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Biomedical subjects

R A Zager

Publications and source records attributed to R A Zager.

122 records · Page 7Linked to original sources
PubMed1983

Acute amino acid nephrotoxicity.

Previous clinical and experimental data suggest that a limited number of AAs with particular molecular characteristics can adversely affect renal function. The present investigation was conducted to better define the scope and the molecular basis of this nephrotoxicity. Sprague-Dawley rats (N = 31) undergoing a solute diuresis were subjected to 80 min infusions (125 mumol/kg/min) of cationic AAs (lysine, arginine), anionic AAs (glutamic acid, aspartic acid), or neutral AAs (alanine, glycine). Rats infused for 80 min with equimolar amounts of urea or dextrose served as controls (N = 8). GFR (Cioth) were measured 40 min before, during, and 140 min after these infusions. Albumin excretion rates were determined by radioimmunoassay. All AA infusates induced significant (p less than 0.001) reductions in GFR compared to the control infusates (cationic AAs: 62% +/- 4; anionic AAs: 57% +/- 5; neutral AAs: 33% +/- 1; controls: 8% +/- 4) (X +/- S.E.M.). However, only cationic AAs induced a significant increase in albumin excretion (360% +/- 72; p less than 0.001). AA-treated rats had histologic changes with mild tubular injury compared to control rats. These data indicate the following. (1) AAs have in common a nephrotoxic potential. (2) This nephrotoxicity arises, in part, from the nonvariable portion of AA molecules since glycine, which has no variable (R) group, induced a significant reduction in GFR (32% +/- 1). (3) The ability of AAs to decrease GFR is enhanced by certain R groups. However, R group charge is not a critical factor in producing this response. (4) AA-induced increments in albumin excretion and reductions in GFR must arise via independent mechanisms. Since AA infusions are commonly used in patients with ARF the possibility that such therapy might have a deleterious effect on renal function and on the subsequent recovery from ARF should be entertained.

Acute Kidney Injury↗
PubMed1982

Susceptibility of the proximal tubular brush border to acute obstructive injury.

The purpose of this investigation was to determine the susceptibility of proximal renal tubular epithelial cells to the effects of acute urinary tract obstruction. Brush border derived-renal tubular epithelial antigens (RTE) were quantitated in urine by radioimmunoassay both before and after the induction of bilateral ureteral obstruction of 15-150 minutes duration in anesthetized diuretic rats. Glomerular filtration rates (GFR) before and after obstruction were determined by calculating renal clearances of Na iothalamate 125I. Light microscopic examination of renal tissue was performed. Post obstructive renal function was well preserved in all rats with GFRs ranging from 76-100 per cent of control values. However, in the immediate post-obstructive period RTE excretion increased dramatically in all rats. Up to 10 fold increases in urine antigen concentrations were observed under conditions of isosthenuria and stable urine flow rates. The degree of elevation correlated with the length of obstruction and with the severity of histologic changes in the proximal tubules (progressive proximal tubular dilatation and brush border loss). It is concluded that proximal tubular cells are highly susceptible to obstructive insults as brief as 15 minutes in duration. The mechanism of this injury and its effect on post-obstructive renal function remain to be clarified.

Animals↗
PubMed1982

Quantitating the severity of proximal tubular brush border injury by a simple direct binding radioimmunoassay.

The purpose of this investigation was: (1) to establish a simplified radioimmunoassay (RIA) for quantitating renal tubular epithelial antigens (RTE) in urine; (2) to ascertain whether urine RTE concentrations as measured by this technique correlate with the severity of acute nephrotoxic and ischemic injury; and (3) to ascertain whether increased urinary RTE is a specific marker of renal tubular injury. A direct binding RTE RIA was established using 125I labelled anti-RTE antibody and 10% polyethylene glycol to separate bound from unbound anti-RTE 125I. This RIA is simpler than previously described RTE assay methods since: (1) double antibody separation techniques are eliminated; (2) RTE antigen purification from crude proximal tubular fragments is no longer necessary; and (3) immunoglobulin G(IgG) rather than more radiosensitive RTE is used as the radioligand. To test the utility of this assay as a marker of acute tubular injury anesthetized rats were subjected to graded nephrotoxic (HgCl2: 0--20 mg/kg) or bilateral renal ischemic (0--32 min) insults. Glomerular filtration rates (GFR) (clearance iothalamate 125I) and RTE concentrations were measured sequentially. Post-renal injury, RTE concentrations rose above control values and the degree of elevation strongly correlated with the severity of GFR depression (r = 0.72--0.81; p less than 0.02--0.05). The source of this increased urinary RTE was the proximal tubule since brush border loss was demonstrated histologically and because no RTE could be detected in serum. Rats whose GFRs were acutely depressed by inducing either volume depletion or acute experimental glomerulonephritis (nephrotoxic serum nephritis) all had normal urine RTE concentrations. These results suggest that RTE quantitation by this technique may provide a specific and early quantitative index of the severity of acute nephrotoxic and ischemic renal injury.

Animals↗
PubMed1982

A search for nephrotoxic factors within the uremic milieu.

The purpose of this study was to ascertain whether selected components of the uremic milieu adversely affected glomerular filtration rate (GFR), the glomerular protein filtration barrier, or the integrity of the proximal renal tubular brush border membrane. To achieve these goals, GFR and the excretion rates of albumin and of brush border derived-renal tubular epithelial antigens (RTE) were measured in normal rats and in rats with experimental nephropathies before and after the intravenous infusion of concentrated urine. This experimental protocol uniformly produced severe biochemical manifestations of uremia (for example 10-50-fold increases in BUN and creatinine, hyperphosphatemia, hyperkalemia, metabolic acidosis). However, despite these perturbations, GFR, albuminuria, and RTE excretion remained constant. To assess the influence of uremic hormonal derangements on renal function, GFR, albuminuria, and RTE excretion were measured in normal rats before and after inducing acute serum elevations of seven hormones whose concentrations are known to be increased in uremia (parathyroid hormone, growth hormone, insulin, glucagon, gastrin, prolactin, gastric inhibitory peptide). Again, GFR, albuminuria, and RTE excretion were not adversely affected. These results suggest that glomerular capillary function and proximal tubular brush border membranes are acutely resistant to many of the solute and hormonal derangements which are characteristic of uremia.

Albuminuria↗
PubMed1982

Hyperphosphatemia: a factor that provokes severe experimental acute renal failure.

UNLABELLED: The purpose of this study was to determine whether pre-existent hyperphosphatemia potentiates the severity of evolving ARF. Normal rats were subjected to graded phosphate infusions (0 to 0.07 mmol/kg/hr) in order to induce differing degrees of hyperphosphatemia (6.8 to 10.3 mg/dl). After a 40 min control period, ARF was induced either by HgCl2 administration (12 mg/kg) or by bilateral renal pedicle cross-clamping (25 min). GFRs before and after renal injury were determined by measuring the Cioth. The percent decrease of GFR after renal injury strongly correlated with the degree of phosphate loading (r = 0.71, HgCl2; r = 0.82, ischemia) (p less than 0.001). In addition, phosphate-treated ARF rats showed striking histologic changes not seen in their non-phosphate-treated counterparts, i.e., marked vacuolization of the proximal tubules and variable degrees of glomerular capillary collapse. Renal calcium/phosphate deposition could not be demonstrated in any kidney by the Von Kossa or the alizarin red histochemical techniques. Terminal serum phosphate concentrations ranged from 7.5 to 19.1 mg/dl. Phosphate-infused control rats had stable GFRs and normal renal histology. CONCLUSION: Hyperphosphatemia may significantly exacerbate the functional and histologic correlates of acute renal failure. The pathogenesis of this response remains unknown.

Acute Kidney Injury↗
PubMed1981

Effects of glucocorticoid administration on urinary albumin excretion by the normal kidney.

In an effort to elucidate mechanisms by which glucocorticoids enhance urinary protein excretion, albumin and lysozyme excretion patterns were studied in normal rats which had been subjected to a variety of experimental protocols. On the basis of these studies the following conclusions were reached: (1) The acute administration of glucocorticoids produces an immediate increase of both glomerular filtration rate (GFR) and of urinary albumin and lysozyme excretion rates. (2) A delayed albuminuric response to glucocorticoids occurs 14-32 h after drug administration. This second period of albuminuria is quantitatively far more significant than the acute albuminuric response and it occurs at a time when GFR is not statistically different from control experimental animals. (3) Lysozyme excretion 14-32 h following glucocorticoid administration is normal, suggesting an intact tubular protein reabsorption mechanism at the time of maximal albuminuria. (4) The delayed albuminuric period cannot be acutely reproduced by infusion of 5 ml of serum harvested from dexamethasone pretreated albuminuric rats. (5) Dietary Na intake (and presumed activity of the renin/angiotensin axis) does not appear to influence the magnitude of the glucocorticoid-induced albuminuric reaction. Further work is needed to more fully delineate the pharmacologic pathway by which glucocorticoids affect urinary protein excretion and to ascertain whether this response differs between the normal and pathologic kidney.

Albuminuria↗
PubMed1980

Rapid radioimmunoassay for diagnosing acute tubular necrosis.

A previously described method for recovering a proximal renal tubular epitheal antigen (HRTE-1) from normal human kidney was modified by using ion-exchange and immunoaffinity chromatography in order to create easily reproducible conditions for antigen isolation. Radioiodinated HRTE-1 was then used to establish a 3-hour, double-antibody radioimmunoassay (RIA) for the purpose of testing whether the urinary excretion of this antigen might seve as a useful marker of acute tubular necrosis (ATN). Urines from 51 patients (ATN, 22: chronic nephropathies, 24; prerenal azotemia, 5) and from 36 normal subjects were assayed for HRTE-1. 79% of ATN patients had abnormal antigen concentrations while 100% of all other urines had urine antigen concentrations within a previously established range for random normal urine samples. When used as a differential diagnostic test of either ATN versus chronic nephropathies, or of ATN versus prerenal azotemia, 90 and 81% discrimination was achieved, respectively. The majority of ATN and prerenal azotemia patients presenting with atypical conventional diagnostic parameters (urine Na, urine osmolality, urine sediment, fractional Na excretion) were correctly diagnosed by RIA. Further study of HRTE-1 excretion in acute and chronic renal diseases seems indicated, both to elucidate pathophysiologic mechanisms and to determine whether HRTE-1 is a clinically useful marker of ATN.

Acute Kidney Injury↗
PubMed1980

Lysozyme and albumin radioimmunoassays. New techniques for the study of proteinuria.

To facilitate the study of mechanisms and patterns of proteinuria, radioimmunoassays for human lysozyme (LZM) and albumin (alb) were established to permit quantitation of physiologic amounts of these proteins in urine. Commercially available LZM and alb preparations were radiolabeled with I125, and single antibody, competitive protein binding assays were developed. Separation of free and antibody-bound radioprotein was achieved with 20 per cent polyethylene glycol. LZM and alb 24-hr excretion rates for 12 normal subjects were 7 to 64 microgram and 2.3 to 16.1 mg, respectively. Of 6 renal disease patients with undetectable urine LZM by bioassay, 5 were shown to have elevated LZM concentrations by radioimmunoassay. The ease of establishing and performing these assays and their reproducibility suggest that they may have clinical and investigative value.

Albumins↗
PubMed1980

Urinary protein markers of tubulointerstitial nephritis.

In an effort to identify new diagnostic features of tubulointerstitial nephritis (TIN), urinary total protein concentrations and urinary excretion rates of four serum proteins and of proximal renal tubular epithelial antigens were determined for five normal subjects and for 44 patients with well-characterized renal diseases. Four urinary protein indices correlated with TIN: clearance of lysozyme/clearance of albumin > 20; clearance of immunoglobulin G/clearance of albumin % > 55 per cent; renal tubular epithelial antigen excretion > 10 units per min; urinary albumin/urinary total protein concentrations < 50 per cent. Of TIN patients, 86 per cent were (+) to one or more of these criteria whereas 89 per cent of glomerular disease patients were (-) to all criteria. By combining these criteria into multiphasic testing profiles, 88 per cent of patients could be successfully categorized as having either tubulointerstitial or glomerulonephritis. This finding suggests the potential diagnostic value of these new testing parameters.

Albuminuria↗
PubMed1979

Membranous nephropathy: a radioimmunologic search for anti-renal tubular epithelial antibodies and circulating immune complexes.

In an effort to elucidate immunopathogenic of membranous nephropathy (MN), freshly collected sera from patients with biopsy proven MN were assayed of circulating immune complexes (ICs) by the Raji cell method and for anti-renal tubular epithelial (RTE) antibodies by a newly established radioimmunoassay (RIA) and by indirect immunofluorescence. 6 of 26 MN patients tested by the Raji cell assay had detectable circulating ICs. However, 5 of these 6 patients had other medical conditions which might also explain the IC reactivity. 29 MN patients and 11 patients with other glomerular diseases had no demonstrable circulating anti-RTE antibodies. This study suggests that if RTE antigens possess a nephritogenic potential for man it is probably only rarely expressed. The inconstant detection of circulating immune complexes in idiopathic MN raises an speculation as to their immunopathogenic significance.

Adult↗
PubMed1978

Radioimmunoassay for urinary renal tubular antigen: a potential marker of tubular injury.

A human proximal renal tubular epithelial antigen (designated HRTE-1) was isolated and purified from a crude tubular preparation (Fx1A) by a process of salt fractionation, DEAE anion-exchange chromatography, and Sephadex G-200 gel filtration. Utilizing 125I-HRTE-1 and a rabbit antiserum specific for the proximal tubular brush border, as determined by immunofluorescent microscopy, a radioimmunoassay by competitive protein-binding was developed. HRTE-1 was demonstrated in serum and urine and in extracts of a variety of body organs. A range of concentrations for normal random urine samples and 24-hr urine excretion rates were determined. Random urine samples from 36 patients with a variety of functional and pathologic renal disorders were assayed for the HRTE-1 antigen. Twenty-three of 24 patients with either chronic nephropathy or pre-renal azotemia had normal urinary antigen concentrations, despite wide differences in urine flow rates, the degree of existing renal function, and the amount of proteinuria. Ten of 12 patients with acute tubular necrosis, however, had statistically abnormal HRTE-1 concentrations (high in eight patients, undetectable in two). These findings suggest that HRTE-1 antigen can be detected in both normal and pathologic urines, that altered antigen concentrations can be documented in at least one renal disorder, and that quantitation of HRTE-1 in urine may have clinical value as a marker of acute rubular injury.

Acute Kidney Injury↗
PubMed1978

Pathologic localization of Tamm-Horsfall protein in interstitial deposits in renal disease.

Interstitial periodic acid-Schiff positive deposits of amorphous or fibrillar material were observed in 32% of kidneys with a variety of tubulointerstitial diseases, including medullary cystic disease (60%), chronic pyelonephritis (20%), and hydronephrosis (33%). Immunofluorescent staining for Tamm-Horsfall protein showed interstitial localization of this protein which was identical in distribution, shape, size, and fine detail with the periodic acid-Schiff positive deposits. The deposits appeared to originate from disrupted tubules and were sometimes surrounded by inflammatory infiltrate. The intrarenal localization of Tamm-Horsfall protein outside of distal tubules in pathologic states indicates that this protein may have a role in the pathogenesis of renal disease.

Fluorescent Antibody Technique↗