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The Pathophysiology of Uremia
... Plantae, being abundant in fruits, vegetables, nuts, and herbs (Abramowitz, Meyer, & Hostetter, 2010). More than 8000 phenolic compounds that naturally occur in substances from plants have been reported (Tungmunnithum et al., 2018). ...
... This group has considerable structural diversity and is characterized by the presence of hydroxyl substituents on aromatic rings, collectively known as phenol groups. The structural diversity of phenols has also brought about various bioactive properties and functions (Abramowitz, Meyer, & Hostetter, 2010). ...
... These compounds are also responsible for the colors and sensory characteristics of most plants (Chikezie, Ibegbulem, & Mbagwu, 2015). Various studies have revealed the pharmacological profiles of phenolic compounds including anti-inflammatory, anti-cancer, and antioxidant properties (Abramowitz, Meyer, & Hostetter, 2010;Panche, Diwan, & Chandra 2016). Most notably, the antiangiogenic activity of phenolic compounds has been extensively proven and studied over the last two decades, which along with their ubiquity, may have led this phytochemical group to be the most widely cited in the review. ...
The potential of natural angiogenesis inhibitors (AIs) which downregulate blood vessel formation necessary for tumor sustenance has led to widespread interest in the antiangiogenic activities of phytochemical-rich plants. Consequently, this resulted in the publication of several studies concerning this subject. However, there is still an absence of a comprehensive synthesis of researches evaluating extracts from Philippine medicinal plants (PMPs). Hence, this study aimed to create a systematic review of literature from 2010-2020 that explored the antiangiogenic activities of PMP extracts using the chorioallantoic membrane assay. Particularly, the qualitative trends among the characteristics of the extracts in the included studies were determined and their antiangiogenic activities were compared quantitatively. Among the 56 extracts examined, most of their plant sources belong to the family Lamiaceae (14.55%) and are accessible throughout the Philippines (22.97%). It was also observed that the most common part, technique, and solvent utilized in preparing these extracts were the leaves (60.42%), maceration (57.10%), and methanol (33.20%), respectively. The most cited phytochemicals deemed responsible for the extracts' antiangiogenic activities were phenolic compounds (45.55%), while the most reported antiangiogenic mechanisms were endothelial cell migration inhibition (n = 7) and free radical scavenging (n = 7). In terms of their concentrations and doses, no definite trends were observed. Upon comparing the mean percent inhibitions + SEM of the extracts in the quantitative analysis, the Callistemon viminalis extract was determined to have the highest antiangiogenic activity (67.76 + 0.45) and deemed the most viable source of natural AIs.
... Plantae, being abundant in fruits, vegetables, nuts, and herbs (Abramowitz, Meyer, & Hostetter, 2010). More than 8000 phenolic compounds that naturally occur in substances from plants have been reported (Tungmunnithum et al., 2018). ...
... This group has considerable structural diversity and is characterized by the presence of hydroxyl substituents on aromatic rings, collectively known as phenol groups. The structural diversity of phenols has also brought about various bioactive properties and functions (Abramowitz, Meyer, & Hostetter, 2010). ...
... These compounds are also responsible for the colors and sensory characteristics of most plants (Chikezie, Ibegbulem, & Mbagwu, 2015). Various studies have revealed the pharmacological profiles of phenolic compounds including anti-inflammatory, anti-cancer, and antioxidant properties (Abramowitz, Meyer, & Hostetter, 2010;Panche, Diwan, & Chandra 2016). Most notably, the antiangiogenic activity of phenolic compounds has been extensively proven and studied over the last two decades, which along with their ubiquity, may have led this phytochemical group to be the most widely cited in the review. ...
The potential of natural angiogenesis inhibitors (AIs) which downregulate blood vessel formation necessary for tumor sustenance has led to widespread interest in the antiangiogenic activities of phytochemical-rich plants. Consequently, this resulted in the publication of several studies concerning this subject. However, there is still an absence of a comprehensive synthesis of researches evaluating extracts from Philippine medicinal plants (PMPs). Hence, this study aimed to create a systematic review of literature from 2010-2020 that explored the antiangiogenic activities of PMP extracts using the chorioallantoic membrane assay. Particularly, the qualitative trends among the characteristics of the extracts in the included studies were determined and their antiangiogenic activities were compared quantitatively. Among the 56 extracts examined, most of their plant sources belong to the family Lamiaceae (14.55%) and are accessible throughout the Philippines (22.97%). It was also observed that the most common part, technique, and solvent utilized in preparing these extracts were the leaves (60.42%), maceration (57.10%), and methanol (33.20%), respectively. The most cited phytochemicals deemed responsible for the extracts' antiangiogenic activities were phenolic compounds (45.55%), while the most reported antiangiogenic mechanisms were endothelial cell migration inhibition (n = 7) and free radical scavenging (n = 7). In terms of their concentrations and doses, no definite trends were observed. Upon comparing the mean percent inhibitions + SEM of the extracts in the quantitative analysis, the Callistemon viminalis extract was determined to have the highest antiangiogenic activity (67.76 + 0.45) and deemed the most viable source of natural AIs.
... Diabetes and hypertension are the most common causes of CKD worldwide . Other causes can include glomerulonephritis, pyelonephritis, and polycystic kidney disease (Meyer & Hostetter, 2012). One of the major causes of death in CKD patients is cardiovascular (CV) disease. ...
... Such events can further contribute to uremic toxicity, inflammation, and CV risk in CKD patients (Vaziri, Wong, et al., 2013). More than 80 uremic toxins are known (Meyer & Hostetter, 2012) and probably most of them are secreted into the gut altering intestinal milieu, inducing changes in the structure, composition, and function of the gut microbiome. A clear example of uremic toxin mechanism is the increased secretion of urea and uric acid into the gut. ...
... Thus, although more studies are needed to exclude non-CKD factors, nowadays it is well established that colonic microbes may produce an important portion of uremic solutes, mostly still unidentified. The most extensively studied colon-derived uremic toxins are indoxyl sulfate and p-cresol sulfate (Meyer & Hostetter, 2012; Wing et al., 2015). P-cresol is a protein-bound solute that results from the fermentation of the amino acids tyrosine and phenylalanine (Cummings, 1983). ...
Chronic kidney disease (CKD) is estimated to affect nearly 500 million people worldwide and cardiovascular (CV) disease is a major cause of death in this population. However, therapeutic interventions targeting traditional CV risks are not effective at lowering the incidence of CV events or at delaying the progression of the disease in CKD patients. In recent years, disturbances of normal gut microbiome were recognized in the pathogenesis of diverse chronic diseases. Gut dysbiosis is being unraveled in CKD and pointed as a nontraditional risk factor for CV risk and CKD progression. The most often reported changes in gut microbiome in CKD are related to the lower levels of Bifidobacteriaceae and Lactobacillaceae and to higher levels of Enterobacteriaceae. Although metagenomics brought us an amplified vision on the microbial world that inhabits the human host, it still lacks the sensitivity to characterize the microbiome up to species level, not revealing alterations that occur within specific genus. Here, we review the current state-of-the-art concerning gut dysbiosis in CKD and its role in pathophysiological mechanisms in CKD, particularly in relation with CV risk. Also, the strategies towards prevention and treatment of gut dysbiosis in CKD progression will be discussed.
... Compounds classified as indoles are characterized with a benzene ring fused with pyrrole ring [84]. In a recent study, Fluvastatin displayed a binding affinity of − 7.7 kcal/mol with significant interactions with Glu166 and His163 residues. ...
Background
The COVID-19 pandemic caused by SARS-CoV-2 has shown an exponential trend of infected people across the planet. Crediting its virulent nature, it becomes imperative to identify potential therapeutic agents against the deadly virus. The 3-chymotrypsin-like protease (3CLpro) is a cysteine protease which causes the proteolysis of the replicase polyproteins to generate functional proteins, which is a crucial step for viral replication and infection. Computational methods have been applied in recent studies to identify promising inhibitors against 3CLpro to inhibit the viral activity.
Main body of the abstract
This review provides an overview of promising drug/lead candidates identified so far against 3CLpro through various in silico approaches such as structure-based virtual screening (SBVS), ligand-based virtual screening (LBVS) and drug-repurposing/drug-reprofiling/drug-retasking. Further, the drugs have been classified according to their chemical structures or biological activity into flavonoids, peptides, terpenes, quinolines, nucleoside and nucleotide analogues, protease inhibitors, phenalene and antibiotic derivatives. These are then individually discussed based on the various structural parameters namely estimated free energy of binding (ΔG), key interacting residues, types of intermolecular interactions and structural stability of 3CLpro-ligand complexes obtained from the results of molecular dynamics (MD) simulations.
Conclusion
The review provides comprehensive information of potential inhibitors identified through several computational methods thus far against 3CLpro from SARS-CoV-2 and provides a better understanding of their interaction patterns and dynamic states of free and ligand-bound 3CLpro structures.
... Although one study showed an association between a longer time since dialysis commencement and a higher gastrointestinal cluster score, 9 additional factors warranted consideration. For example, in one study, 45 nausea and vomiting were attributed to uremia. In other studies, gastrointestinal symptoms were associated with lower eGFR and serum albumin, 46 or with genes that control taste. ...
Context:
Patients with end-stage renal disease (ESRD) undergoing dialysis experience multiple concurrent symptoms. These symptoms cluster together and have negative impacts on patient outcomes. However, information on changes in symptom clusters over time is limited.
Objectives:
This longitudinal study examined the stability of symptom clusters and their impacts on health-related quality of life (HRQoL) and functional status over a period of one year.
Methods:
Eligible patients: diagnosed with ESRD; had received dialysis consecutively for at least three months; and had given written informed consent. Dialysis Symptom Index, Kidney Disease QoL 36, and Karnofsky Performance Status Scale were used to evaluate the impacts of symptom clusters and outcomes. Exploratory factor analyses and multiple regression analyses were used to determine symptom clusters and their associations with patient outcomes.
Results:
Among the 354 recruited patients, 271 completed the 12-month assessment. Four symptom clusters were identified across the three assessments, namely: uraemic, gastrointestinal, skin, and emotional. Within each cluster, the specific symptoms were varied. The uraemic symptom cluster accounted for the largest amount of variability. Across the three assessments, a higher uraemic cluster factor score was associated with poorer physical well-being, whereas a higher emotional cluster factor score was consistently associated with poorer mental well-being.
Conclusion:
Symptoms in patients on dialysis cluster were in relatively stable patterns. The four symptom clusters identified had consistent negative effects on various aspects of patients' well-being. Our findings suggest the need for ongoing symptom assessment and early recognition of symptoms that may contribute to adverse patient outcomes.
... Besides, hyperphosphatemia decreases oxygen transport in the tissues and causes tissue hypoxia (Schmidt and Dalhoff, 2002). Although, urinary zinc and phosphorous were increased in acute toxicity; they were decreased in hyperacute toxicity (Meyer and Hostetter, 2016). This might be explained by the expected associated hepatocellular failure and impaired excretory function of the kidney. ...
... Besides, hyperphosphatemia decreases oxygen transport in the tissues and causes tissue hypoxia (Schmidt and Dalhoff, 2002). Although, urinary zinc and phosphorous were increased in acute toxicity; they were decreased in hyperacute toxicity (Meyer and Hostetter, 2016). This might be explained by the expected associated hepatocellular failure and impaired excretory function of the kidney. ...
It is well established that zinc phosphide (Zn 3 P 2) toxicity occurs through its reduction to the phosphine gas. The study evaluates the effect of acute and hyper-acute Zn 3 P 2 toxicity in rats on liver biochemical parameters, oxidative stress, cholinesterase and histological changes. Also, serum and urine concentrations of Zn & phosphorus (P) were estimated. A total of 24 male Sprague-Dawley rats were divided into 3 groups; a control group, an acute Zn 3 P 2 intoxicated (35 mg/kg) and a hyper-acute Zn 3 P 2 intoxicated (60 mg/kg) groups. We investigated ALT, AST, ALP, serum glucose, plasma cholinesterase, hepatic reduced glutathione (GSH), Malondialdehyde (MDA), serum & urine Zn & P concentrations, and histological hepatic changes. Zn 3 P 2 significantly increased ALT, AST, ALP, MDA and indirect bilirubin, while it decreased GSH and serum glucose. Histopathological changes confirmed the hepatic damage. Serum Zn & P concentrations were increased in the acute and the hyper-acute toxicity, while their urinary concentrations were increased in the acute then decreased in the hyper-acute toxicity as compared to the acute intoxicated group. A significant liver damage occurred following an acute and a hyper-acute Zn 3 P 2 toxicity with more deleterious effects in the hyper-acute toxicity, indicating a dose dependent hepatic damage. We can conclude that metabolic & histological disturbances induced by Zn 3 P 2 were due to the oxidative stress & lipid peroxidation that diversely affects mitochondrial functions and tissue energy production. Zn and P concentrations could be markers of the liver damage and an indication of Zn 3 P 2 ingestion for clinical and forensic purposes.
... Gut dysbiosis itself plays a role in CKD progression and it is starting to be recognized as a non-traditional factor for CV risk in CKD patients [31]. For example, gut microbiome-produced metabolic compounds, such as indoxyl sulfate, p-cresol sulfate, and trimethylamine N-oxide (TMAO), are associated with the promotion of CV events [3,18,[83][84][85][86]. Uremia is also associated to immune dysfunction characterized by immunodepression in CKD patients, contributing to a high prevalence of infections, increased inflammation and CV risk; for a review see [87]. ...
Chronic kidney disease (CKD) is associated with an imbalanced human microbiome due not only to CKD-associated factors such as uremia, increased inflammation and immunosuppression, but also to pharmacological therapies and dietary restrictions. End-stage renal disease patients require renal replacement therapies commonly in the form of hemodialysis (HD) or peritoneal dialysis (PD). HD implies the existence of a vascular access, such as an arteriovenous fistula/graft or a venous catheter, whereas PD implies a long-term peritoneal catheter and the constant inflow of peritoneal dialysate. Also, dietary adaptations are mandatory in both therapies. This revision explores the impact of HD or PD therapies on human microbiome.
HD and PD appear to be associated with different changes in the gut microbiome, for example a decrease in Proteobacteria relative abundance in HD patients and increase in PD patients. Both therapies may also have an impact on the human microbiome beyond the gut, leading to increased relative abundance of specific bacteria in the blood microbiome of HD patients and increased relative abundance of other bacteria in the peritoneal microbiome of PD patients. HD and PD catheter biofilms may also play an important role in the changes observed in these microbiomes.
A more interdisciplinary approach is needed to further clarify the role of microbial groups other than bacteria in all body habitats to allow the complete understanding of the impact of HD or PD on the microbiome of CKD patients. Moreover, strategies that promote a healthy balance of the human microbiome on these patients should be explored.
Meat discoloration starts from the interior and spreads to oxymyoglobin layer on surface. The effects of oxygen exposure within a steak on the metabolome have not been evaluated. Therefore, the objective of this study was to evaluate the impact of oxygen exposure on the metabolome of the longissimus lumborum muscle. Six United States Department of Agriculture (USDA) Low Choice beef strip loins were sliced into steaks (1.91-cm) and packaged in polyvinyl chloride overwrap trays for 3 or 6 days of retail display. The oxygen exposed (OE) surface was the display surface during retail, and the non-oxygen exposed (NOE) surface was the intact interior muscle. The instrumental color was evaluated using a HunterLab MiniScan spectrophotometer. To analyze the NOE surface on d 3 and 6, steaks were sliced parallel to the OE surface to expose the NOE surface. Metmyoglobin reducing ability (MRA) was determined by nitrite-induced metmyoglobin reduction. A gas chromatography-mass spectrometry was used to identify metabolites. The a* values of steaks decreased (P < 0.05) with display time. MRA was greater (P < 0.05) in the NOE surface compared with the OE surface on d 3 and 6. The KEGG pathway analysis indicated the tricarboxylic acid (TCA) cycle, pentose and glucuronate interconversions, and phenylalanine, tyrosine, and tryptophan metabolism were influenced by the oxygen exposure. The decrease in abundance of succinate from d 0 to d 6 during retail display aligned with a decline in redness during display. Furthermore, citric acid and gluconic acid were indicated as important metabolites affected by oxygen exposure and retail display based on the variable importance in the projection in the PLS-DA plot. Citric acid was lower in the NOE surface than the OE surface on d 6 of retail display, which could relate to the formation of succinate for extended oxidative stability. Greater alpha-tocopherol (P < 0.05) in the NOE surface supported less oxidative changes compared to the OE surface during retail display. These results indicate the presence of oxygen can influence metabolite profile and promote migration of the metmyoglobin layer from interior to surface.
Renal diets have been the mainstay of therapy for cats with chronic kidney disease (CKD) for many decades. Clinical trials in cats with CKD have shown them to be effective in improving survival, reducing uremic crises, and improving serum urea nitrogen and phosphorous concentrations. It has shown that, when food intake is adequate, renal diets can maintain body weight and body condition scores for up to 2 years. Although some have questioned whether renal diets provide adequate protein and have advocated feeding higher-protein diets to cats with CKD, there is currently no convincing evidence in support of this proposal.
Patients with CKD display altered plasma amino acid profiles. This study estimated the association between the estimated GFR and urinary and plasma amino acid profiles in CKD patients.
Urine and plasma samples were taken from 52 patients with different stages of CKD, and plasma samples only were taken from 25 patients on maintenance hemodialysis. Metabolic profiling was performed by liquid chromatography coupled with tandem mass spectrometry after phenylisothiocyanate derivatization.
Most plasma amino acid concentrations were decreased in hemodialysis patients, whereas proline, citrulline, asparagine, asymmetric dimethylarginine, and hydroxykynurenine levels were increased (P<0.05). Both plasma levels and urinary excretion of citrulline were higher in the group of patients with advanced CKD (CKD stages 2 and 3 versus CKD stages 4 and 5; in plasma: 35.9±16.3 versus 61.8±23.6 µmol/L, P<0.01; in urine: 1.0±1.2 versus 7.1±14.3 µmol/mol creatinine, P<0.001). Plasma asymmetric dimethylarginine levels were higher in advanced CKD (CKD stages 2 and 3, 0.57±0.29; CKD stages 4 and 5, 1.02±0.48, P<0.001), whereas urinary excretion was lower (2.37±0.93 versus 1.51±1.43, P<0.001). Multivariate analyses adjusting on estimated GFR, serum albumin, proteinuria, and other covariates revealed associations between diabetes and plasma citrulline (P=0.02) and between serum sodium and plasma asymmetric dimethylarginine (P=0.03). Plasma tyrosine to phenylalanine and valine to glycine ratios were lower in advanced CKD stages (P<0.01).
CKD patients have altered plasma and urinary amino acid profiles that are not corrected by dialysis. Depending on solutes, elevated plasma levels were associated with increased or decreased urinary excretion, depicting situations of uremic retention (asymmetric dimethylarginine) or systemic overproduction (citrulline). These results give some insight in the CKD-associated modifications of amino acid metabolism, which may help improve their handling.
Renal handling of urea in subjects with persistent axotemia and normal renal function. Fourteen subjects with persistent azotemia and normal glomerular filtration rate were studied by renal clearances and hormonal determinations to establish the nephron site of altered urea transport and the mechanism(s) responsible for their azotemia. During constant alimentary protein, urea nitrogen appearance was normal and urea clearance was much lower than in 10 age–matched control subjects (23.3 2.1 ml/min and 49.6 2.6 ml/min per 1.73 m2, P < 0.001). Inulin and para-aminohippurate clearances, blood volume and plasma concentration of antidiuretic hormone were within normal limits. During maximal antidiuresis, in spite of greater urea filtered load, the urinary excretion of urea was less, and both the maximum urinary osmolality and the free–water reabsorption relative to osmolar clearance per unit of GFR were greater than in control subjects. After sustained water diuresis, the plasma urea concentration markedly decreased to near normal levels in azotemic subjects. The basal urinary excretion of prostaglandins E2 was significantly reduced in azotemic subjects and was directly correlated with fractional urea clearance (r = 0.857, P < 0.001). An additional group of control subjects (N = 8) showed a marked reduction of fractional clearance of urea after inhibition of prostaglandin synthesis (P < 0.01). These data suggest that azotemia is due to increased tubular reabsorption of urea in the distal part of nephron, presumably because of increased back diffusion in the papillary collecting duct, accounting for the enhanced maximum urinary osmolality and free–water reabsorption. Renal prostaglandin E2 may partecipate in the pathogenesis of azotemia by altering recycling of urea in the medulla.
A database was established from human hemofiltrate (HF) that consisted of a mass database and a sequence database, with the aim of analyzing the composition of the peptide fraction in human blood. To establish a mass database, all 480 fractions of a peptide bank generated from HF were analyzed by MALDI-TOF mass spectrometry. Using this method, over 20 000 molecular masses representing native, circulating peptides were detected. Estimation of repeatedly detected masses suggests that approximately 5000 different peptides were recorded. More than 95% of the detected masses are smaller than 15 000, indicating that HF predominantly contains peptides. The sequence database contains over 340 entries from 75 different protein and peptide precursors. 55% of the entries are fragments from plasma proteins (fibrinogen A 13%, albumin 10%, β2-microglobulin 8.5%, cystatin C 7%, and fibrinogen B 6%). Seven percent of the entries represent peptide hormones, growth factors and cytokines. Thirty-three percent belong to protein families such as complement factors, enzymes, enzyme inhibitors and transport proteins. Five percent represent novel peptides of which some show homology to known peptide and protein families. The coexistence of processed peptide fragments, biologically active peptides and peptide precursors suggests that HF reflects the peptide composition of plasma. Interestingly, protein modules such as EGF domains (meprin Aα-fragments), somatomedin-B domains (vitronectin fragments), thyroglobulin domains (insulin like growth factor-binding proteins), and Kazal-type inhibitor domains were identified. Alignment of sequenced fragments to their precursor proteins and the analysis of their cleavage sites revealed that there are different processing pathways of plasma proteins in vivo.
Endothelial dysfunction and oxidative stress are matters of concern in patients with chronic renal failure (CRF). Uremic solutes retained in these patients could be involved in these processes. Notably, the protein-bound uremic solute indoxyl sulfate induces endothelial dysfunction in vitro, and has shown pro-oxidant effects.
To demonstrate that indoxyl sulfate is a potential mediator of oxidative stress in endothelial cells in vitro.
Indoxyl sulfate-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) was studied by measuring reactive oxygen specie (ROS) production by cytofluorimetry, by analyzing the involvement of the pro-oxidative enzymes NAD(P)H oxidase, xanthine oxidase, and NO synthase, and by measuring the levels of the non-enzymatic antioxidant glutathione.
We showed that indoxyl sulfate induced a significant production of ROS in HUVEC, with or without human serum albumin. We then investigated the role of pro-oxidative enzymes and measured the levels of the antioxidant glutathione. The NAD(P)H oxidase inhibitors, DPI, and apocynin, inhibited ROS production, whereas inhibitors of xanthine oxidase, NO synthase, and mitochondrial ROS had no effect. Interestingly, indoxyl sulfate strongly decreased the levels of glutathione, one of the most active antioxidant systems of the cell. In addition, the ROS production mediated by indoxyl sulfate was inhibited by the antioxidants vitamin C, vitamin E, and NAC.
The uremic solute indoxyl sulfate enhances ROS production, increases NAD(P)H oxidase activity, and decreases glutathione levels in endothelial cells. Thus, indoxyl sulfate induces oxidative stress by modifying the balance between pro- and antioxidant mechanisms in endothelial cells.
The efficiency of dialysis membranes is generally evaluated by assessing their capacity to remove small, water-soluble and non-protein-bound reference markers such as urea or creatinine. However, recent data suggest that protein-bound and/or lipophilic substances might be responsible for biochemical alterations characterizing the uraemic syndrome.
In the present study, the total concentrations of four uraemic retention compounds (indoxyl sulphate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) and p-cresol) and of tryptophan, the only protein-bound amino acid and a precursor of indoxyl sulphate, were compared with those of urea and creatinine in pre- and post-dialysis serum and in dialysate of 10 patients; two high-flux (HF) membranes (cellulose triacetate (CTA) and polysulphone (PS)) and a low-flux polysulphone (LFPS) membrane were compared in a crossover design, using HPLC.
Except for hippuric acid (67.3+/-17.5% decrease), major differences were found in the percentage removal of the classical uraemic markers on one hand (creatinine 66.6+/-7.0% and urea 75.5+/-5.8% decrease) and the studied protein-bound and/or lipophilic substances on the other (indoxyl sulphate, 35.4+/-15.3% and p-cresol 29.0+/-14.2% decrease; tryptophan, 27.5+/-40.3%, and CMPF, 22.4+/-17.5% increase; P<0.01 vs urea and creatinine in all cases). Hippuric acid removal was more pronounced than that of the remaining protein-bound compounds (P<0. 01). After correction for haemoconcentration, per cent increase of tryptophan and CMPF was less substantial, while per cent negative changes for the remaining compounds became more important. There was a correlation between creatinine and urea per cent removal at min 240 (r=0.51, P<0.01), but all the other compounds showed no significant correlation with either of these two. The three membranes were similar regarding the changes of total solute concentrations from the start to the end of dialysis.
Urea and creatinine are far more efficiently removed than the other compounds under study, except for hippuric acid. There are no striking differences between the HF membranes. Moreover, compared with the LF membrane these HF membranes do not appear to be superior in removing the studied compounds.
The kidney possesses most of the common xenobiotic metabolizing enzymes, and is thus able to make an important contribution to the body's metabolism of drugs and foreign compounds. An overview of the renal localization, catalytic activity, developmental regulation, induction, and sex and species differences for the key enzymes involved in phase I and phase II of xenobiotic metabolism is presented. In general, the catalytic activities of the various renal enzymes are lower than those of the liver, although there are exceptions, such as the enzymes involved in the processing of glutathione conjugates to their mercapturic acids. Xenobiotic metabolizing enzymes are not evenly distributed along the nephron; cytochromes P-450 and those enzymes involved in the conjugation of glutathione, glucuronic acid, or sulfate are primarily localized in the proximal tubules. However, some isozymes of cytochrome(s) P-450 and glutathione S-transferases are selectively localized in cells of the thick ascending limb and distal tubules, whereas prostaglandin H synthase is concentrated in the collecting ducts in the medulla. Thus, the proximal tubule, the principal site of xenobiotic biotransformation, is particularly susceptible to chemical insult, and the localization of prostaglandin synthase in the inner medulla and papilla may be a contributary factor to the toxicity produced by chemicals in this part of the nephron. Many of the enzymes discussed, in addition to metabolizing foreign compounds, have important endogenous functions in the kidney, such as the regulation of salt and water balance and the synthesis of vitamin D.
Despite general recognition that the kidneys play an important role in the plasma turnover and in the maintenance of adequate plasma levels of small proteins, the study of the renal handling of these substances still constitutes one of the most underdeveloped areas of research in renal physiology. Nevertheless, recent advances in the field have been considerable and are the subject of the present review. Without attempting to be all inclusive, we will analyze the evidence regarding the extent, pathways, and mechanisms of the renal accumulation, filtration, absorption, and metabolism of small proteins. A final section will then deal with the renal turnover and the homeostatic role of the kidney in the maintenance of adequate plasma levels of these substances. A critical appraisal of the methods used to estimate glomerular sieving coefficients and renal turnover rates of small proteins will be given in some detail, because a correct determination of these parameters is essential to an understanding of the kidney's role in the disposal of circulating small proteins.
The purpose of exploring the potential naturally occurring toxic hazards in food plants is not to persuade a person to avoid these common foods. Rather, it is important to put some perspective on these chemicals (natural pesticides) in our foods, and to clearly show that their toxicology, which is unknown in most cases, needs to be better understood. Many natural pesticides function similarly to synthetic pesticides or other biohazard chemicals. The natural pesticide concentration in our foods may be as much as 10,000 times higher than that of synthetic pesticide residues (Ames 1983). In some cases, these natural chemicals are prime candidates to be monitored by plant producers and plant breeders.
Latest strategies are discussed for the routine chromatographic analysis of clinically important indole derivatives in urine. Analysis of 5-hydroxyindoleacetic acid and, perhaps more importantly, serotonin and 5-hydroxytryptophan remains attractive in the screening for carcinoid tumours and their differentiation. Analyses of two precursors of the skin pigment eumelanin seem to be promising in the monitoring of treatment of malignant melanoma and screening for pigmentation disorders and gallstone formation. Studies on the clinical relevance of the determination of tetrahydro-beta-carbolines and melatonin-related indoles await routine application of chromatographic methods designed to take into consideration the relative instability of these compounds. Application of GC-MS, although confined to larger and/or governmental laboratories remains attractive as a way of improving the specificity of analyses and in establishing reference methods. As for HPLC, the recent development of chromatographic and detection methods for the concurrent determination of different clinically important and metabolically related compounds from the same sample, preferably by direct injection techniques, seems to be fruitful and should be continued.
Anorexia, nausea and vomiting in patients with severe renal failure may cause or contribute to development of protein-energy malnutrition, which is associated with increased morbidity and mortality. However, the specific mechanisms that cause appetite suppression in uremia are poorly understood. This review summarizes the general mechanisms by which appetite is regulated. Various factors are discussed that may potentially be involved in appetite suppression in chronic renal failure.
The sections in this article are:
Publisher Summary
Albumin is best known for its ability to bind smaller molecules of many types. The willingness to take on a varied cargo causes albumin to be likened to a sponge or to a “tramp steamer” of the circulation. The flexibility of the albumin structure adapts it readily to ligands, and its three-domain design provides a variety of sites. The chapter only presents the highlights and conclusions of ligand binding by albumin as literature from protein chemists, cell biologists, nutritionists, pharmacologists, and clinicians still continues to grow. Albumin interacts with a broad spectrum of compounds. Most strongly bound are hydrophobic organic anions of medium size, 100 to 600 Da–long-chain fatty acids, hematin, and bilirubin. Smaller and less hydrophobic compounds such as tryptophan and ascorbic acid are held less strongly, but their binding can still be highly specific. Affinity for the L chiral form of tryptophan exceeds that for the D form by 100-folds.
Insulin resistance is closely associated with atherosclerosis and cardiovascular mortality in the general population. Patients with end-stage renal disease (ESRD) are known to have insulin resistance, advanced atherosclerosis, and a high cardiovascular mortality rate. We evaluated whether insulin resistance is a predictor of cardiovascular death in a cohort of ESRD. A prospective observational cohort study was performed in 183 nondiabetic patients with ESRD treated with maintenance hemodialysis. Insulin resistance was evaluated by the homeostasis model assessment method (HOMA-IR) using fasting glucose and insulin levels at baseline, and the cohort was followed for a mean period of 67 mo. Forty-nine deaths were recorded, including 22 cardiovascular deaths. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly different between subjects in the top tertile of HOMA-IR (1.40 to 4.59) and those in the lower tertiles of HOMA-IR (0.28 to 1.39), and the hazard ratio (HR) was 2.60 (95% confidence interval [CI], 1.12 to 6.01; P = 0.026) in the univariate Cox proportional hazards model. In multivariate Cox models, the positive association between HOMA-IR and cardiovascular mortality remained significant (HR, 4.60; 95% CI, 1.83 to 11.55; P = 0.001) and independent of age, C-reactive protein, and presence of preexisting vascular complications. Further analyses showed that the effect of HOMA-IR on cardiovascular mortality was independent of body mass index, hypertension, and dyslipidemia. In contrast, HOMA-IR did not show such a significant association with noncardiovascular mortality. These results indicate that insulin resistance is an independent predictor of cardiovascular mortality in ESRD.
Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.
Total D-amino acids were measured in plasma for 20 non-dialysed patients (creatinine clearance < 12 ml/minute), 20 on CAPD, 20 on haemodialysis and 20 normals. Plasma D-tyrosine and D-phenylalanine were measured in 8 of each group by HPLC. Total D-amino acids, D-tyrosine and D-phenylalanine were significantly greater for patients than normals. D-amino acids and D-tyrosine correlated with creatinine and were decreased during HD. During dialysis, the mean losses for D-tyrosine and D-phenylalanine were similar, about 0.2 mg/CAPD exchange and 3 mg/4 hour haemodialysis (i.e. 2% of the total amino acid, as in plasma). Clearance was unaffected by stereochemical configuration. Urinary losses/24 hour in the non-dialysed patients were 0.35 mg D-tyrosine and 0.25 mg D-phenylalanine. Clearance for D-phenylalanine was greater than for the L-enantiomer. Increases in D-amino acids in renal failure are probably due to depletion of D-amino acid oxidase, but may be enhanced by a D-amino acid rich diet, peptide antibiotics and D-amino acid oxidase inhibiting drugs and metabolites. Possible toxic effects need further investigation.
Although Urea is officially described as a buffering agent, humectant, and skin-conditioning agent-humectant for use in cosmetic products, there is a report stating that Urea also is used in cosmetics for its desquamating and antimicrobial action. In 2001, the Food and Drug Administration (FDA) reported that Urea was used in 239 formulations. Concentrations of use for Urea ranged from 0.01% to 10%. Urea is generally recognized as safe by FDA for the following uses: side-seam cements for food contact; an inhibitor or stabilizer in pesticide formulations and formulations applied to animals; internal sizing for paper and paperboard and surface sizing and coating of paper and paper board that contact water-in-oil dairy emulsions, low-moisture fats and oils, moist bakery products, dry solids with surface containing no free fats or oil, and dry solids with the surface of fat or oil; and to facilitate fermentation of wine. Urea is the end product of mammalian protein metabolism and the chief nitrogenous compound of urine. Urea concentrations in muscle, liver, and fetuses of rats increased after a subcutaneous injection of Urea. Urea diffused readily through the placenta and into other maternal and fetal organs. The half-life of Urea injected into rabbits was on the order of several hours, and the reutilization rate was 32.2% to 88.8%. Urea given to rats by a bolus injection or continuous infusion resulted in distribution to the following brain regions: frontal lobe, caudate nucleus, hippocampus, thalamus plus hypothalamus, pons and white matter (corpus callosum). The permeability constant after treatment with Urea of whole skin and the dermis of rabbits was 2.37 +/- 0.13 (x 10(6)) and 1.20 +/- 0.09 (X 10(3)) cm/min, respectively. The absorption of Urea across normal and abraded human skin was 9.5% +/- 2.3% and 67.9% +/- 5.6%, respectively. Urea increased the skin penetration of other compounds, including hydrocortisone. No toxicity was observed for Urea at levels as high as 2000 mg/kg in acute oral studies using female rats or mice. No signs of toxicity were observed in male piglets dosed orally with up to 4 g/kg Urea for 5 days. Dogs dosed orally with 5 to 30 g/L Urea for 4 to 10 days had signs of toxicity, including weakness, anorexia, vomiting and retching, diarrhea and a decreased body temperature, which led to a deep torpor or coma. No significant microscopic changes were observed in the skin of male nude mice dermally exposed to 100% Urea for 24 h. No observable effect on fetal development was seen in rats and mice dosed orally with an aqueous solution of Urea (2000 mg/kg) on days 10 and 12 of gestation. The mean number of implants, live fetuses, percent fetal resorptions, mean fetal weight, and percent fetuses malformed were comparable to control group. A detergent containing 15% Urea was injected into pregnant ICR-JCl mice and dams and fetuses had no significant differences when compared to control animals. Urea given orally did not enhance the developmental toxicity of N-nitrosomethylurea. Female Sprague-Dawley rats injected in the uterine horn with 0.05 ml Urea on day 3 (preimplantation) or on day 7 (post implantation) exhibited no maternal mortality or morbidity; a dose-dependent reduction in embryo survival was seen with preimplantation treatment. Urea injected intra-amniotically induces mid-trimester abortions in humans. Urea was not genotoxic in several bacterial and mammalian assays; although in assays where Urea was used at a high concentration, genotoxicity was found, many in in vitro assays. Urea is commony used in studies of DNA because it causes uncoiling of DNA molecules. Urea was not carcinogenic in Fisher 344 rats or C57B1/6 mice fed diets containing up to 4.5% Urea. Exposure of normal human skin to 60% Urea produced no significant irritation in one study, but 5% Urea was slightly irritating and 20% Urea was irritating in other reports. Burning sensations are the most frequently reported effect of Urea used alone or with other agents in treatment of diseased skin. Overall, there are few reports of sensitization among the many clinical studies that report use of Urea in treatment of diseased skin. The Cosmetic Ingredient Review (CIR) Expert Panel determined the data provided in this report to be sufficient to assess the safety of Urea. The Panel did note that Urea can cause uncoiling of DNA, a property used in many DNA studies, but concluded that this in vitro activity is not linked to any in vivo genotoxic activity. Although noting that formulators should be aware that Urea can increase the percutaneous absorption of other chemicals, the CIR Expert Panel concluded that Urea is safe as used in cosmetic products.
Intestinal intubation was carried out in 21 subjects: 9 with end-stage renal failure, 2 with early renal insufficiency, 7 untreated patients with blind-loop syndrome, and 3 normal volunteers. All 9 patients with uraemia had significantly raised duodenal dimethylamine (D.M.A.) concentrations compared with the other groups tested. Alteration of the intestinal bacterial flora with antibiotics markedly reduced serum D.M.A. and trimethylamine concentrations and modified the symptoms. Potentially toxic metabolites in the small bowel might have significant nutritional and toxic sequelae in uraemia and these findings suggest that current therapeutic approaches to the treatment of end-stage kidney disease should be re-examined in relation to bowel flora.
Isolation and chemical identification of inhibitors of plasma ligand binding. The binding by serum albumin of many drugs and endogenous metabolites is impaired in humans and animals with renal failure. Unknown solute(s) retained in renal failure have been extracted from uremic fluids. When added to normal plasma they induce a similar binding defect. Similar activity can be extracted from normal urine. We have devised a series of extraction and purification techniques that yielded three binding inhibitory ligands from normal human urine in sufficient quantity and of a high degree of purity. Rigorous methods have been applied to determine chemical identity of the ligands. Purification steps consisted of: (a) adsorption at pH 3.0 to polystyrene–divinylbenzene resin (XAD-2); (b) elution from the resin with methanol followed by drying and solution in dilute formic acid; (c) passage through SP-Sephadex to remove cations, especially yellow–brown pigments; (d) adsorption to the anion exchanger QAE-Sephadex, and separation into three zones of inhibitory activity with a formic acid gradient; (e) purification to homogeneity with C-8 or C-18 silica reversed–phase chromatography. Using this isolation procedure, followed by mass spectroscopy and nuclear magnetic resonance spectroscopy, we have shown that the binding inhibitory activity is due not to one ligand, but to a family of aromatic acids. To date hippurate, -(m-hydroxyphenyl)–hydracrylate and p-hydroxyphenylacetate have been identified as binding inhibitors. Other active ligands remain to be identified.
1. The volume of work reporting insulin resistance in multiple forms of chronic hypertension has generated tremendous interest in whether this abnormality is an important factor in causing hypertension. Insulin resistance, however, is an imprecise term used interchangeably to describe widely disparate types of impairment in insulin action throughout the body and the type of insulin resistance has major ramifications regarding its potential for inducing long-term increases in blood pressure (BP).
2. Hepatic insulin resistance (impaired insulin-mediated suppression of hepatic glucose output) is the primary cause of fasting hyperinsulinaemia and is a cardinal feature of obesity hypertension. Evidence from chronic insulin infusion studies in rats suggests hyperinsulinaemia can increase BP under some conditions; however, conflicting evidence in humans and dogs leaves in question whether hyperinsulinaemia is a factor in hypertension induced by obesity.
3. Peripheral insulin resistance (impaired insulin-mediated glucose uptake, primarily of an acute glucose load in skeletal muscle) also present in obesity hypertension, but now reported in lean essential hypertension as well, is linked most notably to impaired insulin-mediated skeletal muscle vasodilation. This derangement has also been proposed as a mechanism through which insulin resistance can cause hypertension.
4. The present review will discuss the lack of experimental or theoretical support for that hypothesis and will suggest that a direct link between insulin resistance and BP control may not be the best way to envision a role for insulin resistance in cardiovascular morbidity and mortality.
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.
The blood-urea of a 43-year-old woman with normal renal function was 150 mg. per 100 ml. because she regularly consumed about 400 g. of protein daily. She had no symptoms of uraemia and her haemoglobin concentration was normal. Although she had a very large body-urea pool she degraded no more urea than healthy individuals on a normal diet. The failure of endogenous urea hydrolysis to increase in proportion to the blood-urea in renal failure has tentatively been ascribed to toxic effects of compounds retained with urea in renal failure; the findings in this azotaemic patient, who had neither signs nor symptoms of uraemia, cast doubt upon that explanation.
How toxic are phenols? The phenolic acids cannot all be detoxified. Phenyl-glucuronide, although water soluble, can still disturb cell membrane transport mechanisms. Apprecialbe amounts of toxic-free phenols form a lipid pool in the uremic patient. These findings are also relevant to hepatic coma.
Five main aspects were addressed: 1)The demonstration that creatinine is an endogenous precursor of dimethylamine (DMA) in chronic renal failure. 2) The size of the body amine pool measured in transplant patients suggests sequestration in some intracellular compartment. This illustrates the possible error in directly relating serum concentrations to neurological toxicity. 3) Bacterial overgrowth and increased generation of duodenal DMA in the small intestine becomes apparent at a serum creatinine above 8 mg/dl. Two cases show that bacterial overgrowth preceded the increased duodenal DMA. 4)Clinical toxicity is demonstrated by i) correlation of abnormal neurobehavioral parameters with serum amine levels, and ii) by improvement with administration of nonabsorbable broad spectrum antibiotics. Results with adsorption agents are inconclusive. 5) Preliminary tests of behavior modification in a rat model by direct instillation of amines into the brain are positive for TMA but negative for DMA, but no DMA entry into brain cells is demonstrated in the latter. The generation of aliphatic amines represents only one part of a spectrum of alteration induced by proximal intestinal bacterial enzyme action that occurs in renal failure. It is possible that some bacterial activity is beneficial and that the net clinical result is a balance between the "good" and the "evil" bacterial effects.
The metabolism of phenylalanine and tyrosine was evaluated in six normal men, five chronically uremic men, and three men undergoing maintenance hemodialysis. Phenylalanine, tyrosine, and 13 acidic metabolites of those amino acids were measured in plasma postabsorptively and in plasma and urine after a phenylalanine load of 100 mg/kg. In addition, five normal subjects and five dialysis patients ingested L-[14C]-phenylalanine (uniformly labeled) with the load. In uremic and dialysis patients, plasma phenylalanine rose higher and fell more gradually after the load, and tyrosine rose more slowly. The 24-hr urinary concentrations of phenylalanine and tyrosine were similar in the three groups. At 24 hr, cumulative expiration of 14CO2 was 20.2% in the dialysis patients and 28.4% in the normal subjects. Plasma phenylalanine levels and 14CO2 expiration varied with protein intake in normal subjects. In uremic and dialysis patients, plasma phenyllactic acid, p-hydroxyphenylacetic acid, and p-hydroxybenzoic acid were elevated, the last one markedly so. Moreover, plasma phenylpyruvic acid (PPA) and mandelic acid were detected only in dialysis patients. After the phenylalanine load, plasma conjugated phenylacetic acid rose in uremic patients, and PPA increased transiently in some dialysis patients. In urine of dialysis patients, concentrations of benzoic acid and conjugated o-hydroxyphenylacetic acid were decreased, and PPA was sometimes increased. The data suggest a mild impairment in the hydroxylation of phenylalanine which does not result in marked changes in plasma or in urinary metabolites after a phenylalanine load.
Electrochemical disturbances of skeletal muscle cells in untreated uremia are characterized by an increase in the intracellular sodium and chloride content, a decrease in intracellular potassium, and a low resting membrane potential. In this study, we have reexamined the foregoing and, in addition, have examined the effects of hemodialysis. Three groups of patients were studied. In the first group of 22 uncomplicated uremic patients, whose creatinine clearance (Ccr) ranged from 2 to 12 cm(3)/min per 1.73 m(2), resting transmembrane potential difference (Em) of skeletal muscle cells was measured. In each of the nine patients whose Ccr ranged between 6.3 and 12 cm(3)/min, the Em was normal (i.e., -90.8+/-0.9 mV, mean+/-SEM). However, as Ccr dropped below 6.3 cm/min, the Em became progressively reduced and assumed a linear relationship with the Ccr. In the second study, nine individuals with end-stage renal disease, whose mean Ccr was 4.3 cm(3)/min, underwent measurement of Em and intracellular electrolyte concentration before and after 7 wk of hemodialysis. Before dialysis, the Em was -78.5+/-2.1 mV, intracellular sodium and chloride were elevated, and the intracellular potassium was reduced. After 7 wk of hemodialysis the Em rose to -87.8+/-1.3 mV, and the intracellular sodium, chloride, and potassium became normal. In the third study, seven patients who were stable on 6-h thrice-weekly dialysis were studied before and after reduction of dialysis to 6 h twice weekly. In those individuals whose Em remained normal after 6 wk, dialysis time was reduced further. On thrice-weekly dialysis the Em was -91.2+/-1.0 mV. With reduced dialysis, the Em fell to -80.1+/-0.8 mV (P < 0.001). In each case, the Em became abnormal before significant signs or symptoms of uremia were noted. These findings demonstrate that end-stage renal disease is associated with serious electrochemical changes in the muscle cell which are reversed by hemodialysis and recur when dialysis time is reduced. Thus, serial observations of muscle Em may be a potentially powerful tool to assess adequacy of dialysis therapy.
20 patients with moderate renal failure (serum creatinine 4.5--12.0 mg/dl) and some uremic symptoms on a diet ad libitum were treated with a high caloric diet containing 0.5--0.7 g/kg/day protein, supplemented with eight essential amino acids and histidine in the form of solution and/or granules. During the treatment uremic symptoms subsided or diminished without the signs of malnutrition, SUN and the ratio SUN/S-creatinine fell and the nitrogen balance and the ratio N-balance/intake N improved. The serum concentration and the urinary excretion of MG and GSA of the 12 patients were determined by Stein's method using the modified Sakaguchi reaction. In all patients, the serum concentration and the urinary excretion of MG and GSA diminished remarkably during the treatment with a low protein diet alone and furthermore with a low protein diet and essential amino acid supply. We concluded that conservative treatment -- low nitrogen diet supplemented with sufficient calories and essential amino acids -- improved the nutritional state of uremic subjects, and decreased the metabolic production of MG and GSA. The results show that the supplementation of essential amino acids to uremic patients may be a useful treatment.
There are many cAUSES OF ALTERED AMINO ACID AND PROTEIN METABOLISM IN UREMIA WHICH MAY Lead to impaired growth, wasting, malnutrition, and other aspects of the uremic syndrome. These causes have complex interrelationships that are not well understood. The factors include altered nutrition due to poor intake, losses of nutrients during dialysis, and abnormal metabolism of many nutrients. Uremic toxins, superimposed catabolic illnesses, elevated or reduced serum hormone levels, reduced capacity of the kidney to synthesize certain amino acids and to degrade other amino acids, peptides, and small proteins, and decreased excretion of certain amino acids and peptides may also contribute to altered amino acid and protein metabolism. The response of certain plasma amino acids to protein restriction appears to differ in uremic patients as compared to normal subjects. Increased plasma levels of many products of amino acids and proteins in renal failure are due primarily to decreased urinary clearance by the kidney. However, for some metabolites, increased synthesis or decreased degradation may also contribute to elevated levels. These latter compounds include guanidinosuccinic acid, methylguanidine, certain middle molecules, and in some patients, phenylpyruvic acid.
The small intestinal bacterial flora of 15 patients with chronic renal insufficiency was compared with that of subjects with blind loop synDROME. 9 patients were on regular hemodialysis with high protein intake and 6 (serum creatinine 7.5 to 12.5 mg/dl) were maintained on low protein diet. The chronic renal patients harbored a greatly increased microbial flora of both anaerobes and aerobes in the duodenum and jejunum, quantitatively comparable to those in blind loop subjects. The composition did not differ significantly in the two groups. Some organisms may have the potential to metabolize substrates which reach the intestinal lumen from the diet and bile, and perhaps to generate toxic metabolites that could contribute to uremic toxicity or malabsorption.
We attempted to define the substances that contribute to the characteristic "uremic breath" of patients with end-stage renal disease. Breath samples from nine patients underwent direct analysis before and after hemodialysis with use of gas chromatography and confirmation by mass spectrometry, and indirectly assessment by an organoleptic panel. Concentrations of secondary and tertiary amines, dimethylamine and trimethylamine were increased, with subsequent reduction after hemodialysis (dimethylamine from 2.00 +/- 0.19 [S.E.M.] to 0.88 +/- 0.12 microng per 30 minutes, P less than 0.001, and trimethylamine from 0.79 +/- 0.22 to 0.44 +/- 0.15 microng per 30 minutes, P less than 0.003). Treatment with nonabsorbable antibiotics in two patients reduced both serum and breath amine levels without dialysis. Loss of nitrogen via the breath was not quantitatively important. We conclude that uremic breath reflects the systemic accumulation of potentially toxic volatile metabolites, among which dimethylamine and trimethylamine have been positively identified and correlated with the classic fishy odor.
Guanidinosuccinic acid (GSA) was measured in serum and urine from six normal subjects, 26 chronically uremic patients, and 17 patients undergoing maintenance hemodialysis. All normal subjects and 22 chronically uremic patients were fed diets providing 21 gm of essential amino acids or 20, 40, or 60 gm/day of protein. Serum GSA was usually undetectable in normal subjects and was increased in uremic patients (0.99 +/- S.D. 044. mg/100 ml). Serum creatinine and urea nitrogen were each correlated with serum GSA in the normal and uremic subjects combined and in uremic patients alone. Serum GSA was greater in hemodialysis patients (1.43 +/- 0.56 mg/100 ml) than in uremic patients (p less than 0.02) and decreased by 39% +/- 21 during hemodialysis in five patients. Serum GSA and the serum GSA/creatinine ratio tended to decrease with low protein intake in the uremic patients. Urinary GSA was increased in uremic patients (30.5 +/- 12.9 mg/day) as compared to that in normal subjects (7.5 +/- 1.9 mg/day), was greater in uremic patients than in normal subjects at each level of protein intake, and was directly correlated with protein intake and urinary urea and total nitrogen in both normal and uremic subjects. In three uremic patients who developed intercurrent illnesses, urinary GSA rose transiently. These results indicate four factors which affect serum or urinary GSA levels: (1) renal function, (2) protein intake, (3) catabolic stress, and (4) hemodialysis therapy.
Fifty-three samples in 26 patients were analyzed for aliphatic amines (DMA and TMA), and the levels correlated with 2 neurophysiological tests, choice reaction time (CRT), and electroencephalogram (EEG). A significant correlation was found between TMA and CRT and EEG (p less than 0.001 and 0.003, respectively) and between DMA and CRT (p less than 0.01). These amines reflect part of the spectrum of toxic compounds which accumulate in uremia. Dissociation of neurophysiological functions may be helpful in evaluating various classes of potentially toxic compounds found in renal failure, as exemplified by short-chain aliphatic amines.
1. Methylguanidine administered orally to normal volunteers was almost completely recovered in the urine, indicating that it is absorbed in the gastrointestinal tract and is not converted into other compounds. In normal persons at least, its urinary output therefore corresponds to its metabolic production rate plus the amount ingested.
2. In normal persons, diets based on foods not containing methylguanidine (e.g. vegetarian, protein-free and milk-egg diets) caused a fall in the urinary output of methylguanidine as compared with the output of the same subjects on a free diet. Conversely, higher amounts of methylguanidine were excreted on a diet rich in broth and in boiled beef, which contain large amounts of methylguanidine formed from the oxidation of creatinine, caused by boiling.
3. Oral administration of creatinine to normal volunteers induced an immediate and marked increase in urinary excretion of methylguanidine, and the ingestion of [methyl-14C]creatinine by uraemic patients was followed by the urinary excretion of labelled methylguanidine. These findings indicate that creatinine is partly converted into methylguanidine in both normal and uraemic subjects and accounts for the high metabolic production of methylguanidine in patients with renal failure, in whom the body pool of creatinine is high.
4. Creatinine, incubated at 38°C for 24 h in Krebs bicarbonate solution (pH 7.38) through which was bubbled oxygen with 15% carbon dioxide, was partially oxidized to methylguanidine. This raises the possibility that even in vivo such a conversion may occur ‘non-enzymatically’.
The influence of diet on aryl acid metabolism was determined in normal and azotemic subjects. Aryl acid content of serum and urine was estimated by fluorometry in relation to hippuric acid as a standard (FI-Hipp). Secretory activity, a reflection of the biological potency of aromatic acids in serum and urine, was determined by bioassay. The urinary excretion of FI-Hipp and secretory activity of five normal persons on an ad lib diet was 0.78 and 2.25 mM/day, respectively; similar values were observed in two subjects with chronic renal insufficiency. Subjects were fed prunes and cranberries, since these foods contain abundant quantities of hippurate precursors. Prunes 1.5 g/kg body weight, caused the urinary excretion of both FI-Hipp and secretory activity to increase about tenfold in normal and azotemic subjects. Prune feeding caused the serum levels of FI-Hipp and secretory activity to increase about threefold. Cranberries increased the renal excretion of FI-Hipp and secretory activity as did the ingestion of a beverage containing benzoate as a preservative. On the basis of these studies it is clear that diet is an important determinant of the load of aryl acids for urinary excretion; in patients with renal insufficiency the ingestion of foods containing precursors may cause serum level of biologically active aryl acids to increase strikingly.
Twelve neutral free amino acids, i.e. serine, threonine, glutamine, asparagine, alanine, proline, methionine, tyrosine, valine, leucine, isoleucine and phenylalanine, were surveyed for the presence of D-enantiomers in plasma samples from patients with renal diseases and from normal subjects. D-serine, D-alanine and D-proline were found in the patient's plasma. The highest concentrations (D/L ratio) of D-serine, D-alanine and D-proline were 0.2362, 0.2087 and 0.0986, respectively. The sum of the contents of the three D-amino acid was shown to be present in the plasma proteins.
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Systemic and renal oxygen consumption and hemodynamics were studied in patients with normal renal function (NI; serum creatinine concentration (Screat), 1.0 +/- 0.04 mg/dL) and those with moderate chronic renal failure with diabetes mellitus Screat, 2.7 +/- 0.2 mg/dL) or without diabetes mellitus (Screat, 2.4 +/- 0.1 mg/dL). Patients with chronic renal failure were anemic and had normal systemic oxygen consumption (NI, 10,564 +/- 277; chronic renal failure, 9,669 +/- 362 mumol of O2/min) and elevated systemic oxygen extraction (NI, 22.9 +/- 1; chronic renal failure, 30.9 +/- 1.2%) (P less than 0.02). Cardiac output and index and arterial oxygen saturation were equivalent in normal patients and in patients with chronic renal failure. Patients with chronic renal failure had higher renal oxygen extraction (NI, 7.3 +/- 0.8; chronic renal failure, 13.9 +/- 1%), lower RBF (NI, 572 +/- 146; chronic renal failure, 197 +/- 20 mL/min/kidney), and lower renal oxygen consumption per kidney (NI, 391 +/- 101; chronic renal failure, 177 +/- 20 mumol of O2/min/kidney) than did normal patients (P less than 0.02). There was a linear relationship between hemoglobin and RBF (r = 0.47, P less than 0.02). Patients with chronic renal failure and diabetes had lower RBF (diabetes mellitus, 146 +/- 23; without diabetes, 242 +/- 28 mL/min/kidney) and renal oxygen consumption per kidney (diabetes mellitus, 131 +/- 21; without diabetes, 218 +/- 29 mumol of O2/min/kidney (P less than 0.03) but equivalent renal oxygen extraction when compared with patients without diabetes. Patients with chronic renal failure without diabetes mellitus had higher renal oxygen consumption when expressed per 100 mL of creatinine clearance (diabetes mellitus, 1,016 +/- 150; without diabetes mellitus, 1,453 +/- 175 mumol of O2/min/100 mL of creatinine clearance; P less than 0.03). There was a significant linear relationship (P less than 0.005, r = 0.38) between calculated creatinine clearance and renal oxygen consumption with a y intercept representing basal renal oxygen consumption (115 mumol of O2/min/kidney) and a slope of 2.3 mumol of O2/mL. Patients with moderate chronic renal failure have normal systemic oxygen consumption but reduced RBF and renal oxygen consumption. The latter parameters are even lower in patients with chronic renal failure and diabetes. Renal hypermetabolism is more likely to exist in nondiabetic than diabetic renal disease. Basic human renal physiology and pathophysiology are described by the relationships between renal oxygen consumption, blood flow, oxygen extraction, and creatinine clearance in patients with normal and abnormal renal function of varied cause.
We describe the purification and initial characterization of a hitherto unrecognized fluorescence (excitation/emission maxima at 380/440 nm and 400/460 nm) reported from this laboratory in patients with chronic renal failure (Clin Chem 31: 1988, 1985). Purification was achieved using Sephadex G-10 gel chromatography combined with reverse phase and ion exchange high-performance liquid chromatography (HPLC). Purity of the "blue-green" fluorescent compound was determined to be greater than 99% by HPLC, and two-dimensional thin layer chromatography using an acidic and basic solvent system. The excitation/emission maxima were shown to be 390 nm/456 nm, and ultraviolet scans, at pH 1.0, 7.0, and 13.0, gave absorbance optima at 261 nm/356 nm, 278 nm/390 nm, and 255 nm/394 nm, respectively. The isoelectric point of 4.05 in conjunction with the fluorescent and ultraviolet spectra suggests that the fluorophore belongs to the class of compounds known as pteridines.
Each of creatinine (Cr), guanidinoacetic acid (GAA) and arginine (Arg) was administered intraperitoneally to rats with renal failure, and the levels of methylguanidine (MG) in the serum, liver, kidney, muscle and urine were determined at certain intervals. The levels of MG in the serum, liver, kidney, muscle and urine after Cr administration increased markedly with time. The amount of total MG at 24 h was estimated to be 114 micrograms/100 g body weight, which accounted for 0.46% of the Cr dose. In contrast, changes in MG levels after administration of GAA or Arg were only slight in comparison with those after Cr administration. Thus, MG was proved to be produced mainly from Cr.
The impact of renal failure on the elimination and hydrolysis of three sources of tyrosine for parenteral nutrition, the dipeptides alanyltyrosine (Ala-Tyr), glycyltyrosine (Gly-Tyr), and N-acetyltyrosine (NAc-Tyr) was investigated in eight patients on regular hemodialysis therapy (HD) and seven healthy controls (CON). In CON, whole body clearance (Ctot) of Ala-Tyr (3,169 +/- 198 ml/min) was higher than Gly-Tyr (1,781 +/- 184, P less than 0.001), and both exceeded NAc-Tyr (284 +/- 24, P less than 0.001). In HD, Ctot of Ala-Tyr was not different from CON, but Ctot of Gly-Tyr (858 +/- 73, P less than 0.001) and NAc-Tyr (129 +/- 30, P less than 0.02) was decreased. The rise in plasma levels of constituent amino acids was higher in Ala-Tyr vs. Gly-Tyr (P less than 0.01). In HD, the pattern was similar, although the increase in Tyr was less than in CON. Plasma Tyr did not increase with NAc-Tyr in either group. Urinary loss of peptides was neglible, but 60% of NAc-Tyr infused was excreted by CON. The half-life of peptides incubated in CON and HD plasma was unchanged for Ala-Tyr (12.3 +/- 0.9 vs. 14.6 +/- 1.9 min) and prolonged for Gly-Tyr in HD (101.7 +/- 4.9 vs. 131.3 +/- 12, P less than 0.05). Thus renal failure does not impair Ala-Tyr disposal and delays Gly-Tyr utilization. These differential effects on peptide assimilation underscore the importance of peptide structure on metabolism. Both peptides, but not NAc-Tyr, may serve as a nutritional substrate in renal failure patients.
Phenylacetyglutamine (PAG) and hippuric acid (HA) were determined in protein-free filtrates of plasma and urine from patients with chronic renal failure and healthy subjects, using reverse phase high performance liquid chromatography. Plasma accumulation of the metabolites was detected when the creatinine clearance was below 15 ml/min. Protein-binding studies showed that PAG was not bound to plasma proteins but that HA was partly bound. Concentrations of PAG and free HA in plasma did not correlate with values of serum urea or creatinine. Hemodialysis decreased the plasma concentration of PAG and free HA to about the same extent as that of urea and creatinine. The average renal clearances of PAG and HA were about 1.4 and 5 times higher, respectively, than the creatinine clearance. The daily excretion rates of PAG, HA, urea, and creatinine were similar in non-dialysis patients with a creatinine clearance higher than 15 ml/min and in healthy subjects, whereas patients with a creatinine clearance below 15 ml/min had lower excretion rates of urea, creatinine, and HA. However, the average excretion rate of PAG was in the same range in uremic and healthy subjects. The excretion rate of HA, but not of PAG, correlated with that of urea and creatinine.
In order to assess the influence of renal failure and nutritional status on the fasting concentrations of free plasma amino acids, we studied 81 ambulatory adult patients with varying degrees of chronic renal failure. Each of the patients was in good general and nutritional condition. Compared to 33 healthy controls, patients with mild renal failure (Ccr greater than 25 ml/mn) exhibited significantly (p less than 0.01, Student's t test) raised concentrations of cystine, citrulline, ornithine, taurine and 3-methyl-histidine and low level of serine. Concentrations of cystine, citrulline, and 3-methyl-histidine in plasma but not of taurine or ornithine rose in parallel with the progression of renal failure. A significant, but moderate decrease in valine, leucine and isoleucine concentrations was observed in patients with the most marked degree of renal failure (Ccr less than 10 ml/mn). We conclude that changes in the plasma concentration of several non essential amino acids are already present in the early stage of renal failure in patients with no sign of protein malnutrition: these may result from altered metabolic pathways of amino acids related to uremia and/or nephron loss per se whereas the moderate decrease in branched-chain amino acids that is observed only in the advanced stage of renal failure may be, at least in part, nutritional in origin.
This review summarizes the evidence for the defect in Na+-K+ pump in chronic renal failure, considers the role of various factors in causing this defect, and discusses the clinical implications thereof. Intracellular Na is elevated in erythrocytes, leukocytes, and muscle cells from some patients with chronic renal failure (CRF). Recent evidence suggests that this elevation of cell Na may be, in large part, a consequence of decreased number of Na+-K+ pump units per cell. Maintenance dialysis over a period of weeks ameliorates the defect in intracellular Na+, and this improvement is contemporaneous with an increase in the number of Na+-K+ pump sites per cell. In erythrocytes with normal cell Na+, acute hemodialysis increases the rate of Na+ and K+ transport. Many factors such as the presence of retained toxic metabolite or circulating inhibitor in the uremic plasma, or biochemical changes produced by acute hemodialysis, may explain this finding. In cells with high cell Na+, the pump-mediated K+ transport is normalized at the expense of a raised cell Na+. The decreased muscle membrane potential in uremic subjects has been attributed to a decreased activity of Na+-K+ pump. Enzymatic Na+-K+-ATPase activity of the uremic erythrocyte, leukocyte, sarcolemma, and intestines is also decreased. We discuss the role of hormonal abnormalities and circulating inhibitors, which may cause an acute inhibition of the pump and of other factors such as K+ depletion, which may cause more chronic alterations. The implications of alteration of Na+ and K+ pump transport and raised cell Na+ on other non-pump-mediated transport pathways are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine whether so-called uraemic toxins exhibit direct toxic effects on Schwann cells, the latter were cultured in a monolayer with the addition of uraemic toxins. Proliferation of Schwann cells was estimated with [³H]-thymidine incorporation into DNA synthesis. Myoinositol, methylguanidine, guanidinosuccinic acid, parathyroid hormone, phenol, p-cresol, 4-hydroxypheny-lacetic acid, 4-hydroxybenzoic acid, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid were added at various concentrations to the culture medium.
Addition of myoinositol at concentrations between 50 and 100 μg/ml, values analogous to those in uraemic serum, inhibited proliferation of Schwann cells in a dose-dependent way. Myoinositol also inhibited axolemma-stimulated proliferation of Schwann cells. The other compounds at concentrations occurring in uraemic serum did not show any toxic effect on Schwann cells.
These results suggest that myoinositol has a neurotoxic effect on Schwann cells, and uraemic polyneuropathy seemed to be caused by a defect in maintaining normal myelin due to accumulation of myoinositol.
Serum concentrations of accumulated solutes, standard clinical biochemistry, and parameters of clinical neuropathy, were determined in hemodialyzed patients with chronic renal failure. Analyses by high-performance liquid chromatography included creatinine, pseudouridine, urate, p-hydroxyhippuric acid, hippuric acid, indoxylsulfate, tryptophan, tyrosine, 3-indoleacetic acid, and a number of as-yet unidentified solutes. Standard biochemical parameters were measured; aluminium, parathyroid hormone, serum electrolytes and enzymes, hemoglobin, bilirubin, phosphate and urea. Measures of clinical neuropathy were: maximal motor nerve conduction velocities, and Hoffmann reflex latency. Several solutes had higher concentrations when nerve function was impaired. Serum total LDH, and total calcium levels correlated positively with values of the Hoffmann reflex, as did serum hippuric acid concentrations. Concentrations of p-hydroxyhippuric acid and two fluorescent compounds correlated negatively with motor nerve conduction velocities. In principal component analysis a number of 'organic acid-like' substances, like hippuric acid and p-hydroxyhippuric acid, were shown to associate multivariately with the neurophysiological variables while urea, creatinine, urate and phosphate were not.
1. Minute but appreciable amounts of d-amino acids were detected in normal human plasma.
2. The content was significantly higher in an elderly population (age 76 ± 6 years, mean ± sd, n = 41) than in a younger group (age 42 ± 4 years, n = 26), i.e. 6.9 ± 4.8 nmol/ml (mean ± sd, range 0–18.8 nmol/ml) and 2.5 ± 1.8 nmol/ml (range 0–6.3 nmol/ml) for the elderly and the younger groups, respectively.
3. Elevation of plasma d-amino acid level was observed in a group of patients with renal disease (3.6–52.6 nmol/ml), in proportion to the serum level of creatinine (n = 50, r = 0.726, P < 0.001), β2-microglobulin (n = 34, r = 0.551, P < 0.005), and to glomerular filtration rate (n = 39, r = 0.556, P < 0.001).
In rats, oxygen consumption is reduced by about 40-50% 24 h after bilateral nephrectomy. This is also the case when the animals are pretreated with triiodothyronine, 3 x 0.75 mg/kg body weight orally, for 2-3 days. Indole, cresol, putrescine, methylguanidine or acetoine was given intraperitoneally to normal rats at doses of between 5 and 300 mg/kg body weight. Only low single doses of indole (5 mg/kg) reduced oxygen consumption significantly. Single doses of the other substances studied were ineffective even at tenfold higher doses. Some combinations of these substances, however, (10 mg/kg each), reduced the metabolic rate significantly. In contrast to the results in vivo, plasma of uremic rats, as well as the uremic toxins, dissolved in Krebs-phosphate buffer pH 7.4 at concentrations of 30 mg/dl each, had no influence on respiration of rat diaphragma or liver slices in vitro (single substances and different combinations).