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.

Requirement of Zn to demonstrate HCO3-stimulated ATPase activity of rat small intestinal brush border.

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.

A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease.

The recent research findings concerning syndromes of muscle wasting, malnutrition, and inflammation in individuals with chronic kidney disease (CKD) or acute kidney injury (AKI) have led to a need for new terminology. To address this need, the International Society of Renal Nutrition and Metabolism (ISRNM) convened an expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI. The ISRNM expert panel recommends the term 'protein-energy wasting' for loss of body protein mass and fuel reserves. 'Kidney disease wasting' refers to the occurrence of protein-energy wasting in CKD or AKI regardless of the cause. Cachexia is a severe form of protein-energy wasting that occurs infrequently in kidney disease. Protein-energy wasting is diagnosed if three characteristics are present (low serum levels of albumin, transthyretin, or cholesterol), reduced body mass (low or reduced body or fat mass or weight loss with reduced intake of protein and energy), and reduced muscle mass (muscle wasting or sarcopenia, reduced mid-arm muscle circumference). The kidney disease wasting is divided into two main categories of CKD- and AKI-associated protein-energy wasting. Measures of chronic inflammation or other developing tests can be useful clues for the existence of protein-energy wasting but do not define protein-energy wasting. Clinical staging and potential treatment strategies for protein-energy wasting are to be developed in the future.

A low-protein diet restricts albumin synthesis in nephrotic rats.

High-protein diets increase albumin synthesis in rats with Heymann nephritis but albuminuria increases also, causing serum albumin concentration to be suppressed further than in nephrotic animals eating a low-protein diet. Experiments were designed to determine whether dietary protein augmentation directly stimulates albumin synthesis, or whether instead increased albumin synthesis is triggered by the decrease in serum albumin concentration. Evidence is presented that dietary protein augmentation directly stimulates albumin synthesis, accompanied by a proportional increase in steady-state hepatic albumin mRNA concentration (AlbmRNA) and by an increase in AlbmRNA transcription. When the increased albuminuria resulting from dietary protein augmentation is blunted with enalapril, serum albumin concentration is shown to increase in nephrotic rats. Both albumin synthesis and AlbmRNA increase in these animals despite the greater serum albumin concentration. Albumin synthesis correlates inversely with both serum albumin and serum oncotic pressure in nephrotic rats fed 40% protein, but does not correlate with serum albumin concentration in nephrotic rats fed 8.5% protein (LP), even when serum albumin concentration is reduced. Albumin masses are preserved in LP primarily because of reduced albuminuria. Reduced serum oncotic pressure and dietary protein augmentation combine to stimulate albumin synthesis in nephrotic rats at the level of gene transcription.

Proteinuria, not altered albumin metabolism, affects hyperlipidemia in the nephrotic rat.

It has been established previously that nephrotic hyperlipidemia is characterized by both an increase in lipid synthesis and a defect in removal of lipoproteins. The relationship between these defects and altered albumin metabolism is uncertain. One hypothesis is that hepatic lipogenesis increases in parallel with albumin synthesis. To test this hypothesis, albumin synthesis was increased in nephrotic rats fed an 8.5% protein diet (LPN) by increasing dietary protein to 40% (HPN). Proteinuria was modulated in half of the rats fed 40% protein by enalapril (HPE). Albumin synthesis was the same in both HPN and HPE, but proteinuria was reduced in HPE compared to HPN, and so were serum cholesterol and triglycerides (TG). To examine the effect of serum albumin on lipid clearance in the absence of proteinuria, plasma clearance of chylomicrons (CM) and VLDL was measured in Nagase analbuminemic rats (NAR) and found to be no different than in normal SD rats. When proteinuria was induced in NAR and in SD rats, a severe and identical defect in both CM and VLDL clearance was acquired in both groups and blood lipid levels were increased to a similar degree in both groups. Neither hyperlipidemia nor defective removal of lipoproteins from the circulation are linked to albumin synthesis or serum albumin concentration but result, at least in part, from proteinuria. Postheparin lipoprotein lipase (LPL) activity was reduced slightly in nephrotic animals compared to nonnephrotic controls, but the most striking finding was a highly significant decrease in postheraprin LPL activity in normal NAR compared to SD rats (P less than 0.001), suggesting that reduced LPL activity is not responsible for reduced clearance of CM and VLDL in nephrotic rats.

Effects of chronic renal failure on protein synthesis and albumin messenger ribonucleic acid in rat liver.

Previously we reported that chronic renal failure in rats leads to preferential disaggregation of liver membrane-bound polysomes associated with a decrease in albumin synthesis. To determine whether reduced albumin synthesis results from reduced cellular levels of albumin messenger RNA (mRNA) or some other molecular mechanism, we have employed mRNA-DNA hybridization in conjunction with cell-free protein synthesis to determine albumin mRNA sequence content and biological activity in subcellular fractions from control and uremic rat liver. Using high specific activity albumin [3H]-complementary DNA prepared from purified-albumin mRNA, we found that total liver polysomes and albumin mRNA sequence content are increased in uremic animals. The extra polysomes are located within the membrane-bound subcellular fraction. These polysomes, however, have reduced ability to synthesize albumin in the cell-free system, and mRNA isolated from membrane-bound polysomes of uremic liver showed reduced albumin synthesis. Evaluation of albumin mRNA size by hybridization analysis revealed a reduced content of intact albumin mRNA molecules per microgram of RNA in the liver of uremic animals. This was associated with increased ribonuclease activity in uremic cytosol. The diminished albumin synthesis by membrane-bound polysomes of uremic rat liver can, therefore, be explained by enhanced degradation of albumin mRNA.

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.

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.

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.

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.

Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen.

Combined hepatocellular injury and renal tubular necrosis developed in five alcoholic patients who were receiving acetaminophen therapeutically. Two patients were taking doses prescribed by a physician. The hepatitis was characterized by extremely high serum transaminase values that were maximal on admission. Two patients died, and autopsy disclosed hepatic centrizonal necrosis and acute renal tubular necrosis. The three who survived had clinical features typical of acute tubular necrosis. All five had measurable concentrations of acetaminophen in plasma, although measurements were requested on admission only in two patients. When an alcoholic presents with combined hepatic and renal insufficiency, acetaminophen should be considered as a possible inciting agent. This diagnosis should be considered when serum transaminase levels are markedly elevated and when renal failure is due to acute tubular necrosis.

Insulin-like growth factor I and its binding proteins in the experimental nephrotic syndrome.

Insulin-like growth factor I (IGF-I) is present in serum in association with specific IGF-binding proteins (IGFBPs) primarily in a large (approximately 150K) ternary or a smaller (approximately 50K) binary protein complex or in the free form (< or = 1%). We hypothesized that glomerular proteinuria results in urinary excretion of IGF-I/IGF-binding protein complexes and that the nephrotic syndrome induces abnormal serum distribution and liver synthesis of IGF-binding proteins. In nephrotic rats, serum IGF-I levels are reduced compared with pair-fed control animals. In nephrotic rat serum, binding to IGFBP-3 is reduced and Western immune analysis demonstrates an approximately 27K fragment that does not bind IGF-I, suggesting in vivo proteolysis of IGFBP-3. In contrast, binding and serum levels of IGFBP-2 are increased in nephrotic rats, which results from increased synthesis in the liver. In Nagase analbuminemic rats, the IGF-I levels and IGFBP-distribution in serum are normal suggesting that the reduced albumin levels in the nephrotic syndrome do not cause the increased liver synthesis and serum levels of IGFBP-2. Nephrotic rat urine contains IGFBP-3 and IGFBP-2 as well as strong activity of an IGFBP-3 protease. Because the 150K ternary complex in serum but not the smaller binding protein complex is restricted to the intravascular space, the shift of binding from IGFBP-3 (ternary complex) to IGFBP-2 (binary complex) in nephrotic rat serum may help to maintain tissue availability despite the reduction in serum IGF-I levels.

Role of the kidneys in the metabolism of circulating mevalonate in humans.

Previous studies in several animal species have demonstrated that the kidneys are the primary site of mevalonate metabolism by the oxidative or shunt pathway. To determine the role of the human kidney in mevalonate oxidation, we studied mevalonate shunt activity in patients undergoing hemodialysis for varying degrees of renal failure. Surprisingly, at least half of the uremic patients and even anephric patients had normal ability to oxidize mevalonate by the shunt pathway. In addition, we found a strong negative correlation (R = -0.94) between mevalonate shunt activity and serum phosphorus levels in uremic patients. The resulting inhibition of mevalonate oxidation by high serum phosphorus levels was reversed by lowering the serum phosphorus in one patient. Finally, a positive correlation was found between mevalonate oxidation and serum PTH levels. The results of this study suggest that, in humans, extrarenal tissues can be major contributors to mevalonate oxidation. It is therefore probable that in humans, in contrast to other animals, the kidney is not the primary site of mevalonate metabolism by this oxidative pathway. Finally, the strong negative correlation between serum phosphorus levels and the ability of uremic patients to oxidize mevalonate suggests a regulatory role for the phosphate ion in the mevalonate shunt pathway.

Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects.

Twenty patients who underwent uninephrectomy for kidney donation between 1964 and 1968 participated in a long-term study of the function of the solitary kidney. Mean follow up after uninephrectomy was 15.8 +/- .3 years. One patient with a strong family history of essential hypertension developed de novo mild hypertension. The current creatinine clearance of the donors was 80 +/- 4 ml/min. The 1-week, 3-6 months and 14-18 years postuninephrectomy percentages of predonation creatinine clearance were 72 +/- 3%, 76 +/- 3% and 78 +/- 2%, respectively. The 24-hr urine protein excretion in kidney donors was significantly higher than in controls (141 +/- 20 mg vs. 74 +/- 3 mg, respectively, P less than .0005). Except for one donor who may have developed glomerulonephritis, the donors had normal urinary albumin excretion. The cause of the slightly elevated nonalbumin proteinuria is not known. However, this long-term study of kidney donors shows no adverse effects on the blood pressure and renal function after many years of compensatory hyperfiltration.

Pretransplant systemic inflammation and acute rejection after renal transplantation.

BACKGROUND: There are presently no established pre-transplant tests that consistently identify patients who may be at increased risk for acute rejection episodes after renal transplantation. We studied whether pretransplant serum levels of C-reactive protein (CRP), a marker for the presence of systemic inflammation, would predict the occurrence of acute rejection episodes after renal transplantation. METHODS: Pretransplant serum was tested for CRP level in 97 consecutive renal transplant recipients. Time to acute rejection after transplantation was stratified by CRP level and compared using the Kaplan-Meier method. In addition, Cox regression multivariate analysis was performed to assess whether any pretransplant covariates could independently predict the subsequent occurrence of acute rejection episodes. RESULTS: Pretransplant mean CRP levels were higher in patients who subsequently had a rejection episode versus those who had no rejection (22.2+/-2.9 vs. 11.7+/-1.8 microg/ml, respectively, P=0.003). Patients less than the median CRP value had a significantly longer time to rejection compared to those with higher CRP levels (P=0.002). Similarly, patients within the lowest CRP quartile had longer times to rejection when compared with the highest quartile (P=0.006). Cox proportional hazards regression multivariate analysis identified CRP level as the only independent pretransplant risk factor for rejection identified (P=0.044). CONCLUSIONS: Pretransplant systemic inflammation as manifested by elevated serum CRP level independently predicts the risk of acute rejection after renal transplantation and may be useful in stratifying patients at the time of transplantation according to immunological risk. Thus, assessment of pretransplant systemic inflammatory status may be helpful in prospective individualization of immunosuppression therapy after renal transplantation.

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.

C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.

Hypoalbuminemia predicts death in dialysis patients. Although hypoalbuminemia has been attributed to malnutrition, evidence of inflammation (C-reactive protein [CRP] and cytokine levels) has recently been recognized to predict albumin concentration in dialysis patients. We measured CRP and albumin levels in October 1995 in 91 hemodialysis (HD) patients. During a 34-month follow-up period, we determined the incidence and cause of death. Patients were divided into four groups based on serum albumin levels (<3.5 [lowest quartile], 3.5 to 3.8, 3.9 to 4.0, and >4.0 g/dL [highest quartile]). Survival differed among the four groups (P = 0.0063). Patients with albumin levels greater than 4.0 g/dL had the greatest survival. Kaplan-Meier survival estimates of patients from varying CRP quartiles (<2.6, 2.6 to 5.2, 5.3 to 11.5, and >11.5 microg/mL) differed among the four groups (P < 0.0001). The group with the greatest CRP level (>11.5 microg/mL) had the lowest survival. Multivariate analysis using the Cox proportional hazards model showed that only CRP level (chi-square = 21.11; P < 0.0001) and age (chi-square = 5.44; P = 0.020) predicted death. Albumin level (chi-square = 0.16; P = 0.69) was not predictive. Only when CRP was excluded from the model did low serum albumin level (chi-square = 12. 04; P = 0.0004) predict death. CRP level (chi-square = 16.79; P < 0. 0001) and age (chi-square = 6.38; P = 0.012) also superceded albumin level (chi-square = 0.45; P = 0.51) in predicting cardiovascular mortality. Although values for blood urea nitrogen, creatinine, and normalized protein catabolic rate were significantly less among patients who died, these parameters, as well as cholesterol level and diabetes, were not important predictors of death in multivariate analysis. The acute-phase response or the cause of the acute-phase response is largely responsible for the effect of hypoalbuminemia on mortality in HD patients.

Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients.

We defined erythropoietin (EPO) resistance by the ratio of the weekly EPO dose to hematocrit (Hct), yielding a continuously distributed variable (EPO/Hct). EPO resistance is usually attributed to iron or vitamin deficiency, hyperparathyroidism, aluminum toxicity, or inflammation. Activation of the acute-phase response, assessed by the level of the acute-phase C-reactive protein (CRP), correlates strongly with hypoalbuminemia and mortality in both hemodialysis (HD) and peritoneal dialysis (PD) patients. In this cross-sectional study of 92 HD and 36 PD patients, we examined the contribution of parathyroid hormone (PTH) levels, iron indices, aluminum levels, nutritional parameters (normalized protein catabolic rate [PCRn]), dialysis adequacy (Kt/V), and CRP to EPO/Hct. Albumin level serves as a measure of both nutrition and inflammation and was used as another independent variable. Serum albumin level (deltaR2 = 0.129; P < 0.001) and age (deltaR2 = 0.040; P = 0.040) were the best predictors of EPO/Hct in HD patients, and serum albumin (deltaR2 = 0.205; P = 0.002) and ferritin levels (deltaR2 = 0.132; P = 0.015) in PD patients. When albumin was excluded from the analysis, the best predictors of EPO/Hct were CRP (deltaR2 = 0.105; P = 0.003) and ferritin levels (deltaR2 = 0.051; P = 0.023) in HD patients and CRP level (deltaR2 = 0.141; P = 0.024) in PD patients. When both albumin and CRP were excluded from analysis in HD patients, low transferrin levels predicted high EPO/Hct (deltaR2 = 0.070; P = 0.011). EPO/Hct was independent of PTH and aluminum levels, PCRn, and Kt/V. High EPO/Hct occurred in the context of high ferritin and low transferrin levels, the pattern expected in the acute-phase response, not in iron deficiency. In well-dialyzed patients who were iron replete, the acute-phase response was the most important predictor of EPO resistance.

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.

Nephrotic proteinuria has No net effect on total body protein synthesis: measurements with (13)C valine.

In nephrotic syndrome, significant amounts of plasma proteins, mostly of hepatic origin, are lost in urine. Total hepatic protein synthesis increases, suggesting that other protein pools must be conserved to maintain steady state. This can be accomplished either by decreased amino acid oxidation or decreased protein synthesis in other organs to replace lost liver-derived proteins. To determine the effect of nephrotic syndrome on total-body protein metabolism, we compared whole-body valine use in seven nephrotic patients and five controls using a primed continuous infusion of [1-(13)C]-valine, with additional priming of NaH(13)CO(3). Plasma [(13)C]-valine, (13)C alpha ketoisovaleric acid, and the expired (13)CO(2) enrichments were used to assess whole-body valine flux, valine oxidation, and nonoxidative valine disposal (NOVD). The valine flux into the blood compartment (97.7 +/- 3.0 versus 95.3 +/- 3.3 micromol/kg/h), oxidation of valine (19.4 +/- 1.9 versus 21.2 +/- 2. 8 micromol/kg/h), and NOVD (78.3 +/- 2.5 versus 74.2 +/- 2.7 micromol/kg/h) were not statistically different in patients compared with controls. Valine oxidation correlated positively with urinary urea excretion (r = 0.70; P = 0.01) in all subjects. Compared with control subjects who have similar urinary urea excretion, nephrotic subjects do not compensate for urinary loss of protein by decreased amino acid oxidation or decreased nonoxidative valine disposal. Previous studies have shown that synthesis of several hepatic proteins increases when subjects are fed the same dietary regime, whereas the present study shows that total-body protein synthesis does not increase. This would imply reduced synthesis of nonhepatic protein pools.