November 1979

The J o u r n a l o f P E D I A T R I C S

787

Postnatal development of renal sodium handling in premature infants

To estimate the contribution o f the specific defect in proximal and distal tubular reabsorption of sodium to renal salt wasting, fractional sodium excretion, distal tubular sodium delivery, and distal tubular sodium reabsorption were determined in 11 healthy premature infants. The study was performed on the seventh day and at weekly intervals thereafter up to the sixth week o f life. Sodium clearance and fractional sodium excretion decreased significantly with increasing postnatal age (P < O.001). There was no significant alteration in either osmolar or free-water clearances. Distal tubular sodium delivery steadily decreased from 4.96 +_ 0.66 (mean +_SE) in the first week to 3.3 +_ 0.41 ml/minute/dl GFR in the sixth week o f life (P < 0.05). Distal tubular sodium reabsorption was 69.5 +_ 2.36% in the first week, then rose significantly to reach a value of 83.7 + 1.85% in the second week (P < 0.001) and remained practically unchanged thereafter. It is suggested that the rapid improvement of distal tubular sodium reabsorption in premature infants might result from forced stimulation by the excessively activated renin-angiotensin-aldosterone system.

E. Sulyok,* F. Varga, E. Gy6ry, K. Jobst, and I. F. Csaba, P b c s , H u n g a r y

BECAUSE OF increased urinary sodium excretion, negative sodium balance with subsequent hyponatremia develops within a few weeks of birth in about one-third of low-birth-weight premature infants. 1-5 The reason for the renal salt loss is not apparent. Because of the high activity of the renin-angiotensin-aldosterone system during the period of hyponatremia,3' 6.7 the possible role of hypoaldosteronism can be excluded. However, distal tubular unresponsiveness to aldosterone~' 9 or a proximal tubular defect in sodium reabsorption or both should be considered. It has also been suggested that the increased urinary sodium loss during the first week of life may reflect the isotonic contraction of the extracellular fluid compartment and the disposal of extracellular fluid solute through the kidney. 16 In a study using clearance techniques, we attempted to delineate the specific tubular defect of sodium reabsorption in one-week-old healthy premature and term neonates. We could demonstrate that the higher fractional sodium excretion in premature infants was due to the *Reprint address: Department of Obstetrics and Gynecology, University of Pbcs, 7624 Pbcs, Hungary.

0022-3476/79/110787+06500.60/0 9 1979 The C. V. Mosby Co.

inability of the distal tubule to cope with the increased sodium load resulting from decreased proximal tubular reabsorption of sodium. The mean distal tubular sodium delivery and the mean distal tubular sodium reabsorption in premature infants was 4 m l / m i n u t e / d l GFR and 69.9% as compared to the values of 2 ml/minute/dl GFR (P < 0.05) and 85.8% (P < 0.01), respectively, in term newborn infants. 11 Abbreviations used C: clearance GFR: glomular filtration rate RAAS: renin-angiotensin-aldosterone system The present longitudinal study was undertaken to. investigate the postnatal changes in proximal and distal tubular reabsorption of sodium in a group of healthy premature infants during the first six weeks of life.

MATERIAL AND METHODS Eleven healthy male premature infants with mean birth weight of 1,670 gm (range: 1,140 to 2,120 gin) and mean gestational age of 31.7 weeks (range: 27 to 35 weeks) were selected for study. The birth weight of all infants was

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Sulyok et al.

The Journal of Pediatrics November 1979

Table I. Clinical data a n d p l a s m a and urine values in p r e m a t u r e infants d u r i n g the first six weeks of life

Clinical data

Plasma

Urine

Body Age (wk)

weight (gm)

1

1,594

2

1,735

3

1,866

4

1,982

5-6

2,120

Fluid intake (ml/kg/day) Mean n SE • Mean n SE• Mean

184 11 3,36 199.6 1l 8,19 208.3

n

9

SE• Mean n SE_+ Mean

6.11 223.0 8 8.27 224.7

n

SE•

Sodium (mEq/l)

Osmolality (mOsm/kg)

136.64" ll 1.26 134.18 11 1.28 135.44

293.64t 1l 6,36 290.91 11 7.53 290.00

9

1.08 133.62 8 1.05 130.89"

9

6.51 286.25 8 6.83 266.67~

9

9

9

7.53

2.24

6.77

Volume (ml/min/ 1.73 m ~)

Sodium excretion (l~E/min/ 1.73 m ~)

Osmolalitv (mOsm/kg)

1.08"~ 11 0,13 1.17 11 0,12 1.32 9 0.15 1.67~ 8 0.16 1.44 9 0.22

30.21:~ 11 4.94 17.33t 11 3.47 14.775 9 2.08 19.05 8 4.62 11.40 9 1.79

159.09" 11 8.00 135.91 11 10.59 159,44 9 27.83 152.62 8 13.44 132.79" 9 6.61

*P < 0.05. "~P< 0.025. SP < 0.01. consistent with their gestational age. T h e infants were delivered vaginally a n d h a d A p g a r scores of 7 or m o r e at one m i n u t e o f age. M a t e r n a l history did n o t reveal toxemia, hypertension, or renal disease in any p a t i e n t s studied. T h e i m m e d i a t e n e o n a t a l period was u n e v e n t f u l a n d all infants r e m a i n e d well during the p e r i o d o f study. Clinically a p p a r e n t e d e m a or i n a p p r o p r i a t e weight gain suggesting e d e m a was not observed. Breast milk was fed to all infants a n d 5% glucose in water was a d d e d to provide a m e a n daily fluid intake o f 184 m l / k g o n the s e v e n t h day. Later it was gradually increased to attain a rate o f 200 m l / k g , 210 m l / k g , a n d 220 m l / k g by the second, third, a n d fourth weeks, respectively. The infants were kept in incubators w i t h o u t r a d i a n t heater. T h e studies were carried out o n the seventh day o f life a n d at weekly intervals thereafter up to the sixth week of life. F o r m e a s u r e m e n t s o f sodium, osmolality, and creatinine in plasma, blood was t a k e n from a scalp vein. U r i n e was fractionally collected for a period of 24 hours. Plasma a n d u r i n a r y sodium c o n c e n t r a t i o n was m e a s u r e d b y flame p h o t o m e t r y . Osmolality in p l a s m a a n d u r i n e was d e t e r m i n e d cryoscopically uging a K n a u e r o s m o m e t e r ? ~ U r i n e a n d p l a s m a creatinine concentrations were d e t e r m i n e d according to the m e t h o d of Jaffe with some modificationsJ ~ I n f o r m e d p a r e n t a l consent was o b t a i n e d for blood s a m p l i n g a n d urine collection.

Calculations. Creatinine (Cc~), s o d i u m (Cx~), and osmolar (Co~m) clearances were calculated f r o m the standard clearance formula. F r e e - w a t e r clearance (CH~o) was calculated from the formula: CH2o = V - Cosm,

where V = urine flow in m l / m i n u t e / 1 . 7 3 m ~. Distal sodium delivery was estimated as the sum o f s o d i u m and free water clearances: CNa .~. Ci120,14, 15

Distal tubular sod{urn reabsorption was according to the following formulaTM 1(s.

CH2o C,2o + C~a

assessed

x 100.

Fractional s o d i u m excretion (C~JCo,,) was d e t e r m i n e d by the following calculations: Cx~/Cc~ -

U~a x V x 100 Px~ • Co,,

where Ux~ = N a c o n c e n t r a t i o n in urine, V = u r i n e flow in m l / m i n u t e / l . 7 3 m2; Px, = N a c o n c e n t r a t i o n in plasma; a n d Ccr = creatinine clearance. Creatinine clearance was expressed per 1.73 m ~ body

Volume 95 Number 5, part 1

R e n a l sodium handling in p r e m a t u r e infants

789

Table II. Postnatal changes in creatinine, sodium, osmolar and flee-water clearances as well as in fractional sodium excretion, distal tubular sodium delivery and distal tubular sodium reabsorption in premature infants during the first six weeks o f life

ell, C~r Age (wk)

1

2

3

4

5-6

Cx~

ml/min/ 1.73 m e

Mean n • SE Mean n + SE Mean n • SE Mean n • SE Mean n • SE

16.31" 11 2.15 15.20 11 2.14 18.65 9 1.64 22.33* 8 2.38 25.17 9 1.99

Costa

CH2o

Cx~ + C.._,o

Cx,/C,.~

%

m l / m i n / d l GFR

1.565 11 0.28 0.93 11 0.23 0.57~ 9t 0.07 0.66 8 0.18 0.37I 9 0,06

3.98 11 0.56 3.79 11 0.80 3.87 9 0.78 4.17 8 0.63 2.89 9 0.37

x lOO

c._.,, + c.,,,

3.40 11 0.44 4.79 11 1.30 3.75 9 0.73 3.65 8 0.48 2.97 9 0.40

4.96* 11 0.66 5.70 11 0.81 4.25 9 0.74 4.31 8 0.42 3.33* 9 0.41

1.55.2 11 0.28 0.93 11 0.23 0.57~ 9 0.08 0.66 8 0.18 0.36 .9 0.06

69.53~: 11 2.36 83.71 11 1.85 79.48 8 6.90 84.96 8 4.64 88.36 9 2.93

*P < 0.05. tP < 0.025. 1:P < 0.01.

surface area as calculated from height and weight using the Du Bois and Du Bois nomogram. Cxa, C ..... and C.2o were provided as m l / m i n u t e / d l G F R to compare tubular functions in infants with different creatinine clearances. Statistical analysis was performed using the Student t test. RESULTS Sequential changes in body weight, fluid intake, plasma and urinary sodium concentration, osmolality, and urine volume are summarized in Table I. Plasma sodium concentration and osmolality decreased steadily at a similar rate, and reached their lowest values by 5 to 6 weeks of life. Because of the increasing fluid intake, urine volume increased until the fourth week and the urine remained hypotonic during the whole period of study. The urinary sodium excretion was highest in the first week, decreased significantly in the next two weeks, and remained at about the same levels thereafter. The results of clearance studies and those derived from these data are given in Table II. Creatinine clearance gradually increased after the second week, and sodium clearance as expressed per deciliter G F R markedly decreased with advancing postnatal age. There was no significant alteration in either osmolar or free-water clearances. As indicated by the steady decline in percent

fractional sodium excretion, renal tubular sodium reabsorption significantly improved as infants grew older. The sum of free-water and sodium clearances, which is believed to represent sodium delivery to the distal tubule, significantly decreased with age, particularly after the second week, suggesting a continuous improvement in defective proximal tubular sodium reabsorption with increasing postnatal age (Figure A). The fractional sodium reabsorption in the distal tubule, assessed by the formula C.~o/CH~o + C • 100, was 69.5% in the first week, then rose significantly (P < 0.001) to reach a value of 83.7%, characteristic of term neonates already by the end of the second week of life. Later, an inconsistent rise without statistical significance was seen (Fig. lb). DISCUSSION After discovery of the characteristic pattern of postnatal development of plasma sodium concentrations in lowbirth-weight premature infants, ~ increasing attention has been given to define the pathogenetic factors. Recent studies indicated severe impairment of the renal tubular sodium reabsorptive mechanism, by demonstrating an h:tcreased rate of urinary sodium excretion, in particular the high fractional sodium excretion, in young premature infantsY- 3. ~. 1o. ~3.17-2o

790

Sulyok et al.

The Journal of Pediatrics November 1979

CH20,CNamllmin/100mlGFR 6.0 50

L.,0

4-

3,0

4

I

5-6

weeks

/-,

5-6

wee~

2,O I

1,0' 1

2

3 postne~l ~ j e

CH~ x 100 CH,20"CNaI00% 90"

-]8070. 60

| 1

2

3

postnetot age Figure. A, Postnatal changes in distal tubular sodium delivery and B, distal tubular sodium reabsorption in premature infants during the first 6 weeks of life. The fact that the increased urinary sodium loss and hyponatremia were accompanied by limited renal potassium excretion and hyperkalemia ~ :,-5 seemed to suggest an important role of the RAAS. However, the activity of RAAS is elevated in the immediate neonatal period? .... Moreover, plasma renin activity,~ pli~sma aldosterone concentration, ~ and urinary aldosterone excretiona" ~ of premature infants have been reported to increase further during the second and third weeks of life, when the late hyponatremia appears. On the basis of these findings, it seemed relevant to assume that the renal salt wasting in premature infants might be ascribed either to renal tubular unresponsiveness to aldosterone or to massive proximal natriuresis exceeding the reabsorptive capacity of the distal nephron. In the present study we used clearance:~methods to differentiate between proximal and distal sodium reabsorption, and an attempt was made to .d,etermine their developmental pattern during a period of six weeks. Our experimental design, however, was different from those applied by others "-'~'2o because we did not administer an

oral water load plus hypotonic saline infusion to induce free-water diuresis and to inhibit antidiuretic hormone activity. Instead, a relatively high daily oral fluid intake was provided, exceeding the usual fluid intake for premature infants of similar weight and age by about 40 ml/kg/day, In this wa~ adequate urine flow and hypotonic urine could be e-~ured, which together with marked plasma hypotonicity suggested minimal antidiuretic hormone activity, The importance of high urine flow in estimating tubular sodium transport is stressed by the observations by Stein et al 1~on dogs. During hypotonic saline loading the rise in urine flow was associated initially with a progressive increase i~ C~; o until urine flow reached the value of 20 to 25% of GFR. Late in the diuresis, Cu2o tended to stabilize at the maximal level of 15% of the filtered load in spite of further increments in urine flow. These findings indicate that the maximal rate of distal sodium transport can only be attained at urine flow greater than 20% of G F R ? ~ Similarly, a direct relationship was found between C~o and urine volume in a group of healthy premature infants

Volume 95 Number 5, part 1

with mean birth weight and mean gestational age of !,126 gm and 30 weeks, respectively, at study age of 3 to 16 days. However, the maximal rate for C.2o could not be established at urine flow under 15 ml/minute dl GFR. 26 In our study the mean urine flow was about 7 ml/ minute/dl GFR and remained relatively stable during the whole period of observation. This value was certainly lower than that necessary for ensuring transport maximum; however, its constancy allowed us to assess the changes occurring in renal tubular sodium transport. With these considerations in mind, our results on the rate of renal tubular sodium transport shotild be intei'preted with caution because direct comparison with other findings might be misleading by underestimating sodium supply to the distal nephron. Nevertheless, the results presented herein can be regarded as indicating that significant improvement occurs in both proximal and distal tubular sodiumreabsorption as the postnatal age of premature infants advances. The development of these two renal tubular functions does not progress together. Sodium reahsorption in the proximal tubule, as approximated by a decrease in the sum of sodium and free-water clearances, gradually increased during the whole period of study. On the Other hand, there was a rapid rise in fractional distal tubular reabsorption of sodium from the end of the first to the second week, and it remained practically Unchanged thereafter. This latter finding may have resulted from forced stimulation by the excessively activated RAAS. In support of this possibility we could demonstrate that the activity of RAAS is closely related to urinary sodium excretion in one-week-old neonates27 and the postnatal development of the function of RAAS in healthy premature infants was also found to be related to the changes taking place in sodium balance. Thus, plasma renin activity, plasma aldosterone concentration, and urinary aldosterone excretion were already high as 18.2 _+ 4.1 ng/ml/hour, 1.7 _+ 0.5 ng/ml and 2.6 _+ 0.4 /~g/day, respectively, in the first week. Subsequently, all these values increased tremendously and reached their peak values of 78.6 _+ 18.1 n g / m l / h o u r (plasma renin activity), 6.8 _+ 3.7 n g / m l (plasma aldosterone concentrations) and 26.4 _+ 2.9/~g/day (urinary aldosterone excretion) by the end of the third week, when the increased urinary sodium excretion and negative sodium balance resulted in late hyponatremia. 7 Our observations suggest that the renal salt wasting found in low-birth-weight neonates during the first few weeks of life is due to deficient proximal and distal tubular reabsorption of sodium. The rapid improvement of these functions results in decreasing fractional sodium excretion and in restoration of positive sodium balance.

Renal sodium handling in premature infants

79 1

REFERENCES

1. Day GM, Radde IC, Bafle JW, and Chance GW: Electrolyte abnormalities in very low birthweight infants, Pediatr Res 10:522, 1976. 2. Engelke SC, Shah BL, Vasan U, and Raye JR: Sodium balance in very low-birth-weight infants, J P~DIATR93:83% 1978. 3. Honoui"JW, Valman HB, and Shackleton CHL: Aldostetone and sodium homeostasis in preterm infants, Acta Pediatr Scand 66:103, 1977. 4. Roy RN, Chance GW, Radde IC, Hill DE, Willis DM, and Sheepers J: Late hyponatremia in very low birthweight infants (< 1.3 kilograms), Pediatr Res 10:526, 1976. 5. Sulyok E: The relationship between electrolyte and acidbase balance in the premature infant during early postnatal life, Biol Neonate 17:227, 1971. 6. Richer C, Hornich H, Amiel-Tison C, Relier J-P and Giudicelli J-P: Plasma renin activity and its postnatal development in preterm infants. Preliminary report, Biol Neonate 31:301, !977. 7. SulyokE, N6meth M, T6nyi!, Csaba IF, GyOryE, Ertl T, and Varga F: Postnatal development of renin-angiotensinaldosterone system (RAAS) in relation to electrolyte balance in prematur e infants, Pediatr Res (In press). 8. Greenberg AJ, McNamara H, and McCrory WW: Renal tubular response to aldosterone in normal infants and children with adrenal disorders, J Clin Endocrinol Metab 27:1197, 1967. 9. Solc J, and Knorr D: Die Wirkung von Aldosteron und Spir01acton auf die Ausscheidung von Natrium und Kalium im Ham bei Neugeborenen und Sfiuglingen,Z Kinderheilk 116:143, 1974. 10. Ross B, Cowett RM, and Oh, W.: Renal functions of low-birth-weight infants during the first two months of life, Pediatr Res 11:1162, 1977, J 1. SulyokE, Varga F, Gy6ry E, Jobst K, and Csaba IF: On the mechanism of renal sodium handling in the newborn infants, Biol Neonate (accepted for publication). 12. Aperia A, BrobergerO, Thodenius K, and ZetterstrOm R: Developmental study of the renal response to an oral salt load in preterm infants. Acta Paediatr Scand 63:517, 1974. 13. Heinegard D, and TiderstrOm G: Determination of serum creatinine by a direct colorimetric method, Clin Chim Acta 43!305, 1973. 14. SteinRM, Abramson RG, Bercovitch DD, and Levitt MF: Effect of Unilateral renal arterial constriction on tubular reabsorption of sodium and water during an osmotic diuresis, J Clin Invest 44:1720, 1965. 15. SteinRM, Abramson RG, Kahn 1, and Levitt MF: Effect of hypotonic saline loading in hydrated dog: evidence for a saline-induced limit on distal tubular sodium transport, J Ciin Invest 46:1205, 1967. 16. Kaloyanides GJ; Cacciagvida NCP, and Porush JG: Increased sodium reabsorption in the proximal and distal tubule of caval dogs, J Clin Invest 48:1543, 1969. 17. Arant BS: Developmental patterns of renal functional maturation compared in the human neonate, J PEDIATR 92:705, 1978. 18. Kerpel-Fronius E, Helm T, and Sulyok E: The development of the renal acidifying processes and their relation to acidosis in low-birth-weight infants, Biol Neonate 15:156, 1970.

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19. Siegel SR, and Oh W: Renal function as a marker of human fetal maturatiofi,, Acta Paediatr Scand 65:481, 1976. 20. Sulyok E, Heim T, Solthsz G, and J/tszai V: The influerice of maturity on renal control of acidosis in newborn infants, Biol Neonate 21:418, 1972. 21. Hayduk K, Krause DK, Huengers R, and Unbehaun V: Plasma renin concentration at delivery and during the newborn period in humans, Experimentia 28:1489, 1972. 22. Katz PH, Beck P, and Makowski EL: The renin-aldosterone system in motlier and fetus at term, Am J Obstet Gynecol 118:51, 1974. 23. Kotchen TA, Strickland AL, Rice TW, and Walters DR: A study of the renin-angiotensin system in newborn infants, J PEDIATk 80:938, 1972.

The Jourhal of Pediatrics November 1979

24.

Chaimovitz C, Levi J, Better C, Oslander L, and Benderli A: StU,d!es on the site .of.renal salt loss in a patient with Bartter's syhdrome, Pediatr Res 7:89, 1973. 25, Rodrigtiez-Soriano J, Vallo A, and Garcia-Fuentes Mi Distal renal tubular acidosis in infancy: A bicarbonate wasting state, J. PEbIATR 86:524, 1975. 26. Leake RD, zakauddin-S, Trygstad CV, Fu P, and Oh W: The effects of large volume intravenous fluid infusion on neonatal renal function, J PEDtATR89:968, 1976. 27. Sulyok E, N6meth M, T6riyi I, Csaba IF. Varga F, Gy6ry E, and Thurz6 V: Relationship between maturity, electrolyte balance and the function of the renin-angiotensin-aldosterone system in newborn infants, Biol Neonate 35:60, 1979.

Postnatal development of renal sodium handling in premature infants.

November 1979 The J o u r n a l o f P E D I A T R I C S 787 Postnatal development of renal sodium handling in premature infants To estimate the co...
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