Mabel L. Purkerson

Lovastatin Ameliorates the Development of Glomerulosclerosis and Uremia in Experimental Nephrotic Syndrome

The nephrotic syndrome was induced in uninephrectomized Sprague-Dawley rats using repeated injections of puromycin and protamine sulfate. Preliminary studies demonstrated that the administration of lovastatin (4 mg/kg body weight [BW] subcutaneously [SC] daily) was effective at lowering plasma cholesterol over a 63-day period, although not to normal values. Subsequently, two groups of rats that had been made nephrotic were studied; one group (n = 8) received lovastatin, the other (n = 9) received the vehicle alone. Blood and urine collections were made at days 0, 23, and 60. Clearance studies and renal histology were obtained at day 60. Lovastatin-treated rats had significantly lower cholesterol at day 23 and 60 than vehicle-treated rats (270.5 +/- 39.7 v 501.7 +/- 81.9 and 148.2 +/- 10.7 v 268.2 +/- 40.8 mg/dL, P less than 0.05). Both groups of rats developed equivalent degrees of proteinuria and hypoalbuminemia. At day 60, the lovastatin-treated rats had a lower urea: 18.3 +/- 4.1 v 55.8 +/- 9.6 mmol/L (blood urea nitrogen [BUN] 51.2 +/- 111.5 v 156.2 +/- 27.0 mg/dL, P less than 0.02) and greater unulin clearance (1.83 +/- 0.42 v 0.82 +/- 0.41 mL/min/kg BW, P less than 0.05) than the vehicle-treated rats. Neither group was hypertensive and the blood pressure (BP) was similar in both groups. The percentage of glomeruli showing no changes or minimal histological changes was significantly greater in the lovastatin-treated group (26.5% +/- 5.7% v 8.33% +/- 3.33%, P less than 0.02), and there were more glomeruli with global sclerosis in the vehicle-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of Reduced Glomerular Filtration Rate in Chronic Malnutrition

To determine the physiological basis for the low glomerular filtration rate in chronic malnutrition, micropuncture studies were performed in Munich-Wistar rats chronically pair-fed isocaloric diets of either low (group 1, nine rats) or high protein content (group 2, nine rats). Despite the absence of hypoalbuminemia, average values for single nephron and total kidney glomerular filtration rate were nearly 35% lower in group 1 than in group 2. Mean values for glomerular capillary and Bowmans space hydraulic pressures were essentially identical in the two groups, thereby excluding glomerular transcapillary hydraulic pressure difference as the cause for the low filtration rates in group 1 animals. On the other hand, average glomerular capillary plasma flow rate and glomerular capillary ultrafiltration coefficient were significantly lower (by approximately 25 and approximately 50%, respectively) in group 1 than in group 2. The fall in glomerular capillary plasma flow rate was the consequence of increased afferent and efferent arteriolar resistances. Plasma and erythrocyte volumes were found to be equal in five additional pairs of group 1 and group 2 rats. Thus, the substantial alterations in the ultrafiltration coefficient, glomerular capillary plasma flow rate, and renal arteriolar resistances responsible for the low filtration rate in group 1 animals were not merely a consequence of decreased circulating blood or plasma volumes. Mean values for glomerular cross sectional area were significantly lower in group 1 than in group 2 despite similar values for kidney weight in the two groups. This reduction in glomerular cross sectional area in group 1 rats is presumed to reflect a decrease in effective filtration surface area and therefore likely accounts, at least in part, for the decline in ultrafiltration coefficient observed in this group.Finally, since the daily caloric intake of group 2 animals was restricted because of pair feeding requirements tied to the group 1 rats, we studied a third group of seven rats (group 3) allowed an ad lib. intake of the same high protein diet as given to group 2 rats. Average values for single nephron glomerular filtration rate and its determinants were found to be indistinguishable between groups 2 and 3. These results suggest that low protein intake, rather than calorie deficiency per se, is primarily responsible for the reduction in filtration rate seen in this experimental model of chronic malnutrition.

Effects of obstruction on renal functions

Following ureteral obstruction there is a progressive fall in glomerular filtration rate (GFR) due to a reduction in single nephron glomerular filtration rate (SNGFR) and a reduced number of filtering nephrons. Renal plasma flow also declines after a transient, prostaglandin-dependent increase, due to afferent and efferent arteriolar vasoconstriction. The vasoactive hormones thromboxane A2 and angiotensin II are implicated in the pathogenesis of the vasoconstriction following ureteral obstruction and they also reduce the glomerular ultrafiltration coefficient by causing mesangial contraction. Ureteral obstruction also leads to profound changes in renal tubular cell function. These include altered sodium and water handling resulting in a post-obstructive diuresis and natriuresis and a failure to dilute or concentrate the urine. Potassium and divalent cation exchange is also affected, as is urinary acidification. Furthermore, the response of the tubule to hormones such as antidiuretic hormone and parathyroid hormone is impaired. The pathophysiology of these alterations in renal function is discussed.

On the influence of extracellular fluid volume expansion and of uremia on bicarbonate reabsorption in man

The patterns of bicarbonate reabsorption during increasing plasma concentrations were studied in subjects with a range of glomerular filtration rates (GFR) from 170 to 2 ml/min. In a group of five subjects with GFR values above 30 ml/min, paired bicarbonate titration studies were performed first under conditions which minimized extracellular fluid (ECF) volume expansion, and second under conditions which were conducive to exaggerated expansion of ECF volume. In patients with GFR values below 30 ml/min, a single protocol was employed. Studies also were performed on two patients with far advanced renal disease who were nephrotic and exhibited a sodium-retaining state. When ECF volume expansion was minimized in the nonuremic subjects, values for bicarbonate reabsorption were well in excess of the usually accepted Tm level and over the range of plasma bicarbonate concentrations employed, no evidence of a Tm phenomenon was observed. A similar pattern emerged in the two nephrotic patients despite the presence of uremia. However, with both exaggerated expansion of ECF volume (GFR greater than 30) and in patients with advanced renal disease in the absence of exaggerated ECF volume expansion a tendency towards saturation kinetics for bicarbonate reabsorption was demonstrable. In comparing the minimized with the exaggerated expansion studies, evidence emerged for a decrease in both bicarbonate reabsorption per unit of GFR and the absolute rate of bicarbonate reabsorption. When ECF volume expansion was exaggerated in uremic patients after stable rates of bicarbonate reabsorption had been achieved, a decrease in reabsorption per unit of GFR and in absolute bicarbonate reabsorption occurred. The possible relationship of the factors controlling sodium excretion to the observed patterns of bicarbonate reabsorption is considered in the text.

The Pathophysiology of Obstructive Nephropathy: The Role of Vasoactive Compounds in the Hemodynamic and Structural Abnormalities of the Obstructed Kidney

Vasoactive compounds such as angiotensin II, thromboxane A2, nitric oxide, and eicosanoids have a role in the hemodynamic and structural abnormalities that occur following obstruction of the urinary tract. Inhibition of angiotensin II and thromboxane synthesis increases glomerular filtration rate and renal plasma flow significantly in the postobstructed kidney. Angiotensin II also appears to mediate tubular interstitial fibrosis in the obstructed kidney. Indeed, use of angiotensin-converting enzyme inhibitors decreases the degree of interstitial fibrosis and the increased deposition of collagen seen in rats with prolonged ureteral obstruction.

Lactate metabolism: Studies of a child with a serious congenital deviation

After a short summary of experiences with sodium lactate in the treatment of metabolic acidosis over a 30 year period, we present clinical and metabolic findings in a child born with a serious defect in the metabolism of lactate. The consequences were a constant threat of severe and perhaps fatal acidosis and tetany-like episodes leading to severe respiratory obstruction on the basis of bronchiolar muscle spasm and sometimes laryngeal spasm which would superimpose severe respiratory acidosis on an already severe metabolic acidosis. It is our opinion that no such case has previously been described.

Renal function and metabolism after relief of unilateral ureteral obstruction.

Renal handling of electrolytes and water may be altered following the relief of obstructive uropathy with increased excretion of salt and water. Mechanisms proposed to explain this increased salt and water excretion include retention of solutes (1), production of a natriuretic material during obstruction (2), and expansion of the extracellular fluid volume (3). In addition, it has been postulated that structural damage to the kidney may also play a role in the altered handling of electrolytes and water (2). Recent observations demonstrating increased fractional excretion of salt and water following release of unilateral ureteral obstruction in experimental animals (4) indicated that structural damage or some other intrinsic change within the kidney may be responsible for the altered electrolyte and water handling. The presence of a contralateral normal kidney during the period of obstruction would prevent extracellular fluid volume expansion and solute retention during the period of obstruction, and thus exclude these as major factors in the altered excretory pattern of electrolytes and water. It has been suggested that structural alterations such as flattening of proximal tubular microvilli (5) will decrease the total luminal surface area of the epithelial cells which makes contact with the tubular fluid and thereby decrease tubular reabsorption (2). Of interest is the fact that certain histochemical alterations are observed following obstruction. Alkaline phosphatase has been found to be greatly reduced (6, 7) while glucose-6-phosphate dehydrogenase and 6-phosphogluconic dehydrogenase activities were increased in the proximal tubules of obstructed kidneys (8). Following release of obstruction the activity of these enzymes remained elevated during the initial 48 hr and returned to normal 6 days postobstruction. Decreases in Na-K ATPase activity also have been described following obstruction of 48-72 hr duration (9). Despite these observations, little attention has been paid to the possible role of renal metabolic alterations in the handling of electrolytes and water following relief of obstruction.

Investigation of Single Nephrons in the Chronically Diseased (Pyelonephritic) Kidney of the Rat Using Micropuncture Techniques

Unilateral pyelonephritis was induced in the rat and micropunture techniques were used to assess nephron function in individual nephrons from chronically diseased and normal kidneys in the same animal

Protein Intake Conditions the Diuresis Seen after Relief of Bilateral Ureteral Obstruction in the Rat

Abstract Natriuresis and diuresis occur in experimental animals after release of bilateral ureteral obstruction. Accumulation of urea and/or other natriuretic factors during the interval of complete obstruction may play a role in the ensuing postobstructive diuresis. The present experiments examine the potential role of dietary protein intake in conditioning the magnitude of the postobstructive diuresis after unilateral release of bilateral ureteral obstruction of 24-hr duration in the rat. Rats were fed isocaloric diets containing high (40% casein) or low (6% casein) protein for 4 weeks prior to obstruction. Rats fed a high protein diet had greater urine flows and fractional excretion of sodium and potassium after relief of obstruction than rats fed a low protein diet. Increased excretion of urea accounted for only part of the greater diuresis seen in rats fed a high protein diet. Hence, greater accumulation of other natriuretic factors during the period of obstruction in rats fed a high protein diet must play a role in the increased diuresis seen in this group of animals after release of obstruction.

A History of Eclampsia, Toxemia and the Kidney in Pregnancy

Eclampsia, accompanied by convulsions, is one of the most dangerous complications of pregnant women. This condition was known to the ancient Greeks, who named it eclampsia. Prior to the 18th century, the term eclampsia was used only to refer to the visual phenomena which accompanied the neurologic aspects of the malady. Rayer’s landmark contribution (1839–1841) provided evidence for renal involvement with the observation of protein in the urine of pregnant, edematous women. Lever (1843) reported finding proteinuria in eclampsia and concluded that disappearance of proteinuria after delivery of the child was evidence that eclampsia was different from Bright’s disease.