The effect of etanercept on suppression of the systemic inflammatory response in chronic hemodialysis patients.

BACKGROUND: Inflammation strongly predicts all-cause and cardiovascular mortality among dialysis patients. The negative acute-phase proteins, albumin and prealbumin are both inversely associated with mortality. Both albumin and prealbumin levels are decreased by inflammation. We carried out a pilot study to establish whether treatment with the tumor necrosis factor-alpha; receptor antagonist etanercept would be safe and result in improved levels of albumin and prealbumin in inflamed hypoalbuminemic (albumin < 3.8 g/dl, CRP > 8.0 mg/l) prevalent hemodialysis patients. METHODS: We excluded patients who had infectious risk (hepatitis C or B positive, HIV positive, purified protein derivative (PPD) positive or having a history of tuberculosis, having a tunneled dialysis catheter) to find patients having both hypoalbuminemia and inflammation. Of 433 less than 6% met the inclusion criteria. 10 patients were randomized to receive etanercept or placebo twice weekly for 44 weeks. RESULTS: There were no adverse infectious events. There was no significant difference for any of the measurements between the two groups. However there was a significant difference in the time-dependent effects of etanercept on prealbumin: increasing 20% in the etanercept group while decreasing in the placebo group. CONCLUSIONS: Administration of a TNF-alpha; receptor antagonist appears safe in this selected population, despite the large increase in infectious risk observed in the dialysis patient population. The effect on surrogate markers of inflammation is small.

Hyperlipidemia in chronic kidney disease.

The risk of cardiovascular events and mortality increases as renal function declines. The standard Framingham risk factors contributing to the relative risk of mortality (RRM) are altered or replaced. While obesity predicts loss of renal function, among dialysis patients obesity predicts survival rather than mortality. Among dialysis patients, Low Density Lipoprotein cholesterol (LDL) does not predict mortality; however other risk factors, such as low High Density Lipoprotein cholesterol (HDL) and increased intermediate density lipoproteins (IDL), remain cardiovascular risk factors. While HDL levels are decreased as a result of an increased fractional catabolic rate (FCR) both among obese patients with normal renal function and among dialysis patients, the mechanisms responsible for increased HDL FCR may differ. In patients with advanced kidney disease, HDL fails to mature normally as a result of decreased lecithin cholesterol ester transfer protein (LCAT), leaving cholesterol ester-poor, triglyceride (TG)-rich HDL3 and pre-beta-HDL. Chronic kidney disease (CKD) is associated with insulin resistance, providing another potential mechanistic link to low HDL levels. Increased TG levels are found in an expanded Intermediate Density Lipoprotein (IDL) pool and are associated with mortality risk. Lipoprotein (a) (LP(a)) levels are increased. In patients without renal disease, the concentration of Lp(a) is inversely associated with the size of the apo (a) isoform inherited; Lp (a) levels are increased in patients with kidney disease as consequence of increased concentrations, primarily of the high molecular weight isoform resulting from decreased clearance. Lp (a) levels are also associated with cardiovascular outcome among dialysis patients.

Dialysis removes apolipoprotein C-I, improving very low-density lipoprotein clearance.

Chronic kidney disease (CKD) is associated with dyslipidemia, characterized by increased levels of triglyceride-rich lipoproteins (TRLPs), including very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), with no change or a reduction in low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) levels. Serum triglycerides and IDL are risk factors for vascular disease in dialysis patients, whereas LDL is not. The principal cause of the increase in TRLPs is decreased removal, not increased synthesis. The clearance defect arises from a reduction in specific lipoprotein receptors, decreases in the activity of lipases, and increased levels of low-molecular weight apolipoproteins that inhibit the interaction between TRLPs and both the receptors and the lipases that catabolize them. VLDL from dialysis patients is structurally abnormal and is not metabolized at a normal rate by lipoprotein lipase (LPL).

Metabolic syndrome and renal failure: similarities and differences.

The metabolic syndrome (MS) and chronic kidney disease (CKD) share many similar risk factors for cardiovascular disease. Both are associated with increased triglyceride (TG) levels, both associated with increased small dense low density lipoprotein (LDL), both with decreased high density lipoprotein (HDL) levels. In both cases HDL particle size is reduced. The TG content of HDL and very low density lipoprotein (VLDL) and remnants are increased, resulting in a dyslipidemia. Both are associated with increased inflammation, a hypercoagulable state and insulin resistance. Establishing whether these similarities are the result of identical biological processes or instead represent similar end results of different processes is further confounded by the associated both of adiposity and of MS with the incidence and progression of renal failure. Differences are present however. In MS hepatic VLDL synthesis is increased driven by increased flux of free fatty acids from muscle, adipose tissue and gut to the liver. VLDL is catabolized to LDL and the transfer of TG to HDL by cholesterol ester transfer protein destabilizes HDL leading to its rapid clearance. In CKD HDL fails to mature due to reduced activity of lecithin cholesterol transfer protein. In MS inflammation primarily arises from increased visceral adipose tissue, while inflammation is largely unrelated to body composition in CKD. Increased production of TG rich lipoproteins predominates in MS, while decreased disposal of TG rich proteins predominates as the cause of increased TG levels in CKD. Whether treatment of elements of MS, with the exception of hypertension, will avoid the onset and progression of renal failure is unknown.

Metabolic consequences of body size and body composition in hemodialysis patients.

Small body mass index is associated with increased mortality in chronic hemodialysis patients. The reasons for this observation are unclear but may be related to body composition. This study aimed to investigate the body composition in chronic hemodialysis patients. The difference between body mass and the sum of muscle, bone, subcutaneous, and visceral adipose tissue masses, measured by whole body magnetic resonance imaging, was defined as the high metabolic rate compartment representing the visceral mass. Protein catabolic rate was calculated from urea kinetics. Forty chronic hemodialysis patients (mean age 54.7 years; 87.5% African Americans; 45% females) were studied. High metabolic rate compartment expressed in percent of body weight was inversely related to body weight (r=-0.475; P=0.002) and body mass index (r=-0.530; P<0.001). In a multiple linear regression model, protein catabolic rate was significantly correlated only with high metabolic rate compartment (r=0.616; P<0.001). Assuming that protein catabolic rate in addition to protein intake reflects urea and uremic toxin generation, it follows that high metabolic rate compartment is the major compartment involved in their generation. Consequently, uremic toxin production rate may be relatively higher in patients with low body weight and low body mass index as compared to their heavier counterparts. The poorer survival observed in smaller dialysis patients may be related to these relative differences.

Endothelial bound lipoprotein lipase (LpL) depletion in hypoalbuminemia results from decreased endothelial binding, not decreased secretion.

Hypertriglyceridemia in nephrotic (NS) and Nagase analbuminemic rats (Analb) results from reduced triglyceride clearance. NS and Analb have reduced or absent albumin, reduced plasma oncotic pressure (pi), but Analb lack proteinuria. The heparin releasable lipoprotein lipase (LpL) pool in both models is greatly reduced, suggesting reduced LpL is related to low albumin or pi and not proteinuria. To determine the cause of endothelial LpL reduction, we studied effectors of endothelial LpL (eLpL) levels from gene expression, to delivery and endothelial binding. eLpL was measured as heparin releasable activity. eLpL and secretion rate was measured in isolated hearts perfused with heparin. mRNA levels were measured in rat hearts by kinetic RT-PCR. Finally, binding of (125)I-LpL by competition assays rat endothelial cells measured serum-induced changes in affinity. eLpL in vivo was reduced in nephrotic and Analb rats. While the eLpL pool was reduced in isolated perfused hearts, neither LpL secretion by isolated hearts nor myocardial mRNA was reduced in NS or Analb. Binding of LpL to RAEC preincubated with serum from either NS or Analb was reduced compared to control. LpL mRNA levels and release rate was not altered in hearts from NS rats, while eLpL is depleted, suggesting that reduced eLpL in NS is not the result of reduced delivery. The finding that NS serum alters LpL binding to RAEC suggests LpL depletion results from decreased binding rather than defective delivery. This in turn is a consequence of reduced serum albumin or pi but does not require proteinuria.

Measuring partial body potassium in the arm versus total body potassium.

Skeletal muscle (SM), the body's main structural support, has been implicated in metabolic, physiological, and disease processes in humans. Despite being the largest tissue in the human body, its assessment remains difficult and indirect. However, being metabolically active it contains over 50% of the total body potassium (TBK) pool. We present our preliminary results from a new system for measuring partial body K (PBK) that presently are limited to the arm yet provide a direct and specific measure of the SM. This uniquely specific quantification of the SM mass in the arm, which is shielded from the body during measurement, allows us to simplify the assumptions used in deriving the total SM, thereby possibly improving the modeling of the human body compartments. Preliminary results show that PBK measurements are consistent with those from the TBK previously obtained from the same subjects, thus offering a simpler alternative to computed tomography and magnetic resonance imaging used for the same purposes. The PBK system, which can be set up in a physician's office or bedside in a hospital, is completely passive, safe, and inexpensive; it can be used on immobilized patients, children, pregnant women, or other at-risk populations.

Segment-specific resistivity improves body fluid volume estimates from bioimpedance spectroscopy in hemodialysis patients.

Discrepancies in body fluid estimates between segmental bioimpedance spectroscopy (SBIS) and gold-standard methods may be due to the use of a uniform value of tissue resistivity to compute extracellular fluid volume (ECV) and intracellular fluid volume (ICV). Discrepancies may also arise from the exclusion of fluid volumes of hands, feet, neck, and head from measurements due to electrode positions. The aim of this study was to define the specific resistivity of various body segments and to use those values for computation of ECV and ICV along with a correction for unmeasured fluid volumes. Twenty-nine maintenance hemodialysis patients (16 men) underwent body composition analysis including whole body MRI, whole body potassium (40K) content, deuterium, and sodium bromide dilution, and segmental and wrist-to-ankle bioimpedance spectroscopy, all performed on the same day before a hemodialysis. Segment-specific resistivity was determined from segmental fat-free mass (FFM; by MRI), hydration status of FFM (by deuterium and sodium bromide), tissue resistance (by SBIS), and segment length. Segmental FFM was higher and extracellular hydration of FFM was lower in men compared with women. Segment-specific resistivity values for arm, trunk, and leg all differed from the uniform resistivity used in traditional SBIS algorithms. Estimates for whole body ECV, ICV, and total body water from SBIS using segmental instead of uniform resistivity values and after adjustment for unmeasured fluid volumes of the body did not differ significantly from gold-standard measures. The uniform tissue resistivity values used in traditional SBIS algorithms result in underestimation of ECV, ICV, and total body water. Use of segmental resistivity values combined with adjustment for body volumes that are neglected by traditional SBIS technique significantly improves estimations of body fluid volume in hemodialysis patients.

The role of improved water quality on inflammatory markers in patients undergoing regular dialysis.

Hemodialysis utilizes large quantities of water for the preparation of dialysis fluid. Such water meets national standards and international standards but a considerable disparity exists between such standards with respect to microbiological purity. This study collated and retrospectively analyzed the impact of upgrading water systems from that specified in the US standards to those specified in European standards on clinical measures associated with inflammation in four metropolitan dialysis units for two periods. Two periods were compared, three months prior to and six months post upgrading the water treatment systems. The monthly total erythropoietin dosage and intravenous iron supplementation for each patient were also compared over these periods. Variables with significant pre-post differences were assessed using multivariate models to control for confounding factors. The results indicated significant increases in hemoglobin, ferritin and TSat (all p < 0.0001) and albumin (p = 0.0001) were associated with improvement in water quality. Decreases in CRP and creatinine (both p < 0.0001) were also noted. These findings suggest that the current regulations in the United States set the microbiological limits of water and dialysis fluid inappropriately high, and the limits should be revised downwards, since such an approach is reflected in improvement in markers of inflammation.

Pharmacokinetics of thalidomide in patients with impaired renal function and while on and off dialysis.

There is a renewed interest in thalidomide for use in malignancies and systemic inflammatory diseases. Reduced renal function is not uncommon among patients with these disease states but the pharmacokinetics has not been fully investigated. The aim of this study was to investigate the pharmacokinetics of thalidomide in haemodialysis patients while on and off dialysis and in myeloma patients with varying degrees of renal function. Two studies were performed. To establish the pharmacokinetics of thalidomide in patients with mild to moderate renal failure, blood samples were taken over 12 weeks from 40 patients with multiple myeloma. A second study was performed in six patients with end-stage renal disease both on a non-dialysis day and before and during a haemodialysis session. Thalidomide concentration was determined by HPLC. A one-compartment open model with first-order absorption and elimination was used to fit total thalidomide concentration to population pharmacokinetics and statistical models using the NONMEM program. Clearance and volumes were slightly below 10 L h-1 and 1 L kg-1, respectively, in both patient groups. The inter- and intra-patient variability was low. Clearance was doubled during dialysis. There was no correlation between thalidomide clearance and renal function. In conclusion, the pharmacokinetics of thalidomide in patients with renal failure are very similar to values reported by others for patients with normal renal function. Although clearance during dialysis is doubled, thalidomide dose need not be changed for patients with decreased kidney function. There is also no need for a supplementary dose due to haemodialysis.

Levels of alpha1 acid glycoprotein and ceruloplasmin predict future albumin levels in hemodialysis patients.

BACKGROUND: Serum albumin concentration predicts mortality in hemodialysis (HD) patients. While serum albumin concentration correlates with serum concentration of C-reactive protein (CRP) and is dependent upon CRP in multiple regression models in cross sectional studies, CRP does not predict future albumin levels, possibly because CRP changes rapidly, yielding large month-to-month variability in CRP. If inflammation causes rather than is simply associated with hypoalbuminemia, then changes in the levels of acute phase proteins should precede changes in serum albumin concentration. METHODS: The levels of long-lived positive and negative acute-phase proteins (APPs) (C-reactive protein, ceruloplasmin, alpha1 acid glycoprotein, transferrin and albumin) were measured longitudinally in 64 HD patients and a regression model was constructed to predict future albumin levels. Normalized protein catabolic rate (nPCR) was measured monthly. The number of repeated measurements ranged from 9 to 39 in each patient (median 22 and a mean of 23 measurements). To construct a model that would predict serum albumin concentration at any time j, values of all longitudinally measured APPs, positive and negative at any time j - 1, approximately 30 days prior to time j, were used. Other demographic factors (such as, race, access type, and cause of renal failure) also were incorporated into the model. RESULTS: The model with the best fit for predicting serum albumin at time j included albumin, ceruloplasmin, and alpha1 acid glycoprotein measured at time j - 1. The only demographic variable with subsequent predictive value was diabetes. CONCLUSIONS: The finding that changes in the concentration of the long lived APPs measured one month earlier are associated with predictable changes in the future concentration of serum albumin suggest that changes in inflammation are likely to be causal in determining serum albumin concentration in hemodialysis patients.

Endothelial chylomicron binding is altered by interaction with high-density lipoprotein in Heymann's nephritis.

Very-low-density lipoprotein (VLDL) catabolism is impaired in the nephrotic syndrome, partly as a result of structural changes that impair endothelial binding in the presence of lipoprotein lipase. Previous results suggested that postsynthetic modification of VLDL by high-density lipoprotein (HDL) in nephrotic syndrome rats causes their failure to bind endothelia normally. It is unknown (1) whether the structure of secreted lipoproteins is normal before exposure to nephrotic syndrome serum and (2) whether the same structural or functional defects are imparted to chylomicrons (CMs) through their interaction with HDL from nephrotic syndrome rats. CMs were isolated from thoracic duct lymph from rats with passive Heymann's nephritis (HN) and normal controls. CMs from control rats were incubated with HDL from either HN or control rats and reisolated, and apolipoprotein E (apo E) content and endothelial binding were determined. We found that CMs secreted by HN and control rats had similar apo E/B-48 ratios. HDL from HN rats had significantly lower apo E/A-I ratios than controls. Incubation of nascent control CMs with control HDL resulted in a 4-fold increase in CM apo E content, but binding was unaffected. Incubation with HDL from HN resulted in only a 50% increase in CM apo E content but reduced binding of these treated CMs by 50% compared either with nascent control CMs or with CMs incubated with control HDL. HDL from rats with HN alters CM binding to lipoprotein lipase by a mechanism that does not involve reducing the content of apo E already present on CMs at the time of secretion.

Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients.

BACKGROUND: Cross-sectional studies have shown an inverse correlation between serum C-reactive protein (CRP) and serum albumin concentration in hemodialysis patients. The net effects of inflammation and dietary protein intake on nutritional markers over time are unknown. METHODS: To explore the effects of CRP and normalized protein catabolic rate (nPCR) on serum albumin and creatinine, we analyzed six consecutive months of laboratory data from 364 hemodialysis patients, using a multivariable Mixed model with conservative biases. RESULTS: The overall trend over time in serum albumin was slightly positive (0.039 g/dL/month) and in serum creatinine slightly negative (-0.052 mg/dL/month). With increasing CRP, serum albumin declined significantly (-0.124 g/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes, and nPCR, P < 0.0001). Serum albumin increased with increasing nPCR (0.021 g/dL/month per 0.1 g/kg/day, P < 0.0001). The effect of CRP on albumin was attenuated in African Americans and at a higher nPCR. Corresponding values for creatinine mirrored those for albumin. With increasing CRP, creatinine declined significantly [-0.142 mg/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes (time since initiation of dialysis; vintage), Kt/V, and nPCR, P = 0.002]. Serum creatinine increased with increasing nPCR (0.183 mg/dL/month per g/kg/day, P < 0.0001). CONCLUSIONS: Proxies of inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. These data provide a rationale for prospective testing of dietary protein supplementation in hemodialysis patients with biochemical evidence of ongoing inflammation and "malnutrition."

Leptin is a negative acute phase protein in chronic hemodialysis patients.

BACKGROUND: Hypoalbuminemia strongly predicts death in hemodialysis patients and results from both inflammation and malnutrition. One potential link between malnutrition and inflammation is appetite suppression triggered by inflammation. Leptin is secreted by adipose tissue and suppresses appetite, and it is also a positive acute phase protein in the rat. Factored for body weight, leptin is known to be increased in hemodialysis patients, but its relationship to inflammation is unknown. METHODS: We examined the relationship between spontaneously occurring activation of the acute phase response and leptin levels in 29 chronic hemodialysis patients. Serum samples were obtained three times weekly for six weeks and then monthly from 29 chronic hemodialysis patients, and the levels of the positive acute phase proteins [C-reactive protein (CRP), alpha1-acid glycoprotein (alpha1 AG), serum amyloid A, ceruloplasmin] and the negative acute phase proteins (albumin and transferrin) as well as leptin and interleukin-6 (IL-6) were measured. RESULTS: Positive and negative acute phase proteins were evaluated at the maximum CRP (mean, 9.42 +/- 1.14 mg/dL) and minimum values (mean, 0.41 +/- 0.09 mg/dL). When CRP was elevated, leptin levels were significantly reduced, as were the negative acute phase proteins albumin and transferrin. Serum amyloid A, ceruloplasmin, alpha1 acid glycoprotein, and IL-6 were all significantly increased at the maximum CRP level, compatible with general activation of the acute phase response. The change in leptin correlated negatively with the change in CRP (R = 0.437, P = 0.018), as did changes in albumin (R = 0.620, P < 0.001). CONCLUSIONS: Leptin is not increased as a consequence of inflammation in hemodialysis patients, but behaves as a negative rather than as a positive acute phase protein. Inflammation is unlikely to reduce appetite in dialysis patients through a leptin-mediated mechanism.

Proteinuria and plasma compositional changes contribute to defective lipoprotein catabolism in the nephrotic syndrome by separate mechanisms.

Triglyceride (TG)-rich lipoproteins are primarily increased in the nephrotic syndrome (NS) as a result of decreased catabolism. Lipoprotein lipase (LpL) is the rate limiting enzyme for lipolysis of TG. The biologically active endothelial bound LpL pool is reduced in NS providing one mechanism for decreased clearance of very low density lipoprotein (VLDL). LpL, however, is also reduced in the Nagase Analbuminemic Rat (NAR) to the same extent as in NS, suggesting that other factors contribute to decreased VLDL clearance. Hyperlipidemia worsens with the onset of proteinuria and is reduced when proteinuria abates. We established that while VLDL from NS rats bind poorly to bovine aortic endothelial cells (BAEC) in the presence of saturating LpL while, VLDL from NAR bind more avidly than control. We then established that rat aortic endothelial cells (RAEC) incubated with serum from NAR or from NS rats bind significantly less exogenous LpL. Thus decreased clearance of VLDL in NS results from: 1) reduced endothelial bound LpL; an effect of serum from animals with reduced oncotic pressure (pi) that makes cells unable to bind LpL; and 2) an alteration in VLDL binding to endothelial bound LpL. The former has no relationship to proteinuria while the latter occurs as a consequence of proteinuria. These effects combine to suppress VLDL clearance.

Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome.

BACKGROUND: Hypertriglyceridemia is a result of reduced triglyceride (TG)-rich lipoprotein (TRL) catabolism and occurs in rats with nephrotic syndrome (NS) and in Nagase analbuminemic rats (NARs). While the heparin-releasable lipoprotein lipase (LpL) pool in NAR and in NS is similar, TG levels are significantly greater in NS, suggesting that factors other than reduced LpL alone act in NS but not in NARs. Furthermore, clearance of chylomicrons (CM) and very low-density lipoprotein (VLDL) is normal in vivo in NAR despite low LpL levels. We tested the hypotheses that impaired binding of VLDL and impaired VLDL-high density lipoprotein (HDL) interactions contribute to hyperlipidemia in NS. METHODS: TG and apoB secretion was measured using Triton WR 1339. Clearance of CMs by perfused hearts from NS and NAR was determined. Binding of VLDL from control, NS and NAR to rat aortic endothelial cells (RAECs) was measured prior to and following incubation with HDL from NS, NARs, and control. ApoE, protein, and TG content was determined. RESULTS: TG levels were greatest in NS (516 +/- 95 mg/dL), intermediate in NAR (193 +/- 20), and least in control (97 +/- 16, P = 0.05), while in contrast, TG secretion was least in NS (178 +/- 33 mg/dL/hour) versus 212 +/- 17 in NAR and 294 +/- 15 in control (P < 0.001 vs. NS). Clearance of CMs by NS and NAR hearts was the same and significantly reduced versus control (P < 0.005). Binding of NS-VLDL to endothelial cells was reduced, while NAR-VLDL binding was increased versus control (P < 0.001). Incubation of NS-VLDL with control or NAR HDL increased VLDL binding compared with binding following incubation with NS HDL (P < 0.001). CONCLUSION: Increased TG levels in both NS and NAR are the result of decreased TRL clearance. TG levels are greater in NS because of the presence of a combined defect: (1) a decrease in endothelial-bound LpL that occurs as a consequence of reduced serum albumin concentration, and (2) a defect in VLDL binding to endothelial-bound LpL. This latter defect occurs only in the presence of proteinuria and is conferred by HDL.

C-reactive protein, oxidative stress, homocysteine, and troponin as inflammatory and metabolic predictors of atherosclerosis in ESRD.

Mortality in patients with end-stage renal disease remains high, with cardiovascular disease accounting for half of these deaths. Novel risk factors such as inflammation, oxidative stress, hyperhomocysteinemia, and high troponin levels are associated with cardiovascular risk in the general population. While there are substantial epidemiologic data confirming that these novel risk factors are associated with cardiovascular risk in end-stage renal disease patients, a causal relationship has not been established. Inflammation is readily identified by the presence of high levels of C-reactive protein, while studies of oxidative stress are hampered by the lack of a standardized test. The cause of both is unknown. Hyperhomocysteinemia results from decreased remethylation to methionine, although vitamin supplementation only partially corrects the defect, suggesting that uremic inhibition of the enzymatic process may be important. The most promising strategies for correcting oxidative stress and hyperhomocysteinemia are vitamin E and folinic acid therapy, respectively. Troponin I appears to be a more specific marker of myocardial injury than Troponin T, but troponin T retains its ability to predict cardiovascular mortality as well as all-cause mortality. Sorting out the role of each of these risk factors may be difficult since the factors may influence each other, may increase oxidative stress, and may mediate atherosclerosis through oxidative modification of lipids.