K. Solez

Effects of indomethacin on renal inner medullary plasma flow

Abstract The effects of the prostaglandin system on renal hemodynamics were studied by treating rats with a single intraperitoneal dose of indomethacin, an inhibitor of prostaglandin synthesis. Medullary plasma flow was significantly reduced 30–45 minutes after indomethacin, but was elevated 3–6 hours after indomethacin. These changes in medullary plasma flow correlated well with circulating levels of prostaglandins A and E. Total renal blood flow decreased following indomethacin treatment, but returned to normal levels within an hour. These results indicate that the inhibition of prostaglandin synthesis following a single intraperitoneal dose of indomethacin is short-lived and is followed by a significant elevation in prostaglandin synthesis. It is likely that prostaglandin levels play an important role in the control of renal medullary plasma flow.

Central nervous system toxicity of cyclosporine in a rat model.

The central nervous system toxicity of cyclosporine, which is known to be neurotoxic clinically, was investigated in a rat model. Munich-Wistar rats were divided into 3 groups for a 2-week protocol. After baseline EEG and behavioral testing, group 1 (control) received a weight-adjusted volume of parenteral cyclosporine vehicle i.p., group 2 (low-dose) received 5 or 10 mg/kg/day i.p., and group 3 (high-dose) received 20 mg/kg/day i.p. Spontaneous behavior was observed, simple sensorimotor testing performed daily, and awake EEGs recorded 3 times per week. Four of 12 high-dose animals died during study, one after a witnessed tonic-clonic seizure, and two after recording of frankly epileptiform EEGs; there were no deaths in control or low-dose animals. Significant EEG abnormalities developed only at high-dose, with frankly epileptiform EEGs and/or seizures seen in 58 +/- 15% of these rats (P = 0.005, different from controls by life-table analysis). Although some high-dose animals demonstrated hyperirritability and dystonic posturing, behavioral changes were subtle, and animals were often still or rocking slightly during recording of frankly epileptiform EEGs. Walking latency and alley escape behaviors were delayed in high-dose rats, the latter correlating with abnormal EEGs. Serum urea nitrogens were mildly elevated in high-dose animals, but serum creatinine, electrolytes, bilirubin, body magnesium stores, and blood pressure remained normal in all groups. Kidneys showed only mild vacuolation histologically. The brain showed only very focal cortical injury sites related to electrode placement, which did not correlate with EEG changes or mortality. These results suggest that there may be a direct effect of cyclosporine on the central nervous system. This model system should prove useful in defining mechanisms of cyclosporine-related neurotoxicity.

MONOCLONAL CHARACTERISTICS OF ORGANISING ARTERIAL THROMBI: SIGNIFICANCE IN THE ORIGIN AND GROWTH OF HUMAN ATHEROSCLEROTIC PLAQUES

The clonal characteristics of 26 arterial thrombi at different stages of organisation were determined using the X-linked enzyme, glucose-6-phosphate dehydrogenase (G.-6-P.D.), as a clonal marker in 13 women heterozygous for electrophoretically separable G.-6-P.D. isoenzymes. A gradation of increasing monoclonality was observed with increasing organisation of the thrombi, such that only 21% of poorly organised (red) thrombi displayed monoclonal characteristics similar to those of atherosclerotic plaques, whereas 78% of moderately organised (pink) thrombi and 91% of well-organised (white) thrombi showed such characteristics. These results provide objective evidence for the role of thrombosis in the formation of human atherosclerotic plaques.

Early renal pathophysiology in an acute model of cyclosporine nephrotoxicity in rats.

We have recently described a rat model of acute cyclosporine nephrotoxicity characterized by rapid onset of reproducible mild to moderate renal failure. In the present studies, we have examined early pathophysiologic events and morphologic changes in this model. Following acute intraperitoneal administration of 60 mg/kg of parenteral cyclosporine, renal blood flow (RBF) fell 24% from baseline. Intraperitoneal administration of an oral cyclosporine preparation (60 mg/kg) also reduced RBF (25%), as did administration of an equivalent volume of parenteral cremophore (23%). Renal vascular resistance (RVR) increased significantly in all these groups. In contrast, intraperitoneal administration of mineral oil or olive oil oral vehicle produced no significant change in RBF (4% fall from baseline), and RVR actually decreased in these control animals. Following 2 daily doses of these agents, RBF remained significantly lower in rats given parenteral cyclosporine (5.10 mL/min vs 8.54 mL/min in cremophore rats and 7.28 mL/min in oil control rats) and renal vascular resistance remained high. Systemic blood pressure was also significantly lower in cyclosporine-treated rats at 2 days, and GFR was depressed. Morphologic studies revealed a correlation at 2 days between tubular vacuolation and renal blood flow and renal vascular resistance in cyclosporine-treated rats.

Renal blood flow, glomerular filtration rate, and renal morphology in cyclosporine-induced acute renal failure in Munich-Wistar rats

The mechanism of clinical cyclosporine nephrotoxicity has remained unclear. We have established an animal model of cyclosporine-induced acute renal failure in the male Munich-Wistar rat by giving four daily doses of parenteral cyclosporine 60 mg/kg intraperitoneally (IP). In this model, 20 minutes of bilateral renal ischemia preceding the first cyclosporine dose did not significantly increase the renal failure, but did increase mortality (65% v 17%), which was due in part to the CNS effect of cyclosporine. Pair-fed and pair-watered vehicle and saline controls were used. The renal morphologic changes induced by the castor oil vehicle of the commercial parenteral cyclosporine solution were quantitatively similar to those induced by cyclosporine, although the severity of the changes by light microscopy was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum were also seen in other groups. Renal blood flow determined by electromagnetic flow probe showed a significant decline during 2 hours after a single IP injection of cyclosporine (6.6 +/- 0.4 to 5.0 +/- 0.6 mL/min). A similar decline was seen following injection of the castor oil vehicle of the commercial cyclosporine parenteral preparation (6.6 +/- 0.5 to 5.1 +/- 0.5 mL/min), but not after an injection of a similar volume of mineral oil (6.7 +/- 0.3 to 6.3 +/- 0.2 mL/min). These studies suggest that brief renal ischemia does not increase cyclosporine nephrotoxicity significantly in this rat model.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective Inhibition of Thromboxane Synthesis in Glycerol-Induced Acute Renal Failure

It has recently been postulated that thromboxane A2 may participate in the pathogenesis of acute myohemoglobinuric experimental acute renal failure. To investigate this further, the effect of selective inhibition of thromboxane synthesis on the course of glycerol-induced acute renal failure was determined. Despite significant inhibition of thromboxane synthesis by 4-imidazole-yl-acetophenone, the functional and morphologic disturbance induced by glycerol was unaltered. Moreover, pretreatment with 4-imidazole-yl-acetophenone failed to prevent the fall in renal blood flow seen following glycerol administration. These results argue against a major role for thromboxane A2 in the pathogenesis of this form of experimental acute renal failure.

The Anatomy of the Renal Circulation

There is no organ with a blood vascular system more complex than that of the mammalian kidney. To draw an analogy with electrical circuits, the renal vasculature represents an intricate system of constantly varying resistances, arranged in series and parallel, which control the flow of energy required for the many homeostatic roles the kidney must play. Morphologic studies demonstrate the many different routes which blood may take in its passages through the kidney. Such studies cannot capture the dynamic nature of the renal circulation but are important nonetheless in delineating the anatomic substrate upon which functional and disease-related alterations in vessel structure and caliber take place.

Renal Morphology and Function and Urine Electrolytes in Experimental Acute Renal Failure Produced by Cyclosporine and Ischemia

It has been difficult to produce a good animal model for cyclosporine nephrotoxicity. It has been suggested that by following 20 minutes of renal ischemia with four daily doses of cyclosporine 60 mg/kg intraperitoneally, one can create a model of reproducible renal failure. We observed excessive mortality (65%), due in part to cyclosporines CNS effects, with these combined insults in the Munich Wistar rat. In contrast, cyclosporine alone in this dosage produced only 17% mortality and resulted in a similar degree of renal failure. Pair-fed and pair-watered vehicle and saline controls were used. The morphologic changes brought about by the castor oil vehicle of the parenteral cyclosporine solution were qualitatively similar to those brought about by cyclosporine by light microscopy, although the severity of the changes was considerably less in the vehicle-treated groups. However, by electron microscopy, pale lipid vacuoles were seen only in the cyclosporine-treated groups, whereas dense alterations in lysosomes and dilated endoplasmic reticulum also were seen in other groups. Urine sodium determined by flame photometry and urine chloride determined by Saltex reagent strips tended to be high in the initiation phase of cyclosporine-induced acute renal failure and low in the maintenance phase. In animals that developed acute renal failure following the combination of ischemia and cyclosporine, the initial urine sodium and chloride were significantly correlated with the eventual degree of renal failure. The use of Saltex urine chloride sticks in clinical urine samples showed that the readings correlated well with urine sodium and chloride determined by conventional methods, suggesting that these strips may be useful in making a quick diagnosis in the setting of acute renal failure.

The Renal Circulation: Physiology and Hormonal Control

Although much attention has been paid to the immunologic aspects of kidney disease (Germuth and Rodriguez, 1973; McCluskey, 1974; Wilson and Dixon, 1974), it is clear that many of the more common afflictions have a predominantly circulatory rather than an immunologic basis. Vascular abnormalities and altered renal perfusion play a key role in the renal disorders associated with arteriosclerosis, hypertension, shock, liver disease, sepsis, trauma, diabetes, and the toxic effects of certain drugs (Barger, 1966; Siper-stein et al., 1968; Hollenberg, 1973; Hollenberg and Adams, 1974). Disturbed renal hemodynamics are pathogenetically important even in disorders of undisputed immunologic origin, such as renal transplant rejection (Hollenberg et al., 1972).