Regional myocardial blood flow.

A method is described which measures the local effectiveness of the myocardial circulation, expressed as a clearance constant. Uniform clearance constants have been demonstrated in the normal canine and human myocardium. A distinct difference in clearance constants has been demonstrated between the normal canine myocardium and areas of naturally occurring disease. Heterogeneous clearance constants have been found in a majority of human subjects with coronary artery disease-the lowest rates being noted in areas of fibrous aneurysm.

cis-diamminedichloroplatinum(II) nephrotoxicity: tubular function after rescue with sodium diethyldithiocarbamate in rats.

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.

Herpes simplex type 1 hepatitis in renal transplantation.

Herpes simplex is a rare but usually fatal cause of acute hepatitis in adults. Most previously reported cases have occurred in debilitated or immunosuppressed patients. We report two additional fatal cases that occurred in renal transplant recipients. In case 1, there is evidence that the allograft may have been the initial nidus of infection. In case 2, dissemination from a genital infection occurred and failed to respond to vidarabine therapy that was started early in the clinical course. We also review the literature concerning previously reported cases of herpes hepatitis.

Severe mixed metabolic acidosis secondary to rhabdomyolysis.

A patient with severe metabolic acidosis in association with rhabdomyolysis and nonoliguric acute renal failure is presented. Evaluation of his acidosis indicated a large excess of unmeasured anions as well as evidence of a renal acidifying defect. We conclude that the metabolic acidosis seen with myoglobinuric acute renal failure may represent a mixed acid-base disturbance.

Percutaneous aspiration biopsy of renal allografts using ultrasound localization.

Percutaneous aspiration of renal allografts was done employing ultrasound localization and the Jamshidi renal biopsy needle-syringe. Adequate tissue for pathologic assessment was obtained in 19 of 20 biopsy attempts. There were no complications. Ultrasound provides a convenient, nonradiologic means of renal localization for allograft biopsy. The aspiration needle-syringe is well suited for percutaneous transplant biopsy.

Bis (2,3-dibromopropyl) phosphate nephrotoxicity: effect of sex and CoCl2 pretreatment.

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.

Treatment of primary syphilis.

Reports in the English language of the treatment of primary syphilis are reviewed. Except for benzathine penicillin, the efficacy of the currently recommended dosage schedules are documented only by Schroeter et al. Although these investigators reported generally acceptable failure rates, further study is necessary to determine: (1) if differences in efficacy exist among regimes; (2) if the current schedules are equally effective in both primary and secondary syphilis; and (3) if increased dosages reduce failure rates.

Aminoglycoside-mediated calciuresis.

Gentamicin and calcium compete for binding to various tissues including renal tubular brush border. Moreover, gentamicin has calcium channel blocking properties in cardiac and vascular tissue. Calcium channel blockade in vitro by nifedipine or verapamil decreases calcium uptake by renal tubular epithelial cells. To determine the acute in vivo effects of gentamicin on renal calcium handling, we administered gentamicin 10 mg/kg as an i.v. bolus to F344 rats. Within 30 min of administration fractional excretion of calcium increased from a mean of 11 +/- 2% (S.E.M.) to 128 +/- 37%. There was no change in glomerular filtration rate, or urinary sodium, potassium or phosphate excretion. Maximum calciuria occurred immediately after administration, was dose-related and was correlated to preadministration urinary calcium. Urine calcium concentration was also correlated to urinary gentamicin concentration. Urinary calcium returned to base-line values within 90 min of bolus gentamicin administration, but remained elevated if a gentamicin infusion was continued. Parathyroidectomy and dietary calcium content did not affect gentamicin calciuria. Tobramycin, a less nephrotoxic aminoglycoside in the F344 rat, had calciuric effects similar to gentamicin. Verapamil, a calcium channel blocker which is largely excluded from the urine, and potassium dichromate, a nonaminoglycoside proximal tubular nephrotoxin, had no effect on urinary calcium. The mechanism of aminoglycoside calciuria is unclear, but may be related to competition between aminoglycosides and calcium for brush border binding, intraluminal calcium channel blockade by aminoglycosides or aminoglycoside inhibition of basolateral calcium ATPase or Na-K ATPase.

Gentamicin-induced loss of basolateral surface area of rat proximal convoluted tubules.

This study was performed to find the quantitative relationship between basolateral surface alterations of proximal convoluted tubules (PCT) and renal failure in 26 Fisher 344 rats receiving 20 mg/kg of gentamicin twice daily up to 28 days. They were sacrificed on day 14 (renal failure, 13 rats) and day 28 (recovering, 13 rats). Control rats were used for morphologic studies (19) and serum creatinine studies (6 of 19). PCTs (14th and 28th day) were graded as to severity with transmission electron microscopy into grades 1 (normal-mild injury), 2 (moderate injury) and 3 (severe injury) using brush border and basolateral surface alterations. Scanning electron microscopy confirmed these grades using kidney slices and isolated tubular cells. With scanning electron microscopy greater than 3400, PCTs were graded and counted from 14th and 28th day kidneys, day 14 (grade 1, 18%, grade 2, 22%, and grade 3, 60%), day 28 (grade 1, 89% grade 2, 4%, and grade 3, 7%). The basolateral surface contour lengths (BSCL) per length of underlying tubular basement membrane were measured using a computer-assisted digitizer on transmission electron microscopy prints. Control PCTs had a mean BSCL of 268 microns, SD +/- 79, SE +/- 19 per 40 microns of tubular basement membrane. Likewise, the mean BSCL of grade 1 tubules measured 249 microns, SD +/- 87, SE +/- 21; the mean BSCL of grade 2 tubules was 125 microns, SD +/- 40, SE +/- 9 and grade 3 tubules BSCL was 90.5 the BSAI values showed that the 14th day rats had 28% of control BSAI and 28th day rats 80%. 2, grade 3, p less than 0.005). Squaring the mean BSCL of each group gave a basolateral surface area index (BSAI). Combining the percentage of the 3 grades of tubules of 14th and 28th day rats with the BSAI values showed that the 14th day rats had 28% of control BSAI and 28th day rats 80%. Mean serum creatinines (milligrams/deciliters) were: 14th day, 0.86; 28th day, 0.54; and control, 0.39. These data indicate loss of function correlates with lower BSAI (decreased basolateral surface area).

The role of ischemia in acquired cystic kidney disease.

Acquired cystic kidney disease (ACKD) is the result of cyst formation in failing noncystic kidneys. This condition occurs in patients with chronic renal failure and becomes more common with increasing time on renal replacement therapy. Its complications include hemorrhage and tumor formation, which have acquired greater significance as more patients are started on dialysis treatment. The causes of ACKD remain speculative thus far. Its occurrence in nondialyzed patients suggests that dialysis itself is not a necessary factor in its pathogenesis. Five cases of severe unilateral renovascular disease and associated cyst formation are reported. The authors conclude that ACKD may derive from primary renovascular occlusion or from the secondary arterial and arteriolar occlusions seen in the end-stage kidney.

Effect of calcium on in vitro para-aminohippurate accumulation by rat renal cortical slices.

In previous studies para-aminohippurate (PAH) accumulation by renal cortical slices was reduced in calcium-free medium when slices are pretreated with calcium (Ca) chelators. Addition of Ca to the incubation medium of these slices reversed the effects of Ca chelation. Based on these studies, it has been proposed that Ca is required for maximum PAH transport by renal cortical epithelium. However, in the studies presented here, we found that PAH accumulation by rat renal cortical slices not exposed to a chelator varied inversely with incubation medium Ca. Differences in accumulation of PAH was not demonstrable until 90 minutes incubation. Also unaffected was the apparent Vmax and Km of initial accumulation and efflux constant. Addition of EDTA to Ca++-free medium reduced PAH accumulation suggesting chelating agents act by a different mechanism than removal of extracellular calcium.

Effects and interactions of gentamicin, polyaspartic acid and diuretics on urine calcium concentration.

Gentamicin causes isolated, reversible calciuria in rats by an unknown mechanism. We hypothesized that gentamicin calciuria is related to nonantibacterial properties that may interfere with transtubular calcium transport (calcium channel blockade, Na,K-ATPase inhibition or competition with calcium for binding to the brush-border membrane). The calciuric effect of gentamicin was compared to the calcium channel blockers lanthanum and cobalt, the Na,K-ATPase inhibitor ouabain and the polycation aprotinin (which competes with gentamicin for brush-border membrane binding). Although gentamicin 0.02 mmol/kg caused a 6-8-fold increase in urine calcium concentration, none of the other agents was calciuric. We also found that the calciuric effects of gentamicin and furosemide were additive, whereas the noncalciuric diuretic chlorothiazide had no effect on gentamicin calciuria. We also determined the effect of poly-L-aspartic acid (PAA), which binds gentamicin and prevents nephrotoxicity. PAA caused isolated calciuria similar in magnitude and character to gentamicin. However, PAA pretreatment decreased the magnitude of gentamicin calciuria to insignificance. PAA pretreatment did not prevent furosemide calciuresis. These results indicate that: 1) gentamicin and furosemide calciuria are caused by different mechanisms; 2) gentamicin calciuria is probably not mediated by calcium channel blockade, Na,K-ATPase inhibition or displacement of brush-border membrane-bound calcium; 3) gentamicin and PAA calciuria may reflect interference with intracellular events related to transtubular calcium transport.

Effect of parathyroid hormone activity on gentamicin nephrotoxicity.

Dietary calcium (CA++) supplementation attenuates gentamicin nephrotoxicity in rats. It has been proposed that this protective effect results from the ability of Ca++ to interfere with gentamicin binding to renal cell membranes. However, calcium supplementation also suppresses parathyroid hormone (PTH) activity, which may affect gentamicin nephrotoxicity by altering renal brush border phospholipid composition or renal calcium handling. We therefore compared gentamicin nephrotoxicity in PTH-stimulated control rats and parathyroidectomized (PTX) rats. Although their pretreatment serum ionized calcium concentration was significantly higher (1.27 +/- 0.01 vs. 0.88 +/- 0.06 mmol/L; P less than 0.001), PTH-stimulated rats had higher peak renal cortical gentamicin concentrations (543 +/- 20 vs. 395 +/- 49 micrograms/gm; P less than 0.025) and serum creatinine concentrations (3.0 +/- 0.8 vs. 0.9 +/- 0.3 mg/dl; P less than 0.05). Structural injury and depression of renal cortical slice uptake of p-aminohippurate were also less severe in PTX rats. Gentamicin treatment also caused increased urinary Ca++ excretion in control rats (from 2.12 +/- 0.64 mumol/mg creatinine per day [pretreatment] to 16.86 +/- 2.07 mumol/mg creatinine per day; P less than 0.001) but not in PTX rats. Control rats ingesting chow containing a standard Ca++ content (1.2%) resembled PTX rats. These results indicate that PTH stimulation exacerbates gentamicin nephrotoxicity. Increased peak renal cortical gentamicin concentrations in PTH-stimulated rats may be caused by increased gentamicin transport across the brush border as a consequence of PTH-mediated alteration of plasma membrane phospholipid composition, turnover, or both.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of parathyroid hormone on gentamicin plasma membrane binding and tissue accumulation.

Reportedly, the initiating event in the renal uptake of gentamicin is its binding to anionic, plasma membrane phospholipids. Because parathyroid hormone is known to affect phospholipid metabolism, the plasma membrane binding and tissue accumulation of gentamicin were examined as a function of the parathyroid hormone status of the animal. The experiments were conducted by evaluating the parameters in isolated brush border and basolateral membranes from control, hyper- and hypoparathyroid rats. Scatchard analysis revealed that [125I]gentamicin bound with equal affinity to either membrane to a single class of noninteracting sites. The basolateral membrane had more binding sites than did the brush border, 28 +/- 0.5 vs. 1.8 +/- 0.3 nmol/mg of protein, respectively. Neither the affinity constants nor the number of binding sites were affected by the parathyroid hormone status of the donor animal. On the other hand, in the hypoparathyroid state the amount and the rate of gentamicin accumulation were less than in the hyperparathyroid state. The difference in accumulation cannot be explained on the basis of a change in the number or affinity of the putative receptor. Therefore, the alteration must reflect some difference subsequent to the binding site.

Sulfamethoxazole-trimethoprim synergism for Neisseria gonorrhoeae.

Sulfamethoxazole and trimethoprim are synergistic against many bacteria in sulfamethoxazole/trimethoprim concentrations of 20:1, but single-dose therapy of gonorrhea with the combination is disappointing. We used agar dilution techniques to determine minimal inhibitory concentrations of sulfamethoxazole and trimethoprim for 168 gonococci isolated from men with acute urethritis in Atlanta, Ga. The geometric mean minimal inhibitory concentrations were 5.6 microgram of sulfamethoxazole per ml and 24.3 microgram of trimethoprim per ml, a ratio of 1:4. The concentration of sulfamethoxazole inhibiting 50% of gonococcal strains dropped only from 4.7 microgram/ml to 2.9 microgram/ml with the addition of a 1/20 dilution of trimethoprim. We studied synergism with various ratios of sulfamethoxazole to trimethoprim against 20 random strains. A ratio of 1:1 was always synergistic and was the most synergistic ratio for 15 strains, whereas the 19:1 ratio was never the most syngergistic. The 19:1 ratio failed to show synergism against seven strains, but showed antagonism at this ratio with five of these seven. The sulfamethoxazole/trimethoprim ratio of 19:1 usually achieved in serum after oral administration is minimally syngergistic and is sometimes antagonistic for gonococci.

Comparative nephrotoxicity of dibekacin and gentamicin in rats.

To evaluate the nephrotoxicity of the new aminoglycoside, dibekacin, relative to gentamicin, we administered both drugs in doses of 40 and 120 mg/kg per day to male and female Fischer 344 rats. At sacrifice, we determined serum creatinine, in vitro renal cortical uptake of 14C N-methyl nicotinamide and para-aminohippurate, renal cortical antibiotic concentrations, and real histology. Dibekacin and gentamicin were similar in overall toxicity. Dibekacin differed from gentamicin and other aminoglycosides (1) in failing to cause early transient stimulation of para-aminohippurate uptake in male rats and (2) in the location of histologic damage at the 120 mg/kg dose. We conclude that: 1) in this model, dibekacin is comparable to gentamicin in nephrotoxic potential, and 2) the lack of early stimulation of para-aminohippurate uptake in male rates after dibekacin treatment may be related to greater initial injury to the late proximal tubule than is caused by gentamicin.