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Biomedical subjects

T A Depner

Publications and source records attributed to T A Depner.

At least 37 records · Page 2Linked to original sources
PubMed1996

Equations for normalized protein catabolic rate based on two-point modeling of hemodialysis urea kinetics.

The normalized protein catabolic rate (PCRn) can be calculated from predialysis and postdialysis BUN measurements in patients receiving intermittent dialysis. This measure of net protein catabolism, adjusted for body size, is a useful clinical measure of nutrition that correlates with patient outcome and, in patients who are in nitrogen balance, is a reasonable estimate of dietary protein intake. Whereas simplified formulae that estimate the per-treatment dose of hemodialysis, expressed as Kt/Vurea (Kt/V), are in common use, simplified methods for determining PCRn have only recently appeared. In the study presented here, equations were derived for calculating PCRn from the predialysis BUN and Kt/V. The equations were of the general form: PCRn = C0/(a + bKt/V + c/(Kt/NLL)) + 0.168, where Co is the predialysis BUN in mg/dL. Three sets of coefficients were developed for patients dialyzed thrice weekly: one for patients dialyzed after the long interval at the beginning of the week, one for patients dialyzed at midweek, and the third for patients dialyzed at the end of the week. Two similar sets of coefficients were developed for patients dialyzed twice weekly. For patients with remaining function in the native kidney remnant, equations were developed and refined for upgrading PCRn by adjusting C0 upward. The equations were validated by comparing the calculated PCRn with PCRn determined by a formal iterative model of urea kinetics in a series of 119 dialyses in 51 patients dialyzed thrice weekly (r = 0.9952; mean absolute error, 1.97 +/- 1.39%) and in a series of 71 dialyses in 25 patients dialyzed twice weekly (r = 0.9956; mean absolute error, 2.17 +/- 1.56%). These simple yet accurate equations should be useful in epidemiologic studies or in clinical laboratories where limited data are available for each patient or when iterative computer techniques cannot be applied.

Algorithms↗
PubMed1995

Mechanisms of hypoalbuminemia in hemodialysis patients.

Hypoalbuminemia is the most powerful predictor of mortality in end-stage renal disease. Since protein-calorie malnutrition can decrease albumin synthesis it is assumed that hypoalbuminemia results principally from malnutrition in these patients, but albumin synthesis may also be decreased as part of the acute-phase response, and hypoalbuminemia can also result from redistribution of albumin pools or from albumin losses. We measured albumin synthesis, fractional catabolic rate, and distribution from the turnover of [125I] human albumin in six hemodialysis patients with plasma albumin less than 35 mg/ml and in six patients with plasma albumin greater than 40 mg/ml. Patients with liver disease, HIV, or other infection were excluded. Both groups were maintained with high-flux polysulfone dialyzers for more than three months. Kt/Vurea and PCR were measured during each dialysis (N = 12 to 18/patient). A four-day calorie and protein intake was determined by dietary history and long-term nutritional status was determined anthropometrically. Measured variables included serum urea, creatinine, transferrin, and the positive acute-phase proteins alpha 2- macroglobulin, C-reactive protein, ferritin, and IGF-1. Albumin synthesis was significantly reduced in the low albumin group. There were no differences in dietary intake, body composition, PCR, BUN, creatinine, or Kt/Vurea. Plasma albumin concentration correlated negatively with ferritin, C-reactive protein and alpha 2-macroglobulin. Albumin synthesis rate correlated negatively with both alpha 2-macroglobulin and Kt/Vurea. Both plasma albumin concentration and synthesis rate correlated positively with IGF-1, and both were independent of PCR and all other nutrition-related variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Proteins↗
PubMed1994

A nomogram approach to hemodialysis urea modeling.

Two sets of nomograms were developed for modeling hemodialysis urea kinetics. The first set is designed to arrive at an initial dialysis prescription. One nomogram estimates the mass transfer area coefficient (KoA) based on urea clearances of a dialyzer, based on urea clearances provided in the manufacturer's product literature. A second nomogram uses the dialyzer KoA value to estimate the expected in vivo urea clearance (K) based on the nominal blood flow rate. The computations include corrections for blood flow-related errors in urea clearance, blood water content, and cardiopulmonary recirculation. Mean urea clearance measured in a series of patients was 226 +/- 22 mL/min and did not differ significantly from mean clearance estimated using this nomogram (232 +/- 8 mL/min). Another pair of nomograms, based on an anthropometric formula, can be used to estimate urea distribution volume (V) from patient sex, height, and weight. The first set of nomograms is designed to estimate an initial dialysis prescription because the nomograms propose an estimated K and an estimated V. Once the target Kt/V is chosen, the appropriate initial treatment time (t) is computed algebraically. The second set of nomograms was developed to verify delivery of the dialysis prescription and to estimate the normalized protein catabolic rate (PCRn). Kt/V is estimated from the postdialysis to predialysis blood urea nitrogen ratio and the ratio of ultrafiltrate volume to postdialysis weight (UF/W). The PCRn is estimated from the predialysis blood urea nitrogen and Kt/V. In a series of 115 patients, Kt/V and PCRn determined from the nomograms correlated highly with corresponding values determined from formal urea modeling (r = 0.99).(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1994

Techniques for prospective detection of venous stenosis.

The vascular access device continues to be a bottleneck in the quest for improved dialysis efficiency and cost reduction. Stenotic lesions occur frequently in synthetic arteriovenous fistulas (AVFs), usually at the venous end, and less often in native AVFs. The reduction in blood flow and other thrombogenic effects of the stenosis, such as local turbulence, eventually lead to loss of the access. Before thrombosis occurs, reduced blood flow through the AVF limits inflow to the dialyzer and predisposes to local recirculation. Recirculation decreases the effective solute clearance of the dialyzer, jeopardizing the adequacy of treatment. Regular evaluation of the access using methods such as routine physical examination, measurement of recirculation, measurement of venous dialysis pressure, and radiographic or ultrasonic imaging when combined with percutaneous or surgical interventions have been shown to prolong access life and eliminate recirculation. Physical examination includes inspection and palpation to detect edema, palpation and auscultation to detect local increases in the intensity of a thrill or bruit, and optional occlusion of the fistula during dialysis to detect recirculation. Recirculation can be measured directly using classical solute dilution techniques or indicator dilution methods provided by a variety of devices now appearing on the market. Recirculation may also be detected indirectly from the results of urea modeling. The difference between modeled and expected urea clearance is a measure of recirculation provided no other error (eg, in blood flow) contributes to the difference. Pressure monitoring has proven useful in many centers. A strict protocol is required to normalize other influences such as blood flow and needle size that may alter pressure independently of access stenosis. Duplex Doppler ultrasonography has been evaluated and found useful in several studies but suffers from relatively high cost and operator dependency. Controlled studies of these screening techniques are needed, especially for those that incur high costs.

Blood Circulation↗
PubMed1992

Adequacy of hemodialysis.

Despite technical advances in the delivery of hemodialysis over the past decade, the mortality rate of hemodialysis-dependent, end-stage renal disease (ESRD) patients in the United States remains high. The increase in the number and severity of comorbid conditions of patients entering ESRD is a factor contributing to this high mortality. Nevertheless, there is increasing evidence that the dose of dialysis received by US patients is inadequate and that this plays a major role in the observed high mortality. In this review, we examine some of the parameters used to judge the adequacy of dialysis, as well as factors that can result in differences between prescribed and delivered dose of hemodialysis. Based on available evidence, we propose that for most patients the optimum dose of dialysis, above which further improvement of morbidity and mortality is doubtful, is represented by a delivered dose of dialysis equivalent to a Kt/V of 1.4 or greater, using biocompatible membranes. The prescription of this optimal dose of dialysis must be coupled with an ongoing effort to monitor delivery of the appropriate dose.

Blood Urea Nitrogen↗
PubMed1986

Isolation and chemical identification of inhibitors of plasma ligand binding.

The binding by serum albumin of many drugs and endogenous metabolites is impaired in humans and animals with renal failure. Unknown solute(s) retained in renal failure have been extracted from uremic fluids. When added to normal plasma they induce a similar binding defect. Similar activity can be extracted from normal urine. We have devised a series of extraction and purification techniques that yielded three binding inhibitory ligands from normal human urine in sufficient quantity and of a high degree of purity. Rigorous methods have been applied to determine chemical identity of the ligands. Purification steps consisted of: adsorption at pH 3.0 to polystyrene-divinylbenzene resin (XAD-2); elution from the resin with methanol followed by drying and solution in dilute formic acid; passage through SP-Sephadex to remove cations, especially yellow-brown pigments; adsorption to the anion exchanger QAE-Sephadex, and separation into three zones of inhibitory activity with a formic acid gradient; purification to homogeneity with C-8 or C-18 silica reversed-phase chromatography. Using this isolation procedure, followed by mass spectroscopy and nuclear magnetic resonance spectroscopy, we have shown that the binding inhibitory activity is due not to one ligand, but to a family of aromatic acids. To date hippurate, beta-(m-hydroxyphenyl)-hydracrylate and p-hydroxyphenylacetate have been identified as binding inhibitors. Other active ligands remain to be identified.

Adsorption↗
PubMed1985

Aromatic amino acid metabolites as potential protein binding inhibitors in human uremic plasma.

Decreased binding of aromatic acidic drugs and endogenous metabolites to plasma proteins of patients with severe renal failure appears to be due to accumulation of unknown solutes. Both the warfarin and indole binding sites of albumin, the principal binding protein for these ligands, are affected. We used a large number of endogenous aromatic acids and synthetic congeners as displacers (a) better to characterize the chemical requirements for binding to each site and (b) to derive clues to the chemical structure of the undefined binding inhibitors in uremic plasma. 14C-tryptophan, 14C-warfarin and 14C-salicylate were used as bound ligands. Numerous indoles, quinolines and phenyl derivatives were moderate to strong displacers with several structural correlates. Increasing apolar side chain length enhanced displacing potency. A hydroxyl group at the 5 position of indoles and at the para position of phenyl derivatives severely reduced activity. The two ends of amphophilic molecules showed opposite requirements for displacement of tryptophan: the greater the polarity at the hydrophilic end, the greater the tryptophan displacing potency. Conversely, the greater the total hydrophobic mass of the remainder of the molecule, the more potent the inhibition of binding. The dipeptides l-tryptophyl-l-tryptophan and l-tryptophyl-l-phenylalanine were potent displacers. Computer-assisted analysis of warfarin binding in the presence of xanthurenic acid revealed inhibition by a mechanism other than simple competition, probably via a third albumin binding locus. We conclude that decreased binding in uremic plasma is most likely the summation effect of a number of retained aromatic acids, peptides, or both types of ligands.

Amino Acids↗
PubMed1984

Suppression of para-aminohippurate transport in the isolated perfused kidney by an inhibitor of protein binding in uremia.

Serum from patients with advanced renal failure contains substances that inhibit binding of small ligands to albumin. The extractable inhibitors of binding to albumin (lx), which were previously shown in rat kidney slices to inhibit para-aminohippurate (PAH) transport, were added to the in vitro perfused rat kidney in an attempt to investigate effects on organic acid transport in the intact organ. Following addition of extract to the perfusate there was an immediate and profound decrease in whole kidney PAH secretion. Mean PAH clearance fell an average of 60% +/- 7% after addition of extract from human uremic pleural exudate and an average of 62% +/- 6% after addition of similarly prepared extract from normal human urine. There was no change in inulin clearance, vascular resistance, urine flow, or fractional reabsorption of sodium. The effect was shown to be as marked when bovine serum albumin (4.0 g/dL) was added to the perfusate, clearances falling 66% +/- 7%. Controls showed no change in PAH or inulin clearance during 90 minutes of in vitro perfusion. An increase in ultraviolet (UV) absorbance by the urine within minutes after addition of inhibitor to the perfusate suggested tubular secretion of a major portion of the extract. Partial recovery of PAH clearance was observed after 20 to 40 minutes in most kidneys and near complete recovery occurred in some kidneys. The inhibitory effect was duplicated by addition of hippurate at 24 mg/dL (1.2 mmol/L) to the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1984

Inhibition of salicylate binding to normal plasma by extracts of uremic fluids.

We previously reported that an extract of uremic plasma reduces binding of phenytoin and tryptophan by normal plasma and plasma albumin. This effect appears to reproduce the impaired binding of many drugs and several endogenous metabolites by uremic plasma. In the present study we further characterized the properties of extracts from uremic sera and body fluids using binding of salicylate as a model. Salicylate was chosen because it binds to both of the main albumin binding loci for aromatic, acidic drugs. Using a computer-assisted, least-squares, curve-fitting program, LIGAND, we found that the most satisfactory model for salicylate binding to 1:10 diluted normal plasma was a binding number (n) of 2 mol of salicylate per mole of albumin with an association constant (k) of 2.85 X 10(4) L/mol, an additional binding of 0.5 mol to other sites on albumin or to other proteins, and nonspecific binding of 21%. Addition of uremic pleural fluid extract to diluted normal plasma produced a monotonic decline in k to 0.17 X 10(4) L/mol with no change in n except possibly at the highest dose of uremic inhibitor. This pattern of competitive inhibition indicates presence of unknown ligands in the uremic extract that compete at both binding loci. More efficient extraction methods might also yield additional ligand(s) that inhibit through a noncompetitive mechanism.

Adult↗
PubMed1982

Immune complex glomerulonephritis and dermal vasculitis following intestinal bypass for morbid obesity.

A kidney and skin biopsy were performed on a patient who developed cryoglobulinemia, polyarthritis, a purpuric skin rash, and acute renal failure four years following jejunoileal bypass for morbid obesity. Morphologic studies revealed a diffuse glomerulonephritis characterized by the presence of numerous subendothelial deposits containing IgG, IgA, C3, Clq, C4, and properdin, and an acute dermal vasculitis associated with similar immune complex deposits. Identical immunoglobulin and complement components were present in the cryoglobulin. In addition, both the cryoglobulin and a renal biopsy eluate containing anti-IgG antibody and antibody against Klebsiella pneumoniae which were present in the patient's stool in large numbers. Combined therapy with steroids and chloramphenicol resulted in marked improvement in the patient's arthritis, skin rash, and renal function. The findings indicate that glomerulonephritis and dermal vasculitis due to the deposition of bacterial antigen-antibacterial antibody complexes may occur as part of a systemic immune complex disease complicating small intestinal bypass.

Adult↗
PubMed1982

Nephrotic syndrome secondary to lithium therapy.

Overt nephrotic syndrome developed in a young housewife treated with lithium carbonate from manic-depressive psychosis. Complete spontaneous remission was observed 1 month after discontinuing the drug but the nephrotic state reappeared 8 years later when lithium therapy was re-instituted. The renal biopsy showed minimal glomerular lesions without interstitial disease.

Adult↗
PubMed1981

Suppression of tubular anion transport by an inhibitor of serum protein binding in uremia.

Extraction of acidified uremic serum yields an inhibitor of phenytoin binding to normal serum proteins and improves binding to the uremic serum proteins. The extract contains binding inhibitors (Ix) that may accumulate because of poor renal excretion and that are presumed to compete for binding sites on albumin, the principle binding protein in serum. If substantially bound to protein, the normal mode of excretion may be via tubular secretion. In this study, individual extracts from six stable hemodialyzed patients caused significant inhibition of para-aminohippurate (PAH) uptake by rat kidney slices incubated in vitro. During a 90-min incubation, slice-to-medium ratios fell in a curvilinear dose-related pattern to 29.8% +/- (SEM) 3.6% (N = 6) of control values, compared with 56.4% +/- 2.1% after incubation with a similar extract from six normal serum samples. The dose-response curve is similar to that of a known competitive inhibitor, hippuric acid, and the average inhibitory activity of uremic extract as derived from these curves was 3.5 times that of an extract from six normal controls. The effect was easily reversed by washing the slices in medium containing no inhibitor. Whole serum from these same patients had no effect on PAH uptake. These findings suggest that Ix or other constituents of the extract may compete for the organic acid secretory pathway in the proximal nephron. A correlation was seen between inhibition of phenytoin binding to plasma protein and inhibition of PAH transport in the slice. Both factors were only partially removed after prolonged dialysis in vitro, suggesting substantial protein binding. Despite the clinical stability of these hemodialyzed patients, their serum samples contain unidentified inhibitors of ligand binding to plasma proteins and of organic anion transport that share some physiochemical properties.

Animals↗