Renal function in very low birth weight infants: Normal maturity reached during early childhood

Renal function in very low birth weight infants: Normal maturity reached during early childhood Mireille V a n p ~ e , MD, Mats Blennow, MD, T o m m y Linn6, MD, PhD, Peter Herin, MD, PhD, a n d A n i t a A p e r i a , MD, PhD From the Department of Pediatrics, Karolinska Institute, St. GOran's Children's and Karolinska Hospital, Stockholm, Sweden Development of glomerular and tubular renal function is d e l a y e d in preterm infants. To study the pattern of maturation during infancy and childhood, we ree v a l u a t e d renal function in 22 very low birth weight infants--in 14 of the infants at 18 months postconceptional a g e (9 months corrected a g e ) and in the remaining 8 infants at 8 years of age. The glomerular filtration rate remained lower at 9 months corrected a g e than in term infants of the same postconceptional age: 82 _+ 23 versus 125 _+ 18 ml/min per 1.73 m 2 (p <0.001). At 8 years of a g e the glomerular filtration rate did not differ from that of healthy control subjects. Effective renal plasma flow, filtration fraction, albumin excretion, maximal concentrating abilitY, and kidney size determined by ultrasonography were all normal at 8 years of age. We conclude that renal function, which is markedly red u c e d during the neonatal period in very low birth weight infants, reaches normal maturity by 8 years of a g e but not by 9 months corrected age. (J PEDIATR 1992;121:784-8)

In infants born at term there is a rapid rise in both glomerular and tubular function during the immediate postnatal period, but this abrupt increase is not seen in preterm infants with a gestational age -<34 weeks. 16 In very low birth weight infants with a GA --<30 weeks, a very slow rise in renal function has been observed during the first 2 months of life.7 This difference between preterm and term infants has been considered to be related to immaturity of the kidney at birth and to delayed adaptation to extrauterine life in preterm infants. 1, 5-10 It is not known whether renal function in the preterm infant ultimately reaches full maturity. The aim of this study was to determine whether the slow postnatal development Supported by grants from the Medical Research Council, the First of May Flower Annual Campaign for Children's Health, the Karolinska Institute Research Funds, Clas'Groschinsky's Minnesfond, and S/illskapet Barnavfird. Submitted for publication Feb. 20, 1992; accepted June 17, 1992. Reprint requests: Mireille Vanp~e, MD, St. G6ran's Children's Hospital, S-112 81 Stockholm, Sweden. 9/23/40328

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in renal function in VLBW infants is only another aspect of immaturity with final normalization. METHODS Patients. Twenty-two VLBW infants with a mean G A of 28.2 _+ 1.5 weeks (range, 25 to 30 weeks) were studied at a mean postnatala~e of 21/2 weeks (range, 6 to 37 days). Of the 22 infants, 14 were initially studied in 1988 and 1989 and then reexamined at 18 months postconceptional age, I

GA GFR VLBW

Gestational age Glomerular filtration rate Very low birth weight

I

corresponding to 9 months corrected age (range, 8.2 to 9.2 months). The remaining eight infants were initially studied in 1980 through 1982 and then reexamined at 8 years of age (range, 7.1 to 8.8 years). All infants were found to be appropriate in size for GA as determined from the maternal menstrual history and by examination according to Dubowitz et al. 11 Of the 22 neonates, 6 were moderately asphyxiated at birth (Apgar score,

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~<6 at 5 minutes). At the time of the first study, 1 l infants were being treated with mechanical ventilation and 7 with continuous positive airway pressure. Aminoglycosides (gentamicin, netilmicin, or vancomycin) were given to 14 and theophylline to 6 of the infants. Indomethacin had been given 3 days or more before the time of study to 2 of the infants who had a patent ductus arteriosus. The 14 VLBW infants reexamined at 9 months corrected age were in good health at the time of the second study, except for one infant who had bronchopulmonary dysplasia still requiring supplemental oxygen and neurologic sequelae after an intracranial hemorrhage (grade IV). The infants had achieved an average length and weight of 1.0 SD below the mean. The eight VLBW infants reexamined at 8 years of age were in good health except for one boy who had symptoms of attention deficit disorder. Their length was 0.2 SD below the mean and their weight was at the mean for age. Control subjects. Three control groups were used for comparison: 1. Twenty-five healthy term infants (range, 38 to 40 weeks GA) previously studied in our laboratory were used as the control group for the evaluation of renal function at 2~/2 weeks in the early postnatal period. 1 2. For the VLBW infants studied at 9 months corrected age, 9 term infants (range, 37 to 42 weeks GA) well matched with regard to age (range, 8.2 to 9.5 months) were used as a control group. All the infants had normal Apgar scores at birth and breathed spontaneously without requiring ventilatory support. The infants had been healthy after the neonatal period up to the time of contact for the renal function study. The control subjects were significantly larger than the VLBW infants at 9 months corrected age with regard to both length and weight. 3. A group of 12 healthy children and young adults (range, 2.0 to 25.3 years) were used as control subjects for the VLBW infants studied at 8 years of age. No age-related trend was found in the glomerular filtration rate values. Because GFR, when related to body surface area, has been found to remain unchanged in the healthy individual after 1 to 2 years of age, the young adults are considered to be appropriate control subjects.12, 13 Procedures. In the neonatal period and when the subjects had reached 9 months corrected age, the GFR was estimated from endogenous creatinine values, which at this age has been shown to correlate well with inulin clearance, l, 14 For this purpose, urine was collected for a period of 6 to 8 hours in a plastic bag and emptied with a catheter after each micturition. In the middle of the collection period a capillary blood sample was taken. Urine and serum specimens were analyzed with a creatinine analyzer (Beckman Instruments, Inc., Brea, Calif.) in the period 1980 through 1982,

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and after 1988 by the modified kinetic Jaff6 reaction with a Cobas Mira analyzer (Hoffmann-La Roche & Co. AG, Basel, Switzerland). In four of the nine control infants at 9 months of age, the urine collection was unsuccessful. In these cases the GFR was calculated from the serum creatinine level according to the Schwartz formula: Ccr = K L / Pcr, where K is a constant dependent on muscle mass, L is the length, and Pcr is the plasma creatinine concentration.15, 16 When the study subjects were 8 years of age, GFR was measured as inulin clearance, and effective renal plasma flow as the clearance of para-aminohippuric acid. The studies were performed during water diuresis to allow for urine collection by spontaneous micturition. After a priming dose, a continuous infusion of inulin (Inutest, LaevosanGesellschaft) and para-aminohippuric acid (Merck Sharp & Dohme) was started, t7 Urine was collected during four 30-minute periods and blood samples were drawn in the middle of each period. Diuresis was induced by intake of tap water (20 ml/kg during 60 minutes, followed by 10 ml/kg during the next 60 minutes). A few days later, maximal urine concentrating ability was evaluated after nasal administration of desmopressin acetate (Minirin). The kidneys were examined for size and parenchymal damage by ultrasonography. In VLBW infants, creatinine clearance tends to overestimate GFR at the high range compared with inulin clearance; thus the control values for GFR at 9 months of age, measured as creatinine clearance, were higher than the GFR values found at 8 years of age, measured by inulin clearance. We therefore expressed GFR as the percentage of the control values for the respective age groups. Serum and urine sodium were measured with a flame photometer. Urine osmolality was determined in a Hermann Roebling microosmometer (Roebling Messtechnik, Berlin, Germany). Urinary albumin excretion was analyzed by radioimmunoassay (Pharmacia AB, Uppsala, Sweden) and related to GFR in all groups. The infants' blood pressure was measured by the oscillometric method with a Dinamap apparatus (Critikon, Inc., Tampa, Fla.). The study was approved by the ethical committee of the Karolinska Institute, Stockholm, Sweden. Informed parental consent was obtained in all Cases studied. For statistical evaluation the Student t test was used. Data are given as mean + SD. RESULTS The GFR, measured in milliliters per minute per 1.73 m 2, was significantly lower in the VLBW infants than in the historical control subjects at the average age of 21/2 weeks (Table). The values found in the VLBW infants in our study correspond to the values found in VLBW infants in

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80

E

9..

Fullterm, n=25 previous study {1)

--

VLBW, n=16 previous study (7)

9

VLBW, n = 2 2 present study

60

i--

E

4o

E 9

u_

20

9

00

9

0

0

I

I

I

I

10

20

30

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Postnatal age, days Fig. t. Glomerular filtration rate in 25 term infants ( . . . ) from previous study,1 in 16 VLBW infants _<30 weeks GA (--) from another previous study, 7 and in 22 VLBW infants ( 9 in our study during the first 6 weeks of life.

Table. G l o m e r u l a r filtration rate, effective renal plasma flow (measured as the clearance of p a r a - a m i n o h i p p u r i c acid), filtration fraction, a n d urinary albumin excretion in control subjects and in V L B W infants at the various ages Age 21/2 wk Control GFR (ml/min/1.73 m 2) CpAH (ml/min/1.73 m 2) Filtration fraction (%) Urinary albumin excretion (#g/min/100 ml GFR)

50 + 5 ----

VLBW 16 + 6* --156.0 + 163

A g e 9 mo Control 125 _+ 18 --3.3 • 2.1

VLBW 82 • 23* --5.9 ___5.2"~

A g e 8 yr Control 107 541 20.0 11.1

_+ 10 _+ 43 • 1.8 + 5.5

VLBW 103 535 19.4 5.4

• • + •

127 79"~ 1.7]" 4.5t

Values are expressed as mean _+SD. --, Data not measured; CpAmclearance of para-aminohippuric acid. Significance: *p <0.001 versus control value. tNot significant versus control value. a previous study (Fig. 1). The G F R had increased in the V L B W infants a t 9 m o n t h s corrected age but was still significantly lower t h a n in the corresponding control subjects. In the five control infants in whom the urine collection was successful, the calculated G F R at 9 months of age correlated well with the G F R m e a s u r e d by the creatinine clearance technique (125 _+ 10 vs 132 _+ 13, respectively). T h e difference at this age between the V L B W infants and the control subjects was highly significant irrespective of the values used for comparison (p < 0 . 0 0 I ) . , A t 8 years of age, however, there was no significant difference in G F R between the V L B W infants and the control subjects. T h e development of G F R , represented as the percentage of the control subjects' G F R , is summarized in Fig. 2.

Clearance of p a r a - a m i n o h i p p u r i c acid (in milliliters per m i n u t e per 1.73 m 2) a n d the filtration fraction (as a percentage) were similar in both groups at 8 years of age (Table). U r i n a r y albumin excretion was high in the V L B W infants at 21/2 weeks of age; however, at 9 m o n t h s corrected age and at 8 years of age, values were n o r m a l and similar to the control values. S e r u m creatinine concentration was 71 + 26 # m o l / L (0.8 + 0.29 m g / d l ) in the V L B W infants at 21/2 weeks of age; at 9 m o n t h s corrected age it was significantly higher in the V L B W infants t h a n in the control infants (36 + 12 [0.41 + 0.14] vs 24 _+ 3 [0.27 _+ 0.03]; p <0.005). T h e urinary fractional excretion of sodium was 1.41% _+ 0.67% in the V L B W infants at 21/2 weeks versus 0.02% + 0.10%

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/ / / / / /

/ / / / / /

/ / / / / /

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/ I / i / / i I

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/ / / / / / / /

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0 2.5 weeks

9 months

8 years

Fig. 2. Glomerular filtration rate in VLBW infants at 21/2weeks of age, 9 months corrected age, and 8 years of age, expressed as percentage of control GFR values for the respective ages. Values are mean _+ SD. ***p <0.001. in the control subjects (p <0.001) and had decreased to 0.84% _+ 0.59% versus 0.45% _+ 0.25% (not significant) at 9 months corrected age. The mean arterial blood pressure in the VLBW infants at 21/~ weeks of age was 49 + 11 mm Hg, which is lower than the reference value of 62 _+ 12 mm Hg for 1-week-old, term infants. 18 When the VLBW infant reached 9 months corrected age, mean arterial blood pressure was 79 + 8 versus 69 + 10 mm Hg in control subjects (not significant), and at 8 years of age it was 89 + 6 mm Hg, which is in the normal range for term infants at that age. 19 Maximal urine concentrating ability after nasal administration of synthetic antidiuretic hormone (desmopressin [Minirin]) was normal in all the VLBW infants at 8 years of age (mean, 1069 + 109 mOsm/kg [range, 889 to 1223 mOsm/kg]). Ultrasonography of the upper urinary tract showed normal kidney size in all VLBW infants examined at 8 years of age. The mean kidney length, adjusted to the first to third lumbar vertebrae, was 0.5 SD below the mean (range, - 2 . 0 to +0.2 SD). The parenchyma appeared normal except in one patient who had a minor parenchymal reduction in one of the kidneys. DISCUSSION In the term neonate, birth seems to be a potent stimulus for maturation of renal function.l6 The immature kidney in the preterm infant seems less able to adapt to the demands of extrauterine life; maturational changes occur later and more slowly. Clinical complications such as asphyxia, sepsis, respiratory distress syndrome, and patent ductus arteriosus may further delay the maturational process. 20-22

The GFR was low at birth in the VLBW infants whom we studied and remained lower than control values at 9 months corrected age. It was normal in infants studied at 8 years of age. The delay in renal maturation is most likely due to organ immaturity but could also be explained partly by neonatal clinical problems. Low blood pressure could be a contributing factor for low GFR at 21/2 weeks of age but cannot explain lower GFR at 9 months corrected age. High blood pressure was correlated with low birth weight in a recent study23; further investigations are required to evaluate the effect of blood pressure on renal function in these infants. In healthy infants born at a GA of 30 to 40 weeks, the serum creatinine level is high at birth, reflecting maternal creatinine levels, but declines rapidly to stabilize at about 35 #mol/L (0.4 mg/dl) after the fifth day of life.24 However, it remains higher in preterm infants than in term infants during the neonatal period. 25 We found that the serum creatinine concentration in the VLBW infants at 9 months corrected age was still significantly higher than in the control subjects born at term. Five of these infants had values greater than 40 ~mol/L (0.45 mg/dl), higher than normal for this age group. 26, 27 The slightly but significantly elevated serum creatinine values, despite less muscle mass, are believed to reflect the lower GFR. The high albumin excretion rate at 21/2weeks of age in the VLBW infants could reflect glomerular leakage and reduced tubular reabsorption by immature nephrons. In the VLBW infants, fractional excretion of sodium was high at 21/2weeks of age but not significantly higher than normal at 9 months corrected age. Even if sodium intake had been es-

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timated as similar in t h e groups, studies with carefully controlled sodium intake are needed to d e t e r m i n e whether tub u l a r i m m a t u r i t y remains. W e conclude t h a t t h e markedly reduced glomerular and t u b u l a r renal function observed during the n e o n a t a l period in p r e t e r m infants reaches normal m a t u r i t y by 8 years of age b u t not by 9 m o n t h s corrected age. This delayed renal m a t u r a t i o n d u r i n g the first year of life m i g h t have implications for fluid-and-electrolyte balance in certain clinical situations, and also for drug administration. F u r t h e r investigations are needed to determine the exact age at which renal function reaches n o r m a l maturity. We thank Eivor Zettergren, Mona Agr6n, and Kerstin Gram~n for their invaluable clinical and laboratory assistance. REFERENCES

1. Aperia A, Broberger O, Elinder G, Herin P, Zetterstr6m R. Postnatal development of renal function in pre-term and fullterm infants. Acta Paediatr Scand 1981;70:183-7. 2. Arant B. Developmental patterns of renal functional maturation compared in the human neonate. J PEDIATR 1978;92:70512. 3. Guignard JP, Torrado A, Da Cunha O, Gautier E. Glomerular filtration rate in the first three weeks of life. J PEDIATR 1975;87:268-72. 4. Leake RD, Trygstad CW. Glomerular filtration rate during the period of adaptation to extrauterine life. Pediatr Res 1977;11:959-62. 5. Sertel H, Scopes J. Rates of creatinine clearance in babies less than one week of age. Arch Dis Child 1973;48:717-20. 6. Siegel S, Oh W. Renal function as a marker of human fetal maturation. Acta Paediatr Scand 1976;65:481-5. 7. Vanp~e M, Herin P, Zetterstr6m R, Aperia A. Postnatal development of renal function in very low birthweight infants. Acta Paediatr Scand 1988;77:191-7. 8. Ai-Dahhan J, Haycock GB, Chantler C, Stimmler L. Sodium homeostasis in term and preterm neonates. I. Renal aspects. Arch Dis Child 1983;58:335-42. 9. Rodriguez-Soriano J, Vallo A, Oliveros R, Castillo G. Renal handling of sodium in premature and full-term neonates: a study using clearance methods during water diuresis. Pediatr Res 1983;17:1013-6. 10. Sulyok E, Varga F, Gy6ry E, Jobst K, Csaba IF. Postnatal development of renal sodium handling in premature infants. J PEDIATR 1979;95:787-92. 11. Dubowitz LMS, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J PEDIATR 1970: 77:1-10.

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12. Rubin ME, Bruch E, Rapoport M. Maturation of renal function in childhood: clearance studies, J Clin Invest 1949;28:114462. 13. Aperia A, Broberger O, Thodenius K, Zetterstr6m R. Development of the renal control of salt and fluid homeostasis during the first year of life. Acta Paediatr Scaud 1975;64:393-8. 14. Stonestreet BS, Bell EF, Oh W. Validity of endogenous creatinine clearance in low birthweight infants. Pediatr Res 1979; 13:1012-4. 15. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J PEDIATR 1986;109:698-707. 16. Schwartz G J, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children and adolescents. Pediatr Clin North Am 1987;34:571-90. 17. Linn6 T, K6rner A, Rudberg S, Persson B, Aperia A. Renal functional effects of prostaglandin synthesis inhibition in patients with insulin-dependent diabetes mellitus of long duration without nephropathy. Horm Metab Res 1991;23:383-6. 18. Tan KL. Blood pressure in full-term healthy neonates. Clin Pediatr 1987;26:21-4. 19. Blomenthal S, Epps RP, Heavenrich RM. Report of the task force on blood pressure control in children. Pediatrics 1977; 59(suppl):797-820. 20. Alward CT, Hook JB, Helmrath TA, Bailie MD. Effects of asphyxia on renal function in the newborn piglet. Pediatr Res 1978;12:225-8. 21. Heijden AJ, Guignard JP. Effect of hypercapnic acidosis on renal function in the newborn rabbit. Pediatr Res 1986;20:798801. 22. Robert DS, Haycock GB, Dalton RN, et al. Prediction of acute renal failure after birth asphyxia. Arch Dis Child 1990; 65:1021-8. 23. Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989;298:564-7. 24. Feldman H, Guignard J-P. Plasma creatinine in the first month of life. Arch Dis Child 1982;57:123-6. 25. Trompeter RS, Al-Dahhan J, Haycock GB, Chik G, Chantler C. Normal values for plasma creatinine concentration related to maturity in normal term and preterm infants. Int J Pediatr Nephrol 1983;4:145-8. 26. Schwartz G J, Haycock GB, Spitzer A. Plasma creatinine and urea concentrati~m in children: normal values for age and sex. J PEDIATR 1976;88:828-30. 27. Chantler C, Barratt TM. Laboratory evaluation. In: Holliday MA, Barratt TM, Vernier RL. Pediatric nephrology. Baltimore: Williams & Wilkins, 1987:282-99.