We measured glomerular filtration rate (GFR) estimated by plasma disappearance of 99mTc-labeled diethylenetriaminepentaacetic acid, serum concentrations of thyroxine (T4), creatinine, and urea nitrogen, and urine specific gravity in 13 cats with naturally acquired hyperthyroidism before and 30 days after treatment by bilateral thyroidectomy, and in a group of 11 control cats. Mean (+/- SD) serum T4 concentration decreased from a pretreatment value of 120.46 (+/- 39.21) nmol/L to a posttreatment value of 12.15 (+/- 6.26) nmol/L (P < 0.0001; reference range, 10 to 48 nmol/L). Treatment of hyperthyroidism resulted in a decrease in mean (+/- SD) glomerular filtration rate, from 2.51 (+/- 0.69) ml/kg of body weight/min to a posttreatment value of 1.40 (+/- 0.41) ml/kg/min (P < 0.0001). Mean serum creatinine concentration increased from 1.26 (+/- 0.34) mg/dl to 2.05 (+/- 0.60) mg/dl (P < 0.01). Mean serum urea nitrogen concentration increased from 26.62 (+/- 6.83) mg/dl to a mean postthyroidectomy concentration of 34.92 (+/- 8.95) mg/dl (P < 0.01). All changes were significant. Two cats developed overt renal azotemia after treatment of hyperthyroidism. Our results provide further evidence that treatment of hyperthyroidism can result in impaired renal function. In addition, our results suggest that, in some instances, thyrotoxicosis might mask underlying chronic renal insufficiency.

Effective renal plasma flow (ERPF) was evaluated, using the measurement of p-aminohippurate clearance (CLPAH) and quantitative renal scintigraphy (QRS) with 99mTc-mercaptoacetyltriglycine (99mTc-MAG3). The CLPAH and QRS determinations were made in 6 dogs: 2 determinations for each dog before, and 1 determination after induction of renal failure by administration of amphotericin B. Least-squares regression analysis was used to derive an equation to estimate ERPF from QRS data. The results indicated that QRS, using 99mTc-MAG3, correlated reasonably well (r = 0.82, P < 0.001) with ERPF determined from the CLPAH value. The right kidney contributed 53.3% of global ERPF (P = 0.002). Hepatobiliary excretion of 99mTc-MAG3 was variable within each dog. There was not a consistent pattern with respect to time or renal function. All dogs had nausea or emesis, or both, after IV administration of 99mTc-MAG3. The QRS method with 99mTc-MAG3 provides an adequate means to estimate ERPF in healthy dogs and dogs with renal failure.

Thirty-one clinically normal Cocker Spaniels, Miniature Schnauzers, and Doberman Pinschers (28 female, 3 male) 7 to 8 years old were uninephrectomized (month -2) to increase the risk of renal damage associated with reduction of renal mass. Two diets, differing principally in protein concentration, were used to test the hypothesis that high dietary protein intake causes renal damage in aging dogs. For 2 months after uninephrectomy, all dogs were fed diet A (18% protein). After glomerular filtration rate (GFR) was measured (month 0), 16 dogs were assigned to group A and were fed diet A for an additional 48 months. The other 15 dogs were assigned to group B, and were fed diet B (34% protein) for the subsequent 48 months. At 6-month intervals, GFR and urine protein-to-creatinine ratio (UP/C) were determined. At 48 months, terminal studies were done, survivors were euthanatized, and tissues were examined. Of 16 dogs in group A, 10 survived, compared with 13 of 15 in group B. Among survivors, a significant difference in GFR was not found between groups A and B, and decrease in GFR was not evident with time in either group. At 48 months, oral administration of casein caused minor acute effects on GFR and renal plasma flow in dogs of groups A and B. The UP/C values increased significantly (P = 0.001) from baseline values, but the increase was not progressive. The UP/C values were not affected by diet. Some dogs in both groups developed UP/C > 1.0. Morphologic studies performed on kidneys removed at -2 months (nephrectomy) and at 48 months (necropsy) revealed increased kidney weight in both groups at month 48, compared with month -2 (P = 0.003); at month 48, kidney weight change was significantly (P = 0.004) greater in group-B than in group-A dogs. Increased glomerular area at month 48, compared with month -2, was significantly (P= 0.000) related to time, but not to diet. Significant (P = 0.000) increase in glomerular mesangial matrix, interstitial fibrosis (P = 0.001), cell infiltration (P = 0.000), and lesions of the renal pelvis (P = 0.04) was observed between month -2 and month 48. Time, representing combined effects of uninephrectomy and aging, was the major factor responsible for the morphologic changes. Diet effects were significance (P = 0.008) for cell infiltration, but did not reach significance for mesangial matrix accumulation, fibrosis, or pelvic lesions. Kidney mineral analysis revealed no renal mineralization in either group between -2 and 48 months. Results indicated that GFR did not decrease with time during the geriatric period studied, but severity of renal lesions was increased. Effects of time and uninephrectomy, although not separable, were more important than those of dietary protein intake on progression of renal lesions.

We determined whether administration of cisplatin in hypertonic saline solution would prevent significant decrease in renal function, as measured by exogenous creatinine clearance, in healthy dogs. A single dose of cisplatin (70 mg/m2 of body surface) was mixed in 3% saline solution and was infused IV (6.5 ml/kg of body weight) over a 20-minute period to 6 healthy dogs. Exogenous creatinine clearance was determined prior to treatment of dogs with cisplatin and again on days 3 and 21 after administration of cisplatin. All 6 dogs vomited at least once within 12 hours of treatment with cisplatin; however, clinically important changes in appetite, body weight, or hydration status were not apparent during the 21-day study. Although mean values for exogenous creatinine clearance decreased from baseline on days 3 and 21, changes were not significantly different. Renal histologic lesions included mild, chronic, lymphoplasmacytic interstitial nephritis in 5 dogs, and presumably, were unrelated to treatment with cisplatin. Mild renal tubular atrophy (n = 2) and tubular necrosis (n = 1) may have developed secondary to treatment with cisplatin. Results of this study indicated that administration of a single dose of cisplatin in 3% saline solution to healthy dogs was not associated with significant decrease in glomerular filtration rate. This is a convenient protocol for administering cisplatin; however, additional study is required before it can be recommended for clinical patients, especially those with preexisting renal disease or those receiving multiple doses of cisplatin.

Pharmacokinetic variables of phenolsulfonphthalein (PSP) were determined in sheep after rapid IV injection and IV infusion to steady state. In Suffolk wethers, an average of < 75% of an IV administered dose was eliminated in urine, indicating that measures of systemic clearance overestimate renal clearance in this species. Furthermore, PSP elimination from plasma was more rapid in Suffolk than Rambouillet wethers and, in Suffolk ewes, systemic clearance decreased from mean +/- SD 7.8 +/- 0.3 ml/min/kg of body weight to 4.7 +/- 1.1 ml/min/kg at steady-state plasma concentration of 2.4 +/- 0.3 and 151.3 +/- 31.8 micrograms/ml, respectively. These observations indicate that, similar to that in other species, systemic clearance of PSP in sheep is concentration-dependent and that significant differences may exist between breeds.

To investigate the determinants of glomerular ultrafiltration, renal micropuncture studies were performed in 9 cats. Mean single nephron glomerular filtration rate (SNGFR), directly measured in outer cortical nephrons, was 29.4 +/- 3.0 nl/min. This was similar to the estimated value for SNGFR (31.3 +/- 4.6 nl/min) obtained by dividing left kidney total glomerular filtration rate (1.41 +/- 0.12 ml/min/kg of body weight) by left glomerular count (175,200 +/- 13,600 glomeruli/kidney). In micropuncture studies performed at mean renal perfusion pressure of 101.3 +/-1.0 mm of Hg, the glomerular capillary hydrostatic pressure was 58.0 +/- 1.4 mm of Hg. The glomerular transcapillary hydrostatic pressure gradient (40.0 +/- 1.8 mm of Hg) exceeded colloid osmotic pressure at the efferent end of the glomerular capillaries (28.4 +/- 2.1 mm of Hg) in all cats studied, indicating existence of positive effective filtration pressure throughout the glomerular capillary bed. These results indicate that glomerular capillary pressure is sufficiently high to prevent forces from reaching filtration pressure equilibrium in feline outer cortical nephrons. Thus, the value of SNGFR in feline nephrons depends on the glomerular transcapillary hydrostatic pressure gradient and the glomerular ultrafiltration coefficient.

It has been established that L-gamma-glutamylated derivatives of alpha-amino acids are delivered more efficiently to the kidneys than are the parent alpha-amino acids. Therefore, we synthesized L-gamma-glutamyl-S-(1,2-dichlorovinyl)-L-cysteine (L-gamma-glutamyl-L-DCVC), the simplest L-gamma-glutamylated derivative of the nephrotoxic alpha-amino acid S-(1,2-dichlorovinyl)-L-cysteine (L-DCVC), and investigated its effects on renal function and ultrastructure in pentobarbital-anesthetized dogs. Intravenous doses of 23.15 and 92.60 micromoles of L-gamma-glutamyl-L-DCVC/kg of body weight induced significant increases in urinary protein output and significant decreases in the clearance of inulin during the 6-hour post-injection period. Changes were not observed in any of the other 13 renal function variables or in the 11 plasma and blood variables that were monitored throughout the same period. Both doses of L-gamma-glutamyl-L-DCVC induced renal ultrastructural lesions in the S1 and S2 cells of the canine proximal tubule; the remaining 8 cell types downstream and the glomeruli were not damaged. The onset and magnitude of renal function changes and the cell types affected by L-gamma-glutamyl-L-DCVC were virtually identical to those observed previously following IV administration of equivalent doses of L-DCVC to pentobarbital-anesthetized dogs. Rapid removal of the L-gamma-glutamyl group from L-gamma-glutamyl-L-DCVC (ie, deglutamylation) resulting in formation of the parent alpha-amino acid, L-DCVC, can best explain the extreme similarity in the nephrotoxic profiles of these 2 toxicants.

The respiratory, renal, hematologic, and serum biochemical effects of hypertonic saline solution (HSS) treatment were examined in 12 endotoxic, pentobarbital-anesthetized calves (8 to 20 days old). Escherichia coli endotoxin (055:B5) was infused IV at a rate of 0.1 microgram/kg of body weight over 30 minutes. Endotoxin induced severe respiratory effects, with marked hypoxemia and increases in arterial-alveolar O2 gradient (P[A-a]O2), physiologic shunt fraction (Qs/Qt), and physiologic dead space to tidal volume ratio (Vd/Vt). Oxygen consumption was decreased, despite an increase in the systemic O2 extraction ratio. Peak effects were observed at the end of endotoxin infusion. The renal response to endotoxemia was characterized by a decrease in free-water reabsorption and osmotic clearance, as well as a decrease in sodium and phosphorus excretion. Endotoxemia induced leukopenia, thrombocytopenia, hyperphosphatemia, hypoglycemia, acidemia, and increased serum alkaline phosphatase concentrations. Calves were treated with HSS (2,400 mosm/L of NaCl, 4 ml/kg, n = 4) or an equivalent sodium load of isotonic saline solution (ISS; 300 mosm/L of NaCl, 32 ml/kg, n = 4) 90 minutes after the end of endotoxin administration. Both solutions were infused over a 4- to 6-minute period. A control group (n = 4) was not treated. Infusion of HSS or ISS failed to induce a significant change in PaO2, P(A-a)O2, (Qs/Qt), (Vd/Vt), or oxygen consumption. Both solutions increased systemic oxygen delivery to above preendotoxin values. Hypertonic saline infusion induced significant (P < 0.05) increases in serum Na and Cl concentrations and osmolality, whereas ISS induced a significant increase in serum Cl concentration and a significant decrease in serum phosphorus concentration. Both HSS and ISS reversed the endotoxin-induced changes in renal function, with increases in free water reabsorption and osmotic clearance, as well as increases in sodium and phosphorus excretion. Sodium retention was greater following HSS administration. On the basis of these findings, hypertonic saline solutions can be rapidly and safely administered to endotoxic calves.