Increased Protein Loss Research Articles

Changes in the clinical and laboratory features of lupus patients after the big earthquake in Taiwan.

In order to understand the impact of the massive earthquake on disease activity, 60 patients with systemic lupus erythematosus (SLE) living in the earthquake area (group 1) and 31 patients living away from the area (group 2) were enrolled in this study. A questionnaire was used to record demographic data and clinical manifestations before and 6 months after the earthquake. Laboratory tests, including serum C3, C4, creatinine, anti-DNA antibody, CBC and 24 h urine protein were taken. The results showed that nine patients in group 1 had obvious disease flare-up as evidenced by fever, arthralgia, malar rash and photosensitivity, increased protein loss or edema, and other symptoms. However, there were no significant changes in either group 1 or 2 patients. In contrast, the comparison of laboratory parameters in group 1 patients before and after the earthquake showed a significant decrease of C4 from 17.3 +/- 15.3 to 14.1 +/- 7.33 and a significant increase of creatinine from 1.20 +/- 1.54 to 1.27 +/- 1.70 (P < 0.05), respectively. No significant difference for either C4 or creatinine was found in group 2 patients. In conclusion, there was no striking change in the clinical aspects for lupus patients. However, some laboratory results became abnormal in group 1 patients after the earthquake, indicating that their lupus status may have worsened.

Pathogenic Effects of a High Peritoneal Transport Rate

Recent studies have shown that patients with high peritoneal transport characteristics have substantially increased morbidity and mortality. This finding is counter-intuitive, since HTs will a priori achieve higher clearances. There are many possible causes: increased protein losses with consequent hypoalbuminemia; poor ultrafiltration capacity causing fluid retention, ventricular hypertrophy and hypertension; increased glucose absorption leading to anorexia, hyperinsulinism, and local AGE formation; and the development of an atherogenic lipid profile. While common pathogenic causes of high peritoneal transport and atherosclerosis have been hypothesized, it is more likely that CAPD as currently practiced is unsuitable for HTs, who should be switched to HD or NIPD. Renal and peritoneal clearances have different clinical effects and should be assessed separately. Current measures of dialysis adequacy, such as total Kt/V, do not therefore describe the patient's clinical situation accurately and are insufficient.

The Problem of the High Transporter: Is Survival Decreased?

The mechanisms responsible for the problem status of high transporters are diverse. High transporters have increased protein losses that may play a role in the presence of hypoalbuminemia and malnutrition. On the other hand, high transport induces increased glucose absorption, which may in turn be responsible for anorexia and increased atherogenesis--issues not discussed here, but clearly of major importance. And finally, the impaired ultrafiltration present in the high transporter leads to fluid overload, which is one of the driving forces for ventricular hypertrophy, hypertension, and increased cardiovascular risk--cardiovascular events being most prevalent cause of death in dialysis patients. All of the factors previously discussed--and others--may preclude some high transporters from being good candidates for peritoneal dialysis. Yet many others may still do well if the prescription is individually tailored to the particular patient.

Inhibition of nitric oxide synthase reverses changes in peritoneal permeability in a rat model of acute peritonitis

Acute peritonitis is the most frequent complication of peritoneal dialysis (PD), and nitric oxide (NO) is thought to play a role in the structural and permeability changes observed in this condition. We have used a combination of expression, enzymatic and pharmacological studies to substantiate the potential role(s) played by NO during peritonitis. The peritoneal equilibration test was performed in control rats and rats with acute peritonitis (originating from skin flora), using standard dialysate supplemented or not with the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). In parallel, peritoneal NOS enzymatic activities were measured and expression studies for NOS isoforms and S-nitrosocysteine reactivity performed in the peritoneum. In comparison with controls, rats with acute peritonitis were characterized by inflammatory changes, increased S-nitrosocysteine immunoreactivity, and increased NOS activities in the peritoneum, due to the up-regulation of endothelial and inducible NOS. In parallel, rats with acute peritonitis showed increased permeability for small solutes; decreased sodium sieving; loss of ultrafiltration (UF); and increased protein loss in the dialysate. Addition of L-NAME to the dialysate did not induce permeability changes in control rats, but significantly improved UF and reversed permeability modifications in rats with peritonitis. The effect of L-NAME was reflected by a mild but consistent increase in blood pressure during PD exchange. Our results demonstrate that local generation of NO, secondary to up-regulation of NOS isoforms, plays an important role in the regulation of peritoneal permeability during acute peritonitis in rats. By itself, NOS inhibition improves UF and reverses permeability changes, which might offer new therapeutic perspectives in acute peritonitis.

Management of High Peritoneal Transporters

High transporters on chronic peritoneal dialysis are challenged by increased protein losses, high glucose absorption with associated metabolic abnormalities, and poor ultrafiltration. Furthermore, the relative risk of mortality and technique failure is higher in high transporters than in patients of other transport types. An approach for satisfactory management of such patients on peritoneal dialysis (PD) has not been clearly demonstrated.

Increased protein loss during peritonitis associated with peritoneal dialysis is neutrophil dependent

Peritonitis in peritoneal dialysis patients is accompanied by an enhanced migration of neutrophils (PMNs) and increased protein loss into the peritoneal cavity; however, the role of PMNs in governing increased protein loss during peritonitis associated with peritoneal dialysis is unknown. We determined the importance of PMNs in governing changes in peritoneal permeability to protein in New Zealand White rabbits in which acute peritonitis was induced by adding 4 x 106 colony-forming units of Escherichia coli to 35 mL/kg of 0.9% saline dialysate. The total leukocyte and PMN migration into the peritoneal cavity was assessed by differential cell counts in the dialysate, and peritoneal permeability to protein was evaluated by calculating the dialysate to plasma concentration ratio for total protein as a function of time during a six- or eight-hour dwell. In series 1 experiments, leukocytes were depleted from the rabbit circulation by an intravenous injection of mustine (1.2 mg/kg) three days before the experiment; in series 2 experiments, integrin-dependent PMN migration into the peritoneal cavity was inhibited by an intravenous injection of monoclonal antibody (mAb) 60.3 (2 mg/kg) directed against the integrin CD18 on leukocytes five minutes before the experiment. In series 1 experiments, mustine decreased circulating leukocytes by 82 +/- 5% (mean +/- SEM) and circulating PMNs by 93 +/- 3%. Total leukocyte and PMN migration into the peritoneal cavity and peritoneal permeability to protein were decreased in mustine-treated rabbits after exposure to E. coli in the dialysate to levels similar to those found in rabbits without bacterial peritonitis. In series 2 experiments, an intravenous injection of anti-CD18 antibody also abrogated both the enhanced PMN migration into the peritoneal cavity and the increased peritoneal permeability to protein after exposure to E. coli in the dialysate. PMN migration into the peritoneal cavity is integrin dependent. Increased protein loss during acute, gram-negative bacterial peritonitis in a rabbit model of peritoneal dialysis is PMN dependent.

Stability of subtilisin and lysozyme under high hydrostatic pressure.

The stabilities of subtilisin and lysozyme under hydrostatic pressures up to 200 MPa were investigated for up to 7 days at 25 degrees C. Methods were chosen to assess changes in tertiary and secondary protein structure as well as aggregation state. Tertiary structure was monitored in situ with second derivative UV spectroscopy and after pressure treatment by dynamic light scattering and second derivative UV spectroscopy. Secondary structure and potential secondary structural changes were characterized by second derivative FTIR spectroscopy. Changes in aggregation state were assessed using dynamic light scattering. Additionally, protein concentration balances were carried out to detect any loss of protein as a function of pressure. For the conditions tested, neither protein shows measurable changes in tertiary or secondary structure or signs of aggregation. Lysozyme concentration balances show no dependence on pressure. Subtilisin concentration balances at high protein concentration (4 mg/mL and higher) do not show pressure dependence. However, the concentration balances carried out at 0.4 mg/mL show a clear sign of pressure dependence. These results may be explained by protein interaction with the vial surface and appear to be rate limited by the equilibrium between active and inactive protein on the surface. Pressure increases protein loss, and the estimated partial molar volume change between the two states is estimated to be -20 +/- 10 mL/mol.

Clinical Implications of Membrane Transport Characteristics on the Adequacy of Fluid and Solute Removal

It is important to identify the peritoneal transport characteristics of each patient and to guide the peritoneal therapy accordingly. High transporters on CAPD are prone to protein malnutrition because of increased protein losses and suppression of appetite with excessive carbohydrate loading from the peritoneal cavity. Anephric high transporters often do better on short-cycle therapies. Anephric low transporters of large size cannot readily meet clearance targets on standard peritoneal dialysis prescriptions. In patients with low rates of peritonitis, changes in peritoneal dialysis prescriptions are more commonly dictated by changes in residual renal function rather than changes in peritoneal transport.

Variability of Peritoneal Protein Loss in Diabetic and Nondiabetic Patients on Continuous Ambulatory Peritoneal Dialysis

In order to evaluate the influence of diabetes mellitus on peritoneal membrane permeability, we studied the peritoneal protein loss in two groups of patients. Group A consisted of 16 patients (9 nondiabetics and 7 diabetics) who were in the first month of treatment on continuous ambulatory peritoneal dialysis (CAPD). Group B consisted of 13 patients (7 nondiabetics and 6 diabetics) who had been on CAPD for approximately 15 months. In both groups we measured the body weight, serum total protein, albumin, and total protein, urea, and glucose in the peritoneal fluid. We did not find any difference in groups A and B between diabetics and nondiabetics as far as the estimated parameters were concerned. Age, body weight, serum biochemistry, and protein and urea content in peritoneal fluid were similar, when group A was compared to group B. Patients of group B had on average higher protein losses than those who had been on the method for a short period (mean 7.9 g/dL, vs 6.09 g/dL). Six patients were followed for over 15 months and were found to have significantly increased protein losses (p = 0.02). Glucose levels in peritoneal fluid were significantly lower in patients in group B, p < 0.05 (mean 51.8 g/dL vs 37.1 g/dL). Peritoneal protein loss does not seem to differ between diabetic and nondiabetic patients with end-stage renal disease treated with CAPD, at any given time of the treatment. We observed an increase in protein loss in some patients and a tendency to increase the protein loss in others.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of tumor bulk on the metabolic response to cancer.

The derangements in energy/substrate metabolism seen in oncology patients are similar regardless of the tumor's site of origin, and in advanced disease these metabolic derangements can be manifested as cancer cachexia. The relationship between tumor size and the degree of metabolic abnormality, however, remains unclear. Using primed constant infusions of stable and radiolabeled isotopes and indirect calorimetry, the authors have determined the rates of net protein catabolism (NPC), glucose oxidation, Cori cycling of glucose, and oxygen consumption in 85 patients with cancer. They have assessed the association between bulk of tumor and metabolic abnormality using regression analysis. A positive correlation was found between tumor bulk and the rates of NPC (r2 = 0.8), plasma glucose appearance (r2 = 0.72), plasma glucose clearance (r2 = 0.70), the percentage of tissue glucose uptake recycled to lactate (r2 = 0.62), and oxygen consumption (r2 = 0.79). The percentage of tissue glucose uptake oxidized was negatively correlated with tumor bulk (r2 = 0.75). The data indicate that the degree of metabolic abnormality seen in cancer patients is closely related to the quantity of malignant tissue present. Progressive increase in tumor size is associated with an increase in peripheral substrate mobilization, an increase in the rate of hepatic glucose production, an increase in tissue glucose uptake, an increase in energy-expensive glucose cycling to lactate, and an increase in protein loss.

The role of histamine1 and histamine2 receptors in the ethanol-induced jejunal plasma protein loss

Histamine and other mediators have been shown to be involved in the ethanol-induced jejunal plasma protein loss. In this study we have investigated whether the histamine (H)-related component of this protein loss is mediated by H1-receptors, H2-receptors or both. Four groups of dogs (n = 12 in each) were studied. They were: untreated, H1 + H2-receptor blockade, H1-receptor blockade and H2-receptor blockade. Chlorpheniramine and ranitidine were used to block H1 and H2-receptor blockade. Chlorpheniramine and ranitidine were used to block H1 and H2-receptors respectively. In all animals, jejunal protein loss was measured over 10 min periods for 90 min. Ethanol increased protein loss in all time periods (p less than 0.001). This protein loss was depressed by H1 + H2-receptors blockade throughout 90 min (p less than 0.01). H1-receptor blockade caused a similar depression of ethanol effect but only during 20 to 40 min (p less than 0.05). In contrast, H2-receptor blockade aggravated the protein losing effect of ethanol throughout 90 min (p less than 0.01). Analyses of data tend to suggest that the ethanol-induced protein loss is mediated principally by H1-receptors, and that a complete inhibition of the histamine-related ethanol-induced protein loss can be achieved only by a simultaneous blockade of both H1 and H2-receptors, and not by H1- or H2-receptor blockade alone.

Development of Progressive Glomerulosclerosis in Experimental Chronic Serum Sickness

A rat model of chronic serum sickness was used to study the pathogenesis of progressive glomerulosclerosis complicating experimental immune-complex glomerulonephritis. Chronic serum sickness was induced by immunising rats with bovine serum albumin followed by intraperitoneal administration of the antigen. Early lesions consisted of mesangial deposits of rat immunoglobulins, followed later by transient subendothelial and persistent subepithelial immune aggregates. On the basis of the peak level of proteinuria around day 80, three groups of rats were distinguished: I physiological proteinuria; II 50-500 mg/24 h; and III greater than 500 mg/24 h. The animals were killed at day 220 and the presence of mesangial proliferation, epithelial proliferation, and synechiae, as well as focal glomerulosclerosis was scored. It appeared that all and only proteinuric animals developed progressive glomerulosclerosis, although all three groups of animals passed through a phase with mesangial and subendothelial immune deposits. A strong correlation was found between the degree of proteinuria and the proportion of glomeruli affected. We conclude that the combination of mesangial and subendothelial deposits on the one hand and subepithelial deposits associated with increased protein loss on the other constitute a conditio sine qua non for the development of progressive glomerulosclerosis in this model. The use of specific antibodies to investigate the composition of the sclerotic lesions showed the presence of laminin and type IV collagen, but not of types I and III collagen in sclerotic areas of glomeruli. This indicates that the development of progressive glomerulosclerosis in this model is due to an increased production of glomerular basement membrane components by presumably solely glomerular cells after the occurrence of immunological glomerular injury.

Loss of mesothelial electronegative fixed charges during murine septic peritonitis.

Previous studies showed that murine septic peritonitis induced a substantial reduction of the anionic site density distribution in mesenteric and diaphragmatic microvessels. The present study shows that acute experimental septic peritonitis induces a severe reduction of the anionic site density distribution along the submesothelial basement membrane. Five days after induction of peritonitis, there was a partial recovery of anionic sites which even at 13 days was not completed. This observation suggests that the increased protein losses observed during peritonitis are the consequence of increased microvascular and mesothelial permeability to anionic plasma proteins secondary to neutralization and/or disappearance of the anionic sites located in the microvascular wall and in the mesothelial layer.

Evidence for the involvement of 5-lipoxygenase products in ethanol-induced intestinal plasma protein loss.

In this study we investigated whether the products of 5-lipoxygenase (5-LO) were involved in the jejunal microvascular injury induced by intraluminal ethanol (ETH). A group of rabbits was given orally a selective inhibitor of 5-LO (L-651,392, Merck Frosst Canada) in two 10-mg doses, 24 and 2 h before the experiments (treated group). Another group received no such treatment (untreated group). In each animal of both groups, a jejunal segment was perfused with a control solution (control segment) and an adjacent segment with an ETH-containing (6% wt/vol) solution (ETH-perfused segment). In a series of experiments, we measured 5-LO activity of the jejunal segments of both groups using the generation of leukotriene B4 (LTB4) as an index. In a second series of experiments, we determined the ETH-induced intraluminal protein loss, which was taken as a measure of mucosal microvascular damage. In the untreated group, LTB4 generation (pg/mg tissue) by the ETH-treated segment (2.49 +/- 0.70) was higher (P less than 0.005) than that by the control segment (0.68 +/- 0.14). In the treated group, the LTB4 generation decreased (P less than 0.05) both in the control (0.15 +/- 0.03) and the ETH-perfused segments (0.44 +/- 0.09), but the difference between the two segments still remained significant. ETH caused a 13-fold increase (P less than 0.01) in jejunal protein loss in the untreated group but only a 5-fold increase (P less than 0.05) in the treated group. The ETH-induced increase in protein loss was significantly lower in the treated than in the untreated group (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Exaggerated Protein Loss Complicating Sterile Peritonitis Results from Increased Diffusion

To assess the mechanism of protein loss during chemical peritonitis, dialyses with sodium desoxycholate added to the instilled solution were compared to controls in rabbits. Sodium desoxycholate caused an inflammatory reaction characterized by increased protein loss, leukocyte exudation, decreased ultrafiltration and increased clearance of solutes including neutral dextrans. It is suggested that increased protein loss accompanying peritonitis which is due to increased diffusion through capillaries unrelated to effects of membrane anionic charge. Exaggerated protein loss is a recognized sequel of the peritonitis that complicates peritoneal dialysis (I, 2). Such excessive protein loss can contribute to malnutrition, impeding recovery from infection. It has been assumed that the augmented protein loss is due to increased diffusion but this has not been verified. Secretion from inflammed cells adjacent to the peritoneum could account for increased protein loss. Enhanced transfer of plasma proteins across the capillary wall may be due to an overall increase in permeability following capillary dilation which stretches pores, or alternatively it might represent a loss of the anionic charges, which line the pores and retard transport of anionic macromolecules. Previously the transfer rate of polydispersed dextrans from plasma to peritoneal dialysate has been used to assess peritoneal porosity, presumably reflecting capillary-wall permeability (3). The transfer of neutral dextrans should not be inhibited by the fixed anionic charges of the capillary wall interstices. Moreover, these carbohydrates would not be secreted by injured cells; their distribution is extracellular. An increased rate of transfer from plasma to peritoneal dialysate should indicate enhanced diffusion, when there is no increase in convective transport accompanying ultrafiltration. Sodium desoxycholate, the solvent used with amphotericin B, is an irritant that has been shown to induce a sterile peritonitis characterized by dialysate leukocytosis, increased diffusion of small solutes such as urea, and decreased ultrafiltration, owing to the loss of the glucose-induced osmotic gradient (4). These studies were designed to determine whether sodium desoxycholate would increase the peritoneal transfer rate of neutral dextrans from plasma to dialysate. The higher rate of dextran transfer observed with this agent is interpreted to support the hypothesis that proteins, lost excessively during peritonitis, derive from plasma.

Giant Hypertrophic Gastropathy (Ménétrier's Disease): Pharmacologic Effects on Protein Leakage and Mucosal Ultrastructure

Seven patients with giant hypertrophic gastropathy participated in a gastric intubation perfusion study to investigate the route and mechanism of protein leakage associated with this disease. All patients had gastric tight junctions wider than those in healthy controls. Acute administration of propantheline bromide reduced gastric albumin leakage (-50.7%, p less than 0.05) and concurrently decreased width of tight junctions (p less than 0.05) in all patients. Another antisecretory agent, cimetidine, had no consistent effect on protein leakage or on the width of tight junctions. Pentagastrin and bethanechol chloride increased protein loss but had no effect on the width of tight junctions. These results are consistent with the hypothesis that proteins may take a paracellular route via the tight junctions as they traverse the gastric mucosa and that this may have a cholinergic mechanism.

Protein losses during peritoneal dialysis

The losses of protein into dialysate have been considered a major limitation of maintenance peritoneal dialysis. We, therefore, undertook a comprehensive evaluation of protein losses in 30 patients undergoing maintenance intermittent peritoneal dialysis (IPD), 12 patients undergoing acute IPD, and 8 patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The weekly loss of protein based upon the usual treatments per week was relatively similar with the three modes of dialysis. Protein losses during repeated dialyses were similar for a given patient, but there was repeated dialyses were similar for a given patient, but there was marked interpatient variation. During maintenance IPD, protein loss was 12.9 +/- (SD) 4.4 g per 10 hours of dialysis; albumin loss was 8.5 g, and IgG loss was 1.3 g. Approximately 50% of the protein loss was from the ascitic fluid accumulated during the interdialytic interval, and concentrations of most proteins in the ascitic fluid correlated with their serum levels. Serum protein concentrations were in the low, normal range and did not change during dialysis. The development of peritonitis markedly increased protein losses. During acute IPD, 23.3 +/- 16.5 g of protein were lost per 36 hours of dialysis, lower losses than those previously reported. With CAPD, 8.8 +/- 1.7 g of protein were removed per 24 hours; also immunoglobulin losses correlated with their serum concentrations. The results of these studies suggest that, in the absence of peritonitis, dialysate protein losses do not appear to limit the usefulness of peritoneal dialysis.

Intestinal Protein Loss in Rats with Blind Segments on the Small Bowel

Summary A blind self-filling segment was made on the middle jejunum or on the distal ileum in rats, and determination of intestinal protein loss was performed by measuring fecal radioactivity after the intravenous injection of Cr 51 chloride. Rats with a blind segment on the jejunum showed a significantly increased protein loss. Ingestion of chloramphenicol caused a decrease, but not a full normalization of the loss. Rats with an ileal blind segment did not have a significantly increased protein loss with the feces, but ingestion of chloramphenicol caused a significant lowering of the loss. Chloramphenicol treatment did not alter the protein loss in normal rats. The results indicate that the increased fecal nitrogen excretion and hypoproteinemia in blind loop syndrome are, at least partly, due to an increased protein loss from the small intestine.

Chronic Hypoalbuminemia and Edema Associated With Intestinal Lymphangiectasia

THE PRESENCE of edema with associated hypoproteinemia in a person who has no manifest renal or liver disease should alert one to the possibility that loss of protein into the intestines may be causative. Increased protein loss into the gut has been demonstrated in a variety of inflammatory and neoplastic diseases of the gastrointestinal tract. Diseases associated with this have been designated protein-losing gastroenteropathies or hypercatabolic protein-losing enteropathies. This category includes celiac disease, sprue, acute gastroenteritis, regional enteritis, ulcerative colitis, intestinal lipodystrophy (Whipple's Disease), Menetrier's disease, and intestinal lymphangiectasia. The use of radioisotopes has clarified the site of loss of serum albumin, and the introduction of the biopsy tube for the small intestine has made tissue available for study of the underlying pathological abnormality. <h3>Report of a Case</h3> The patient, a 52-year-old white woman was first admitted to Methodist Evangelical Hospital on Dec 8, 1962. Her illness dates back approximately