Pathogenesis Of Uremia Research Articles

New insights into the pathogenesis of uremia and the significance of nitrogen retention

There is a view on azotemic uremia that it depends on nitrogen retention in the body.

Mitochondria as a Source and a Target for Uremic Toxins.

Elucidation of molecular and cellular mechanisms of the uremic syndrome is a very challenging task. More than 130 substances are now considered to be “uremic toxins” and represent a very diverse group of molecules. The toxicity of these molecules affects many cellular processes, and expectably, some of them are able to disrupt mitochondrial functioning. However, mitochondria can be the source of uremic toxins as well, as the mitochondrion can be the site of complete synthesis of the toxin, whereas in some scenarios only some enzymes of the pathway of toxin synthesis are localized here. In this review, we discuss the role of mitochondria as both the target and source of pathological processes and toxic compounds during uremia. Our analysis revealed about 30 toxins closely related to mitochondria. Moreover, since mitochondria are key regulators of cellular redox homeostasis, their functioning might directly affect the production of uremic toxins, especially those that are products of oxidation or peroxidation of cellular components, such as aldehydes, advanced glycation end-products, advanced lipoxidation end-products, and reactive carbonyl species. Additionally, as a number of metabolic products can be degraded in the mitochondria, mitochondrial dysfunction would therefore be expected to cause accumulation of such toxins in the organism. Alternatively, many uremic toxins (both made with the participation of mitochondria, and originated from other sources including exogenous) are damaging to mitochondrial components, especially respiratory complexes. As a result, a positive feedback loop emerges, leading to the amplification of the accumulation of uremic solutes. Therefore, uremia leads to the appearance of mitochondria-damaging compounds, and consecutive mitochondrial damage causes a further rise of uremic toxins, whose synthesis is associated with mitochondria. All this makes mitochondrion an important player in the pathogenesis of uremia and draws attention to the possibility of reducing the pathological consequences of uremia by protecting mitochondria and reducing their role in the production of uremic toxins.

Microarray based circRNA expression profiles in uremic plasma and PBMCs due to chronic glomerulonephritis

Circular RNAs (circRNAs) have been identified in many diseases and shown to play important roles in pathological processes. The expression patterns of circRNA in uremia remains unknown. The aim of this study was to screen circRNA in plasma and peripheral blood mononuclear cells (PBMCs)in healthy controls and patients with uremia due to chronic glomerulonephritis, and to provide evidence for further exploration of the pathogenesis, diagnosis and treatment of uremic patients. Twenty individuals were included in this study, of which 10 were healthy and 10 were patients with uremia caused by chronic glomerulonephritis without systemic lupus erythematosus(SLE). Peripheral blood was collected from each individual in the two groups and the PBMCs were separated. The circRNAs expression profile was examined using a human circRNA microarray. The expression of differently expressed circRNAs was further validated by qRT-PCR. Seven hundred ten circRNAs were differentially expressed in the plasma in the two groups, accounting for 27.58% of the total circRNA(710/2578). Three hundred eighty-five up regulated circRNAs accounted for 14.93% and 325 down regulated circRNAs accounted for 12.60% of the total circRNAs. Additionally, 968 circRNAs were differentially expressed in PBMCs in the two groups, accounting for 29.24% of all circRNAs (968/3310).Six hundred seventy upregulated circRNAs accounted for 20.24% and 298 down regulated circRNAs accounted for 9.00% of the total circRNAs. The results of qRT-PCR validation were consistent with the microarray gene expression results. The expression profile of circRNAs was altered in the plasma and PBMCs of patients with uremia, which suggests that the changed circRNAs may be potential diagnostic biomarkers that play an important role in the pathogenesis of uremic patients. We speculate that hsa_circ_0053958, hsa_circ_0103281 may be associated with the pathogenesis of uremia and may be potential biological molecular markers for the diagnosis and prognosis of uremia.

Abstract 12938: Circulating Long Noncoding RNAs Predicts Adverse Cardiovascular Outcomes in Patients With End-Stage Renal Disease

Introduction: Cardiovascular (CV) disease is the major cause of death in uremic patients. Conventional risk factors fail to predict adverse CV outcomes with uremia. This study aimed to test the hypothesis that circulating long non-coding RNAs (lncRNA) can be a useful biomarker to predict CV events and death in uremic patients. Methods: Cell free, circulating lncRNA profiling was conducted using plasma RNA from end-stage renal disease (ESRD, n=33), chronic kidney disease (CKD, n=8) and healthy (n=19) subjects by RNA sequencing. Participants were followed up for 3 years for major adverse CV events (MACE: acute coronary syndrome, heart failure, stroke and CV death). Results: A total of 512 million sequencing reads were obtained from 60 plasma RNA samples. Among the 1897 lncRNAs detected in human plasma, 486 (363 up,123 down) and 41 (34 up, 7 down) were significantly dysregulated with ESRD and CKD, respectively. Hierarchical clustering analysis revealed that plasma lncRNA expression pattern discriminates ESRD and CKD from control samples. Pathway analysis of the dysregulated lncRNAs in ESRD based on their nearby mRNAs (cis-mRNA) showed significant enrichment of genes involved in unfolded protein response and fatty acyl-CoA biosynthesis, both of which have been implicated in the pathogenesis of uremia. Analysis on an independent microarray dataset obtained from renal biopsy samples of 48 patients with advanced kidney disease and 8 healthy subjects (GSE66494) revealed that ~15% (72 out of 486) of the dysregulated plasma lncRNA with ESRD are similarly dysregulated in diseased kidney tissues, suggesting that circulating lncRNA expression profiles can mirror, at least in part, the changes of lncRNA expression in diseased kidneys. During the follow-up period, 10 ESRD patients experienced MACE; 129 lncRNAs were differentially expressed in ESRD patients with MACE, compared to those without one. Among them, lncRNA FAM66D was a significant predictor of MACE (Hazard ratio 1.2, 95% CI 1.05-1.36, P =0.003) and could discriminate between ESRD patients with and without high risks for MACE (ROC curve AUC 0.92, 95% CI 0.76-1.00). Conclusions: Circulating lncRNAs reflect the disease states of uremia and could serve as a useful biomarker to predict the CV outcomes in uremic patients.

Determination of total, free, and reduced homocysteine and related aminothiols in uremic patients undergoing hemodialysis by precolumn derivatization HPLC with fluorescence detection

Homocysteine (Hcy) and its metabolically related aminothiols cysteine (Cys), cysteinylglycine (CysGly), and glutathione (GSH) play important roles in the pathogenesis of uremia. Most of these aminothiols exist in plasma as disulphide and mixed disulphide forms. A new, simple, sensitive and reliable precolumn derivatization HPLC method, with fluorescence detection, for the determination of four kinds of aminothiols, including total, free and reduced fractions, in plasma simultaneously was established and validated. After a simple derivatization using N-(1-pyrenyl) maleimide (NPM), the assay was performed using a C-18 column with gradient elution. The method used for the total aminothiol determinations was linear in the range of 2.00–80.0, 10.0–1500, 1.00–120, and 3.00–240 μmol L−1 for GSH, Cys, Hcy, and CysGly, respectively. The method used for the reduced aminothiols was linear in the range of 0.10–8.00, 1.25–50.0, 1.25–50.0, and 0.01–4.00 μmol L−1 for GSH, Cys, Hcy, and CysGly, respectively. The method was successfully applied to the analysis of plasma from uremic patients (n = 29) and healthy subjects (n = 28). The results showed that the concentrations of the total, free and reduced forms of Hcy, Cys and CysGly were higher, while the concentrations of the three forms of GSH were lower (p < 0.05) in uremic patients than in the healthy controls. The concentrations of the three forms of Hcy and Cys were significantly decreased, but the concentrations of the three fractions of GSH and CysGly had no significant change, during hemodialysis. In conclusion, the developed method is simple, fast, accurate, and suitable for clinical measurements.

Genome-wide analysis of DNA 5-hmC in peripheral blood of uremia by hMeDIP-chip

Background: Treatment of uremia is now dominated by dialysis; in some cases, patients are treated with dialysis for decades, but overall outcomes are disappointing. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of uremia, but the specific biomarkers of uremia have not been fully elucidated. To date, our knowledge about the alterations in DNA 5-hydroxymethylcytosine (5-hmC) in uremia is unclear, to investigate the role of DNA 5-hmC in the onset of uremia, we performed hMeDIP-chip between the uremia patients and the normal controls from the experiment to identify differentially expressed 5-hmC in uremia-associated samples. Methods: Extract genomic DNA, using hMeDIP-chip technology of Active Motif companies for the analysis of genome-wide DNA 5-hmC, and quantitative real-time PCR confirmation to identify differentially expressed 5-hmC level in uremia-associated samples. Results: There were 1875 genes in gene Promoter, which displayed significant 5-hmC differences in uremia patients compared with normal controls. Among these genes, 960 genes displayed increased 5-hmC and 915 genes decreased 5-hmC. 4063 genes in CpG Islands displayed significant 5-hmC differences in uremia patients compared with normal controls. Among these genes, 1780 genes displayed increased 5-hmC and 2283 genes decreased 5-hmC. Three positive genes, HMGCR, THBD, and STAT3 were confirmed by quantitative real-time PCR. Conclusion: Our studies indicate the significant alterations of 5-hmC. There is a correlation of gene modification 5-hmC in uremia patients. Such novel findings show the significance of 5-hmC as a potential biomarker or promising target for epigenetic-based uremia therapies.

Genome-wide analysis of histone H3 lysine9 trimethylation by ChIP-seq in peripheral blood mononuclear cells of uremia patients

Treatment of uremia is now dominated by dialysis, in some cases, patients are treated with dialysis for decades, but overall outcomes are disappointing. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of uremia, but the specific biomarkers of uremia have not been fully elucidated. Studies of the epigenome have attracted little interest in nephrology, especially in uremia. However, to date, our knowledge about the alterations in histone methylation in uremia is unclear. H3K9me3 variations were analyzed in peripheral blood mononuclear cells from 10 uremia patients and 10 healthy subjects, using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq). There were 96 genes with significantly different expressions in the uremia patients compared with the normal controls. Forty-two increased and 54 decreased H3K9me3 genes displaying significant differences were found in uremia patients compared with healthy subjects. Five positive genes, ras-related C3 botulinum toxin substrate 3 (RAC3), polycomb group ring finger 2 (PCGF2), myosin heavy chain 3 (MYH3), noggin (NOG), serpin peptidase inhibitor 8 (SERPINB8), were selected and quantified. Our studies indicate that there are significant alterations of H3K9me3 in uremia patients; these significant H3K9me3 candidates may help to explain the immunological disturbance and high cardiovascular complications in uremia patients. Such novel findings show the significance of H3K9me3 as a potential biomarker or promising target for epigenetic-based uremia therapies.

Uremic toxicity: urea and beyond.

Successful replacement of renal function with dialysis supports the concept that uremia is a toxic state resulting from accumulated solutes and that toxicity results from high concentrations of these solutes in body fluids. Dialyzer clearance of urea, a surrogate toxin, is the currently accepted best measure of dialysis and dialysis adequacy, but it is admittedly a compromise due to current lack of knowledge about and inability to measure more toxic solutes. This failure could be explained if uremic toxicity is actually a summation effect of multiple toxins, each at individual subtoxic levels in the patient. Other solutes could be used as surrogates to measure clearance, but urea happens to be available in high concentrations, is easily measured by all clinical laboratories, and is easily dialyzed, so changes in concentration are sensitive indicators of clearance. Measurements of creatinine clearance are confounded by the disequilibrium that occurs across red cells within the dialyzer and in the patient. Other solutes probably behave more like creatinine than urea, so urea stands out as uniquely diffusible, a property that actually spoils its effectiveness as a surrogate toxin, especially when applied to more frequent and continuous dialysis. Accumulation of other solutes may correlate better with toxic uremic symptoms and the residual syndrome. More studies are needed to examine the kinetics of other solutes, their generation rates, and their distribution volumes to provide clinicians with more knowledge and tools to optimize dialysis treatments. Examination of the effectiveness of solute removal in patients dialyzed more frequently may provide significant insight into the pathogenesis of uremia.

Purification and biochemical characterization of xanthopterin from patients with chronic renal failure. II. Biochemical elucidation and structural analysis

We have identified the primary endogenous fluorescent substance, which has characteristic excitation/emission maxima at 380/440 nm and 400/460 nm, found in the sera of patients with chronic renal failure (Clin Chem 32: 1276, 1988). Preliminary studies, using thin layer chromatography (with cellulose) in conjunction with pteridine standards, indicated that the compound is an unconjugated pteridine. Characterization by gas chromatography-mass spectrometry (electron impact), direct probe-mass spectrometry (electron impact/chemical ionization), and Fourier Transform Infrared analysis showed this compound to be xanthopterin (2-amino 4,6 pteridinedione), an unconjugated pteridine known to be present in man in trace quantities. An authentic sample of this compound had a retention time with high-performance liquid chromatography (HPLC) identical to that of the purified fluorophore. The physiological role of xanthopterin in the pathogenesis of uremia has yet to be elucidated.

Are recent findings on 1,25-dihydroxycholecalciferol metabolism relevant for the pathogenesis of uremia?

Are recent findings on 1,25-dihydroxycholecalciferol metabolism relevant for the pathogenesis of uremia?

Recent findings on 1,25(OH)2 vitamin D3 may provide new concepts for understanding the pathogenesis of uremia.

Recent findings on 1,25(OH)2 vitamin D3 may provide new concepts for understanding the pathogenesis of uremia.

Phenolic acids in experimental uremia. I. Potential role of phenolic acids in the neurological manifestations of uremia.

MANY ORGANIC acids accumulate in renal failure. 1 The role of phenolic acids in the pathogenesis of uremia has been reviewed by Schreiner and Maher 2 and others. 3-10 Blood phenols are primarily derived from the action of intestinal bacteria on protein derivatives containing aromatic amino acids. They are absorbed from the gut, conjugated in the liver, and excreted principally by the kidneys. Normally total plasma phenols including various amino acids, phenols, and aromatic hydroxy acids do not exceed 0.1 mg/100 ml. Marked elevations of free and conjugated phenols have been detected in uremia and reported to correlate with uremic symptoms, especially those of central nervous system (CNS) depression. 3-6 The present study was undertaken to evaluate in vivo the potential contribution of the phenolic compound, 3,4-dihydroxybenzoic acid (3,4-DHBA) (protocatechuic acid) to the pathogenesis of uremia. This compound was selected because it is excreted in considerable amounts (46

Some Aspects of Ammonia Toxicity in Animal Cells

Ammonia is produced by metabolic processes in cells and is a substance to which cells of all phylogenetie levels are accustomed (25, 100). Despite its constant presence in living protoplasm, ammonia can produce deleterious effects which are well known to many areas of biology and medicine. These harmful effects a r e believed to arise from the action of ammonia at intracellular sites, and may become manifest : a) when normal detoxifieation processes a r e impaired as by disease, b) when ammonia is introduced too rapidly, e) when the quantities of ammonia are excessive, or d) when the form of ammonia introduced is highly toxic. Since entry of ammonia into cells appears to be prerequisite for its toxicity, penetration of cell membranes by ammonia has been studied under a variety of circumstances. Such studies have employed blossoms of rhododendron, starfish eggs, erythrocytes (37, 38), peach t r e e s (15), fish (19), the mammalian kidney (57, 60, 63), and intact animals (33, 43, 94, 97). The data obtained have permitted the formulation of some general theories regarding the behavior of ammonia in biological systems which are pertinent to problems of intoxication arising from incorporation of non-protein nitrogen (NPN) in animal diets. Mammals and birds have efficient systems for excreting ammonia or converting it to nontoxic end products (4). Not only does ammonia arise from body tissues but also from bacterial enzymes acting upon nitrogenous substrafes in the lumen of the alimentary tract. The alimentary tract is the major source of ammonia outside of the tissues, and in conventional animals hydrolysis of endogenous urea is believed to be the major source of ammonia liberated by bacteria (22, 61, 77, 85, 93). Portal vein blood contains ammonia concentrations which a r e s e v e r a l times those of the peripheral arterial or venous blood (22, 51, 68). One passage of blood through the normal liver removes virtually all of the ammonia delivered from the intestines. Even with 70% of the liver removed mammals can tolerate concentrations o£ blood ammonia which are fa r in excess of those found under conditions of normal metabolism (35). Peripheral and cerebral uptake of ammonia is known to occur (6, 7, 81), and it is well recognized that shunting of blood past the liver to the systemic eirculation leads to neurological complications which are readily reproduced by administration of ammonia or other nitrogenous substances (61, 75, 76). Such shunting occurs in liver cirrhosis, an important cause of morbidity and nortal i ty in man. Many investigations have been carried out since the beginning of this century in attempts to understand cirrhosis and the syndrome of portohepatoencephalopathy commonly referred to as hepatic coma. Ammonia is one, if not the pr imary toxin which can precipitate this syndrome (76). Diseases of the kidney, an important site of ammonia production, lead to elevations in blood of nonprotein nitrogen. Thus, extensive research has also emphasized the renal metabolism of ammonia and the pathogenesis of uremia (74). Much of the experimental work on all forms of ammonia intox~ica tion has been done in animals.

Toxicity of urea and its role in the pathogenesis of uremia.

Toxicity of urea and its role in the pathogenesis of uremia.