The mean values of IL-6 and sCD14 in each study Study 1 Study 1 Study 2 HD on-line HDF on-line HD... more The mean values of IL-6 and sCD14 in each study Study 1 Study 1 Study 2 HD on-line HDF on-line HDF IL-6 (pg/ml) Pre-treatment 2.0 Ϯ 0.3 2.5 Ϯ 0.7 1.60 Ϯ 0.84 Post-treatment 2.0 Ϯ 0.3 0.5 Ϯ 0.1 2.27 Ϯ 1.59 sCD14 (g/ml) Pre-treatment 6.0 Ϯ 0.2 6.1 Ϯ 0.3 4.65 Ϯ 0.36 Post-treatment 5.7 Ϯ 0.2 6.4 Ϯ 0.3 4.78 Ϯ 0.35 Conclusions: Microbiological contaminations in ET free dialysate induce the chronic inflammatory response in chronic hemodialysis patients. On-line HDF should be performed with UPD proved to be ET free and viable bacterial free. O3
The glomerulus is a complex structure containing a remarkable capillary bed which is freely perme... more The glomerulus is a complex structure containing a remarkable capillary bed which is freely permeable to water and solutes up to the size of inulin. Many small proteins are filtered, reabsorbed, and catabolized by the kidney; but most large proteins, such as albumin or immunoglobulins, are almost entirely excluded from the glomerular ultrafiltrate due to the charge-size permselectivity of the glomerular capillary basement membrane. These large proteins appear in the urine when diseases reduce the charge selectivity or result in the development of large pores in this membrane. The reabsorptive capacity of the renal tubules for these proteins is overwhelmed. Hypoalbuminemia results when increased synthetic and decreased catabolic rates of albumin fail to compensate for the urinary loss of the protein. The resulting decrease in serum oncotic pressure increases the flux of fluid out of systemic capillaries into the interstitial space, a process that increases lymphatic flow and returns the relatively protein-poor ultrafiltrate to the plasma compartment. Interstitial proteins are swept into the plasma by the increased lymphatic flow, leading to a depletion of the extravascular pool of albumin even more severe than the depletion of albumin in the plasma compartment. The rate of albumin synthesis is increased but not sufficiently to replace losses and restore the serum concentration to normal. The rate of albumin catabolism is decreased. This decrease from the normal catabolic rate is as important as the increased rate of albumin synthesis in maintenance of albumin homeostasis in nephrosis. Whereas the reduced serum oncotic pressure certainly contributes to edema formation, sodium retention may result from processes intrinsic to the kidney itself; and plasma volume may actually be expanded despite hypoalbuminemia. The hyperlipemia that occurs in nephrosis is due to a combined defect in lipoprotein metabolism: increased hepatic synthesis of VLDL and decreased removal of TG and highly atherogenic remnants of incompletely metabolized CMs. The defects in lipoprotein metabolism may in part be the end result of the urinary loss of highly negative-charged macromolecules of the mucopolysaccharide called orosomucoid, which carries with it heparan sulfate, and important cofactor for LPL.
Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both tr... more Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both transferrin and the iron it carries are lost in the urine in the nephrotie syndrome. Patients may develop hypochromie microcytic anemia and synthesis of transferrin, a protein regulated in large part by iron availability, is increased. Transferrin synthesis has also been reported to be increased in liver slices from rats with hereditary analbuminemia, and their plasma transferrin levels are increased, suggesting that transferrin synthesis may be stimulated by processes other than iron depletion in this hypoalbuminemic condition. Transferrin metabolism was studied in rats with Heymann nephritis (RN), in a strain of Sprague-Dawley (SD) rats with hereditary analbuminemia [Nagase analbuminemic rats (NAR)], and in normal SD rats. Plasma transferrin concentration and mass was decreased significantly in RN, but increased in NAR. Transferrin synthesis was increased both in NAR (measured either as the disappearance of [1251] labeled transferrin or as the incorporation of [3H] phenylalanine) and in RN (incorporation of ['R] phenylalanine). The fractional rate of transferrin catabolism was unchanged in NAR. Thus transferrin mass was increased in NAR entirely as a consequence of increased synthesis. Transferrin and albumin synthesis correlated with one another in both RN and SD (P < 0.001). Transferrin mRNA was increased in both RN and NAR and was unaffected by administration of iron to RN. Repatic transferrin and albumin mRNA levels were also correlated positively in RN and SD, suggesting that increased hepatic synthesis of both proteins might be responding to the same stimuli. Transferrin gene transcription was increased in both RN and NAR and was unaffected by administration of iron to HN. Transferrin mRNA was not increased in the testis in either RN or NAR, suggesting that augmentation in transferrin gene expression is driven by a non-iron dependent process and is confined to the liver. Transferrin synthesis is increased in patients with the nephrotic syndrome [1]. Transferrin is the principal iron carrying protein in plasma [2]. Its urinary loss in the nephrotic syndrome is sufficient to reduce plasma transferrin levels [31 and may produce sufficient iron losses to cause microcytic anemia [4-6]. Thus increased synthesis of transferrin in the nephrotic syndrome could well be a normal physiologic response to this well recognized regulatory stimulus. Although transferrin is synthesized in extrahepatic tis
American Journal of Physiology-renal Physiology, Jul 1, 1984
Albumin catabolism and the relationship between plasma albumin concentration and albuminuria were... more Albumin catabolism and the relationship between plasma albumin concentration and albuminuria were studied in male Sprague-Dawley rats with Heymann nephritis. The rats were placed on isocaloric diets of 8.5, 21, or 40% protein. Serum albumin concentration correlated negatively with urinary albumin excretion for each of these dietary groups, but the correlation was dependent on dietary protein intake. The magnitude of albuminuria reflected the increase in albumin synthesis rate plus the decrease in albumin catabolic rate. Maximal urinary albumin loss was dependent on dietary protein intake. Albumin catabolism was studied in the different groups of nephrotic animals. Albumin catabolism correlated inversely with the rate of albuminuria in the 21 and 40% protein-fed rats and contributed nearly half of the albumin that was lost in these groups of animals. Albumin catabolism was independent of albuminuria in the rats fed 8.5% protein. The rats were fed 18% of their normal caloric intake, and albumin catabolism was studied in nephrotic and control animals. Albumin catabolism increased with increased albuminuria, in contrast to the well-nourished group, and there was no relationship between serum albumin concentration and urinary albumin excretion. Increased catabolism of albumin plays little or no role in albumin homeostasis in the well-nourished nephrotic rat but may be significant in protein- and calorie-malnourished animals.
American Journal of Physiology-renal Physiology, Feb 1, 1985
Edema formation in nephrotic syndrome has been attributed to intravascular volume depletion resul... more Edema formation in nephrotic syndrome has been attributed to intravascular volume depletion resulting from leakage of plasma water into the interstitial space and activating secondary renal sodium retention. However, clinical studies indicate that edematous patients with nephrotic syndrome may have normal or expanded plasma volumes. We evaluated the relationship between plasma volume and edema formation in control rats and rats with chronic renal failure (CRF) produced by 7/8 nephrectomy. In each group, plasma volume and 22Na space were measured during the control period and after induction of hypoalbuminemia from passive Heymann nephritis. Rats with CRF had expanded plasma volume during the initial period (4.23 +/- 0.46 vs. 3.32 +/- 0.68 ml/100 g body wt) that became significantly more expanded (to 5.44 +/- 1.16 ml/100 g body wt) when they became nephrotic as 22Na space also increased. Plasma volume and 22Na space did not change in the sham-operated rats when nephrosis was produced. Plasma renin activity was lower in the CRF rats during the control period than in the sham-operated rats and fell significantly during the nephrotic period when edema developed. Nonnephrotic rats had a plasma colloid osmotic pressure (COP) of 17.8 +/- 4.3 mmHg compared with 8.5 +/- 2.9 mmHg when nephrotic. Despite this large difference in COP, both nephrotic and nonnephrotic rats exhibited the same relationship between plasma volume and extravascular sodium space, a measure of edema formation. Hypoproteinemia is not sufficient for edema formation in the rat with passive Heymann nephritis; concomitant plasma volume expansion resulting from CRF is a necessary additional component.
Introduction: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare... more Introduction: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare the effects of hemodialysis (HD) given 6 versus 3 times per week. More frequent in-center HD significantly reduced left-ventricular mass (LVM), with more pronounced effects in patients with low urine volumes. In this study, we aimed to explore another potential effect modifier: the predialysis serum sodium (SNa) and related proxies of plasma tonicity. Methods: Using data from the FHN Daily and Nocturnal Trials, we compared the effects of frequent HD on LVM among patients stratified by SNa, dialysate-to-predialysis serum-sodium gradient (GNa), systolic and diastolic blood pressure, time-integrated This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for commercial purposes requires written permission.
American Journal of Physiology-Renal Physiology, 1993
Hepatic lipid and apolipoprotein synthesis is increased in the nephrotic syndrome. Catabolism of ... more Hepatic lipid and apolipoprotein synthesis is increased in the nephrotic syndrome. Catabolism of triglyceride-rich lipoproteins is impaired in nephrotic syndrome but not in rats with hereditary analbuminemia (NA), suggesting that lipid synthesis should be increased by analbuminemia in the absence of proteinuria. In this study the rate of cholesterol and fatty acid synthesis in liver and extrahepatic tissue was measured in female NA and control Sprague-Dawley (SD) rats to determine whether lipid synthesis was indeed increased in isolated analbuminemia and to identify the site(s) of increased lipogenesis. We also measured the concentrations of apolipoproteins (apo) AI, B, and E in plasma, as well as the levels of the respective mRNAs in liver. Plasma cholesterol, triglycerides, and apo AI, B, and E were all increased severalfold in the NA rat (P < 0.001). Although liver apolipoprotein mRNA content was significantly increased (P < 0.001) for apo AI (643%), B (273%), and E (299%),...
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, Jan 27, 2015
To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). ... more To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). Cross-sectional. Two hundred twenty-one patients receiving HD enrolled in seven dialysis facilities in Northern California. We assessed 5 appetite assessment tools (self-assessment of appetite, subjective assessment of appetite, visual analog scale [VAS], Functional Assessment of Anorexia/Cachexia Therapy [FAACT] score, and the Anorexia Questionnaire [AQ]). Reported food intake, normalized protein catabolic rate, and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. Fifty-eight (26%) patients reported food intake ≤ 50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective as...
Catabolism of triglyceride-rich lipoproteins, including chylomicrons (CM), is reduced in the neph... more Catabolism of triglyceride-rich lipoproteins, including chylomicrons (CM), is reduced in the nephrotic syndrome. It has been suggested that hyperlipidemia per se might lead to reduced CM catabolism by saturating catabolic sites. Evidence also implicates disordered high-density lipoprotein function as reducing the activity of lipoprotein lipase (LPL), the final effector of CM lipolysis. To establish whether CM lipolysis would be abnormal in the absence of either abnormal rat lipoproteins or hyperlipidemia, we measured CM lipolysis by isolated perfused hearts of rats with passive Heymann nephritis. We found that lipolysis was significantly reduced by 30% at 30 minutes (246 +/- 40 mumol v 164 +/- 10 mumol fatty acid released/hr, P &lt; 0.05). Uptake of fatty acids was also significantly less in nephrotic hearts than in control hearts (7.25% +/- 0.93% of dose v 3.32% +/- 0.011% of dose, P &lt; 0.01). Total heart LPL activity was reduced by 40% in hearts of nephrotic animals (368.5 +/- 39.4 mumol v 210.6 +/- 25.9 mumol free fatty acid released/hr/g heart, P &lt; 0.01). The heparin-releasable LPL pool is that pool bound to the vascular endothelium and represents the biologically active fraction. We perfused hearts with heparin and found that heparin-releasable LPL was reduced by an order of magnitude in hearts from nephrotic rats (173 +/- 33 mumol v 19.4 +/- 11.7 mumol free fatty acid released/hr/heart, P &lt; 0.001). The decrease in this pool represented nearly entirely the difference in total heart LPL in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Background: Although frailty has been linked to higher risk of falls and fracture in the general ... more Background: Although frailty has been linked to higher risk of falls and fracture in the general population, only few studies have examined the extent to which frailty is associated with these outcomes among patients with end-stage renal disease, who are at particularly high risk for these events. Methods: A total of 1,646 patients who were beginning maintenance hemodialysis in 297 dialysis units throughout the United States from September 2005 to June 2007 were enrolled in the Comprehensive Dialysis Study, and 1,053 Medicare beneficiaries were included in this study. Self-reported frailty was defined by the patients endorsing 2 or more of the following: poor physical functioning, exhaustion or low physical activity. Falls and fractures requiring medical attention were identified through Medicare claims data. We examined the association between frailty and the time to first fall or fracture using the Fine-Gray modification of Cox proportional hazards regression, adjusted for demogra...
Introduction and Aims: Among the 600 to 700 mg of inorganic phosphate (Pi) removed during a 4-hou... more Introduction and Aims: Among the 600 to 700 mg of inorganic phosphate (Pi) removed during a 4-hour hemodialysis session, a maximum of 10% could be extracted from the extracellular space (1). The origin of the other 90% of removed Pi is unknown and two hypothesis have been proposed being either the intracellular compartment or bone. Spalding et al (2) hypothesized that Pi exchanges between intra and extracellular compartments were diffusive, suggesting that the intracellular compartment could be the main source of Pi removed during hemodialysis. Therefore, we proposed to test this hypothesis during a hemodialysis session, by using Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS), which is the only tool allowing in vivo and dynamic measurement of the intracellular Pi concentration as well as the other's phosphate metabolites such as Phosphocreatine (PCr) and ATP. Methods: 3-hour hemodialysis sessions were performed in 6 pigs, after surgical bi-nephrectomy, with a Prismaflex® generator and a M100® dialyser (Hospal). The extra-corporal circulation blood flow was maintained between 100 and 150 mL/min. 31P MRS exams were performed with a 1.5T Siemens Sonata system using a surface coil (20 cm) placed over the gluteal muscle region. 31P MR spectra (TR=10s, TE=0.35ms) were acquired every 2'40" before, during and after dialysis. Blood samples were obtained during the whole examination to measure plasma Pi concentrations. Results: During the dialysis, the mean PCr/Pi ratio decreased significantly (-6.9%, p<0.00001), while the Pi/βATP ratio increased (+22.2%, p<0.00001). Plasma Pi concentration felt rapidly within 60 min from 2.30 ± 0.18 mmol/L to 1.65 ± 0.10 mmol/L (-28,08%, p=0.003) then plateaued. Conclusions: This study demonstrated that intracellular Pi concentration did not decrease in parallel with the extracellular Pi decrease as proposed (2). In contrast, the intracellular Pi increase may reflect a cellular stress induced by hemodialysis and/or a strong intracellular Pi production.
Introduction and Aims: Whole body bioimpedance spectroscopy (wBIS) has become a standard method t... more Introduction and Aims: Whole body bioimpedance spectroscopy (wBIS) has become a standard method to measure extracellular volume (ECV) in dialysis patients. However, the accuracy of wBIS can be influenced by redistribution of fluid within body compartments, since electrical resistance is not uniformly distributed between the trunk and limbs. This bio-physical reality affects resistance and leads to inaccuracy in MP391
The existence of a membrane-bound HCO3-stimulated ATPase in intestinal mucosa is controversial. A... more The existence of a membrane-bound HCO3-stimulated ATPase in intestinal mucosa is controversial. A crude brush border fraction of rat small intestinal homogenates contained HCO3-ATPase activity which was inhibited by preincubation with 3 mM EDTA. Alkaline phosphatase activity of this preparation was also inhibited in a parallel, time-dependent fashion by preincubation with EDTA. When 5 mM ZnSO4 accompanied 3 mM EDTA in the preincubation mix, preservation of both enzyme activities occurred, demonstrating a requirement of Zn for the activity of both these phosphatases. These studies support the earlier contention that HCO3-ATPase and alkaline phosphatase activities may be different properties of the same enzyme, and raise the possibility that the ATPase could play a role in intestinal ion transport. The failure to identify a membrane-bound HCO3-ATPase by other workers could be due to the exposure of EDTA which occurred in their tissue preparation.
Abstract INTRODUCTION AND AIMS: There is currently no consensus about the indications for therape... more Abstract INTRODUCTION AND AIMS: There is currently no consensus about the indications for therapeutic apheresis, also due to the lack of large clinical trials. A registry where all the data can be organized and analyzed therefore becomes a priority for all professionals ...
Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both tr... more Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both transferrin and the iron it carries are lost in the urine in the nephrotie syndrome. Patients may develop hypochromie microcytic anemia and synthesis of transferrin, a protein regulated in large part by iron availability, is increased. Transferrin synthesis has also been reported to be increased in liver slices from rats with hereditary analbuminemia, and their plasma transferrin levels are increased, suggesting that transferrin synthesis may be stimulated by processes other than iron depletion in this hypoalbuminemic condition. Transferrin metabolism was studied in rats with Heymann nephritis (RN), in a strain of Sprague-Dawley (SD) rats with hereditary analbuminemia [Nagase analbuminemic rats (NAR)], and in normal SD rats. Plasma transferrin concentration and mass was decreased significantly in RN, but increased in NAR. Transferrin synthesis was increased both in NAR (measured either as the disappearance of [1251] labeled transferrin or as the incorporation of [3H] phenylalanine) and in RN (incorporation of ['R] phenylalanine). The fractional rate of transferrin catabolism was unchanged in NAR. Thus transferrin mass was increased in NAR entirely as a consequence of increased synthesis. Transferrin and albumin synthesis correlated with one another in both RN and SD (P < 0.001). Transferrin mRNA was increased in both RN and NAR and was unaffected by administration of iron to RN. Repatic transferrin and albumin mRNA levels were also correlated positively in RN and SD, suggesting that increased hepatic synthesis of both proteins might be responding to the same stimuli. Transferrin gene transcription was increased in both RN and NAR and was unaffected by administration of iron to HN. Transferrin mRNA was not increased in the testis in either RN or NAR, suggesting that augmentation in transferrin gene expression is driven by a non-iron dependent process and is confined to the liver. Transferrin synthesis is increased in patients with the nephrotic syndrome [1]. Transferrin is the principal iron carrying protein in plasma [2]. Its urinary loss in the nephrotic syndrome is sufficient to reduce plasma transferrin levels [31 and may produce sufficient iron losses to cause microcytic anemia [4-6]. Thus increased synthesis of transferrin in the nephrotic syndrome could well be a normal physiologic response to this well recognized regulatory stimulus. Although transferrin is synthesized in extrahepatic tis
Background/Aims: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated... more Background/Aims: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated with cardiovascular disease and have been linked to an inflammatory state. The presence of vascular disease is also associated with increased expression of adhesion molecules, including soluble intercellular adhesion molecule (sICAM), vascular endothelial growth factor (VEGF) and leukocyte-derived myeloperoxidase (MPO). These associations suggest potential mechanisms whereby inflammation may injure the vascular endothelium, but the recognition of how these mediators act in concert remain poorly characterized. That the prevalence of atherosclerosis and markers of inflammation are increased in renal failure patients suggests that inflammation causes accelerated vascular disease. Methods: In hemodialysis patients, we examined the relationships between plasma CRP and sICAM, VEGF and MPO longitudinally. We determined whether episodes of a high CRP value were paralleled by simultaneous increa...
In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduc... more In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduced extracellular fluid (ECF) and left ventricular mass (LVM), with more pronounced effects observed among patients with low urine volume (UVol). We analyzed the effect of frequent HD on interdialytic weight gain (IDWG) and a time-integrated estimate of ECF load (TIFL). We also explored whether volume and sodium loading contributed to the change in LVM over the study period. Treatment effects on volume parameters were analyzed for modification by UVol and the dialysate-to-serum sodium gradient. Predictors of change in LVM were determined using linear regression. Frequent HD reduced IDWG and TIFL in the Daily Trial. Among patients with UVol <100 ml/day, reduction in TIFL was associated with LVM reduction. This suggests that achievement of better volume control could attenuate changes in LVM associated with mortality and cardiovascular morbidity. TIFL may prove more useful than IDWG alon...
Journal of the American Society of Nephrology, 2001
. Mortality is markedly elevated in patients with end-stage renal disease. The leading cause of d... more . Mortality is markedly elevated in patients with end-stage renal disease. The leading cause of death is cardiovascular disease. Lipoprotein levels are only slightly elevated in dialysis patients, and cardiovascular risk is inversely correlated with serum cholesterol, suggesting that a process other than hyperlipidemia plays a role in the incidence of cardiovascular disease. Hypoalbuminemia, ascribed to malnutrition, has been one of the most powerful risk factors that predict all-cause and cardiovascular mortality in dialysis patients. The presence of inflammation, as evidenced by increased levels of specific cytokines (interleukin-6 and tumor necrosis factor α) or acute-phase proteins (C-reactive protein and serum amyloid A), however, has been found to be associated with vascular disease in the general population as well as in dialysis patients. The process of inflammation, also called the acute-phase response, additionally causes loss of muscle mass and changes in plasma composition—decreases in serum albumin, prealbumin, and transferrin levels, also associated with malnutrition. Inflammation alters lipoprotein structure and function as well as endothelial structure and function to favor atherogenesis and increases the concentration of atherogenic proteins in serum, such as fibrinogen and lipoprotein (a). Inflammation in dialysis patients is episodic. The causes are likely to be multifactorial and include vascular access infection, less-than-sterile dialysate, dialysate back leak, and nonbiocompatible membranes in addition to clinically apparent infection. In addition, proinflammatory compounds, such as advanced glycation end products, accumulate in renal failure, and defense mechanisms against oxidative injury are reduced, contributing to inflammation and to its effect on the vascular endothelium.
The mean values of IL-6 and sCD14 in each study Study 1 Study 1 Study 2 HD on-line HDF on-line HD... more The mean values of IL-6 and sCD14 in each study Study 1 Study 1 Study 2 HD on-line HDF on-line HDF IL-6 (pg/ml) Pre-treatment 2.0 Ϯ 0.3 2.5 Ϯ 0.7 1.60 Ϯ 0.84 Post-treatment 2.0 Ϯ 0.3 0.5 Ϯ 0.1 2.27 Ϯ 1.59 sCD14 (g/ml) Pre-treatment 6.0 Ϯ 0.2 6.1 Ϯ 0.3 4.65 Ϯ 0.36 Post-treatment 5.7 Ϯ 0.2 6.4 Ϯ 0.3 4.78 Ϯ 0.35 Conclusions: Microbiological contaminations in ET free dialysate induce the chronic inflammatory response in chronic hemodialysis patients. On-line HDF should be performed with UPD proved to be ET free and viable bacterial free. O3
The glomerulus is a complex structure containing a remarkable capillary bed which is freely perme... more The glomerulus is a complex structure containing a remarkable capillary bed which is freely permeable to water and solutes up to the size of inulin. Many small proteins are filtered, reabsorbed, and catabolized by the kidney; but most large proteins, such as albumin or immunoglobulins, are almost entirely excluded from the glomerular ultrafiltrate due to the charge-size permselectivity of the glomerular capillary basement membrane. These large proteins appear in the urine when diseases reduce the charge selectivity or result in the development of large pores in this membrane. The reabsorptive capacity of the renal tubules for these proteins is overwhelmed. Hypoalbuminemia results when increased synthetic and decreased catabolic rates of albumin fail to compensate for the urinary loss of the protein. The resulting decrease in serum oncotic pressure increases the flux of fluid out of systemic capillaries into the interstitial space, a process that increases lymphatic flow and returns the relatively protein-poor ultrafiltrate to the plasma compartment. Interstitial proteins are swept into the plasma by the increased lymphatic flow, leading to a depletion of the extravascular pool of albumin even more severe than the depletion of albumin in the plasma compartment. The rate of albumin synthesis is increased but not sufficiently to replace losses and restore the serum concentration to normal. The rate of albumin catabolism is decreased. This decrease from the normal catabolic rate is as important as the increased rate of albumin synthesis in maintenance of albumin homeostasis in nephrosis. Whereas the reduced serum oncotic pressure certainly contributes to edema formation, sodium retention may result from processes intrinsic to the kidney itself; and plasma volume may actually be expanded despite hypoalbuminemia. The hyperlipemia that occurs in nephrosis is due to a combined defect in lipoprotein metabolism: increased hepatic synthesis of VLDL and decreased removal of TG and highly atherogenic remnants of incompletely metabolized CMs. The defects in lipoprotein metabolism may in part be the end result of the urinary loss of highly negative-charged macromolecules of the mucopolysaccharide called orosomucoid, which carries with it heparan sulfate, and important cofactor for LPL.
Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both tr... more Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both transferrin and the iron it carries are lost in the urine in the nephrotie syndrome. Patients may develop hypochromie microcytic anemia and synthesis of transferrin, a protein regulated in large part by iron availability, is increased. Transferrin synthesis has also been reported to be increased in liver slices from rats with hereditary analbuminemia, and their plasma transferrin levels are increased, suggesting that transferrin synthesis may be stimulated by processes other than iron depletion in this hypoalbuminemic condition. Transferrin metabolism was studied in rats with Heymann nephritis (RN), in a strain of Sprague-Dawley (SD) rats with hereditary analbuminemia [Nagase analbuminemic rats (NAR)], and in normal SD rats. Plasma transferrin concentration and mass was decreased significantly in RN, but increased in NAR. Transferrin synthesis was increased both in NAR (measured either as the disappearance of [1251] labeled transferrin or as the incorporation of [3H] phenylalanine) and in RN (incorporation of ['R] phenylalanine). The fractional rate of transferrin catabolism was unchanged in NAR. Thus transferrin mass was increased in NAR entirely as a consequence of increased synthesis. Transferrin and albumin synthesis correlated with one another in both RN and SD (P < 0.001). Transferrin mRNA was increased in both RN and NAR and was unaffected by administration of iron to RN. Repatic transferrin and albumin mRNA levels were also correlated positively in RN and SD, suggesting that increased hepatic synthesis of both proteins might be responding to the same stimuli. Transferrin gene transcription was increased in both RN and NAR and was unaffected by administration of iron to HN. Transferrin mRNA was not increased in the testis in either RN or NAR, suggesting that augmentation in transferrin gene expression is driven by a non-iron dependent process and is confined to the liver. Transferrin synthesis is increased in patients with the nephrotic syndrome [1]. Transferrin is the principal iron carrying protein in plasma [2]. Its urinary loss in the nephrotic syndrome is sufficient to reduce plasma transferrin levels [31 and may produce sufficient iron losses to cause microcytic anemia [4-6]. Thus increased synthesis of transferrin in the nephrotic syndrome could well be a normal physiologic response to this well recognized regulatory stimulus. Although transferrin is synthesized in extrahepatic tis
American Journal of Physiology-renal Physiology, Jul 1, 1984
Albumin catabolism and the relationship between plasma albumin concentration and albuminuria were... more Albumin catabolism and the relationship between plasma albumin concentration and albuminuria were studied in male Sprague-Dawley rats with Heymann nephritis. The rats were placed on isocaloric diets of 8.5, 21, or 40% protein. Serum albumin concentration correlated negatively with urinary albumin excretion for each of these dietary groups, but the correlation was dependent on dietary protein intake. The magnitude of albuminuria reflected the increase in albumin synthesis rate plus the decrease in albumin catabolic rate. Maximal urinary albumin loss was dependent on dietary protein intake. Albumin catabolism was studied in the different groups of nephrotic animals. Albumin catabolism correlated inversely with the rate of albuminuria in the 21 and 40% protein-fed rats and contributed nearly half of the albumin that was lost in these groups of animals. Albumin catabolism was independent of albuminuria in the rats fed 8.5% protein. The rats were fed 18% of their normal caloric intake, and albumin catabolism was studied in nephrotic and control animals. Albumin catabolism increased with increased albuminuria, in contrast to the well-nourished group, and there was no relationship between serum albumin concentration and urinary albumin excretion. Increased catabolism of albumin plays little or no role in albumin homeostasis in the well-nourished nephrotic rat but may be significant in protein- and calorie-malnourished animals.
American Journal of Physiology-renal Physiology, Feb 1, 1985
Edema formation in nephrotic syndrome has been attributed to intravascular volume depletion resul... more Edema formation in nephrotic syndrome has been attributed to intravascular volume depletion resulting from leakage of plasma water into the interstitial space and activating secondary renal sodium retention. However, clinical studies indicate that edematous patients with nephrotic syndrome may have normal or expanded plasma volumes. We evaluated the relationship between plasma volume and edema formation in control rats and rats with chronic renal failure (CRF) produced by 7/8 nephrectomy. In each group, plasma volume and 22Na space were measured during the control period and after induction of hypoalbuminemia from passive Heymann nephritis. Rats with CRF had expanded plasma volume during the initial period (4.23 +/- 0.46 vs. 3.32 +/- 0.68 ml/100 g body wt) that became significantly more expanded (to 5.44 +/- 1.16 ml/100 g body wt) when they became nephrotic as 22Na space also increased. Plasma volume and 22Na space did not change in the sham-operated rats when nephrosis was produced. Plasma renin activity was lower in the CRF rats during the control period than in the sham-operated rats and fell significantly during the nephrotic period when edema developed. Nonnephrotic rats had a plasma colloid osmotic pressure (COP) of 17.8 +/- 4.3 mmHg compared with 8.5 +/- 2.9 mmHg when nephrotic. Despite this large difference in COP, both nephrotic and nonnephrotic rats exhibited the same relationship between plasma volume and extravascular sodium space, a measure of edema formation. Hypoproteinemia is not sufficient for edema formation in the rat with passive Heymann nephritis; concomitant plasma volume expansion resulting from CRF is a necessary additional component.
Introduction: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare... more Introduction: The Frequent Hemodialysis Network (FHN) Daily and Nocturnal trials aimed to compare the effects of hemodialysis (HD) given 6 versus 3 times per week. More frequent in-center HD significantly reduced left-ventricular mass (LVM), with more pronounced effects in patients with low urine volumes. In this study, we aimed to explore another potential effect modifier: the predialysis serum sodium (SNa) and related proxies of plasma tonicity. Methods: Using data from the FHN Daily and Nocturnal Trials, we compared the effects of frequent HD on LVM among patients stratified by SNa, dialysate-to-predialysis serum-sodium gradient (GNa), systolic and diastolic blood pressure, time-integrated This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for commercial purposes requires written permission.
American Journal of Physiology-Renal Physiology, 1993
Hepatic lipid and apolipoprotein synthesis is increased in the nephrotic syndrome. Catabolism of ... more Hepatic lipid and apolipoprotein synthesis is increased in the nephrotic syndrome. Catabolism of triglyceride-rich lipoproteins is impaired in nephrotic syndrome but not in rats with hereditary analbuminemia (NA), suggesting that lipid synthesis should be increased by analbuminemia in the absence of proteinuria. In this study the rate of cholesterol and fatty acid synthesis in liver and extrahepatic tissue was measured in female NA and control Sprague-Dawley (SD) rats to determine whether lipid synthesis was indeed increased in isolated analbuminemia and to identify the site(s) of increased lipogenesis. We also measured the concentrations of apolipoproteins (apo) AI, B, and E in plasma, as well as the levels of the respective mRNAs in liver. Plasma cholesterol, triglycerides, and apo AI, B, and E were all increased severalfold in the NA rat (P < 0.001). Although liver apolipoprotein mRNA content was significantly increased (P < 0.001) for apo AI (643%), B (273%), and E (299%),...
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, Jan 27, 2015
To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). ... more To test the performance of appetite assessment tools among patients receiving hemodialysis (HD). Cross-sectional. Two hundred twenty-one patients receiving HD enrolled in seven dialysis facilities in Northern California. We assessed 5 appetite assessment tools (self-assessment of appetite, subjective assessment of appetite, visual analog scale [VAS], Functional Assessment of Anorexia/Cachexia Therapy [FAACT] score, and the Anorexia Questionnaire [AQ]). Reported food intake, normalized protein catabolic rate, and change in body weight were used as criterion measures, and we assessed associations among the appetite tools and biomarkers associated with nutrition and inflammation. Patients were asked to report their appetite and the percentage of food eaten (from 0% to 100%) during the last meal compared to usual intake. Fifty-eight (26%) patients reported food intake ≤ 50% (defined as poor appetite). The prevalence of anorexia was 12% by self-assessment of appetite, 6% by subjective as...
Catabolism of triglyceride-rich lipoproteins, including chylomicrons (CM), is reduced in the neph... more Catabolism of triglyceride-rich lipoproteins, including chylomicrons (CM), is reduced in the nephrotic syndrome. It has been suggested that hyperlipidemia per se might lead to reduced CM catabolism by saturating catabolic sites. Evidence also implicates disordered high-density lipoprotein function as reducing the activity of lipoprotein lipase (LPL), the final effector of CM lipolysis. To establish whether CM lipolysis would be abnormal in the absence of either abnormal rat lipoproteins or hyperlipidemia, we measured CM lipolysis by isolated perfused hearts of rats with passive Heymann nephritis. We found that lipolysis was significantly reduced by 30% at 30 minutes (246 +/- 40 mumol v 164 +/- 10 mumol fatty acid released/hr, P &lt; 0.05). Uptake of fatty acids was also significantly less in nephrotic hearts than in control hearts (7.25% +/- 0.93% of dose v 3.32% +/- 0.011% of dose, P &lt; 0.01). Total heart LPL activity was reduced by 40% in hearts of nephrotic animals (368.5 +/- 39.4 mumol v 210.6 +/- 25.9 mumol free fatty acid released/hr/g heart, P &lt; 0.01). The heparin-releasable LPL pool is that pool bound to the vascular endothelium and represents the biologically active fraction. We perfused hearts with heparin and found that heparin-releasable LPL was reduced by an order of magnitude in hearts from nephrotic rats (173 +/- 33 mumol v 19.4 +/- 11.7 mumol free fatty acid released/hr/heart, P &lt; 0.001). The decrease in this pool represented nearly entirely the difference in total heart LPL in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Background: Although frailty has been linked to higher risk of falls and fracture in the general ... more Background: Although frailty has been linked to higher risk of falls and fracture in the general population, only few studies have examined the extent to which frailty is associated with these outcomes among patients with end-stage renal disease, who are at particularly high risk for these events. Methods: A total of 1,646 patients who were beginning maintenance hemodialysis in 297 dialysis units throughout the United States from September 2005 to June 2007 were enrolled in the Comprehensive Dialysis Study, and 1,053 Medicare beneficiaries were included in this study. Self-reported frailty was defined by the patients endorsing 2 or more of the following: poor physical functioning, exhaustion or low physical activity. Falls and fractures requiring medical attention were identified through Medicare claims data. We examined the association between frailty and the time to first fall or fracture using the Fine-Gray modification of Cox proportional hazards regression, adjusted for demogra...
Introduction and Aims: Among the 600 to 700 mg of inorganic phosphate (Pi) removed during a 4-hou... more Introduction and Aims: Among the 600 to 700 mg of inorganic phosphate (Pi) removed during a 4-hour hemodialysis session, a maximum of 10% could be extracted from the extracellular space (1). The origin of the other 90% of removed Pi is unknown and two hypothesis have been proposed being either the intracellular compartment or bone. Spalding et al (2) hypothesized that Pi exchanges between intra and extracellular compartments were diffusive, suggesting that the intracellular compartment could be the main source of Pi removed during hemodialysis. Therefore, we proposed to test this hypothesis during a hemodialysis session, by using Phosphorus (31P) Magnetic Resonance Spectroscopy (MRS), which is the only tool allowing in vivo and dynamic measurement of the intracellular Pi concentration as well as the other's phosphate metabolites such as Phosphocreatine (PCr) and ATP. Methods: 3-hour hemodialysis sessions were performed in 6 pigs, after surgical bi-nephrectomy, with a Prismaflex® generator and a M100® dialyser (Hospal). The extra-corporal circulation blood flow was maintained between 100 and 150 mL/min. 31P MRS exams were performed with a 1.5T Siemens Sonata system using a surface coil (20 cm) placed over the gluteal muscle region. 31P MR spectra (TR=10s, TE=0.35ms) were acquired every 2'40" before, during and after dialysis. Blood samples were obtained during the whole examination to measure plasma Pi concentrations. Results: During the dialysis, the mean PCr/Pi ratio decreased significantly (-6.9%, p<0.00001), while the Pi/βATP ratio increased (+22.2%, p<0.00001). Plasma Pi concentration felt rapidly within 60 min from 2.30 ± 0.18 mmol/L to 1.65 ± 0.10 mmol/L (-28,08%, p=0.003) then plateaued. Conclusions: This study demonstrated that intracellular Pi concentration did not decrease in parallel with the extracellular Pi decrease as proposed (2). In contrast, the intracellular Pi increase may reflect a cellular stress induced by hemodialysis and/or a strong intracellular Pi production.
Introduction and Aims: Whole body bioimpedance spectroscopy (wBIS) has become a standard method t... more Introduction and Aims: Whole body bioimpedance spectroscopy (wBIS) has become a standard method to measure extracellular volume (ECV) in dialysis patients. However, the accuracy of wBIS can be influenced by redistribution of fluid within body compartments, since electrical resistance is not uniformly distributed between the trunk and limbs. This bio-physical reality affects resistance and leads to inaccuracy in MP391
The existence of a membrane-bound HCO3-stimulated ATPase in intestinal mucosa is controversial. A... more The existence of a membrane-bound HCO3-stimulated ATPase in intestinal mucosa is controversial. A crude brush border fraction of rat small intestinal homogenates contained HCO3-ATPase activity which was inhibited by preincubation with 3 mM EDTA. Alkaline phosphatase activity of this preparation was also inhibited in a parallel, time-dependent fashion by preincubation with EDTA. When 5 mM ZnSO4 accompanied 3 mM EDTA in the preincubation mix, preservation of both enzyme activities occurred, demonstrating a requirement of Zn for the activity of both these phosphatases. These studies support the earlier contention that HCO3-ATPase and alkaline phosphatase activities may be different properties of the same enzyme, and raise the possibility that the ATPase could play a role in intestinal ion transport. The failure to identify a membrane-bound HCO3-ATPase by other workers could be due to the exposure of EDTA which occurred in their tissue preparation.
Abstract INTRODUCTION AND AIMS: There is currently no consensus about the indications for therape... more Abstract INTRODUCTION AND AIMS: There is currently no consensus about the indications for therapeutic apheresis, also due to the lack of large clinical trials. A registry where all the data can be organized and analyzed therefore becomes a priority for all professionals ...
Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both tr... more Non-iron mediated alteration in hepatic transferrin gene expression in the nephrotic rat. Both transferrin and the iron it carries are lost in the urine in the nephrotie syndrome. Patients may develop hypochromie microcytic anemia and synthesis of transferrin, a protein regulated in large part by iron availability, is increased. Transferrin synthesis has also been reported to be increased in liver slices from rats with hereditary analbuminemia, and their plasma transferrin levels are increased, suggesting that transferrin synthesis may be stimulated by processes other than iron depletion in this hypoalbuminemic condition. Transferrin metabolism was studied in rats with Heymann nephritis (RN), in a strain of Sprague-Dawley (SD) rats with hereditary analbuminemia [Nagase analbuminemic rats (NAR)], and in normal SD rats. Plasma transferrin concentration and mass was decreased significantly in RN, but increased in NAR. Transferrin synthesis was increased both in NAR (measured either as the disappearance of [1251] labeled transferrin or as the incorporation of [3H] phenylalanine) and in RN (incorporation of ['R] phenylalanine). The fractional rate of transferrin catabolism was unchanged in NAR. Thus transferrin mass was increased in NAR entirely as a consequence of increased synthesis. Transferrin and albumin synthesis correlated with one another in both RN and SD (P < 0.001). Transferrin mRNA was increased in both RN and NAR and was unaffected by administration of iron to RN. Repatic transferrin and albumin mRNA levels were also correlated positively in RN and SD, suggesting that increased hepatic synthesis of both proteins might be responding to the same stimuli. Transferrin gene transcription was increased in both RN and NAR and was unaffected by administration of iron to HN. Transferrin mRNA was not increased in the testis in either RN or NAR, suggesting that augmentation in transferrin gene expression is driven by a non-iron dependent process and is confined to the liver. Transferrin synthesis is increased in patients with the nephrotic syndrome [1]. Transferrin is the principal iron carrying protein in plasma [2]. Its urinary loss in the nephrotic syndrome is sufficient to reduce plasma transferrin levels [31 and may produce sufficient iron losses to cause microcytic anemia [4-6]. Thus increased synthesis of transferrin in the nephrotic syndrome could well be a normal physiologic response to this well recognized regulatory stimulus. Although transferrin is synthesized in extrahepatic tis
Background/Aims: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated... more Background/Aims: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated with cardiovascular disease and have been linked to an inflammatory state. The presence of vascular disease is also associated with increased expression of adhesion molecules, including soluble intercellular adhesion molecule (sICAM), vascular endothelial growth factor (VEGF) and leukocyte-derived myeloperoxidase (MPO). These associations suggest potential mechanisms whereby inflammation may injure the vascular endothelium, but the recognition of how these mediators act in concert remain poorly characterized. That the prevalence of atherosclerosis and markers of inflammation are increased in renal failure patients suggests that inflammation causes accelerated vascular disease. Methods: In hemodialysis patients, we examined the relationships between plasma CRP and sICAM, VEGF and MPO longitudinally. We determined whether episodes of a high CRP value were paralleled by simultaneous increa...
In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduc... more In previous reports of the Frequent Hemodialysis Network trials, frequent hemodialysis (HD) reduced extracellular fluid (ECF) and left ventricular mass (LVM), with more pronounced effects observed among patients with low urine volume (UVol). We analyzed the effect of frequent HD on interdialytic weight gain (IDWG) and a time-integrated estimate of ECF load (TIFL). We also explored whether volume and sodium loading contributed to the change in LVM over the study period. Treatment effects on volume parameters were analyzed for modification by UVol and the dialysate-to-serum sodium gradient. Predictors of change in LVM were determined using linear regression. Frequent HD reduced IDWG and TIFL in the Daily Trial. Among patients with UVol <100 ml/day, reduction in TIFL was associated with LVM reduction. This suggests that achievement of better volume control could attenuate changes in LVM associated with mortality and cardiovascular morbidity. TIFL may prove more useful than IDWG alon...
Journal of the American Society of Nephrology, 2001
. Mortality is markedly elevated in patients with end-stage renal disease. The leading cause of d... more . Mortality is markedly elevated in patients with end-stage renal disease. The leading cause of death is cardiovascular disease. Lipoprotein levels are only slightly elevated in dialysis patients, and cardiovascular risk is inversely correlated with serum cholesterol, suggesting that a process other than hyperlipidemia plays a role in the incidence of cardiovascular disease. Hypoalbuminemia, ascribed to malnutrition, has been one of the most powerful risk factors that predict all-cause and cardiovascular mortality in dialysis patients. The presence of inflammation, as evidenced by increased levels of specific cytokines (interleukin-6 and tumor necrosis factor α) or acute-phase proteins (C-reactive protein and serum amyloid A), however, has been found to be associated with vascular disease in the general population as well as in dialysis patients. The process of inflammation, also called the acute-phase response, additionally causes loss of muscle mass and changes in plasma composition—decreases in serum albumin, prealbumin, and transferrin levels, also associated with malnutrition. Inflammation alters lipoprotein structure and function as well as endothelial structure and function to favor atherogenesis and increases the concentration of atherogenic proteins in serum, such as fibrinogen and lipoprotein (a). Inflammation in dialysis patients is episodic. The causes are likely to be multifactorial and include vascular access infection, less-than-sterile dialysate, dialysate back leak, and nonbiocompatible membranes in addition to clinically apparent infection. In addition, proinflammatory compounds, such as advanced glycation end products, accumulate in renal failure, and defense mechanisms against oxidative injury are reduced, contributing to inflammation and to its effect on the vascular endothelium.
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Papers by George Kaysen