European Journal of Clinical Pharmacology
Europ. J. din. Pharmacol. 11,317-320 (1977)
© by Springer-Verlag 1977
Effect on Maturation of Kidney Function in Newborn Infants of Repeated Administration of Water and Electrolytes J. Frenzel 1, H. Br~iunlich2, D. Schramm1, L. Kersten 2 and G. Zwacka 1 Department of Paediatrics 1 and Institute of Pharmacology and Toxicology ~, Friedrich Schiller University, Jena, German Democratic Republic
Summary. In newborn infants of various ages, the influence of repeated administration of water and electrolytes on renal excretion of urine, sodium, potassium, free and bound hydrogen ions and on urine osmolarity was studied. In 14- and 21-day-old infants the repeated administration of water and electrolytes was followed by diminution of renal excretion of hydrogen ions and potassium, possibly caused by stimulation of hormonal regulation of ion exchange in the kidney. In animal studies performed with a larger water and electrolyte load, stimulation of renal excretion of sodium was caused by the pretreatment.
Key words: Electrolyte excretion, H-ion excretion, kidney maturation, postnatal pharmacology.
Kidney function is not fully developed in newborns, as can be demonstrated for urine production as well as for renal excretion of foreign substances (Brfiunlich, 1973). In different species more rapid maturation of kidney function can be produced by prolonged and repeated saturation of the excretory function. In newborn animals the accumulation of p-aminohippurate is increased to adult values after repeated administration of penicillin (Hirsch and Hook, 1970). The renal excretion of potassium can also be increased by repeated administration of potassium (Wright et al., 1971). In similar experiments the toxicity of potassium and the renal excretory capacity for potassium were influenced by repeated administration of potassium in adult but not in young rats (Puschmann and Brfiunlich, 1972). In experiments on 15 day-old rats, renal excretion of sodium was stimulated by repeated administration of saline. The maturation of kidney function was accelerated. The increase in sodium excretion was connected with diminished exchange of
sodium for potassium and hydrogen ions (Br/iunlich and Puschmann, 1972). Increased sodium excretion was also demonstrated by Steichen and Kleinman (1975) in puppies given a high sodium diet. Similarly, renal function in human neonates is characterized by limited capacity for excretion of water and electrolytes. In particular, the poor ability to excrete sodium may result in hyperosmolarity during infusion therapy. It is of practical importance, therefore, whether or not maturation of renal function can be accelerated by a repeated water and electrolyte load in newborn infants. The present paper demonstrates the influence of repeated administration of water and electrolytes on the development of renal function in 4-, 8-, 14- and 21-day old infants.
Materials and Methods The influence of repeated administration of an electrolyte solution (sotutio pro infusione 153, DAB VII) on the renal excretion of water and electrolytes was studied in 4-, 8-, 14- and 21-day old infants. The concentration of ions in the solution was (mval/1000 ml): sodium (140), calcium (5.0), potassium (5.0), magnesium (3.0), chloride (103) and acetate (50). For a period of 4 days 10 ml/kg b. wt. of the solution were given intravenously every day. A special diet was not given. On the 4 th, 8 th, 14th and 21 st days of life, respectively, the renal excretion of water, sodium, potassium, free and bound hydrogen ions (ammonia) and the osmolarity of urine were estimated. On each of these days infants in the control group received their first injection of the same volume of the solution. Analytical methods have been described previously (Kersten and Brfiunlich, 1968). The urine was passed spontaneously. After transformation into values for
318
1-min periods the renal excretion of water and electrolytes was calculated for a period of 4 h, although the actual duration of urine collection in all cases was longer. The ,,t"-test was used to analyze differences between the measurements (p ----0.01). Each of the age groups consisted of 7-12 infants.
J. Frenzel et al.: Maturation of Renal Function in Neonates
z,val Sodium/kg b. wt..4hrs 300
200
Results I N.4.fl
Repeated administration of an electrolyte solution had no effect on renal excretion of sodium by infants of different ages (Fig. 1). There were some differences in potassium elimination between controls and pretreated infants, but they did not reach the level of significance (Fig. 2). The other effects of pretreatment with the electrolyte solution on ion exchange in the kidney are also shown in Fig. 2. Especially in 14- and 21-day old infants, ammonia excretion was reduced. In 21-day old infants the pretreatment also caused diminished renal excretion of free hydrogen ions. The formation of urine and the total amount of osmotically active compounds is listed in Table 1. In 4and 14-day old infants, the urine volume was increased by repeated pretreatment with the electrolyte solution. Like the renal excretion of individual ions, there was no regular or significant effect on the osmolarity of urine.
Discussion The pharmacokinetics of drugs administered repeatedly have rarely been studied. Repeated administration may modify pharmacokinetics in different ways and loss of the therapeutic effectiveness of drugs may be due to such effects. In this paper the different renal effects of single and repeated administration of an electrolyte solution have been demonstrated. The increase in the capacity for sodium excretion after repeated administration of saline had previously been demonstrated by others. Increased sodium excretion and glomerular filtration rate in puppies given a sodium-rich diet was demonstrated by Steichen and Kleinman (1975). Similar effects were reported in full term and premature infants given a daily sodium load (Aperia et al., 1972 and 1974). An increase in glomerular filtration rate or in renal blood flow is associated with greater sodium excretion into tubule fluid, but extensive reabsorption of sodium is possible, so this phenomenon cannot explain the maturation of kidney function, and in particular the changes in urinary ion content, caused by repeated administration of an electrolyte solution. Inhibition of active sodium reabsorption can also pro-
i I-H,~ i I-H.~ t H~,.H i N--I-~
100
H+H-I
I I-t.4-1~ 11-t-t44
11"1-144
i I-I-I-H I I-I-I-H
. - d U.LI3
4
~ttm IH4H
_JB 8 14 Age (Days)
21
Fig. L Renal excretion of sodium in 4-21-day old infants over a 4 h period = controls = infants after repeated administration of water and electrolytes
voke an increase in sodium excretion. In all cases, however, the increased elimination function of the kidney is caused by stimulation of active energy-requiring processes. In this study the repeated administration of a small quantity of sodium was not followed by an increase in sodium excretion. However, the excretion of hydrogen ions in free and bound form (ammonia) and of potassium was progressively diminished during the repeated sodium load. These results can be interpreted as an acceleration of the maturation of hormonal regulation of electrolyte exchange in the kidney. This interpretation is consistent with the results of Aperia et al. (1975). The increased sodium load in the distal tubule is followed by stimulation of electrolyte exchange (sodium for potassium and hydrogen ions); hormonal regulation of this exchange is not fully developed in the postnatal period. It is followed by an extensive, unregulated electrolyte exchange, characterized by potassium loss, formation of acid urine and retention of sodium due to its excessive reabsorption. In experiments on young rats w4th a more intensive sodium load, not only was electrolyte exchange reduced, but sodium excretion too, was increased up to adult levels (Br~iunlich and Puschmann, 1972). In our interpretation the effect on electrolyte exchange is the first step, and a more intense sodium load is necessary to stimulate excretion of sodium. In this case, the smaller dose regime in newborn infants, in compari-
319
J. Frenzel et aL: Maturation of Renal Function in Neonates
u~vol H+/kg b.wt.-L,hrs(.10-z~)
:#val K+lkg b.wt../,hrs
:z,val Ammonia/kg b.wt:Z,hrs 300 -
300 700 600 500
200
200 -
I
/,00 300 I00
1 -
N
200
11
oo
4
Age (Days)
A e (Days)
2
i
t
0
Age(Days)
Fig. 2. Electrolyte exchange in 4, 8, 14 and 21-day old infants after repeated administration of electrolyte solution. The excretion of potassium, free hydrogen ions and ammonia is shown [] = controls = infants after repeated administration of water and electrolytes (* = p N 0,01)
Table 1. Urine volume and renal excretion of osmotically active materials (osmolarity) in 4-21-day old infants after repeated administration of an electrolyte solution (* = p
Europ. J. din. Pharmacol. 11,317-320 (1977)
© by Springer-Verlag 1977
Effect on Maturation of Kidney Function in Newborn Infants of Repeated Administration of Water and Electrolytes J. Frenzel 1, H. Br~iunlich2, D. Schramm1, L. Kersten 2 and G. Zwacka 1 Department of Paediatrics 1 and Institute of Pharmacology and Toxicology ~, Friedrich Schiller University, Jena, German Democratic Republic
Summary. In newborn infants of various ages, the influence of repeated administration of water and electrolytes on renal excretion of urine, sodium, potassium, free and bound hydrogen ions and on urine osmolarity was studied. In 14- and 21-day-old infants the repeated administration of water and electrolytes was followed by diminution of renal excretion of hydrogen ions and potassium, possibly caused by stimulation of hormonal regulation of ion exchange in the kidney. In animal studies performed with a larger water and electrolyte load, stimulation of renal excretion of sodium was caused by the pretreatment.
Key words: Electrolyte excretion, H-ion excretion, kidney maturation, postnatal pharmacology.
Kidney function is not fully developed in newborns, as can be demonstrated for urine production as well as for renal excretion of foreign substances (Brfiunlich, 1973). In different species more rapid maturation of kidney function can be produced by prolonged and repeated saturation of the excretory function. In newborn animals the accumulation of p-aminohippurate is increased to adult values after repeated administration of penicillin (Hirsch and Hook, 1970). The renal excretion of potassium can also be increased by repeated administration of potassium (Wright et al., 1971). In similar experiments the toxicity of potassium and the renal excretory capacity for potassium were influenced by repeated administration of potassium in adult but not in young rats (Puschmann and Brfiunlich, 1972). In experiments on 15 day-old rats, renal excretion of sodium was stimulated by repeated administration of saline. The maturation of kidney function was accelerated. The increase in sodium excretion was connected with diminished exchange of
sodium for potassium and hydrogen ions (Br/iunlich and Puschmann, 1972). Increased sodium excretion was also demonstrated by Steichen and Kleinman (1975) in puppies given a high sodium diet. Similarly, renal function in human neonates is characterized by limited capacity for excretion of water and electrolytes. In particular, the poor ability to excrete sodium may result in hyperosmolarity during infusion therapy. It is of practical importance, therefore, whether or not maturation of renal function can be accelerated by a repeated water and electrolyte load in newborn infants. The present paper demonstrates the influence of repeated administration of water and electrolytes on the development of renal function in 4-, 8-, 14- and 21-day old infants.
Materials and Methods The influence of repeated administration of an electrolyte solution (sotutio pro infusione 153, DAB VII) on the renal excretion of water and electrolytes was studied in 4-, 8-, 14- and 21-day old infants. The concentration of ions in the solution was (mval/1000 ml): sodium (140), calcium (5.0), potassium (5.0), magnesium (3.0), chloride (103) and acetate (50). For a period of 4 days 10 ml/kg b. wt. of the solution were given intravenously every day. A special diet was not given. On the 4 th, 8 th, 14th and 21 st days of life, respectively, the renal excretion of water, sodium, potassium, free and bound hydrogen ions (ammonia) and the osmolarity of urine were estimated. On each of these days infants in the control group received their first injection of the same volume of the solution. Analytical methods have been described previously (Kersten and Brfiunlich, 1968). The urine was passed spontaneously. After transformation into values for
318
1-min periods the renal excretion of water and electrolytes was calculated for a period of 4 h, although the actual duration of urine collection in all cases was longer. The ,,t"-test was used to analyze differences between the measurements (p ----0.01). Each of the age groups consisted of 7-12 infants.
J. Frenzel et al.: Maturation of Renal Function in Neonates
z,val Sodium/kg b. wt..4hrs 300
200
Results I N.4.fl
Repeated administration of an electrolyte solution had no effect on renal excretion of sodium by infants of different ages (Fig. 1). There were some differences in potassium elimination between controls and pretreated infants, but they did not reach the level of significance (Fig. 2). The other effects of pretreatment with the electrolyte solution on ion exchange in the kidney are also shown in Fig. 2. Especially in 14- and 21-day old infants, ammonia excretion was reduced. In 21-day old infants the pretreatment also caused diminished renal excretion of free hydrogen ions. The formation of urine and the total amount of osmotically active compounds is listed in Table 1. In 4and 14-day old infants, the urine volume was increased by repeated pretreatment with the electrolyte solution. Like the renal excretion of individual ions, there was no regular or significant effect on the osmolarity of urine.
Discussion The pharmacokinetics of drugs administered repeatedly have rarely been studied. Repeated administration may modify pharmacokinetics in different ways and loss of the therapeutic effectiveness of drugs may be due to such effects. In this paper the different renal effects of single and repeated administration of an electrolyte solution have been demonstrated. The increase in the capacity for sodium excretion after repeated administration of saline had previously been demonstrated by others. Increased sodium excretion and glomerular filtration rate in puppies given a sodium-rich diet was demonstrated by Steichen and Kleinman (1975). Similar effects were reported in full term and premature infants given a daily sodium load (Aperia et al., 1972 and 1974). An increase in glomerular filtration rate or in renal blood flow is associated with greater sodium excretion into tubule fluid, but extensive reabsorption of sodium is possible, so this phenomenon cannot explain the maturation of kidney function, and in particular the changes in urinary ion content, caused by repeated administration of an electrolyte solution. Inhibition of active sodium reabsorption can also pro-
i I-H,~ i I-H.~ t H~,.H i N--I-~
100
H+H-I
I I-t.4-1~ 11-t-t44
11"1-144
i I-I-I-H I I-I-I-H
. - d U.LI3
4
~ttm IH4H
_JB 8 14 Age (Days)
21
Fig. L Renal excretion of sodium in 4-21-day old infants over a 4 h period = controls = infants after repeated administration of water and electrolytes
voke an increase in sodium excretion. In all cases, however, the increased elimination function of the kidney is caused by stimulation of active energy-requiring processes. In this study the repeated administration of a small quantity of sodium was not followed by an increase in sodium excretion. However, the excretion of hydrogen ions in free and bound form (ammonia) and of potassium was progressively diminished during the repeated sodium load. These results can be interpreted as an acceleration of the maturation of hormonal regulation of electrolyte exchange in the kidney. This interpretation is consistent with the results of Aperia et al. (1975). The increased sodium load in the distal tubule is followed by stimulation of electrolyte exchange (sodium for potassium and hydrogen ions); hormonal regulation of this exchange is not fully developed in the postnatal period. It is followed by an extensive, unregulated electrolyte exchange, characterized by potassium loss, formation of acid urine and retention of sodium due to its excessive reabsorption. In experiments on young rats w4th a more intensive sodium load, not only was electrolyte exchange reduced, but sodium excretion too, was increased up to adult levels (Br~iunlich and Puschmann, 1972). In our interpretation the effect on electrolyte exchange is the first step, and a more intense sodium load is necessary to stimulate excretion of sodium. In this case, the smaller dose regime in newborn infants, in compari-
319
J. Frenzel et aL: Maturation of Renal Function in Neonates
u~vol H+/kg b.wt.-L,hrs(.10-z~)
:#val K+lkg b.wt../,hrs
:z,val Ammonia/kg b.wt:Z,hrs 300 -
300 700 600 500
200
200 -
I
/,00 300 I00
1 -
N
200
11
oo
4
Age (Days)
A e (Days)
2
i
t
0
Age(Days)
Fig. 2. Electrolyte exchange in 4, 8, 14 and 21-day old infants after repeated administration of electrolyte solution. The excretion of potassium, free hydrogen ions and ammonia is shown [] = controls = infants after repeated administration of water and electrolytes (* = p N 0,01)
Table 1. Urine volume and renal excretion of osmotically active materials (osmolarity) in 4-21-day old infants after repeated administration of an electrolyte solution (* = p
