 9100 individuals were enrolled (age of 18-65 and 65.4% male). CKD stage 2 was found in 1989/9100 individuals (21.9%). Male gender (OR=6.711, 95%CI: 5.376-8.403, P<0.001), older age (OR=1.077, 95%CI: 1.068-1.086, P<0.001), hemoglobin levels (OR=1.051, 95%CI: 1.046-1.057, P<0.001), triglycerides levels (OR=1.174, 95%CI: 1.067-1.292, P=0.001), HDL-C (OR=0.539, 95%CI: 0.380-0.763, P<0.001), Lp(a) levels (OR=1.000, 95%CI: 1.000-1.001, P=0.03), and carotid atherosclerosis (OR=1.248, 95%CI: 1.005-1.550, P=0.045) were associated with CKD stage 2 among all subjects. Serum triglycerides levels were associated with CKD stage 2 in the 18-45 and 45-65 years of age subgroups. CONCLUSIONS Factors that are routinely assessed during routine health examinations (male gender, age, hemoglobin levels, triglycerides levels, HDL-C, Lp(a) levels, and carotid atherosclerosis) can help identify individuals at higher risk of having CKD stage 2. The Chinese dyslipidemia is characterized by high triglycerides and low HDL-C and occurs in young and middle-aged individuals. Those factors could help identify individuals at higher risk for CKD stage 2 and who could benefit from preventive treatments.


Assuntos
Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Triglicerídeos/metabolismo , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Doenças das Artérias Carótidas/complicações , China , HDL-Colesterol/sangue , Estudos Transversais , Dislipidemias/diagnóstico , Dislipidemias/metabolismo , Feminino , Taxa de Filtração Glomerular/fisiologia , Hemoglobinas/análise , Humanos , Hipertensão/complicações , Hipertrigliceridemia/complicações , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Triglicerídeos/análise , Triglicerídeos/sangue , Adulto Jovem
19.
J Pak Med Assoc ; 69(3): 343-348, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30890825

RESUMO

OBJECTIVE: To investigate the efficacy of L-carnitine (LC) and conjugated linoleic acid (CLA) supplements on haemoglobin levels and inflammatory markers in chronic kidney disease (CKD) patients with different haptoglobin (HP) genotypes. METHODS: This clinical trial study was conducted at Imam Khomeini Hospital, Ardabil, and Labbafinejad Hospital, Tehran, Iran, from March 2014 to March 2015, and comprised male patients with CKD and anaemia. Anthropometric factors were recorded and demographic data was collected using general questionnaires. LC (1 g/day) and CLA (2.4 g/day) supplements were given to the patients for a month. Blood samples were taken to measure haematological and inflammatory markers at the beginning and end of the study. Haptoglobin genotypes were determined using polymerase chain reaction (PCR). SPSS 21 was used for data analysis. RESULTS: Among the 40 patients in the study, HP2-2 genotype was the most prevalent genotype (62.5%). The level of haemoglobin was significantly increased in the patients at the end of the study (p< 0.05). No significant changes were found in the weight, body mass index and serum levels of Interleukin-6, high-sensitivity C-reactive protein, ferritin, total iron-binding capacity and iron (p>0.05 each). CONCLUSIONS: Regular diet supplementation with LC plus CLA can improve haemoglobin levels in CKD patients with anaemia.


Assuntos
Anemia/terapia , Carnitina/uso terapêutico , Suplementos Nutricionais , Hemoglobinas/metabolismo , Ácidos Linoleicos Conjugados/uso terapêutico , Insuficiência Renal Crônica/metabolismo , Adulto , Anemia/complicações , Anemia/metabolismo , Proteína C-Reativa/imunologia , Ferritinas/metabolismo , Genótipo , Haptoglobinas/genética , Humanos , Inflamação , Interleucina-6/imunologia , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/imunologia
20.
Nutrients ; 11(4)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925738

RESUMO

Obesity and hyperlipidemia are the most prevalent independent risk factors of chronic kidney disease (CKD), suggesting that lipid accumulation in the renal parenchyma is detrimental to renal function. Non-esterified fatty acids (also known as free fatty acids, FFA) are especially harmful to the kidneys. A concerted, increased FFA uptake due to high fat diets, overexpression of fatty acid uptake systems such as the CD36 scavenger receptor and the fatty acid transport proteins, and a reduced ß-oxidation rate underlie the intracellular lipid accumulation in non-adipose tissues. FFAs in excess can damage podocytes, proximal tubular epithelial cells and the tubulointerstitial tissue through various mechanisms, in particular by boosting the production of reactive oxygen species (ROS) and lipid peroxidation, promoting mitochondrial damage and tissue inflammation, which result in glomerular and tubular lesions. Not all lipids are bad for the kidneys: polyunsaturated fatty acids (PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to help lag the progression of chronic kidney disease (CKD). Lifestyle interventions, especially dietary adjustments, and lipid-lowering drugs can contribute to improve the clinical outcome of patients with CKD.


Assuntos
Rim/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Animais , Transporte Biológico/fisiologia , Proteínas de Transporte , Humanos , Rim/patologia
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