David I Goldsmith

The renin angiotensin system in newborn dogs: developmental patterns and response to acute saline loading.

Summary: Plasma renin (PRC) and aldosterone concentrations are known to be high during early postnatal life. Whether this is related to the low rates of renal blood flow or to sodium homeostasis remains unknown. Measurements of PRC, renal blood flow, and its intrarenal distribution were performed in 1- to 3-wk-old puppies subjected to maneuvers known to stimulate or inhibit renin release. In the awake state, PRC was observed to be higher in 2-wk-old puppies than in older or younger dogs, (P < 0.0001). Significant differences in PRC were also found between litters (P < 0.0001), but they did not account for the age-related changes. Anesthesia resulted in a 3- to 5-fold rise in PRC, whereas saline expansion suppressed PRC at all ages, the fall tending to become progressively greater with age (P < 0.09). There was no significant correlation between the age-related changes in PRC and those in renal blood flow or its intrarenal distribution. The results of these experiments demonstrate that in the newborn from a qualitative point of view, PRC changes appropriately in response to various stimuli. However, quantitative age-related differences exist in this regard, reflecting an initial immaturity of the feedback system.Speculation: The lack of correlation between plasma renin concentration and the intrarenal distribution of blood flow, corroborated with the existence of a relationship between plasma renin and the state of the extracellular fluid volume, suggest that during development the renin-angiotensin-aldosterone system is geared toward the maintenance of the positive sodium balance intrinsic to the process of growth.

Ileal segment replacement of ureter I. Effects on kidney of refluxing vs nonrefluxing ileovesical anastomosis

Unilateral partial ureteral obstruction was induced in 32 dogs followed by total ileal replacement of the obstructed ureter. The morphologic and functional effects on the kidney using a freely refluxing versus a nonrefluxing ileovesical anastomosis were compared, as well as the effect of total tapering of the reimplanted ileal segment. The tapered ileovesical anastomosis proved more reliable for prevention of reflux than the nontapered technique. Reflux prevention does not appear necessary for maintaining renal morphology and function when bladder function is normal and the observation period short. Total tapering of the ileal segment did not prove to be advantageous in protecting against hyperchloremic acidosis in this short-term canine study.

The Effect of Captopril on Urinary Protein Excretion in Puromycin Aminonucleoside Nephrosis in Rats

ABSTRACT: We investigated the effect of captopril, an orally active angiotensin converting enzyme inhibitor, on urinary protein excretion in puromycin aminonucleoside nephrotic rats. The administration of captopril (10 mg/100 g body weight) decreased proteinuria on days 10-14 following the administration of puromycin aminonucleoside (73.0 versus 125.0 mg, p < 0.01), without affecting glomerular filtration rate. The beneficial effect of captopril was not abolished by the continuous intravenous infusion of angiotensin II (10 μg/kg/h for 9 days) or subcutaneous injections of aprotinin (50,000 KIU/day for 3 days). Indomethacin, in moderate (5 mg/kg/day for 3 days) or high (10 mg/kg/day) doses, abolished the captopril attenuation in urinary protein excretion. The salutory effect of captopril was characteized by a reduction in the fractional excretion of protein without compromising the glomerular filtration rate. No difference in renal ultrastructure was noted in captopril-treated versus control animals. Captopril was ineffective in reducing urinary protein excretion in rats with adriamycin-induced glomerulopathy. We conclude that captopril acts to reduce proteinuria in renal disease states arising from depletion of the glomerular basement membrane polyanion. The mechanism of action is postulated to be an alteration in renal hemodynamics, namely increased blood flow and a decrease in the ultrafiltration coefficient, that are the consequence of increased intrarenal prostaglandin production.

The relationship between intravascular volume expansion and natriuresis in developing puppies.

Summary: The role played by the relative degree of expansion of the intravascular and extravascular compartments in limiting the natriuretic response of fluid-loaded developing animals was determined in 1-, 2-, 3− and 6-wk-old puppies. Volume expansion was induced by infusing either isotonic saline, 10% body weight or isoncotic albumin in saline 5% body weight, and measurements of glomerular filtration rate, sodium excretion, fractional excretion of sodium, and plasma volume were made. Each expansion procedure resulted in an increase in the absolute excretion of sodium at all ages (P < 0.001). The greatest natriuretic effect was observed in the 3-wk-old puppies, the average of the two solutions being 19, 30, 70, and 28 μEq/min/kg in the 1, 2, 3, and 6-wk-old animals, respectively. The difference in natriuresis among the age groups was due predominantly to differences in the magnitude of the increase in fractional excretion of sodium. At all ages, a greater absolute excretion of sodium was encountered during volume expansion with saline than observed with albumin (P < 0.05). The intravascular volume increased by a similar % at all ages (P > 0.1), and saline and albumin yielded equivalent degrees of intravascular expansion (approximately 50%). The results demonstrate that age-related changes in natriuretic response to volume expansion cannot be attributed to differences in either the degree of expansion or the distribution of the load. In addition, the observations indicate that the mechanism underlying the difference between the response to isotonic saline and isoncotic albumin in saline is already operative at birth, and that it is independent of nephron heterogeneity since the proportion of superficial nephrons must have changed during the period of nephrogenesis.Speculation: The collecting duct, which is sensitive to both isotonic saline and isoncotic albumin, is likely to be responsible for the parallel development of the renal response to these two methods of intravascular volume expansion.

THE ROLE OF ALDOSTERONE IN RENAL ELECTROLYTE TRANSPORT DURING DEVELOPMENT

Indirect evidence has led us to postulate a cause and effect relationship between the high levels of plasma aldosterone concentration (PAC) and the positive electrolyte balance prevailing during infancy. The purpose of this study was to assess directly the relationship between PAC and renal transport of Na+ and K+. PAC measurements and renal clearance of Na+ and K+ were performed in 1 and 6-week-old puppies that received a 5% saline solution, 15 ml/kg b.w. for 3 consecutive days i.p. (E), and in age matched sham operated controls (C). The same variables were then measured during i.v. infusion of increasing amounts of aldosterone (5,10, and 20 μg/kg b.w. for 2 hrs each). In sodium loaded animals, the changes in urinary Na+/K+ ratio were inversely proportional to those in PAC and significantly larger (p < .01) in newborn (from 1.22 ± .32 to 2.38±.60) than in mature dogs (.71 ± .52 to .98 ± .17). The relationship between PAC and Na+/K+ during aldosterone infusion differed between C and E being described respectively by the equations y=1.35-.002x (r=.89) and y=2.25-.005x (r=.94) in the 1-week-old (p<.05), and y=.71-.0002x (r=.99) and y=1.36+.006x (r=.67) in the 6-week-old (p < .05). A direct relationship was observed in each group between PAC and K+ excretion (ΔUKV). However, the slope of the regression line describing the relationship between PAC and ΔUKV was significantly steeper (p <.01) in adults (y=1.32+.02x, r=.73) than in newborn puppies (y=1.04+.003x, r=.64). Thus, the effect of aldosterone on renal Na+ reabsorption is maximal, while the effect on K+ secretion is minimal, during the neonatal period. The resulting retention of both Na+ and K+ is concordant with the needs of the growing organism.

1601 THE EFFECT OF ANGIOTENSIN II (All) ON GLOMERULAR VASCULATURE

There is controversy in the literature regarding the effect of All on various components of the glomerular microcirculation. Experiments were performed on adult male Munich-Wistar rats paired according to weight (n=7 in each group). Following anesthesia, one animal in each pair was given an infusion of All at the rate of 0.5 μg/kg per min for 15-20 min while the other animal was given an identical volume of Ringers lactate only. At the end of the infusion, the kidneys were fixed “in situ” with glutaraldehyde and injected with a silicone rubber compound. Following histological preparation of the tissue, measurements of glomerular tuft, arteriolar, and capillary diameters were performed with a caliper on projections of transparencies. All glomeruli chosen for examination were intact; none of the vessels were sectioned. The values are expressed in μm.The results indicate no significant change in glomerular and capillary diameters, but a significant and similar change (33 and 32%, respectively) in afferent and efferent arteriolar diameters. Thus, All given in the amounts: specified, constricts to a similar extent the afferent and efferent vessels and has no effect on glomerular tuft and capillary diameters.

THE EFFECT OF CHRONIC PARTIAL URETERAL OBSTRUCTION (CPUO) ON RENAL TUBULAR TRANSPORT DURING MATURATION

These studies were designed to determine whether the effect of CPUO on the renal tubule is dependent upon the pattern of transport prevailing at various stages of development. Guinea pigs (n=78) underwent CPUO at birth, 1,2,3 or 4 wks of life and were studied 4 wks later (E). Sham operated littermates served as controls (C). The degree of CPUO, measured by the resistance to a constant flow of fluid, was similar in all groups. TRP averaged 87% in C, was slightly lower in the contralateral kidney (CK) of E (82%) and did not vary with age, whereas it increased with age (p<.05) from 46.6±6.1 to 68.0±6.3% in the affected kidney (AK). FeNa in AK was 7.5±.5 when CPUO was produced at birth and 4.8±1.0 when surgery was done at 4 weeks (p<.05). In C and CK, FeNa was much lower than in AK (p<.001), similar to each other and also decreased with age. UkV (mEq/min/g KW) varied inversely with FeNa in AK. Umax/Posm of C and CK in E were similar (range 4.0-4.3), while the ratio was not different from 1.0 (p>0.9) in AK at all ages. UV (μl/min/100 ml GFR) of the AK was 22.4 ± 3.7 when surgery was performed at birth, 26.7 ± 4.0, when surgery was done at 1 wk, and then decreased rapidly to reach 5.8 ± 1.2 when CPUO was produced at 4 wks (p<.001); no significant differences in UV were observed between C and the CK of E at any age. The results demonstrate an inverse relationship between age at time of CPUO and severity of tubular damage, and suggest the possibility of a major role for the distal nephron in P transport during early life.

1093 NEONATAL NEPHROGENIC DIABETES INSIPIDUS INDUCED BY MATERNAL LITHIUM (Li) CARBONATE USE

There are few reports of transplacental Li intoxication none of which describe renal manifestations, although this is well documented in adults. We studied a 3510 gm male neonate born at 35 weeks gestation to a 38 year old woman who ingested 1.8 gm/day of Li carbonate throughout her pregnancy. Polyhydraminos was noted at delivery. At birth the serum Li concentration was 1.0 mEq/L. By the second day the urinary output exceeded 6.4 ml/kg/hr; polyuria persisted even after serum Li concentration fell to zero at four days of age. CCr was normal (4.8 ml/min). Serum and urinary osmolalities were 294 and 100 mOsm/kg respectively; urea provided 17% of the total urinary solute. At 5 days of age the child was subjected to a vasopressin test (50 mU/kg, I.V.). This resulted in an increase in Uosm from 87 to 156 mOsm/kg and a slight decrease in plasma osmolality from 293 to 287 mOsm/kg; urea accounted for 6.1% of the urinary solute. Cyclic AMP excretion rose from 0.25 before to 0.75 nM/min after vasopressin. A similar response was encountered at one month of age. By 2 months, Uosm rose to 597 mOsm/kg following 6 hours of water deprivation. These data indicate that Li intoxication results in similar but longer lasting effects on the kidney of the newborn than that of the adult. The duration of the concentrating defect may be due to enhanced sensitivity of the newborn tubule to Li or to interference with the development of the renal concentrating mechanisms.

GLOMERULAR CAPILLARY VOLUME AND SURFACE AREA DURING ONTOGENY

The apparent discrepancy between functional glomerulotubular balance and morphologic glomerular preponderance prompted us to develop a new technique to examine if the currently accepted estimates of glomerulor tuft volume (GTV) derived from measurements of diameter bear a constant relationship to glomerular capillary volume (GCV) and capillary surface area (GCA). Kidneys of puppies were fixed in vivo and injected with silastic. GTV was calculated from measurements of the distance between filled capillary loops located at opposite poles. Counts of the neutron activated chromium contained in the silastic served for calculation of GCV. GCA = 2 GCV/r, where r = mean capillary radius. The results are expressed as mean ± SE in mm3·10−5 or mm2 · 10−5 (n=4 in each age group; 50 superficial (S) and 50 iuxtamedullary (J) were measured in each animal).Only the values observed in 6 week old animals are significantly different (p<.05)from the other age groups. in summary, GCV occupies a significantly smaller part of GTV in the newborn than in the 6 week old puppy suggesting that the so called glomerular preponderance might be artifactual.

PAH TRANSPORT IN THE PROXIMAL STRAIGHT TUBULES (PST) OF DEVELOPING RABBITS

PAH secretion in developing rabbits has been shown to increase as a function of age and to be enhanced by pretreatment with penicillin. This may result from increases in tubular mass, transport capacity/mm (TC) or both. Complete (PST) were dissected from 17 rabbits 8-21 days old, and from 8 penicillin pretreated rabbits 10-13 days old. The tubules were measured within an eye piece micrometer, perfused with simulated late proximal tubular fluid, and bathed in rabbit serum containing 2 × 10−4M 3H-PAH. PAH secretion was calculated from the appearance of 3H in the collected fluid. The length (L) of PST increased with age: L (μm) =51.2 × (age in days) - 28.4, r = .84, p<.001. Likewise, TC for PAH increased with age; TC (10−l5 moles/min/mm)= 89.2x -559, r = .59, p<.005. Absolute secretion of PAH/tubule increased 30 fold, 75% of the increment due to TC and 25% to L. Pretreatment with penicillin resulted in a TC of 684±88 (SE) which was 89% greater than the 361 ±84 10−15 moles/min/mm found in age marched controls, p<.02; tubular length was not significantly affected, p>.4. Thus, the bulk of the increase in PAH secretion/tubule with age in rabbits results from enhanced TC; this can be nearly doubled by penicillin pretreatment. Changes in tubular length contribute to the development of PAH secretion but play no role in the phenomenon of substrate stimulation.