Sharon R Siegel

Renal function as a marker of human fetal maturation.

Abstract. Sixty clinically well infants of various gestational ages (27 to 40 weeks) were studied from 24–40 hours after birth to evaluate glomerular filtration rate and renal excretion rate of sodium at various stages of fetal maturation. Creatinine clearance was directly related to gestational age (r=0.643). Fractional sodium excretion was inversely related to gestational age (r=‐0.755). The renal functions of small for gestational age infants were similar to those of full‐term infants whose birth weights were appropriate for gestational age. The data showed that the glomerular functions of an infant below 32 weeks of gestation were more predominant than the tubular function resulting in a greater fractional sodium excretion rate and higher urinary Na loss in infants of this gestational age, when compared with the more mature infants.

Ontogeny of the Renin-Angiotensin-Aldosterone System in the Fetal and Newborn Lamb

Summary: Thirteen chronic fetal Iamb preparations between 95 and 142 days of gestation (term 145–150 days), and 10 newborn lambs were studied before and after the acute (1–2 min) infusion of furosemide (2 mg/kg). The baseline to peak plasma renin activity (PRA) response to furosemide increased from A 3.0 ± 1.3 ng/ml/hr (M and SEM) and 95–106 days of gestation to Δ 18.4 ± 4.0 (P < 0.01) at 123–142 days and Δ 33.6 ± 6.5 (P < 0.001) in the newborn. Baseline plasma aldosterone concentrations were similar in the fetus and pregnant ewe; aldosterone levels were higher in the newborn lamb than in the nonpregnant ewe. The newborn plasma aldosterone response to furosemide via the endogenous rennin-angiotensin system was Δ 17.1 ± 4.2 ng/dl (P < 0.01); the fetal lamb plasma aldosterone level did not increase. The results indicate that the renin-angiotensin system cannot be stimulated by furosemide under 106 days of gestation; the response after 110 days increases with gestational age. Aldosterone concentrations in the fetal lamb are probably maintained primarily by the pregnant ewe and do not increase in response to endogenous renin stimulation as in the newborn.Speculation: Fetal renin responsiveness increases with gestational age, while fetal aldosterone secretion is unresponsive to stimulation by the renin-angiotensin system. Therefore, the fetal adrenal cortex is the limiting factor in the pituitary-renal-adrenal axis before term.

Renal function and serum aldosterone levels in infants with respiratory distress syndrome.

Electrolyte and water balance, renal glomerular and tubular functions, and serum aldosterone concentrations were measured in 11 preterm infants with respiratory distress syndrome (RDS) and in 15 preterm infants without RDS. When the respiratory and circulatory status of the infants with RDS was maintained in an adequately stable state (maintaining Pa o 2 at 62±5 mm. Hg, pH at 7.34±0.02, Pa co 2 at 44±3 mm. Hg, and mean arterial blood pressure above 30 mm. Hg), the electrolyte status, water balance, and renal functional status of infants with RDS were similar to values in the normal infants without RDS. Serum aldosterone concentrations in preterm infants with or without RDS were high (122±28 and 81±19 ng. per 100 ml., respectively), precluding an aldosterone insufficiency state in these infants.

Maternal fetal osmolar homeostasis: fetal posterior pituitary autonomy.

Summary: After the infusion of a bolus of 225 mEq NaCl (HS) to maternal ewes, we studied fetal plasma sodium, osmolality, total serum solids, plasma arginine vasopressin (AVP) and plasma renin activity (PRA) responses in 16 chronically catheterized, 112–139 days of gestation fetal lambs.To examine the degree to which this might have represented transplacental passage of AVP, we infused a large amount of synthetic AVP into the fetal circulation (protocol 3) and detected no change in maternal plasma AVP. The protocol was designed to allow multiple, frequent blood sampling not possible by infusing the synthetic AVP into the maternal circulation.In order to compare the fetal AVP response elicited by HS in the maternal ewe and that after direct HS into the newborn lamb and fetus, we calculated stimulus response ratio (SRR) as:Log (AVP)1 - Log (AVP)2, divided by Δosmolality.The SRR of lamb fetuses after maternal HS was significantly greater (0.16 ± 0.02) than that after direct fetal HS (0.04 ± 0.01). In comparison, the newborn lamb has a SRR of 0.02 ± 0.01, and the ewe has a SRR of 0.02 ± 0.01 after HS. These data suggest that after maternal HS infusion, both a volume and, to a lesser extent, an osmolar stimulus for AVP secretion occurs after an induced water flux from the fetal to maternal compartments. Maternal plasma sodium concentration rose promptly from a base line of 146 ± 2.2 (mean ± SEM) to 157 ± 2.8 mEq/liter by 1–20 min where it remained throughout the hour observation period. Fetal plasma sodium concentration rose more slowly from base line of 143 ± 1.8 to 149 ± 1.8 mEq/liter by 1 hr. When 85 mCi22Na was additionally infused with the HS, fetal 22Na constituted only 10% of maternal 22Na counts by the end of 1 hr.During the same period fetal PRA rose from a base line of 12.9 ± 3.8 to 32.0 ± 3.6 ng/ml/hr, while maternal renin remained unchanged. Maternal AVP rose modestly, 11 min after the HS, but promptly returned to base line. There was a rapid and sustained rise by fetal AVP from a base line of 0.7 μU/ml to a peak of 8.2 μU/ml by 22 min post HS.A fetal SRR, Log (AVP)1-Log (AVP)2/Δosmolality after maternal HS was greater than that after direct fetal HS or HS to the ewe or newborn lamb. In an additional experiment, using five chronically catheterized fetuses, 10 million μU AVP injected in the fetal circulation failed to produce an increase in maternal AVP.These results demonstrate that: 1) AVP does not cross the placenta; 2) the fetal sheep neurohypophysis is autonomous and responsive to both direct and indirect (maternal) osmolar stimulation; and 3) the relatively slow rate of maternal to fetal sodium transfer, the augmented SRR after maternal HS, and the elevated fetal PRA and AVP concentration suggest that there is a rapid fetal to maternal flow of water after maternal HS and a combined volume and osmolar stimulus to the fetus.Speculation: Infusions of hypertonic saline in pregnant ewes resulted in rapid increases of fetal plasma sodium due to transfer of water from fetus to mother. A marked rise in fetal renin activity and AVP was also observed. The increase in AVP exceeded that seen in the mother and that produced by infusing hypertonic saline in the fetus. Fetal secretion of AVP is stimulated by hyperosmolality and volume contraction. Elevated AVP may help the fetal kidney retain water and, thereby, minimize hypotonic urine formation and volume depletion.

Transplacental transfer of aldosterone and its effects on renal function in the fetal lamb.

Summary: Seven chronically catheterized fetal lambs between 100 and 130 days gestation (term, 140 to 145 days) and five newborn lambs were infused with d-aldosterone monoacetate, 100 μg/kg bolus, and 100 μg/kg over 60 min. Fetal lamb plasma aldosterone levels increased from a mean and S.E. baseline of 4.5 ± 0.3 μg/dl to >100 μg/dl. Maternal plasma aldosterone concentrations increased from 10.2 ± 0.8 to 26.2 ± 2.4 μg/dl after 15 min (P < 0.05) of the infusion. Amniotic fluid levels increased from 13.3 ± 0.8 to 23.8 ± 2.3 μg/dl (P < 0.05) after 15 min of the infusion. There was no change in plasma renin activity levels in the fetus or pregnant ewe. Urine sodium excretion decreased from 0.87 ± 0.09 to 0.34 total mEq (P < 0.05), and urine potassium increased from 0.25 ± 0.06 to 0.38 ± 0.07 total mEq (P < 0.05) between 60 and 90 min after the start of the infusion in the fetal lamb. There was no change in creatinine clearance or urinary sodium and potassium excretion in the newborn lamb. These data show that aldosterone crosses the placenta during the last trimester in the fetal lamb and can control sodium and potassium transport in the distal renal tubule. Lack of distal tubular responsiveness to aldosterone in the newborn is not due to maturational factors.Speculation: Aldosterone can cross the placenta during the last trimester in the sheep, but the fetal adrenal cannot be stimulated. Sodium balance in the fetus is dependent on sodium balance in the mother.

Effects of Furosemide and Acute Salt Loading on Vasopressin and Renin Secretion in the Fetal Lamb

Summary: Circulating arginine vasopressin (AVP) and plasma renin activity responses to furosemide (2 mg/kg) and acute hypertonic saline (10 mEq/kg) were studied in the fetal lamb from 100 days gestation to term. The baseline to peak plasma AVP response (Δ3.7 ± 1.2 uU/ml) and area under the response curve (209 ± 57 uU/ml/65 min) in the fetal lambs > 123 days were greater than in those <106 days gestation (Δ1.8 ± 1.1 and (171 ± 61, respectively), P <0.02. The plasma renin activity/AVP ratio after furosemide was similar in the two gestational groups.The log plasma AVP responses corrected for rise in plasma osmolality (0.090 ± .01 uU/ml) 30 min after infusion, and the area under the response curve (253 ± 49 uU/ml/30 min) was greater (P < 0.02) in the fetal lambs > 120 days than in those under 115 days gestation (.035 ± 0.01 and 88 ± 29, respectively), P < 0.02. These results confirm that the fetal lamb responds to an osmotic stimulus with increased plasma AVP levels and documents that this response significantly matures during the last trimester of gestation. The fetal lamb also manifests a hypothalamus-posterior pituitary AVP response to furosemide that is proportional to the maturing renal renin response.Speculation: There is a significant maturational plasma arginine vasopressin response to acute hypertonic saline and furosemide in the fetal lamb during the last trimester of gestation.

The Renin-Angiotensin-Aldosterone System in the Newborn Lamb: Response to Furosemide

Summary: Nine newborn lambs between 24 and 48 hr of age were studied before and after infusion of furosemide (2 ing/kg) over 1–2 min. Plasma renin activity (PRA) increased within 8 min after furosemide from a baseline value of 12.6 ± 3.5 ng/ml/hr (mean and SEM) to a level of 24.1 ± 8.6 ng/ml/hr (P < 0.05), and peaked 20 mins after the furosemide infusion at a level of 33.1 ± 8.0 ng/ml/hr. Plasma aldosterone concentration increased from a baseline of 12.2 ± 3.1 to 22.8 ± 9.1 ng/dl 35 min after the furosemide infusion. P < 0.05. There were no changes in plasma sodium or blood hematocrit and minimal changes in blood pressure and plasma protein concentrations during the first 35 min after the furosemide infusion. The results indicate that the renin-angiotensin-aldosterone system responds promptly to furosemide stimulation despite initially high PRA and aldosterone levels.Speculation: The renin-angiotensin-aldosterone system responds promptly to stimulation with furosemide in the newborn lamb, despite initially high PRA and aldosterone concentrations. The high renin and aldosterone concentrations characteristic of the newborn could be due to a relative end organ insensitivity to aldosterone or to a renal glomerulotubular immaturity leading to salt wasting.

The effects of angiotensin II blockade and nephrectomy on the renin-angiotensin-aldosterone system in the newborn lamb.

Summary: Six newborn lambs were studied during continuous infusion of saralasin acetate, 5 μg/kg/min for 135 min; 40 min after beginning saralasin, furosemide (2 mg/kg) was injected over 1–2 min. In addition, six anephric lambs were studied after injection of furosemide. Plasma renin activity (PRA) increased from 23 ± 2.7 ng/ml/hr (M and SE) to 85.8 ± 16.5 (P < 0.05) during infusion of saralasin alone and remained at this level after injection of furosemide. PRA did not increase above base line after injection of furosemide in the anephric lambs. Blood pressure dropped after saralasin infusion in the normal lambs (P < 0.05), and after furosemide injection (P < 0.05) in both groups. Plasma aldosterone concentrations did not increase in response to furosemide in either group. The results suggest that angiotensin II is important in maintaining blood pressure in the newborn and exerts antagonistic effects on the renal renin secretion mechanism.Speculation: The renin-angiotensin-aldosterone system is activated in the normal newborn. Possible reasons for the activation include decreased circumferential tension of small arteries and salt wasting.

Endogenous angiotensin stimulation of vasopressin in the newborn lamb.

The effect of furosemide on plasma renin, vasopressin (AVP), and aldosterone concentrations was studied in 10 control and 6 nephrectomized lambs during the 1st 2 wk of life. In a separate study in 10 newborn lambs, 1-sarcosine-8-alanine-angiotensin II (saralasin acetate, 5 μg/kg per min) was infused alone for 40 min, after which furosemide 2 mg/kg i.v. was injected in association with continuing saralasin acetate infusion. Plasma renin activity increased from a mean (±SEM) of 21.3±3.4 ng/ml per h in the 10 control lambs to 39.4±8.2 ng/ml per h at 8 min (P < 0.001) and remained high through 120 min after furosemide. Plasma AVP and aldosterone concentrations increased from respective mean values of 2.1±0.4 μU/ml and 12.8±2.5 ng/dl to 9.8±2.0 μU/ml (P < 0.01) and 23.0±7.7 ng/dl (P < 0.05) at 35 min and 13.8±2.1 μU/ml and 23.0±4.4 ng/dl at 65 min after furosemide (each P < 0.01). There was an insignificant AVP response in the 10 lambs treated with angiotensin inhibitor: from a mean base line of 4.7±0.9 to 8.3±2.0 μU/ml at 35 min, and 7.4±2.0 μU/ml at 65 min after furosemide. There was no increase in AVP in the anephric lambs. The mean increment AVP response from base line in the newborn lambs without saralasin, Δ 10.8±2.0 μU/ml, was greater than in the lambs with saralasin, Δ4.0±1.9 (P < 0.05), and greater than in the anephric lambs, Δ3.3±2.1 μU/ml (P < 0.05). The mean blood pressure fell 6 mm Hg in the 10 control lambs (P < 0.05), 7 mm Hg in the anephric lambs (P < 0.05), and 16 mm Hg in the lambs treated with angiotensin inhibitor (P < 0.05) by 35 min after furosemide. However, the changes in plasma AVP were not related to the fall in blood pressure. These data support the view that the observed AVP response to furosemide in the newborn lamb was mediated through the renin-angiotensin system.

The Effects of Salt Loading on the Renin- Angiotensin Control of Blood Pressure in the Newborn Lamb

Summary: The renin-angiotensin system control of newborn blood pressure was studied in six sets of twin newborn lambs. The mean aortic blood pressure and plasma renin activity (PRA) was 79.6 ± 0.96 mmHg (mean and S.E.) and 6.88 ± 0.83 ng/ml/h in the chronically salt-loaded lambs (10 mEq/kg/day for 5 days); 86.16 ± 1.8 mmHg (P < 0.001) and 20.48 ± 2.46 ng/ml/h (P < 0.001), respectively in the control lambs. PRA and % change after angiotensin 11 blockade with saralasin was greater in the control lambs, 181.5 ± 6.09 ng/ml/h and 780% than in the chronically salt-loaded lambs, 40 ± 10.47 and 480%, P < 0.001. Blood pressure decreased 10 mmHg only in the control lambs, P < 0.001. An angiotensin 11 dose of 0.25 μg/kg/min increased blood pressure 32 ± 3.1 mmHg in control mambs, and 0.10 μg/kg/min increased blood pressure 32 ± 3.2 mmHg in acutely salt-loaded (10 mEq/kg in 20 ml 5% dextrose/water) lambs. PRA and mean aortic blood pressure decreased in the acutely salt-loaded lambs from 22.3 ± 3.0 ng/ml/h and 86.6 ± 1.0 mmHg to 11.3 ± 1.1 and 76.4 ± 0.8, P < 0.01, respectively. These data show that sodium loading will suppress the basal renin-angiotensin system levels, and mean aortic blood pressure; decrease the hypotensive and PRA responses to saralasin; and increase the pressor responsiveness to angiotensin 11.