Vacuolization Of Renal Tubular Cells Research Articles

Lethal hypothermia in an animal model, not associated with basal renal epithelial vacuolization

A rodent model was used to evaluate the association between hypothermia and basal vacuolization in renal tubular epithelial cells. 28 Sprague Dawley rats were anaesthetized in non-stressful conditions and placed two at a time into a cooling chamber. Body core temperatures dropped to a minimum of 7–10 °C, causing death under anaesthesia at times varying from 120 to 240 min. The animals were then subjected to necropsy; the kidneys were removed and placed in 10% buffered formalin. Examination of haematoxylin and eosin-stained renal sections failed to reveal basal vacuolization of renal tubular epithelial cells in any of the 28 animals. In this model, no evidence of subnuclear lipid vacuolization of renal tubular cells could be demonstrated despite significant and eventually lethal hypothermia. These results lend support to the hypothesis that the basal vacuolization in hypothermia may be a manifestation of a more complex pathophysiological pathway rather than being due simply to low body core temperatures.

Wischnewski spots and hypothermia: sensitive, specific, or serendipitous?

Hypothermia develops when regulatory mechanisms suchas vasoconstriction and heat production fail to compensatefor heat loss to the environment and the core temperature ofthe body falls below 35 C. Severe cases may be fatal withdeath resulting from myocardial ischemia and/or hypoxia,exacerbated by electrolyte abnormalities and elevated cat-echolamine levels. The mortality rate exceeds 70 % whenthe core temperature drops to 30 C, and reaches 90 % at26 C[1, 2].Causes of hypothermia include accidental exposure tolow environmental temperatures, either outdoors or inside,the latter occurring from inadequately heated houses. It hasbeen shown that hypothermic deaths may occur in areaswhere the external temperatures are not markedly lowered.Exacerbating factors include damp conditions, inadequateor wet clothing and air movement [3]. Individual suscep-tibility is increased by the ingestion of alcohol and certainprescribed or illicit drugs. In addition, low muscle mass,immobility, trauma, open injuries, and certain cardiovas-cular, neurological, endocrine and psychiatric disordersincrease the risk. An age-related susceptibility is alsofound, with children and the elderly being the most vul-nerable [1].The pathological diagnosis of hypothermia may be dif-ficult, as body temperatures at the time of death are usuallynot available at autopsy and so the circumstances of deathare of considerable importance in formulating the diagno-sis. In addition, morphological features are subtle and notwell understood. Characteristic findings that have beendescribed at autopsy include pinkish discoloration of theskin over the extensor surfaces of large joints, such as theelbows, knees and hips, acute pancreatic inflammation withfat necrosis, fatty change in cells of the heart, liver andkidneys, skeletal muscle hemorrhage, vacuolization ofrenal tubular cells, and superficial gastric lesions that havebeen called Wischnewski spots [1, 2, 4–7]. It is the latterfinding that we would like to examine in greater detail.In 1895 a Russian district medical officer, SM Wisch-newski, reported multiple superficial hemorrhagic lesionsof the gastric mucosa in 91 % of the cases of fatal hypo-thermia that he had examined. A contemporary translationof his original paper states: ‘‘On the mucous membrane ofthe stomach in humans who have died exclusively from theeffects of low temperatures, 5–100 hemorrhages areinvariably present. Their size ranges from 0.5 to 1.0 cm.They have a round to oval form. Sometimes they arepunctiform and lie about 1–2 inches apart. These hemor-rhages are raised slightly above the surface of the mucousmembrane, can be very easily scrapped (sic) away andleave behind nothing conspicuous on the gastric mucosa.’’[8] (Fig. 1). They have also been documented in ectopi-cally situated gastric mucosa [9].Although Wischnewski described raised hemorrhagicareas that could be easily removed from the mucosa, theywere subsequently considered to be ulcers or erosions[3, 10, 11]. In an immunohistochemical study by Tsokoset al. however it was proposed that the lesions resultedfrom the action of gastric acid on hemoglobin in areas ofinterstitial mucosal hemorrhage, and not from ulceration[7]. A photomicrograph in a chapter by Madea et al. [2](Fig. 1.4B) clearly demonstrates protrusion of one of thespots above the surface of the surrounding mucosa, and notulceration. Conversely, Hirvonen and Elfving reportedthat the erosions extended ‘‘halfway through the mucosa’’and that hemorrhage was ‘‘not always present’’ [12].

Diagnosis of fulminant type 1 diabetes mellitus in an autopsy case with postmortem changes

A Japanese female in her thirties was found dead in her apartment; the postmortem interval was estimated to be approximately 3 days. Several postmortem changes were evident. Acute gastroenteritis had been diagnosed 3 days earlier. On autopsy, no specific findings other than fatty liver were observed. On hematoxylin eosin staining, mild fibrosis, and invasion of neutrophils in the pancreatic parenchyma, severe fatty liver, and extensive vacuolation of renal tubular cells were observed. Biochemical analyses revealed extremely high β-hydroxybutyrate concentrations in body fluids with moderate elevation of hemoglobin A1c. Toxicological analyses of organ and urine samples were negative. We concluded that severe ketoacidosis had occurred in the deceased. Subsequently, selective destruction of pancreatic β-cells was demonstrated. Considered together, results indicated that the cause of death was fulminant type 1 diabetes mellitus. This report illustrates the fact that a combination of biochemical and immunohistochemical investigations can be useful for diagnosing this condition in cases with evident postmortem changes.

General toxicity study of gadobenate dimeglumine formulation (E7155) (3)--4-week repeated dose intravenous toxicity study followed by 4-week recovery period in rats

A 4-week repeated dose toxicity study of gadobenate dimeglumine formulation (E7155) was conducted in Sprague-Dawley rats to assess its non-clinical safety. E7155 was administered intravenously at doses of 0.3, 1.0 and 3.0 mmol/kg/day to male and female rats once a day during 4 weeks. The reversibility of toxicity was evaluated during a 4-week recovery period at 3.0 mmol/kg/day. At 0.3 mmol/kg/day and higher, vacuolation of the cortical epithelium was seen in the kidneys and an increase in the incidence of local damage at the injection sites. In the 1.0 and 3.0 mmol/kg/day male and female groups, scabbing/ulceration of the tail at the injection sites, macroscopic pale/thickened fundic mucosa in the stomachs, vacuolation of the urinary bladder, and mucosal mineralization with epithelial hyperplasia of the glandular stomach were found. In the 1.0 and 3.0 mmol/kg/day male group and 3.0 mmol/kg/day female group, increases of water consumption and urinary potassium excretion, increased kidney weight and enlargement of the kidneys were observed. In the 3.0 mmol/kg/day male and female group, hepatocyte necrosis with inflammatory cells in the liver and epithelial degranulation in the interlobular ducts of the salivary glands were found. In addition, in the 3.0 mmol/kg/day male group, increases in plasma sodium and decreases of urinary sodium and chloride excretion, and degenerative changes in the testes and epididymides were observed. After the 4-week recovery period, except for an increase in urinary potassium excretion, increased kidney weights and changes in the testes and epididymides, all of the above findings had complete or partial recovery. Vacuolation of renal tubular cells was common, expected, and known as an adaptive change of treatment with hypertonic solutions, and an increase in the incidence of local damage at the injection sites was due to irritation by repeated intravenous dosing with hypertonic solutions. Therefore, these changes were not toxic changes. In conclusion, the dose level of 0.3 mmol/kg/day should be regarded as the No Observed Adverse Effect Level (NOAEL) after repeated administration of E7155 in rats.

Islet Transplantation to the Renal Subcapsular Space Improves Late Complications in Streptozotocin-Diabetic Rats

Transplantation of isolated islets is a promising approach in the treatment of diabetes. We have examined the long-term effects on the late complications of islet transplantation in an experimental diabetes model in the rat. Diabetes was induced by streptozotocin (70 mg/kg i.v.) and the rats were treated with either insulin (daily injection of 40 U) or transplantation of 1,000 freshly isolated, hand-picked, islets into the left renal subcapsular space. Both islet transplantation and insulin treatment completely normalized the increased levels of blood glucose, urine volume and water intake that were observed in the diabetic rats. The decreased growth rate of the diabetic rats was almost normalized by both treatment protocols. As for late complications, after 3 months, all untreated diabetic rats had cataract. They also had swelling and vacuolation of renal tubular cells, and, consistent with this, very high levels of urinary beta 2-microglobulin excretion. Both islet transplantation and insulin treatment completely prevented these late complications. Thus, islet transplantation to the renal subcapsular space is in this experimental model as good as insulin treatment in treating the clinical signs of diabetes and in preventing diabetic complications in the eye and kidney.