International Journal of Technology Assessment in Health Care, 7:Suppl. 1 (1991), 90-93. Copyright © 1991 Cambridge University Press. Printed in the U.S.A.
ELECTROLYTE BALANCE Anita Aperia Peter Herin St. Goran's Children's Hospital, Stockholm
RENAL FUNCTIONAL MATURATION
The kidney is structurally and biochemically immature at birth. As a consequence, renal function is low (3;10;ll;18). Glomerular filtration rate (related to body surface area or to body weight) is approximately 25% of that in adults. The capacity of several different tubular transport systems is lower in the infant than in the adult (2;5;13;21;28). A low transporting capacity of the neonatal kidney will sometimes result in undesired losses of electrolytes, amino acids, and peptides. The capacity to concentrate urine is low (7;29), and disturbances of serum tonicity, therefore, are common. The low concentrating capacity can be attributed to renal immaturity. The capacity of the newborn fullterm as well as preterm infant to release antidiuretic hormone is normal (7;31). Hormones that regulate sodium excretion also appear to be adequately regulated and released in newborn infants, both fullterm and preterm. Both the sodium-retaining hormone aldosterone and the natriuretic hormone atrial natriuretic peptide (ANP) have been extensively studied in infants (4;14;19;26;27;30). It is well documented that the capacity of the newborn kidney to excrete hydrogen ions is low (15;28). The results of recent animal experiments have indicated that the inability of the infant kidney to excrete hydrogen ions is due to a low capacity of the Na+/H+ exchanger (6;21). This transport pathway is present to various extents in most cells. The Na+/H+ exchanger functions in most cell types as an important regulator of intracellular pH. The results of the experimental studies of the ontogeny of the Na+/H + exchanger, therefore, will also imply that the regulation of intracellular pH is not fully developed in the neonate. RENAL FUNCTION IN PRETERM AND FULLTERM INFANTS
There are important differences in renal function between fullterm and preterm infants (31). In fullterm infants, the glomerular filtration rate increases almost twofold in the first week of life. In preterm infants born before the 32nd gestational week, renal function will increase much more slowly and almost linearly during the first 6 weeks of life. The glomerular filtration rate in a 1-month-old infant with a gestational age of around 30 weeks is rarely above 40 ml/1.73 mVmin. The tubular transporting capacity is also much lower in the preterm than in the fullterm infant. Urinary sodium losses are the rule even in preterm infants with a fairly uncomplicated course (4;8;31).
Electrolyte balance RENAL INSUFFICIENCY
In the newborn infant, the glomerular filtration rate is normally around 25 ml/1.73 m2 body surface area/min. This value is close to the limit of renal insufficiency in the adult. Any reduction of renal function in the neonate, therefore, will result in some degree of renal insufficiency (12;23). Typical expressions of renal insufficiency in the neonate are high urinary sodium losses, often resulting in hyponatremia and an inability to excrete hydrogen and reabsorb bicarbonate ions, with acidosis as a frequent consequence. Prerenal insufficiency should be looked for in all sick infants. The degree of hydration critically influences renal function and dehydrated infants are at greater risk of developing prerenal insufficiency. Circulatory factors will significantly influence renal function in the neonate. Preterm infants with patent ductus arteriosis have a very low glomerular filtration rate. FLUID AND ELECTROLYTE DISTURBANCES
Electrolyte disturbances are common in the neonate. In all infants with renal insufficiency, hyponatremia is the rule (16). Hyponatremia is very common in preterm infants aged 4 days to 3 weeks (1;31). It can be attributed to several factors, such as large urinary sodium losses and an imbalance between sodium and water excretion. High levels of antidiuretic hormone will contribute to relative water retention. Hypernatremia is more common during the first days of life and will occur when water losses exceed losses of sodium. Since transepithelial water losses are common during the first days of life in very low birth weight infants, hypernatremia is also common in these infants. Serum sodium should not be allowed to exceed 150 mmol/1 or to be lower than 130 mmol/1. If these limits are exceeded, there is a risk of brain damage. Acidosis is also common in the neonate and can to some extent be attributed to immature renal function. Hyponatremia is quite often associated with acidosis. EFFECTS OF DRUGS
The adverse effects of drugs on the fluid and electrolyte balance are not well known. Both fullterm and preterm newborn infants generally have a well-developed clinical response to diuretics (24). Theophylline influences sodium transport in such a way that it generally has a mild diuretic effect (20). Dopamine, which is often used in infants with prerenal failure, increases the glomerular filtration rate and acts as a mild diuretic (25). Aminoglycosides have a welldocumented nephrotoxic effect (9); they will particularly damage the renal proximal tubular cells and have been shown in animal experiments to cause undesired sodium losses (17). For reasons not well understood, the neonatal kidney appears to be rather insensitive to the nephrotoxic effect of aminoglycosides. REFERENCES
1. Al-Dahhan, J., Haycock, G. B., Chantler, C, & Stimmler, L. Sodium homeostasis in term and preterm neonates. I. Renal aspects. Arch. Dis Child., 1983, 58, 335-42. 2. Aperia, A., & Broberger, U. Beta-2-microglobulin, an indicator of renal tubular maturation and dysfunction in the newborn. Acta Paediatr. Scand., 1979, 68, 669-76. 3. Aperia, A., Broberger, O., Elinder, G., Herin, P., & Zetterstrom, P. Postnatal development of renal function in preterm and fullterm infants. Acta Paediatr. Scand., 1981, 70, 183-87. 4. Aperia, A., Broberger, O., Herin, P., & Zetterstrom, R. Sodium excretion in relation to so-
INTL J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE
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Aperia and Herin
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
20. 21. 22.
23. 24. 25. 26. 27.
92
dium intake and aldosterone excretion in newborn preterm and fullterm infants. Ada Paediatr. Scand., 1979, 68, 813-17. Aperia, A., Broberger, O., Herin, P., & Zetterstrom, R. Extrauterine adaptation of renal function in fullterm and preterm newborn infants. In L. Stern (ed.), Intensive care in the newborn, III. New York: Masson, 1981, 135-42. Aperia, A., Fukuda, Y., & Lechene, C. Ontogenic increase of NA+-H +-exchange induces increase Na~K ATPase in rat proximal convoluted tubule (RPCT). Kidney Int., 1988, 33, 415. Aperia, A., Herin, P., Lundin, S., Melin, P., & Zetterstrom, R. Regulation of renal water excretion in newborn fullterm infants. Ada Paediatr. Scand., 1984, 73, 717-21. Aperia, A., Herin P., & Zetterstrom, R. Sodium, chloride, and potassium needs in very low birthweight infants. In R. C. Tsang (ed.), Vitamin and mineral requirements in preterm infants. New York: Marcel Dekker, 1985, 137-51. Aramaki, Y., Takahashi, M., Inaba, A., Ishii, Y., & Tsuchiya, S. Uptake of aminoglycoside antibiotics into brush-border membrane vesicles and inhibition of (Na+ + K+)-ATP-ase activity of baselateral membrane. Biochem. Biophys. Ada, 1986, 862, 111-18. Arant, B. Developmental patterns of renal functional maturation compared in the human neonate. J. Pediatr., 1978, 92, 705-12. Barnett, H. L. Kidney function in young infants. Pediatrics, 1950, 5, 171-79. Barratt, T. M. Renal disease in the first year of life. In Recent advances in renal medicine. London: Churchill Livingstone, 1982, 197-212. Brodehl, J., & Gellissen, K. Endogenous renal transport of free amino acids in infancy and childhood. Pediatrics, 1968, 42, 395-404. Dillon, M., Gillin, M, Ryness, J., & de Swiet, M. Plasma renin activity and aldosterone concentration in the human newborn. Arch. Dis. Child., 1976, 51, 537-40. Edelmann, C. M., Jr., Soriano, J. R., Boichis, H., Gruskin, A. B., & Acosta, M. I. Renal bicarbonate reabsorption and hydrogen ion excretion in normal infants. /. Clin. Invest., 1967, 46, 1309-17. Engelke, S., Shah, B., Vasan, U, & Raye, J. Sodium balance in very low-birth-weight infants. J. Pediatr., 1978, 93, 837-41. Fukuda, Y, & Aperia, A. Gentamicin inhibition of the NaK pump in rat kidney cells. In manuscript. Guignard, J. P., Torrado, A., Da Cunha, O., & Gautier, E. Glomerular filtration rate in the first three days of life. /. Pediatr., 1975, 87, 268-72. Godard, C, Geering, J.-M., Geering, K., & Vallotton, M. Plasma renin activity related to sodium balance, renal function and urinary vasopressin in the newborn infant. Pediatr. Res., 1979, 13, 742-45. Harkavy, K. L., Scanlon, J. W., & Jose, O. The effects of theophylline on renal function in the premature newborn. Biol. Neonate, 1979, 35, 126-30. Karlen, J., Aperia, A., & Zetterstrom, R. Renal excretion of calcium and phosphate in preterm and fullterm infants. J. Pediatr., 1985, 106, 814-19. Larsson, S. H., Aperia, A., & Lechene, C. Studies on final differentiation of rat renal proximal tubular cells in culture. I. Cellular membrane Na and K effective permeability. Am. J. Physiol., 1986, 251, C455-64. Rahman, N., Boineau, F., & Lewy, J. Renal failure in the perinatal period. Clin. Perinatoi, 1981, 8, 241-50. Roberts, R. J. In Drug therapy in infants; Pharmacologicprinciples and clinical experience. WB Saunders, 1984, 226-49. Seri, I., & Aperia, A. Contribution of dopamine2-receptors to the dopamine-induced increase in glomerular filtration rate. Am. J. Physiol., 1988, 254, F196-201. Shaffer, S., Geer, P., & Goetz, K. Elevated atrial natriuretic factor in neonates with respiratory distress syndrome. /. Pediatr., 1986, 109, 1028-33. Sulyok, E., Nemeth, M., Tenyi, I, Csaba, I., Gyory, E., Ertl, T., & Varga, F. Postnatal devel-
INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE
Electrolyte balance
28. 29. 30. 31.
opment of renin-angiotensin-aldosterone system, RAAS, in relation to electrolyte balance in premature infants. Pediatr. Res., 1979, 13, 817-20. Sulyok, E., Heim, T., Soltesz, G., & Jaszai, V. The influence of maturity on renal control of acidosis in newborn infants. Biol. Neonate, 1972, 21, 418-35. Svenningsen, N. W., & Aronsson, A. S. Postnatal development of renal concentration capacity as estimated by DDAVP-test in normal and asphyxiated neonates. Biol. Neonate, 1974, 25, 230-41. Tulassay, T., Rascher, W., Seyberth, H., Lang, R., Toth, M., & Sulyok, E. Role of atrial natriuretic peptide in sodium homeostasis in premature infants. J. Pediatr., 1986,109,1023-27. Vanpee, M., Herin, P., Zetterstrdm, R., & Aperia, A. Postnatal development of renal function in very low birth-weight infants. Ada Paediatr. Scand., 1988, 77, 191-97.
INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE
93
ELECTROLYTE BALANCE Anita Aperia Peter Herin St. Goran's Children's Hospital, Stockholm
RENAL FUNCTIONAL MATURATION
The kidney is structurally and biochemically immature at birth. As a consequence, renal function is low (3;10;ll;18). Glomerular filtration rate (related to body surface area or to body weight) is approximately 25% of that in adults. The capacity of several different tubular transport systems is lower in the infant than in the adult (2;5;13;21;28). A low transporting capacity of the neonatal kidney will sometimes result in undesired losses of electrolytes, amino acids, and peptides. The capacity to concentrate urine is low (7;29), and disturbances of serum tonicity, therefore, are common. The low concentrating capacity can be attributed to renal immaturity. The capacity of the newborn fullterm as well as preterm infant to release antidiuretic hormone is normal (7;31). Hormones that regulate sodium excretion also appear to be adequately regulated and released in newborn infants, both fullterm and preterm. Both the sodium-retaining hormone aldosterone and the natriuretic hormone atrial natriuretic peptide (ANP) have been extensively studied in infants (4;14;19;26;27;30). It is well documented that the capacity of the newborn kidney to excrete hydrogen ions is low (15;28). The results of recent animal experiments have indicated that the inability of the infant kidney to excrete hydrogen ions is due to a low capacity of the Na+/H+ exchanger (6;21). This transport pathway is present to various extents in most cells. The Na+/H+ exchanger functions in most cell types as an important regulator of intracellular pH. The results of the experimental studies of the ontogeny of the Na+/H + exchanger, therefore, will also imply that the regulation of intracellular pH is not fully developed in the neonate. RENAL FUNCTION IN PRETERM AND FULLTERM INFANTS
There are important differences in renal function between fullterm and preterm infants (31). In fullterm infants, the glomerular filtration rate increases almost twofold in the first week of life. In preterm infants born before the 32nd gestational week, renal function will increase much more slowly and almost linearly during the first 6 weeks of life. The glomerular filtration rate in a 1-month-old infant with a gestational age of around 30 weeks is rarely above 40 ml/1.73 mVmin. The tubular transporting capacity is also much lower in the preterm than in the fullterm infant. Urinary sodium losses are the rule even in preterm infants with a fairly uncomplicated course (4;8;31).
Electrolyte balance RENAL INSUFFICIENCY
In the newborn infant, the glomerular filtration rate is normally around 25 ml/1.73 m2 body surface area/min. This value is close to the limit of renal insufficiency in the adult. Any reduction of renal function in the neonate, therefore, will result in some degree of renal insufficiency (12;23). Typical expressions of renal insufficiency in the neonate are high urinary sodium losses, often resulting in hyponatremia and an inability to excrete hydrogen and reabsorb bicarbonate ions, with acidosis as a frequent consequence. Prerenal insufficiency should be looked for in all sick infants. The degree of hydration critically influences renal function and dehydrated infants are at greater risk of developing prerenal insufficiency. Circulatory factors will significantly influence renal function in the neonate. Preterm infants with patent ductus arteriosis have a very low glomerular filtration rate. FLUID AND ELECTROLYTE DISTURBANCES
Electrolyte disturbances are common in the neonate. In all infants with renal insufficiency, hyponatremia is the rule (16). Hyponatremia is very common in preterm infants aged 4 days to 3 weeks (1;31). It can be attributed to several factors, such as large urinary sodium losses and an imbalance between sodium and water excretion. High levels of antidiuretic hormone will contribute to relative water retention. Hypernatremia is more common during the first days of life and will occur when water losses exceed losses of sodium. Since transepithelial water losses are common during the first days of life in very low birth weight infants, hypernatremia is also common in these infants. Serum sodium should not be allowed to exceed 150 mmol/1 or to be lower than 130 mmol/1. If these limits are exceeded, there is a risk of brain damage. Acidosis is also common in the neonate and can to some extent be attributed to immature renal function. Hyponatremia is quite often associated with acidosis. EFFECTS OF DRUGS
The adverse effects of drugs on the fluid and electrolyte balance are not well known. Both fullterm and preterm newborn infants generally have a well-developed clinical response to diuretics (24). Theophylline influences sodium transport in such a way that it generally has a mild diuretic effect (20). Dopamine, which is often used in infants with prerenal failure, increases the glomerular filtration rate and acts as a mild diuretic (25). Aminoglycosides have a welldocumented nephrotoxic effect (9); they will particularly damage the renal proximal tubular cells and have been shown in animal experiments to cause undesired sodium losses (17). For reasons not well understood, the neonatal kidney appears to be rather insensitive to the nephrotoxic effect of aminoglycosides. REFERENCES
1. Al-Dahhan, J., Haycock, G. B., Chantler, C, & Stimmler, L. Sodium homeostasis in term and preterm neonates. I. Renal aspects. Arch. Dis Child., 1983, 58, 335-42. 2. Aperia, A., & Broberger, U. Beta-2-microglobulin, an indicator of renal tubular maturation and dysfunction in the newborn. Acta Paediatr. Scand., 1979, 68, 669-76. 3. Aperia, A., Broberger, O., Elinder, G., Herin, P., & Zetterstrom, P. Postnatal development of renal function in preterm and fullterm infants. Acta Paediatr. Scand., 1981, 70, 183-87. 4. Aperia, A., Broberger, O., Herin, P., & Zetterstrom, R. Sodium excretion in relation to so-
INTL J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE
91
Aperia and Herin
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
20. 21. 22.
23. 24. 25. 26. 27.
92
dium intake and aldosterone excretion in newborn preterm and fullterm infants. Ada Paediatr. Scand., 1979, 68, 813-17. Aperia, A., Broberger, O., Herin, P., & Zetterstrom, R. Extrauterine adaptation of renal function in fullterm and preterm newborn infants. In L. Stern (ed.), Intensive care in the newborn, III. New York: Masson, 1981, 135-42. Aperia, A., Fukuda, Y., & Lechene, C. Ontogenic increase of NA+-H +-exchange induces increase Na~K ATPase in rat proximal convoluted tubule (RPCT). Kidney Int., 1988, 33, 415. Aperia, A., Herin, P., Lundin, S., Melin, P., & Zetterstrom, R. Regulation of renal water excretion in newborn fullterm infants. Ada Paediatr. Scand., 1984, 73, 717-21. Aperia, A., Herin P., & Zetterstrom, R. Sodium, chloride, and potassium needs in very low birthweight infants. In R. C. Tsang (ed.), Vitamin and mineral requirements in preterm infants. New York: Marcel Dekker, 1985, 137-51. Aramaki, Y., Takahashi, M., Inaba, A., Ishii, Y., & Tsuchiya, S. Uptake of aminoglycoside antibiotics into brush-border membrane vesicles and inhibition of (Na+ + K+)-ATP-ase activity of baselateral membrane. Biochem. Biophys. Ada, 1986, 862, 111-18. Arant, B. Developmental patterns of renal functional maturation compared in the human neonate. J. Pediatr., 1978, 92, 705-12. Barnett, H. L. Kidney function in young infants. Pediatrics, 1950, 5, 171-79. Barratt, T. M. Renal disease in the first year of life. In Recent advances in renal medicine. London: Churchill Livingstone, 1982, 197-212. Brodehl, J., & Gellissen, K. Endogenous renal transport of free amino acids in infancy and childhood. Pediatrics, 1968, 42, 395-404. Dillon, M., Gillin, M, Ryness, J., & de Swiet, M. Plasma renin activity and aldosterone concentration in the human newborn. Arch. Dis. Child., 1976, 51, 537-40. Edelmann, C. M., Jr., Soriano, J. R., Boichis, H., Gruskin, A. B., & Acosta, M. I. Renal bicarbonate reabsorption and hydrogen ion excretion in normal infants. /. Clin. Invest., 1967, 46, 1309-17. Engelke, S., Shah, B., Vasan, U, & Raye, J. Sodium balance in very low-birth-weight infants. J. Pediatr., 1978, 93, 837-41. Fukuda, Y, & Aperia, A. Gentamicin inhibition of the NaK pump in rat kidney cells. In manuscript. Guignard, J. P., Torrado, A., Da Cunha, O., & Gautier, E. Glomerular filtration rate in the first three days of life. /. Pediatr., 1975, 87, 268-72. Godard, C, Geering, J.-M., Geering, K., & Vallotton, M. Plasma renin activity related to sodium balance, renal function and urinary vasopressin in the newborn infant. Pediatr. Res., 1979, 13, 742-45. Harkavy, K. L., Scanlon, J. W., & Jose, O. The effects of theophylline on renal function in the premature newborn. Biol. Neonate, 1979, 35, 126-30. Karlen, J., Aperia, A., & Zetterstrom, R. Renal excretion of calcium and phosphate in preterm and fullterm infants. J. Pediatr., 1985, 106, 814-19. Larsson, S. H., Aperia, A., & Lechene, C. Studies on final differentiation of rat renal proximal tubular cells in culture. I. Cellular membrane Na and K effective permeability. Am. J. Physiol., 1986, 251, C455-64. Rahman, N., Boineau, F., & Lewy, J. Renal failure in the perinatal period. Clin. Perinatoi, 1981, 8, 241-50. Roberts, R. J. In Drug therapy in infants; Pharmacologicprinciples and clinical experience. WB Saunders, 1984, 226-49. Seri, I., & Aperia, A. Contribution of dopamine2-receptors to the dopamine-induced increase in glomerular filtration rate. Am. J. Physiol., 1988, 254, F196-201. Shaffer, S., Geer, P., & Goetz, K. Elevated atrial natriuretic factor in neonates with respiratory distress syndrome. /. Pediatr., 1986, 109, 1028-33. Sulyok, E., Nemeth, M., Tenyi, I, Csaba, I., Gyory, E., Ertl, T., & Varga, F. Postnatal devel-
INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE
Electrolyte balance
28. 29. 30. 31.
opment of renin-angiotensin-aldosterone system, RAAS, in relation to electrolyte balance in premature infants. Pediatr. Res., 1979, 13, 817-20. Sulyok, E., Heim, T., Soltesz, G., & Jaszai, V. The influence of maturity on renal control of acidosis in newborn infants. Biol. Neonate, 1972, 21, 418-35. Svenningsen, N. W., & Aronsson, A. S. Postnatal development of renal concentration capacity as estimated by DDAVP-test in normal and asphyxiated neonates. Biol. Neonate, 1974, 25, 230-41. Tulassay, T., Rascher, W., Seyberth, H., Lang, R., Toth, M., & Sulyok, E. Role of atrial natriuretic peptide in sodium homeostasis in premature infants. J. Pediatr., 1986,109,1023-27. Vanpee, M., Herin, P., Zetterstrdm, R., & Aperia, A. Postnatal development of renal function in very low birth-weight infants. Ada Paediatr. Scand., 1988, 77, 191-97.
INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE
93
