Chronic Uremia Research Articles

Mitochondrial dysfunction in uremic cardiomyopathy.

Uremic cardiomyopathy (UCM) is characterized by metabolic remodelling, compromised energetics, and loss of insulin-mediated cardioprotection, which result in unsustainable adaptations and heart failure. However, the role of mitochondria and the susceptibility of mitochondrial permeability transition pore (mPTP) formation in ischemia-reperfusion injury (IRI) in UCM are unknown. Using a rat model of chronic uremia, we investigated the oxidative capacity of mitochondria in UCM and their sensitivity to ischemia-reperfusion mimetic oxidant and calcium stressors to assess the susceptibility to mPTP formation. Uremic animals exhibited a 45% reduction in creatinine clearance (P < 0.01), and cardiac mitochondria demonstrated uncoupling with increased state 4 respiration. Following IRI, uremic mitochondria exhibited a 58% increase in state 4 respiration (P < 0.05), with an overall reduction in respiratory control ratio (P < 0.01). Cardiomyocytes from uremic animals displayed a 30% greater vulnerability to oxidant-induced cell death determined by FAD autofluorescence (P < 0.05) and reduced mitochondrial redox state on exposure to 200 μM H2O2 (P < 0.01). The susceptibility to calcium-induced permeability transition showed that maximum rates of depolarization were enhanced in uremia by 79%. These results demonstrate that mitochondrial respiration in the uremic heart is chronically uncoupled. Cardiomyocytes in UCM are characterized by a more oxidized mitochondrial network, with greater susceptibility to oxidant-induced cell death and enhanced vulnerability to calcium-induced mPTP formation. Collectively, these findings indicate that mitochondrial function is compromised in UCM with increased vulnerability to calcium and oxidant-induced stressors, which may underpin the enhanced predisposition to IRI in the uremic heart.

Improvement in spatial memory dysfunction by telmisartan through reduction of brain angiotensin II and oxidative stress in experimental uremic mice

AimsWe previously reported that chronic uremia induces spatial working memory dysfunction in mice, and that it is attributed to cerebral oxidative stress. The source of oxidative stress was considered to be uremic toxins, but this remains unclear. In the present study, we examined whether the brain renin–angiotensin system was activated in the CKD mouse model, and whether it contributed to cognitive impairment. Main methodsCKD was induced in 8-week-old male mice by 5/6 nephrectomy. Mice were divided into four groups: control mice administered tap water (Cont-V), control mice treated with 0.5mg/kg/day telmisartan, an angiotensin II (AII) receptor blocker, for 8weeks (Cont-T), CKD mice administered tap water (CKD-V), and CKD mice treated with 0.5mg/kg/day telmisartan for 8weeks (CKD-T). After the treatment period, a radial arm water maze (RAWM) test was performed, and angiotensin II (AII) concentrations and markers of oxidative stress were measured in the brains of mice. Key findingsErrors in the RAWM test were more frequent in the CKD-V group than in the Cont-V group. In addition, errors in the CKD-T group were comparable to control mice. Tissue brain AII concentrations were greater in the CKD-V group compared with the other groups. Oxidative DNA damage and lipid peroxidation in the brain were also greater in the CKD-V group compared with the other groups. SignificanceOur results suggest that brain AII levels were exaggerated in CKD mice, and that this contributes to cognitive impairment through oxidative stress.

Cardiovascular Remodelling In Chronic Kidney Disease

Left ventricular (LV) structure and function abnormalities are frequent in patients with chronic uraemia; these disorders increase the risk of cardiovascular (CV) and overall morbidity and mortality in the predialysed population, during dialysis treatment, and in renal transplant recipients. Since the first description of the association between chronic kidney disease (CKD) and heart disease, many epidemiological studies have confirmed and extended this finding. The risk of cardiovascular disease (CVD) is notably increased in patients with CKD. When adjusted for traditional CV risk factors, impaired kidney function increases the risk of CVD 2 to 4-fold. CVD is frequently underdiagnosed and undertreated in patients with CKD. This review will attempt to summarise current knowledge of the prevalence and pathophysiological mechanisms of LV disease in chronic uraemia, and to discuss useful medical strategies in this population.

S100/Calgranulin-mediated inflammation accelerates left ventricular hypertrophy and aortic valve sclerosis in chronic kidney disease in a receptor for advanced glycation end products-dependent manner.

S100A12 and fibroblast growth factor 23 are biomarkers of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9, and S100A12 was expressed in C57BL/6J mouse (hBAC-S100) to generate a novel humanized mouse model. CKD was induced by ureteral ligation, and hBAC-S100 mice and wild-type mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased fibroblast growth factor 23 in the hearts, left ventricular hypertrophy, diastolic dysfunction, focal cartilaginous metaplasia, and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in wild-type mice with CKD or in hBAC-S100 mice lacking the receptor for advanced glycation end products with CKD, suggesting that the inflammatory milieu mediated by S100/receptor for advanced glycation end products promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including interleukin-6, tumor necrosis factor-α, lipopolysaccarides, or serum from hBAC-S100 mice upregulated fibroblast growth factor 23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a receptor for advanced glycation end products-dependent manner in a mouse model of CKD. We speculate that fibroblast growth factor 23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate left ventricular hypertrophy and diastolic dysfunction in hBAC-S100 mice with CKD.

Comparison of AMG 416 and cinacalcet in rodent models of uremia

BackgroundAMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis.MethodsAMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the “1K1C” model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively).ResultsAdministration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals.ConclusionsAs a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.

The effect of uraemia on the duration of arrhythmias in the context of cardioprotective ischaemic conditioning strategies

BackgroundSudden cardiac death is a leading cause of death in patients with chronic kidney disease and end stage renal disease. Ischaemic conditioning strategies confer profound myocardial protection and, in the...

Antagonisme de l’interleukine 1 dans le diabète de type 1 récent : des résultats décevants… mais attendus ?

Natural interleukin-2 at low dose has been reported to overcome the non-responsiveness of patients with chronic uraemia to hepatitis B vaccine. Therefore, we revaccinated 52 previous such non-responders (24 on maintenance dialysis) with 20 μg of recombinant preS2–containing hepatitis B vaccine with human recombinat interleukin-2 (1 MU) or placebo (randomly allocated). Seroconversion rates (74 vs 80%, respectively) and proportion of patients who elicited anti-HBs titres of 10 m/U/mL or more (56 vs 68%) were similar in both groups. Our rsults do not confirm local injection of interleukin-2 as an effective imunoadjuvant to hepatitis B vaccine in uraemic patients. Lancet 1994; 344: 856–57

Is there a Role for Home Dialysis and what is Home Dialysis Today?

The global economic crisis, the pressure toward de-hospitalization of chronic patients, and the innovations in the treatment of chronic uremia are the basis of the increased interest in “non-conventional or intensive” dialysis treatments, often necessarily performed at home. A first point highlighted in this narrative review is the overcoming of the historical antagonism between home hemodialysis (HHD) and peritoneal dialysis (PD), by the motto “home dialysis first”. In fact, justifying the decreased use of an HHD technique with the competition with another technique, PD, is as simplistic as considering that the ideal HHD patients are those who dropped out from PD. On the contrary, PD and HHD may even potentiate one another in settings requiring specific care. In this review we analyzed the issue of home dialysis also according to the four principles of the so-called principlism bioethics: beneficium, non maleficium, justice, and autonomy. If the benefit is not easy to prove, mainly because of the peculiar selection of the patients, the non maleficium is evident: in all the studies analyzed home hemodialysis (standard, daily, or intensive) led to results that were never significantly lower than conventional treatments, and were actually superior in most of the cases. The principle of justice, considered in a reductive way as “distributive” economical justice, was analyzed by evaluating the cost of treatment. Once more the issue is complex; in brief, direct costs were divided in costs of disposables and machines, and cost of medical and nursing staff. The economic benefit of reducing the workforce is obvious; however, a home treatment needs a “critical mass” of patients to be favorable from the economic point of view. Furthermore, the “indirect” costs (e.g., the hospital “structure”) are difficult to quantify. In any case, in no study the cost of HHD was higher than that of in-center HD. The fourth principle is patient's autonomy: there is however no choice without offer. Hence, physicians should be able to offer HHD to all patients without contraindications, by creating accessible reference centers where patients can be counseled by doctors, nurses, and patients with specific experience.

Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport

The pharmacokinetics of non-renally cleared drugs in patients with chronic kidney disease is often unpredictable. Some of this variability may be due to alterations in the expression and activity of extra-renal drug metabolizing enzymes and transporters, primarily localized in the liver and intestine. Studies conducted in rodent models of renal failure have shown decreased mRNA and protein expression of many members of the cytochrome P450 enzyme (CYP) gene family and the ATP-Binding Cassette (ABC) and Solute Carrier (SLC) gene families of drug transporters. Uremic toxins interfere with transcriptional activation, cause down-regulation of gene expression mediated by proinflammatory cytokines, and directly inhibit the activity of the cytochrome P450s and drug transporters. While much has been learned about the effects of kidney disease on non-renal drug disposition, important questions remain regarding the mechanisms of these effects, as well as the interplay between drug metabolizing enzymes and drug transporters in the uremic milieu. In this review, we have highlighted the existing gaps in our knowledge and understanding of the impact of chronic kidney disease on non-renal drug clearance, and identified areas of opportunity for future research.

Clinical studies and chronic kidney disease: what did we learn recently?

This article summarizes relevant clinical studies that recently were devoted to the role of uremic toxins in outcomes of patients with chronic kidney disease and uremia. We summarize observational data linking uremic toxins (phosphate, the dimethylarginines, uric acid, and several large peptidic middle molecules and protein-bound solutes) to outcomes in observational studies. Interventional studies that evaluate the impact of different removal strategies on uremic toxin concentration in end-stage renal disease are then summarized along with clinical outcome studies with different dialysis strategies. Finally, we focuse on interventions in chronic kidney disease patients who are not yet on dialysis. We conclude that although there are more and more data on how to better remove uremic toxins by dialysis and nondialysis strategies, convincing evidence of the impact of these strategies on hard outcomes is much scarcer.

Esiste oggi un ruolo per l'emodialisi domiciliare e che cos'è oggi l'emodialisi domiciliare?

La crisi economica globale, l'indicazione alla massima deospedalizzazione dei pazienti cronici e le innovazioni nel trattamento dell'uremia cronica sono alla base del rinnovato interesse per trattamenti dialitici “non convenzionali o intensivi”, spesso od obbligatoriamente domiciliari. Un primo punto evidenziato da questa revisione narrativa della letteratura è il superamento dell'antagonismo storico tra emodialisi domiciliare (HHD) e dialisi peritoneale (PD), all'insegna del motto “home dialysis first”: ascrivere il successo di una metodica domiciliare alla competizione con l'altra è riduttivo quanto il considerare che i pazienti ideali per l'HHD siano principalmente i soggetti che hanno dovuto interrompere la dialisi peritoneale. Ciò detto, è possibile scomporre il problema della dialisi domiciliare non solo secondo criteri clinici, ma anche secondo i quattro principi etici di beneficio, non maleficio, giustizia e autonomia. Se il beneficio non è facile da dimostrare, anche per la peculiare selezione dei pazienti, il non maleficio è evidente: in tutti gli studi analizzati, l'emodialisi domiciliare, sia essa standard o quotidiana o intensiva, non risulta mai significativamente inferiore ai trattamenti convenzionali. Il principio della giustizia, inteso in maniera un po' riduttiva come giustizia distributiva, può essere analizzato valutando i costi del trattamento, divisi tra costi diretti (disposable e macchine) e costo del personale medico e infermieristico; il vantaggio economico della riduzione del personale è ovvio, ma va anche ricordato che un sistema domiciliare necessita di una massa critica per essere favorevole dal punto di vista economico e che i costi “indiretti” (struttura ospedaliera in particolare) sono difficili da quantificare. Il quarto principio è l'autonomia dei pazienti: per questo sarebbe necessario offrire l'emodialisi domiciliare a tutti coloro che ne hanno le indicazioni, creando dei Centri di riferimento accessibili, dove i pazienti possano ascoltare il parere di medici, infermieri e pazienti con esperienza specifica.

A Cross-sectional Study by Esophagogastroduodenoscopy for Occult Bleeding in Chronic Hemodialysis Patients at Tanta in Egypt

Background and study aims: Chronic hemodialysis patients are susceptible to a lot of complications. Gastrointestinal bleeding is one of the most serious and important complications in these patients result from many contributing factors like chronic uremia, stress and drugs. The present study is concerned with assessment the magnitude of occult gastrointestinal bleeding in chronic hemodialysis patients. Moreover we analyzed type and site of lesions accused in this bleeding. Patients and methods: this study was performed in the period from April 2013 to October 2013, included a ninety chronic hemodialysis patients; fifty three males (58.9%) and thirty seven females (41.1%), at the Nephrology and Hemodialysis unit of Tanta university hospital, all patients investigated for occult bleeding by fecal occult blood test and detecting iron deficiency anemia, and those positive occult bleeding patients were the target of this study to be investigated by esophagogastroduodenoscopy (EGD). If EGD was normal; further colonoscopy was performed however it is not the interest of this study. Results: 23/90 (25.6%) chronic hemodialysis patients were diagnosed to be suffering from occult bleeding. Fecal occult blood test, iron deficiency anemia and both of them were positive in 9, 11 and 3 patients respectively. EGD succeeded to detect source of bleeding in 11/14 occult bleeding chronic hemodialysis patients (78.6%). Stomach (61.1%) and erosions (38.8%) were the most common site and cause of occult bleeding in the studied chronic hemodialysis patients respectively. Conclusions: Occult bleeding was not infrequent in this study (25.6%); Moreover, Upper gastrointestinal lesions detected by EGD were common in the studied chronic hemodialysis patients with occult bleeding (78.6%). Stomach and erosions were the most common site and type of lesions respectively.

Can We Tackle with Vascular Calcification and Arterial Stiffness in Patients with Chronic Kidney Disease?

Cardiovascular disease remains the leading cause of increased morbidity and mortality in patients with chronic kidney disease and is attributed to early and accelerated atherosclerosis and arteriosclerosis observed in this patient population. Vascular calcifications, particularly of the media, are commonly found in chronic uremia and are a major contributor to arteriosclerosis and increased arterial stiffness. Epidemiologic data support the correlation of vascular calcification and arterial stiffness to adverse cardiovascular outcomes and mortality. Experimental evidence has shed light on the pathogenetic mechanisms of vascular calcification and arterial stiffness and their relation to impaired bone metabolism and imbalance between promoters and inhibitors of extra-osseous bone formation. However further research is needed to clarify their exact contribution and whether their targeting could significantly affect vascular calcification and arterial stiffening and could improve survival in chronic kidney disease patients.

Two tiny injections method in renal MRI

Objective To study tiny injection for raising its success rate.Methods 48 patients corresponding to the selective criteria were diagnosed with of chronic renal insufficiency,chronic renal insufficiency uremia and hypertension.Scalp needle was connected with a 5 ml 0.9％ NS (saline) syringe vein puncture,puncture vein successfully piloted projectile injection 0.9％NS (saline),then renal imaging agent tiny injection.Results The successful rate of tiny injection was 100％ in the observation group and 94％ in the control group.Conclusions The injection method of the observation group can ensure the success of the injection of imaging agent,so that the check is complete on the same day.Methods in the observation group has social benefit,can be popularized clinically. Key words: Method; Injection; Projectile; Renal dynamics

High-density lipoprotein in uremic patients: metabolism, impairment, and therapy

Several studies have shown that HDL has altered antioxidant and anti-inflammatory effects in chronic uremia, either by the reduction in its antioxidant enzymes or by the impairment of their activity. Systemic oxidative stress, which is highly prevalent in chronic kidney disease (CKD) patients, has been shown to decrease antioxidant and anti-inflammatory effects of HDL and even transform it into a pro-oxidant and pro-inflammatory agent. For this reason, we believe that the propensity for accelerated cardiovascular disease in CKD is facilitated by a few key features of this disease, namely, oxidative stress, inflammation, hypertension, and disorders of lipid metabolism. In a nutshell, oxidative stress and inflammation enhance atherosclerosis leading to increased cardiovascular mortality and morbidity in this population. In this detailed review, we highlight the current knowledge on HDL dysfunction and impairment in chronic kidney disease as well as the available therapy.

Conformational Changes of Blood ACE in Chronic Uremia

BackgroundThe pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes.HypothesisToxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors.Methodology/Principal FindingsThe recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The “short” ACE inhibitor enalaprilat (tripeptide analog) and “long” inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors.Conclusions/SignificanceThe estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy.

Response to Letter Regarding Article, “Ischemic Conditioning Protects the Uremic Heart in a Rodent Model of Myocardial Infarction”

We are grateful to Csont and Ferdinandy for their letter in response to our recent article.1 We are encouraged by their work, which demonstrated the cardioprotective effect of postconditioning 10 weeks after a subtotal nephrectomy. The 4-week subtotal nephrectomy model is the most widely used model of chronic uremia and displays many of the common characteristics that define the uremic phenotype. The 4-week subtotal nephrectomy model leads to animals that are growth restricted, hypertensive, anemic, dyslipidemic, …

Blackberry pigment (whitlockite) gallstones in uremic patient

Black pigment gallstones represent nearly the 15% of all gallstones and are usually related with the typical "hyperbilirubinbilia" factors as hemolysis, ineffective erythropoiesis, pathologic enterohepatic cycling of unconjugated bilirubin, cirrhosis and with gallbladder mucosa (parietal) factors as adenomyomatosis. During a prospective study on 179 patients who underwent cholecystectomy for gallstone disease a 69-year-old female with predialysis chronic kidney disease was operated for symptomatic gallstone. The removed gallstones were black pigment gallstones, with an irregular (as small blackberry) surface. Analysis of the stones revealed a great amount of whitlockite (Ca Mg)3 (PO4)2. Recent studies on chronic renal failure patients found that chronic uremia is associated with an increased risk of gallstones formation (22%) as it seems in women affected by primary hyperparathyroidism (30%). The presence of calcium phosphate gallstones in these patients have been never described. In conclusion, further studies could be necessary to establish the role of chronic renal failure and of primary and secondary hyperparathyroidism in gallstones formation and, in particular, if dialysis and predialysis patients have an higher risk to develop cholesterol and black pigment gallstones in particular of the "blackberry" (whitlockite) subtype.

Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1): A POSSIBLE MECHANISM OF METABOLIC NEUROPATHIES

Neuropathic pain can develop as an agonizing sequela of diabetes mellitus and chronic uremia. A chemical link between both conditions of altered metabolism is the highly reactive compound methylglyoxal (MG), which accumulates in all cells, in particular neurons, and leaks into plasma as an index of the severity of the disorder. The electrophilic structure of this cytotoxic ketoaldehyde suggests TRPA1, a receptor channel deeply involved in inflammatory and neuropathic pain, as a molecular target. We demonstrate that extracellularly applied MG accesses specific intracellular binding sites of TRPA1, activating inward currents and calcium influx in transfected cells and sensory neurons, slowing conduction velocity in unmyelinated peripheral nerve fibers, and stimulating release of proinflammatory neuropeptides from and action potential firing in cutaneous nociceptors. Using a model peptide of the N terminus of human TRPA1, we demonstrate the formation of disulfide bonds based on MG-induced modification of cysteines as a novel mechanism. In conclusion, MG is proposed to be a candidate metabolite that causes neuropathic pain in metabolic disorders and thus is a promising target for medicinal chemistry.

Klinische Probleme der Urämie

Uremia describes the consequences of intoxication in chronic renal failure with substances that are renally cleared in healthy individuals. Acute uremia is a syndrome of gastrointestinal symptoms, pericarditis, pleuritis, and central nervous system alterations ending with coma. These symptoms can be resolved by renal replacement therapy. In addition, chronic uremia can result in damage of multiple organ systems, which continues to advance despite dialysis therapy. This is caused by retention of toxins that cannot be adequately removed due to insufficient treatment time or a molecular weight range hampering elimination. Uremic toxins can be generated by the energy or nucleic acid metabolism, they can be proteins or large molecules that are altered chemically by the uremic milieu. Chronic uremia can influence the majority of long-term complications of chronic renal failure: systemic microinflammation, cardiovascular disease, immunodeficiency, malnutrition, anemia, bone metabolism, and polyneuropathy. There are few therapeutic options other than kidney transplantation.