Barry B. Kirschbaum

Acute Aluminum Toxicity Associated with Oral Citrate and Aluminum-Containing Antacids

The authors report the development of a rapidly progressive encephalopathy marked by confusion, myoclonus, seizures, coma, and death in a group of women with renal failure who received an oral solution of citrate and aluminum hydroxide gel concurrently. Two patients were documented as having marked hyperaluminemia far exceeding blood aluminum levels encountered in the chronic state of aluminum intoxication. We ascribe the toxicity to enhanced gastrointestinal absorption of aluminum when complexed with citrate.

Spurious metabolic acidosis in hemodialysis patients

Metabolic acidosis with an increased anion gap (AG) is frequently seen among patients with end-stage renal failure that is corrected to a variable degree by chronic hemodialysis. The degree of acidosis is generally interpreted from the concentration of total carbon dioxide (tCO(2)) in blood drawn from the vascular access used for dialysis. As with many dialysis units in the United States, our laboratory studies for outpatients are performed in a central laboratory several hundred miles away and must be shipped there by air freight. We observed a consistent and clinically important difference between the tCO(2) content of samples reported from the central laboratory compared with results reported from a local university hospital chemistry laboratory. The central laboratory readings were always lower, resulting in an increase in the AG. Delays in centrifugation of the blood to separate the clot from the serum and in the initiation of analysis led to an increase in the lactate content of the samples. That increase, however, was insufficient to explain the difference in tCO(2) levels. These data suggest that something happens to the samples in transit to cause an artifactual reduction of the tCO(2) level. For many dialysis patients, the severity of their acidosis may be falsely represented by the tCO(2) content of blood samples reported from central laboratories.

Total urine antioxidant capacity

Total antioxidant capacity has been determined for several body fluids and provides a convenient means to compare antioxidant defenses among patients with acute or chronic inflammatory illnesses. We have studied urine specimens from a control group and a variety of patients with hypertension and acute and chronic renal diseases using an ABTS antioxidant assay as described for blood. Other urine assays included fluorescence markers for advanced glycosylation end products (AGE) and di-tyrosine (di-tyr), protein, uric acid, and creatinine concentrations. Urine antioxidant activity was standardized against ascorbic acid. We found that both the lag time and the area under the curve (AUC) in the ABTS assay were highly correlated with one another and correlated with the protein and uric acid concentrations, except for those specimens collected from patients with acute renal failure (ARF). The lack of correlation in the ARF group was not associated with significant differences in lag time or AUC. Correlations were seen also between antioxidant parameters and fluorescence for AGE and di-tyr. The results indicate that the predominant antioxidants in the urine of patients with acute renal failure differ from those found in the urine of individuals with hypertension and chronic nephropathies. The ABTS assay provides a convenient marker for the antioxidant content of urine.

Urine electrolytes and the urine anion and osmolar gaps

Urine ammonia concentration is crucial to understanding and quantifying the kidneys response to metabolic acidosis. This test is generally not performed by clinical laboratories. The urine anion gap and osmolar gaps have been proposed as surrogate measures of urine ammonia in patients with hyperchloremic acidosis. We measured ammonium and other electrolytes in the urine of patients attending our renal disease clinic who did not have severe metabolic acidosis and compared the results with those calculated by standard formulae for the anion and osmolar gaps. We found no correlation between measured ammonium values and the anion gap and attributed this lack of agreement to the presence in urine of substantial amounts of unmeasured inorganic anions, which the formula fails to consider. There was significant correlation between measured ammonium and the osmolar gap but not good agreement between the absolute values provided by the 2 methods. Solutes including sulfate and phosphate were quantified in 24-hour urine collections and showed great variability with respect to measured chloride and estimated protein catabolism. We conclude from these studies that there is no substitute for the direct determination of urine ammonium when an accurate concentration is desired.

Proximal tubule brush border alterations during the course of chromate nephropathy.

Abstract Tubular transport abnormalities reportedly predominate over alterations in glomerular filtration rate and epithelial morphology during the early phase of Na-chromate-induced acute renal failure. We have studied the role of the brush border membrane in the sequence of events after the subcutaneous injection of Na2CrO4 (20 mg/kg body weight) to rats. Brush border integrity was evaluated by ultrastructural criteria and the activities of several enzymes assayed in vitro on purified brush border membrane preparations. By electron microscopy, subtle alterations of microvillar morphology were present within 1 hr of chromate injection. Alkaline phosphatase activity declined significantly by 2 hr but represented the only brush border enzyme alteration at this earliest time of study. During 0–2 hr, Cin declined to 0.90 ± 0.04 ml/min from a control value of 1.30 ± 0.04 then increased during the 2–4 hr period to 1.09 ± 0.05 ml/min. The fractional excretion of lysozyme at 0–2 and 2–4 hr and of phosphate at 2–4 hr, and the urine excretion of N-acetyl-glucosaminidase at 0–2 and 2–4 hr increased significantly in chromate rats and exceeded values in saline-injected rats for the corresponding collection periods. [14C]Leucine incorporation into proteins of renal cortex and brush border was 50% or less of control at 2 hr after chromate. By 12–16 hr, brush border enzyme abnormalities were well established and became more severe with longer periods of observation coincident with advancing degrees of renal insufficiency. These results indicate that chromate-induced epithelial cell toxicity and tubular transport defects become operative within the first 2–4 hr after injection of Nachromate. Whereas injury to the brush border membrane is a feature of chromate nephropathy, the available evidence does not strongly favor the view that transport defects are attributable to microvillar pathology.

Study of vascular access blood flow by angiodynography

Angiodynography has been recommended as a safe and accurate way to determine the blood flow through hemodialysis vascular grafts. This information might be used prophylactically to avert total graft occlusion. We examined the blood flows obtained by this technique after an interval of 6 months in a group of hemodialysis patients whose grafts did not require surgical or radiologic manipulation in the interim. No changes in the mean blood flows were noted during the period of observation. Although a significant correlation was found between the original and follow-up blood flows, the coefficient of determination was only 0.27. The Bland-Altman plot of these data showed that both large decreases and increases in graft flows were recorded for many patients whose graft function did not appear to worsen. Dialysis itself did not seem to alter the measured blood flow. We conclude that caution must be used in interpreting changes in blood flow measured over time by angiodynography. More study of the factors accounting for the variability in blood flow estimations by this technique are needed.

Renal function and mercury level in rats with mercuric chloride nephrotoxicity.

The levels of Hg++ in different subcellular compartments of rat kidney cortex were determined after a single subcutaneous injection of 203HgCl2, 4.7 mg/kg body weight. By 30 min after injection, cortical Hg++ level was 46.3 +/- 6.8 micrograms/g protein. A maximal cortical Hg++ value of 429 +/- 49 micrograms/g protein was reached 4 h after injection. Hg++ associated with the brush border membrane showed a progressive increase during the first 15 h after injection, but at each time interval was significantly less than cortical Hg++. The 45-hour values for cortex and brush border were equivalent. No evidence for the presence in plasma or kidney tissue of free Hg++ was obtained. Saline loading protected animals against the development of renal failure and resulted in significant lowering of cortical Hg++ levels without an effect on blood Hg++ concentration.

The effect of hemodialysis on electrolytes and acid–base parameters

BACKGROUND Hemodialysis patients are treated with bicarbonate dialysate to correct the metabolic acidosis, which results from the metabolism of dietary and endogenous protein. The concentration of plasma tCO(2) is used to gauge the success of therapy. Reported low values in pre-dialysis blood suggest incomplete correction of acidosis in a substantial percent of the dialysis population. However, questions have been raised about the reliability of tCO(2) determination in dialysis patients. METHODS Pre- and post-dialysis blood specimens were obtained from chronic hemodialysis patients and analyzed on-site using an OPTI Critical Care Analyzer. Results were compared with reports obtained monthly from the reference laboratory to which the samples were routinely shipped for analysis. In addition, OPTI analyzer whole blood electrolytes were compared with plasma electrolytes determined in a local laboratory. RESULTS Mid-week testing of patients dialyzed against a 40-mmol/l bicarbonate dialysate found that most patients had normal acid-base status pre-dialysis and frank metabolic alkalosis by the end of dialysis. Whole blood tCO(2) values determined on the OPTI CCA were 2.4 mmol/l greater than heparin plasma tCO(2) assayed on the Vitros chemistry analyzer. Small differences were also observed for K(+) and Cl(-). CONCLUSIONS Based on our on-site determination of acid-base and electrolyte concentrations, metabolic acidosis appears to be fully correctable in well-dialyzed renal failure patients. Metabolic alkalosis is apparent in the post-dialysis period.

Increased Anion Gap After Liver Transplantation

Massive fibrinolysis after a liver transplant resulted in oliguric renal failure and necessitated the continuous infusion of large quantities of fresh frozen plasma. With the increase in plasma protein concentration, there was a simultaneous increase in the anion gap. These two parameters, the anion gap and total protein or albumin level in the blood, demonstrated a high degree of correlation. Weaker but significant correlations were found in a retrospective analysis of patients with a variety of renal diseases and a population of long-term peritoneal but not hemodialysis patients. This entity of hyperproteinemic acidosis should be added to the list of high anion gap acidoses.

Platelet activating factor acetylhydrolase activity in the urine of patients with renal disease

Platelet activating factor has been demonstrated in blood and urine and has a broad range of effects on kidney function. The kidney possesses the enzymes responsible for PAF synthesis as well as the specific acetylhydrolase which deactivates PAF. We used a radioactive assay to measure PAF-acetylhydrolase activity in urine samples obtained from normal individuals and patients with various nephropathies. Activity was detected in the majority of normal urines with a mean + 2 SD = 0.70 nmol/30 min/ml. Activity exceeding this value was measured in the urines of 11 of 14 patients with diabetes mellitus, 14 of 22 with glomerulonephritis, and 5 of 16 with hypertensive renal disease. Further study is necessary to relate urine hydrolase activity to specific functional and structural abnormalities of the kidney.