Kinetics of salicylate elimination by anephric patients.

The objectives of this research were to determine the kinetics of salicylate elimination in anephric patients and particularly to establish if these patients form the major metabolite of salicylic acid, salicyluric acid, at a normal rate. This investigation was initiated because of conflicting reports concerning the contribution of the kidneys to the formation of salicyluric acid in man. Six patients, 20-44 yr old, three of whom were anatomically anephric while the other three were physiologically anephric, received an intravenous injection of 500 mg salicylic acid (as sodium salicylate)/1.73 m(2) body surface area on an interdialysis day. Serial blood samples were obtained for 12 or 16 h after injection and the plasma was assayed for salicylic acid, salicyluric acid, total protein, albumin, and creatinine. Detailed pharmacokinetic analysis based on an open, two-compartment linear model revealed no significant differences in apparent volume of distribution and apparent first-order distribution and elimination rate constants between the anephric patients and normal adult subjects. An estimate of salicyluric acid formation rate by the anephric patients, based on the initial rate of increase of salicylurate concentrations in plasma, indicates that the metabolite is formed at a normal rate. These results suggest that the kidneys do not contribute significantly to the formation of salicyluric acid from salicylic acid in man.

Lymphocyte blastogenesis in patients receiving hemodialysis.

Lymphocyte blastogenic transformation in response to plant lectins and allogenic cells was studied in patients with nonuremic, far-advanced, chronic renal failure and in healthy controls. Cell cultures were studied in the presence of normal sera, patient's sera, and with media of different buffering capacities. Minimal blastogenic depression was observed when patient's lymphocytes were cultured in indifferent plasma with effective bicarbonate buffering compared with the use of pooled patient's plasma or HEPES buffer. Fresh plasma in culture depressed concanavalin A (Con A) blastogenesis. The data suggest that, under optimal conditions, lymphocytes from patients with chronic severe renal insufficiency are more responsive to stimuli than previously reported and as a group are near normal control values. Further, the defect observed may be a result of intracellular acidosis.

Resin hemoperfusion: a method of removing circulating thyroid hormones.

The ability of an extracorporeal hemoperfusion system employing neutral Amberlite resin to bind thyroid hormone and to decrease circulating levels of triiodothyronine (T3), thyroxine (T4), and free thyroxine (FT4) was evaluated in dogs made thyrotoxic by the intramuscular administration of thyroid hormone. Since the resin column and tubing were charged with saline, the effects of hemodilution from this source on serum T3 and T4 was assessed by control perfusion through a column which did not contain any resin. After correction for hemodilution, the mean serum T3, T4 and FT4 decreased during 2 hours of resin hemoperfusion by 39%, 35%, and 46%, respectively. Hormonal clearance rates were calculated in two experiments and the estimated net hormone removed averaged 60.4 mug of T3 and 1990 mug of T4. Hematologic indices and routine chemistries did not change significantly in these dogs during the procedure except for a decrease in mean serum albumin concentration and an increase in mean serum glucose concentration. Hemoperfusion through this resin system seems to be a safe, effective means of decreasing serum T3, T4, and FT4 in thyrotoxic dogs and warrants evaluation for the treatment of thyroid storm in man.

Artificial kidneys and clearance calculations.

Clearance of solutes by artificial kidneys can be calculated using plasma flow and solute concentration, whole blood flow and plasma solute concentration, and midpoint of dialysis blood or plasma solute concentration and total amount of solute removed. Using these methods, the clearance of procainamide (PA) and N-acetylprocainamide (NAPA) was determined in 4 patients. In all but one case clearances using total amount recovered were greater than clearances using whole blood flow and plasma concentration. Without exception, clearance determined using amount recovered was substantially greater than clearance using plasma flow and plasma levels, suggesting that both PA and NAPA are removed not only from plasma but also from red blood cells. In vitro clearance of PA, NAPA, quinidine, and phenobarbital by 11 clinically available artificial kidneys and an XAD-4 hemoperfusion column was determined and differences were found.

Effect of hemodialysis on kinetics of acetaminophen elimination by anephric patients.

The pharmacokinetics of acetaminophen elimination were determined in 4 anephric patients during hemodialysis and on an interdialysis day. The biologic half-life of acetaminophen ranged from 119 to 147 min on an interdialysis day and was decreased by 42% to 53% during hemodialysis. Individual mean dialyzer extraction ratios, based on assay of plasma samples from blood flowing into and out of the dialysis unit, were 0.46 to 0.78 for acetaminophen, 0.53 to 0.57 for acetaminophen glucuronide, 0.13 to 0.60 for acetaminophen sulfate, and 0.70 to 0.87 for urea nitrogen. There was a strong correlation between the extraction ratios of acetaminophen and urea nitrogen. Hemodialysis was the major or sole routine of elimination of acetaminophen glucuronide and sulfate in the anephric patients.

N-Acetylprocainamide levels in patients with end-stage renal failure.

Serum concentrations of procainamide (PA) and N-acetylprocainamide (NAPA) were measured by fluorometry in subjects with normal renal function (n = 4) and in patients with end-stage renal failure (n = 3) after administration of 6.5 mg/kg of PA-HCl orally. Two subjects with normal renal function were rapid isonicotinic acid hydrazide (INH) acetylators and two were slow acetylators. The rapid acetylators had higher peak serum levels of NAPA (1.80 mug/ml) than the slow acetylators (0.40 mug/ml). Peak serum levels of PA were essentially identical in both. The half-life (T1/2) of PA was shorter, 2.5 hr, in the rapid acetylators than in the slow, 4.1 hr. The slope of the terminal portion of the blood time curve for NAPA was steeper (-0.087) for slow acetylators than for rapid (-0.078). These apparent differences between rapid and slow acetylators are not conclusive in themselves but tend to support the differences in acetylation previously reported. In the absence of renal function, the serum levels of PA were higher and the T1/2 prolonged. The serum levels of NAPA rose slowly and reached peak levels of 2 to 3 mug/ml and declined only with hemodialysis. In 3 patients measurable levels of NAPA were still present 78 hr (0.62 mug/ml), 94 hr (0.36 mug/ml), and 124 hr (0.70 mug/ml) after the single oral dose of PA. Clearance of NAPA during clinical hemodialysis was 48 +/- 10 cc/min compared to 75 +/- 12 ml/min for PA.

Propoxyphene and norpropoxyphene plasma concentrations in the anephric patient.

The widely used analgesic propoxyphene is subject to extensive presystemic (first-pass) biotransformation after oral administration. There have been indications that presystemic biotransformation of a drug may be less in anephric patients than in healthy subjects. Plasma concentrations of propoxyphene (a drug with dangerous adverse effects at high concentrations) and its major and pharmacologically active metabolite norpropoxyphene have been compared in 7 anephric patients and 7 healthy subjects after oral administration of a 130-mg dose. Maximum propoxyphene concentrations were much higher (177 +/- 16 vs 81 +/- 35 ng/ml, mean +/- SD, p less than 0.001), and areas under the concentration-time curve over 12 hr were much larger (4,310 +/- 1,520 vs 2,250 +/- 1,050 ng hr/ml, p less than 0.02) in the anephric patients than in the normal subjects. These differences were statistically significant even after normalization for dose per body weight. Norpropoxyphene concentrations were also higher and more persistent in the anephric patients. These differences, which appear to result from decreased presystemic biotransformation of propoxyphene and decreased elimintation of norpropoxyphene, indicate that propoxyphene should be used cautiously and at reduced doses in patients with renal failure.

Acetylation of procainamide in man and its relationship to isonicotinic acid hydrazide acetylation phenotype.

To assess the extent of the acetylation of procainamide (PA) to N-acetylprocainamide (NAPA) in man, and its relation to isonicotinic acid hydrazide (INH) acetylation phenotype, the following study was done. Fourteen subjects received 500 mg of PA - HCL orally. INH acetylation phenotype was determined by the serum half-life of INH after 4 mg/kg of INH orally. Each urine voided for 96 hr after procainamide was saved and levels of procainamide and NAPA measured by gas-liquid chromatography. The 14 subjects eliminated 52 plus or minus 4 percent of the dose as procainamide and 16 plus or minus 2 percent of the dose as NAPA. Four fast INH acetylators eliminated 23 plus or minus 3 percent of the dose as NAPA compared to 12 plus or minus 1 percent by the slow acetylators (p smaller than 0.05). The amount of unaltered procainamide excreted by the fast and slow INH acetylators was not significantly different, 50 plus or minus 4 percent and 53 plus or minus 4 percent, respectively. Of the total amount of drug recovered in the urine of the fast and slow INH acetylators, NAPA accounted for 32 percent and 19 percent, respectively (p smaller than 0.01). There appears to be a positive correlation between the ability to acetylate INH and the ability to acetylate procainamide.

Elimination of procainamide in end stage renal failure.

To investigate the effect of end stage renal insufficiency and hemodialysis on the serum half-life of procainamide, 500 mg of procainamide was given orally to control subjects and dialysis patients on interdialysis days. Procainamide was assayed by spectrophotometry and spectrophotofluorometry. Mean half-life in normal subjects was 3.2 hr by spectrophotometry and 3.5 hr by spectrophotofluorometry. Mean half-life in patients was 11.3 hr by spectrophotometry and 16.0 hr by spectrophotofluorometry (p less than 0.001 compared to control subjects). Half-life of procainamide during dialysis in patients given 500 mg of procainamide 1 hr before dialysis was 4.3 hr and 9.6 hr on a nondialysis day (p less than 0.001). Both methods of assay gave higher levels of procainamide when the metabolite, N-acetylprocainamide, was present in serum and the extract allowed to stand in 1 N HCl, but spectrophotometry was less affected. Thus, end stage renal insufficiency greatly prolongs the half-life of procainamide, procainamide is readily dialyzable, and N-acetylprocainamide is hydrolyzed in 1 N HCl to procainamide during routine serum determinations.

Propranolol in hypertensive dialysis patients: efficacy and compliance.

The effect of propranolol therapy on plasma renin activity and blood pressure control was evaluated in 35 uremic patients receiving intermittent center-based outpatient hemodialysis. Patients were determined to be either compliant or noncompliant with therapy based on the steady-state predialysis plasma propranolol concentration. Noncompliance occurred with remarkable frequency and was associated with persistent hyperreninemia and poorly controlled hypertension. Blood pressure control was significantly better in compliant patients, in whom plasma renin activity was generally, but not universally, suppressed. Propranolol can be effectively used in the management of hypertensive dialysis patients, but steady-state plasma propranolol levels should be measured to assess compliance in patients apparently refractory to treatment.

Antiglomerular basement membrane antibody-mediated glomerulonephritis and Goodpasture's syndrome.

The originally dismal prognosis associated with anti-GBM Ab-mediated GN and Goodpasture's syndrome may be changing as we recognize a broader spectrum of disease, improve general supportive care, and improve specific treatment. Immunosuppressive therapy, if started early in the course of disease, may prevent or allow recovery from renal failure and may also result in cessation of recurrent pulmonary hemorrhage in most patients with this form of Goodpasture's syndrome. The administration of pharmacologic doses of corticosteroids intravenously can result in cessation of and dramatic recovery from severe pulmonary hemorrhage and obviate the need for emergency bilateral nephrectomy. Plasmaspheresis may represent a useful therapeutic procedure for the immediate and long term reduction in amounts of circulating anti-GBM Ab, but the definition of its true value and role awaits completion of controlled, prospective trials. Immunosuppressive therapy, with or without plasmapheresis, can reduce quantities of anti-GBM Ab in serum to undetectable levels without nephrectomy. Thus, it is likely, but not proven, that nephrectomy can be discontinued as a routine pretransplantation procedure in patients with anti-GBM Ab mediated GN. Finally, in patients who suffer irreversible renal failure, renal transplantation can be successfully undertaken with minimal risk of recurrent disease, when circulating anti-GBM Ab becomes undetectable.

Zinc deficiency: a reversible complication of uremia.

Subnormal plasma zinc levels and decreased zinc concentration in hair and leucocytes as well as increased plasma ammonia and ribonuclease activity in dialyzed and nondialyzed uremic patients indicate that zinc metabolism is abnormal in uremia and is not corrected by dialysis. The effect of oral supplementation with zinc acetate (12 patients) or placebo (12 patients) on the above biochemical parameters in hemodialysis patients was determined as a part of a double-blind study. The zinc-supplemented, but not the placebo, group demonstrated significant increases in mean (+/- SD), plasma zinc (80 +/- 9 to 110 +/- 14, micrograms/dl), leucocyte zinc (56 +/- 13 to 1098 +/- 18, micrograms/10(10) cells), hair zinc (140 +/- 12 to 190 +/- 16 micrograms/g), and decreases in plasma ammonia (76 +/- 10 to 40 +/- 6 micrograms/dl) and plasma ribonuclease activity (1.49 +/- 0.08 to 0.78 +/- 0.10, OD/min/ml). Abnormalities of taste and sexual function improved significantly in patients receiving zinc but not in those on placebo therapy. These improvements in biochemical as well as clinical parameters confirm and extend our earlier observations of improvement in taste and sexual function after zinc supplementation. Together, they suggest that zinc deficiency is a complicating feature of uremia and can be corrected by oral zinc supplementation.

Improvement of uremic hypogeusia by zinc: a double-blind study.

Diminished taste acuity may account for the persistence of protein and caloric malnutrition observed in a majority of hemodialysis patients inspite of liberalization of the prescribed amount of dietary protein. Twenty-two patients undergoing thrice weekly hemodialysis for more than 6 months were tested for taste acuity and plasma zinc concentration, after which a double-blind study was instituted using a zinc supplement (50 mg of elemental zinc as zinc acetate per day) or a placebo. The threshold of taste detection and recognition for salt (NaCl), sweet (sucrose), and bitter (urea) but not for sour (HCl) improved significantly in all patients on zinc supplementation. None of these parameters improved in those taking placebo. During the study period, the mean plasma zinc level increased from 75 +/- 8 to 97 +/- 10 microgram/dl (P less than 0.001) in patients receiving zinc acetate. There was not significant change in plasma zinc level in the placebo group (75 +/- 15 to 80 +/- 15). The results of this study show that uremic hypogeusia improved in association with zinc supplementation and elevation of plasma zinc concentration.

Effect of cyclic nucleotides on mitogen. Responsiveness of lymphocytes from patients undergoing dialysis.

Lymphocytes from 10 asymptomatic patients undergoing hemodialysis and from eight control subjects were repeatedly cultured with exposure to various concentrations of cyclic nucleotides and theophylline in addition to mitogen. The blastogenic response of the patients' lymphocytes was inhibited by molar concentrations of dibutyryl cyclic AMP which had much less or no inhibitory effected on the response of the control subjects' lymphocytes. This suppressive effect was not potentiated by theophylline. Cyclic GMP enhanced the proliferative response of the patients' lymphocytes as well as that of the controls. In contrast to absolute counts per minute per culture, the suppression by dibutyryl cyclic AMP of mitogen-induced blastogenesis noted in this study clearly separated the in vitro behavior of the patients' lymphocytes from that of the controls' lymphocytes and may serve as a useful marker of cellular dysfunction in such patients.

Plasmapheresis and immunosuppressive agents in antibasement membrane antibody-induced Goodpasture's syndrome.

Four patients with rapidly progressive glomerulonephritis and pulmonary hemorrhage (Goodpasture's syndrome) induced by circulating anti-glomerular basement membrane (GBM) antibodies were treated with immunosuppressive agents and varying amounts of plasma exchange. All four patients showed progressive decreases in circulating anti-GBM antibody during therapy. Two patients with established renal failure before therapy showed no improvement in renal function but had a remission from pulmonary disease. In two other patients, renal failure developed early in the course of therapy and required maintenance hemodialysis. Later, their renal function improved coincident with a decrease in circulating anti-GBM antibody. Aggressive measures to reduce the levels of circulating anti-GBM antibody may have a salutory effect on the clinical course of the disease, particularly when undertaken early.

Studies of mitogen-induced lymphocyte transformation by a semi-microtechnic.

The authors have demonstrated that mitogen-induced lymphocyte transformation can be effectively studied in a semi-microsystem allowing multiple studies from a reasonably small volume of blood, which makes the technic more feasible for clinical studies of cellular immune mechanisms. The variability among individuals, and from day to day in the same individual, makes repeated, careful kinetic studies necessary for valid data. Moreover, the very wide range of normal responses in man makes the interpretation of cellular hyporesponsiveness difficult in pathologic states and necessitates the use of several mitogen concentrations and sequential kinetic studies to establish the validity of results.

Leukocyte metabolism and function in uremia.

Leukocyte metabolism was studied in 13 non-diabetic hemodialysis patients, 8 clinically stable, nondiabetic transplant recipients, and 13 control subjects. Metabolic parameters included rates of oxygen consumption (nmoles/min/10(6) cells), glucose uptake, lactate production (nmoles/hr/10(6) cells), and 14C-l-glucose oxidation to 14CO2 (nmoles/hr/10(6) cells). Granulocyte metabolism was stimulated by phagocytosis of opsonized zymosan (Z) and by the membrane perturbing agent phorbol myristate acetate (PMA). Granulocyte motility in response to zymosan-activated plasma (ZAP) was also studied. Granulocytes from hemodialysis patients showed significantly impaired stimulated oxygen consumption (Z = 2.41 +/- 0.30 vs. 3.73 +/- 0.39; PMA = 2.63 +/- 0.33 vs. 3.67 +/- 0.19), resting glucose uptake (17.7 +/- 2.9 vs. 36.5 +/- 3.5), stimulated glucose uptake (Z = 44.2 +/- 7.1 vs. 71.8 +/- 5.3; PMA = 63.7 +/- 5.5 vs. 92.8 +/- 5.6), stimulated lactate production (Z = 68.4 +/- 5.1 vs. 97.5 +/- 9.3; PMA = 70.7 +/- 4.9 vs. 92.7 +/- 5.4), and ZAP-stimulated granulocyte motility (16 +/- 3 vs. 30 +/- 4 mu). Metabolic responses of granulocytes from transplant recipients were frequently intermediate between those of hemodialysis patients and controls, but not significantly different from controls. Abnormalities of glucose and oxygen metabolism in granulocytes from uremic patients may cause or contribute to granulocyte dysfunction and vulnerability to infection in such patients.

Zinc metabolism and taste acuity in renal transplant recipients.

To determine the effect of renal transplantation on taste acuity and zinc metabolism, we tested 43 patients with functioning allografts for 2.5 to 96 months. They were tested for taste by the 3-drop stimulus technique. In 30 of them, we determined zinc levels in plasma, hair, and urine. Subnormal plasma and hair zinc, as well as hyperzincuria, was present in all of the 15 patients less than 12 months posttransplant. In contrast, 10 patients who were more than 12 months posttransplant had plasma zinc levels, hair zinc, and urinary zinc excretions in the normal range. Zinc concentrations in plasma and hair of 5 patients who were more than 12 months posttransplant with renal failure, were subnormal and were similar to those in hemodialysis patients. Similarly, taste detection and recognition thresholds for sodium chloride, sucrose, urea, and hydrochloric acid were normal only in patients more than 12 months posttransplant with normal renal function. Plasma zinc, hair zinc, and urinary zinc were not related to prednisone or azathioprine dosage. These results suggest that abnormalities of zinc and taste persist up to 12 months posttransplant and may be related to increased urinary zinc losses.

Lymphocyte suppression by rolipram with other immunosuppressive drugs.

Pentoxifylline, a nonselective phosphodiesterase inhibitor, has immunomodulatory activity in vitro and in vivo and potentiates the suppressive effects of glucocorticoids and cyclosporine on lymphocyte proliferation in vitro. Since phosphodiesterase isotypes 3 and 4 predominate in lymphocytes, the authors measured the suppressive effect of rolipram alone and in combination with low concentrations of methylprednisolone and calcineurin enzyme inhibitors, compared to that of pentoxifylline on mitogen-stimulated lymphocyte proliferation. The percent inhibition of 3H-thymidine incorporation by both 10(-5) and 10(-8) mol/L concentrations of rolipram were significantly greater than that by both 10(-4) mol/L pentoxifylline and 10(-8) mol/L methylprednisolone. The percent inhibition by the combination of 10(-5), but not 10(-6), mol/L rolipram and methylprednisolone was significantly greater than that by 10(-4) mol/L pentoxifylline and methylprednisolone. Potentiation of the suppressive effects of cyclosporine and tacrolimus by rolipram was less consistent. Measurement of cell culture supernatant concentrations of interferon gamma and interleukin-10 indicate that one of the mechanisms underlying the immunosuppressive activity of rolipram is a significantly disproportionate inhibition of the proinflammatory cytokine, interferon gamma.

Effects of glucocorticoids and cyclosporine on IL-2 and I kappa B alpha mRNA expression in human peripheral blood mononuclear cells.

To evaluate molecular mechanisms that might account for the heterogeneity in the in vitro responsiveness of individual subjects' peripheral blood mononuclear cells (PBMC) to immunosuppressive drugs, the authors quantitated in normal human cells the suppressive effects of the glucocorticoids prednisolone and methylprednisolone and of cyclosporine on interleukin-2 (IL-2) mRNA expression and IL-2 production, as well as the stimulatory effect of these drugs on IkappaBalpha mRNA expression. As expected, cyclosporine was significantly more suppressive than either glucocorticoid of IL-2 mRNA expression and IL-2 production by mitogen-stimulated PBMC, with variable degrees of inhibition in cells from individual subjects. The authors confirmed in human PBMC the stimulation of IkappaBalphamRNA expression by the glucocorticoid reported by others in HeLa and transfected Jurkat cell lines. In addition, the authors observed a stimulatory effect on IkappaBalpha mRNA expression by cyclosporine as well in 8 of 10 PBMC preparations studied, suggesting a possible role of calcineurin in the regulation of IkappaBalpha production. Interindividual variability in the intracellular mechanisms of action, possibly based on molecular polymorphisms, might be one factor contributing to differences among patients in their clinical responses to treatment with such drugs.