Biomedical subjects
Publications and source records attributed to W M Bennett.
Plasma and ultrafiltrate drug concentrations were determined for 17 drugs in ten patients receiving continuous arteriovenous hemofiltration. Ultrafiltrate concentrations were not always predictable because of multiple factors, which may include altered drug-protein binding in these very ill patients.
Prolonged cold storage following intracellular electrolyte flushing increases the probability of significant acute tubular necrosis after cadaver kidney transplantation. The renal function of primary cadaver kidney grafts was compared in 68 recipients who required dialysis and 92 who did not require dialysis during the first week after transplantation. All kidneys were retrieved from beating-heart cadaver donors by our center, flushed with ice-cold intracellular electrolyte solution and cold-stored until transplantation at our hospital. Recipients requiring dialysis during the first week after transplantation received kidneys with a significantly longer cold storage time (27.4 plus or minus 10.2 versus 23.2 plus or minus 7.6 hours) and had significantly higher 1-month serum creatinine nadirs (2.1 plus or minus 1.3 versus 1.5 plus or minus 0.6 mg./dl.). Actuarial kidney graft survivals and serum creatinine levels 1 to 5 years after grafting were not significantly different. Acute tubular necrosis following primary cadaver kidney transplantation does not adversely affect long-term function of kidney grafts flushed with intracellular electrolyte solution and cold-stored until transplantation.
No kidney transplant center responding to a kidney preservation questionnaire would accept a kidney flushed with an intracellular electrolyte solution and cold-stored for over 40 hours. This study from one center is a comparison of 50 primary cadaver kidney grafts preserved with an intracellular electrolyte flush followed by cold storage for 40 to 61 hours to 82 primary cadaver kidney grafts preserved by the same method for 9 to 24 hours. Kidneys cold-stored for over 40 hours had a significantly increased requirement for dialysis in the 1st week following transplantation (82% versus 34%) and a significantly increased 1-month serum creatinine nadir (2.3 mg/dL versus 1.7 mg/dL). Actuarial graft survivals and serum creatinine levels at 1, 2, and 3 years after grafting were not significantly different. Cadaver donor methylprednisolone (30 to 60 mg/kg) two to nine hours prior to kidney removal significantly reduced the requirement for 1st-week hemodialysis in the kidneys cold-stored for over 40 hours (60% versus 91%). Kidneys preserved by flushing with cold intracellular electrolyte solution can be successfully transplanted after over 40 hours of simple cold storage when the warm ischemia time is very short.
Commercial gentamicin C is a mixture of gentamicin C1, C1a, and C2. The nephrotoxicity of each of these constituents was compared with that of the gentamicin complex. After seven days the mean creatinine level in serum was 0.8 mg/dl in rats given C2 and 0.5 mg/dl in rats given C1, C1a, or the gentamicin complex (P less than .001). Toxicity attributable to C1a was not detected until day 14, and only minimal toxicity was noted in C1-treated rats after 21 days. Nephrotoxicity caused by the gentamicin complex was similar to that caused by C2. By a new high-pressure liquid chromatographic method, the renal concentration of C1, C1a, and C2 was quantified in rats given the gentamicin complex. The results indicated an early, preferential renal accumulation of C2. Subsequently, the C2 content of 12 commercial lots of gentamicin C was measured. The C2 concentration ranged from 12.4 to 20.1 mg/ml. In short, experimental nephrotoxicity from gentamicin C is largely the result of the C2 constituent, and the concentration of this constituent in commercial preparations of gentamicin varies by as much as 7.7 mg/dl.
Because calcium has been reported to modify gentamicin binding to its proximal tubular brush border membrane receptor, we studied the effects of dietary calcium loading and subsequent hypercalciuria on experimental gentamicin nephrotoxicity. Male Fischer 344 rats were fed one of two diets that were identical except for calcium carbonate content: normal (0.5%) and high (4%). The high-calcium diet made rats hypercalciuric but there were no differences between the two groups in inulin clearance, sodium or osmolar excretion, or serum calcium prior to gentamicin administration. Animals on both diets were treated with gentamicin, 20 mg/kg b.i.d., for periods of 3 to 21 days. Both groups developed acute renal failure, but animals on the high-calcium diet had less severe acute toxic injury, as evidenced by studies of inulin clearance, renal histology, and in vitro cortical uptake of NMN and PAH. Furthermore, calcium-loaded animals tended to have lower peak renal cortical gentamicin levels during the period of acute toxicity. The mechanism by which increased dietary calcium protects against gentamicin nephrotoxicity remains speculative. Calcium and gentamicin may compete for the same brush border receptor or alternatively parathyroid suppression may result in diminution in tubular cell membrane drug binding sites. The possibility that high-calcium diets exert a nonspecific salutory effect on proximal tubular cell integrity has not been excluded.
Bis (2,3-dibromopropyl) phosphate (BIS-BP) is one of two identified metabolites of Tris (2,3-dibromopropyl) phosphate (TRIS-BP). We have previously shown that BIS-BP is more acutely nephrotoxic than TRIS-BP. We now report the effect of sex and inhibition of drug metabolism on BIS-BP toxicity. Compared to male rats, age-matched female rats developed less severe and extensive structural damage after BIS-BP. Renal dysfunction, as indexed by serum creatinine and in vitro renal cortical uptake of para-aminohippurate and N-(14C) methylnicotinamide was similar in males and females. Pretreatment of males with the drug metabolism inhibitor, cobaltous chloride, reduced both functional and structural evidence of BIS-BP toxicity. In separate studies, there was no difference in the distribution of radiolabel in male and female rats three days after administration of 14C-TRIS-BP. These studies showing that female rats are resistant to acute BIS-BP structural damage may explain the previously reported lack of carcinogenicity of TRIS-BP in female rats. The reduction of BIS-BP toxicity by CoCl2 suggests that unidentified, nephrotoxic metabolites exist and are responsible for part of the nephrotoxicity of BIS-BP.
Renal handling of the aminoglycoside antibiotics gentamicin and tobramycin were studied before and after one hour of constant intravenous infusions adjusted to maintain a concentration of 15 micrograms/mL. A solitary renal autotransplant model in four conscious volume replete 40 Kg sheep was used. This unique surgical preparation allows sampling of renal arterial and renal venous blood as well as urine drained through an exteriorized parotid-ureteral fistula. This surgical preparation has considerable potential in renal pharmacology since it uses a conscious, large animal. Baseline studies in this preparation demonstrated normal, 51CrEDTA and 125 I PAH, clearances which were unaffected by the drugs. Aminoglycoside binding to pooled sheep sera was 11% at physiologic PH, calcium and magnesium concentrations. A-V difference was 1.3 +/- .3 micrograms/mL and extraction by the kidney was 9 +/- 3.2% with no differences between gentamicin and tobramycin. Clearance of gentamicin was 84% and tobramycin 86% of GFR. There was no evidence of tubular injury as evidenced by unchanged urinary beta-2 microglobulin excretion. Serum Na, K, Ca and Mg did not change over the course of the study. Both drugs caused a prompt decrease in absolute and fractional sodium excretion while only gentamicin produced a kaliuresis. Early aminoglycoside effects on electrolyte balance may be an eventual determinant of nephrotoxic potential rather than differences in renal drug handling.
The data base for rational guidelines to safe, efficacious drug prescribing in adults with renal insufficiency are presented in tabular form. Current medical literature was extensively surveyed to provide as much specific information as possible. When information is lacking, however, recommendations are based on pharmacokinetic variables in normal subjects. Nephrotoxicity, important adverse effects, and special considerations in renal patients are noted. Adjustments are suggested for hemodialysis and peritoneal dialysis when appropriate.
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One hundred and eighty-six renal biopsy specimens from 79 adult patients with mesangial IgA nephropathy were examined and correlated with clinical data at the time of biopsy. Forty patients (group 1) with a history of macroscopic hematuria were compared with 39 patients (group 2) without such a history. Group 1 patients had a higher serum creatinine, 240 +/- 20 mumoles/liter vs. 140 +/- 10 mumoles/liter (P less than 0.01), lower creatinine clearance 69 +/- 36 ml/min vs. 87 +/- 30 ml/min (P less than 0.05), and a higher percentage of patients presenting with serum creatinine greater than 300 mumoles/liter, 22.5% vs. 5.1% (P less than 0.05). Fourteen biopsies were performed in 11 patients during an episode of macroscopic hematuria (group 1A). One hundred percent of these biopsy specimens showed crescents. Ninety-one percent of 11 biopsy specimens from ten patients (group 1B), taken 3 to 27 days following an episode but at a time when urinary red cells were less than 1,000,000/ml, also showed crescent formation. Of 14 biopsy specimens from 13 patients without macroscopic hematuria, but with greater than 1,000,000 red cells/ml in the urine just prior to biopsy (group 2A), 79% had crescents. In conclusion, macroscopic hematuria in adult patients with mesangial IgA nephropathy is associated with a high likelihood of crescents on renal biopsy specimens and worse renal function. Careful quantitative assessment of the urine for renal bleeding may help to better define the activity of disease in these patients.
Renal cyst epithelial transport of organic molecules was investigated during three separate cyst drainage procedures in a non-uremic patient with polycystic kidney disease (PCKD). Following constant intravenous insulin infusion, four of eight sampled cysts achieved concentrations exceeding those expected by glomerular filtration alone. Likewise, cyst concentrations of the filtered radionuclide Tc DTPA were up to 3.7 times simultaneous plasma levels. Both PAH and I-131 hippuran accumulated in all cysts suggesting intact tubular secretory mechanisms. Quantitative amino acid levels in two proximal nephron cysts were identical to serum. Since concentrations of inulin, DTPA, and amino acids exceed levels expected if cystic nephrons had normal glomerular filtration and tubular reabsorptive properties, other mechanisms are likely. Simple diffusion across altered epithelial surfaces could partially account for the observed cyst concentrations of each organic molecule and, by ion trapping, contribute to progressive cyst growth in PCKD.
Review of a large renal transplant experience revealed a 17.3% incidence of posttransplant erythrocytosis. The influence of kidney source, pretransplant hematocrit, duration of pretransplant dialysis, renal transplant function, acute rejection, transplant renal artery stenosis, urinary tract obstruction, smoking, diabetes, retention of native kidneys, splenectomy, parathyroidectomy, immunosuppression, hypertension, and liver enzyme abnormalities on the development of erythrocytosis in 53 recipients was determined. Comparison was made with 49 control recipients matched for kidney function, time after grafting, age, and sex. Erythrocytosis occurred 3 to 90 months after transplantation and persisted for 1 to over 84 months. Risk factors for the development of erythrocytosis were smoking, diabetes, and a rejection free course. In contradistinction to previous smaller series, erythrocytosis occurred in patients with good renal function (serum creatinine 1.62 +/- 0.43 mg/dl) without prominence of graft rejection, transplant artery stenosis or obstruction. Despite therapeutic phlebotomy, 11 thromboembolic events occurred in 10 of the 53 patients with erythrocytosis, but in none of the controls (P less than 0.001). The high incidence of erythrocytosis following renal transplantation and the risk of associated thromboembolic events should encourage awareness and controlled evaluation of therapeutic modalities.
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Chronic psychosocial stress in male mice produces chronic interstitial nephropathy not explained by renal vascular disease or urinary infection. Four groups of male CBA mice were studied. Group 1 and group 2 were placed in Henry-Stephens complex population cages for 5 months. Group 2 had caffeine, 800 micrograms/ml, added to their drinking water. Control groups 3 and 4 were unstressed, but group 4 had 800 micrograms/ml of caffeine added to their water. Stressed animals developed chronic interstitial nephropathy which was more severe in animals drinking caffeinated water. In addition, the percent of cortex involved in interstitial fibrosis was higher in group 2, 18.0 +/- 1.4, than in group 1, 15.2 +/- 2.3 (p less than 0.05). Both groups had more fibrosis than unstressed animals (p less than 0.01). Blood urea nitrogen was more elevated in group 2, 47 +/- 13 mg/dl, than in group 1, 29 +/- 17 mg/dl (p less than 0.05). Again both values exceeded those in unstressed animals (p less than 0.01). It is concluded that prolonged environmental stress can lead to the renal morphologic changes of chronic interstitial nephritis. Both renal pathology and function are worse when there is concurrent high caffeine intake. The relevance of this model to human disease related to analgesic use or with affective illness requires further study.
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Sodium diethyldithiocarbamate (DDTC) administered following cis-diamminedichloroplatinum(II) (DDP) has been reported to attenuate structural renal damage and elevation of blood urea nitrogen in rats. Since DDP damages primarily proximal tubular epithelium in this species, we compared proximal tubular function, glomerular function, and histology in male Sprague-Dawley rats treated with DDP followed by either DDTC or 0.9% NaCl solution (NS) rescue. Male Sprague-Dawley rats received a single i.p. injection of DDP (7.5 mg/kg)-mannitol (75 mg/kg)-NaCl (67.5 mg/kg). Forty-five min later, rats were given i.p. injections of either DDTC (750 mg/kg) dissolved in 0.5 ml of NS (DDP + DDTC group; ten rats) or 0.5 ml NS (DDP + NS group; nine rats); additional rats received either DDTC only (DDTC group; six rats) or no treatment (untreated control group; six rats). All groups were sacrificed 5 days later by ether anesthesia and exsanguination. Compared to the untreated control group, the DDTC group had slightly lower mean blood urea nitrogen at sacrifice [12.5 +/- 0.5 (S.E.) versus 15.4 +/- 0.8 mg/dl; p less than 0.025 by unpaired Student's t test]; there was no difference in serum creatinine. The DDP + DDTC group had no diarrhea and no presacrifice deaths in contrast to diarrhea and three presacrifice deaths in the DDP + NS group. Blood urea nitrogen was also lower in the DDP + DDTC group at sacrifice (187 +/- 30 versus 383 +/- 39 mg/dl; p less than 0.005). However, weight loss and serum creatinine were not different. Structural acute tubular necrosis was marked in both DDP groups but was less severe in the DDP + DDTC group than in the DDP + NS group. Proximal tubular function was indexed by the uptake of the organic base N-[14C]methyl nicotinamide (NMN) and the organic acid p-aminohippurate in renal cortical slices incubated 90 min in Cross and Taggart medium. NMN uptake (expressed as slice to medium ratio) was slightly lower in the DDTC group than in untreated controls (4.1 +/- 0.2 versus 5.0 +/- 0.2; p less than 0.025). Marked depression of p-aminohippurate and NMN uptake occurred in both DDP + DDTC and DDP + NS groups. There was no difference in NMN uptake, but depression of p-aminohippurate uptake was slightly less severe in the DDP + DDTC group (5.3 +/- 0.7 versus 3.1 +/- 0.3; p less than 0.005). We conclude that DDTC rescue attenuates structural DDP injury in this animal model. DDP-mediated proximal tubular dysfunction was only marginally attenuated by DDTC; glomerular filtration rate, as indexed by serum creatinine, was not protected. DDTC attenuation of DDP toxicity may be mediated in part via reducing volume depletion due to DDP-associated diarrhea.