Renal Maturation Research Articles

1497 URINARY BETA-2-MICROGLOBULIN (β2M) AS AN INDEX OF RENAL TUBLAR MATURATION IN HUMAN NEONATES

Tubular reabsorption of β2M was previously reported to increase with conceptional age (CA) and to reflect maturation of renal tubular function. To study this concept further, timed-urine collections and blood samples were obtained on 50 newborn infants (CA 28-42 wks) between 1-12 days of age. Creatinine, sodium and β2M were measured in urine and plasma; creatinine clearance (CCR) and fractional reabsorption of sodium (TNa) and β2M (Tβ2M) were calculated. Plasma β2M concentrations (3.63 ± 0.14 mg/liter, mean ± SE) did not vary with CA (r=0.085). CCR (r=0.715), TNa (r=0.627) and Tβ2M (r=0.693) increased with CA of the infants (p<0.001). Moreover, Tβ2M varied directly with TNa (r=0.474, p<0.001) and inversely with fractional urine flow rate (V/CCR) (r= -0.601, p<0.001). In serial studies of 18 infants 3.64 ± 0.67 (range 1-12) days later, changes in Tβ2M in the same infant were observed to vary inversely with changes in V/CCR (r= -0.470, p=0.05). Although the results of this study confirm previous reports that Tβ2M increases with CA of the infant, these data do not support Tβ2M as a reliable index of renal tubular maturation in the human neonate.

LONG-TERM EFFECT OF CO-TRIMOXAZOLE (CT) ON RENAL FUNCTION

A decrease in creatinine clearance has been described after CT administration. Plasma creatinine (umol/1), inulin and PAH clearances (ml/min x 1.73 m2) were studied prospectively in 16 children, at the start and the end of long-term CT therapy. The drug was given for 4 - 6 months for curative or preventive treatment of urinary tract infection, at a dose of 6 mg/kg·day trimethoprim and 30 mg/kg·day of sulfamethoxazole. GROUP 1: In 4 children aged less than one year, CT did not interfere with normal functional renal maturation. Values before/after treatment: P-creat 56/62, C-in 89/110, C-PAH 347/529. GROUP 2: In 5 children aged 7 years with recurrent urinary tract infection, CT did not significantly affect renal function: P-creat 54/61, C-in 132/130, C-PAH 614/540. GROUP 3: In 7 children aged 5 years with operated vesico-ureteric reflux, CT did not significantly affect renal function: P-creat 72/73, C-in 112/100, C-PAH 520/502. We conclude that CT does not alter renal function when it is normal at the start of treatment and does not interfere with normal functional maturation.

Developmental Toxicity of Methoxyflurane in Mice

The developmental toxicity of trace, subanesthetic, and anesthetic exposure to methoxyflurane was examined in Swiss/ICR mice. No adverse effects on reproduction or fetal development were demonstrated following exposure to trace (2 ppm) and subanesthetic (60 ppm) concentrations of methoxyflurane for 4 hours daily on days 6 through 15 of pregnancy. Exposure to an anesthetic concentration (2000 ppm; 0.2%) for the same period resulted in decreased fetal weight, decreased ossification, and delayed renal maturation. Additionally, the incidence of minor skeletal anomalies was increased. It is concluded that gestational exposure of mice to trace of subanesthetic concentrations of methoxyflurane does not result in reproductive loss or morphologic abnormalities in their offspring.

Developmental patterns of renal functional maturation compared in the human neonate

Observations on the influence of extrauterine life upon renal functional maturation in the human being were made in 49 newborn infants of 25 to 41 weeks' GA during the first 48 hours of life, and in serial studies of 12 of these infants whose GA at birth was less than or equal to 34 weeks. GFR was found to be uniformly low in infants born prior to 34 weeks' GA, and increased rapidly after 34 weeks' GA. Glucosuria was found to occur commonly in infants less than or equal to 30 weeks' GA. Glomerulotubular balance for glucose was noted in every infant studied, regardless of GA or length of time since birth. Mean values for TRP at every age prior to feeding was greater than or equal to 85%, and decreased concomitantly with the rise in serum phosphate concentrations after feedings were introduced. The urinary excretion of alpha amino nitrogen was greatest in infants less than 34 weeks' GA. These studies suggest that renal functional development in the human infant is closely related to conceptional (GA + postnatal age) age, and that the pattern of renal functional development for the premature infant during extrauterine life is similar to that of the fetus in utero of corresponding conceptional age.

Neonatal Parathyroid Secretion and Renal Receptor Maturation in Premature Infants

16 premature infants with normal trophicity were studied during the 1st week of life using serum parathormone (IPTH) dosage and evaluation of renal tubule maturation by the effect of exogenous parathormone (PTE) on urinary elimination of 3':5'-cyclic adenosine monophosphate (cAMP). As of the 1st day, IPTH levels reached or surpassed those in the adult. Prematurity thus does not appear to influence parathormone response. Given the specificity of the dosage antiserum, it appears reasonable that the PTH detected is biologically active. After PTE, urinary elimination of cAMP does not appreciably increase until the 6th day, while still remaining much lower than adult levels. The lower the weight of the premature infant, the less intense the response of the kidney. It thus seems possible that the later development of renal parathormone receptor in the premature infant may be a factor responsible for neonatal hypocalcemia with hyperphosphatemia.

Renal functions of low birth weight infants during the first two months of life.

A postnatal contraction of extracellular fluid occurs in low birth weight infants. Patterns of postnatal renal maturation were assessed with the assumption that changes in body composition were mediated in part by the developing kidney. Twenty-two appropriate for gestational age, low birth weight infants (birth weight mean = 1380 g, gestational age mean 31 weeks) were studied between 12 hr and 61 days of age to evaluate simultaneously glomerular and tubular functional maturation. Since most low birth weight infants have respiratory morbidities (respiratory distress followed by chronic lung disease), the infants were grouped into: group I (13 infants), transient or absent respiratory morbidities; and group II (9 infants), persistent and severe respiratory morbidites. Sodium excretion decreased with postnatal age in both groups. Sodium intake did not vary with postnatal age. The percentage of fractional sodium excretion was inversely related to postnatal age. Creatinine clearance correlated directly with postnatal age in both groups. Increased sodium excretion and percentage of fractional sodium excretion in the first 10 days of life may reflect extracellular fluid solute losses through the kidney. The premature kidney matured in a balanced fashion and persistent respiratory morbidities did not alter this pattern.

PSEUDOHYPOALDOSTERINISM IN TRIPLETS

Premature female triplets were noted to have poor weight gain, end hyponatremia at age one week. Renal function, cortisols, sweat electrolytes and physical exam were normal. Urinary Na+ losses were initially high despite high plasma aldosterone(A). Hypernatremia, induced by p.o. Na+ supplementation, suppressed (A) and renin(R) transiently in only one of the triplets. They hove maintained normal growth and normonatremia on a normal Na+ diet for the past two months, in the presence of high (A) and (R). (Bee table below): The non-suppressabllity of (A) and (R) suggests two mechanisms: 1. Primary proximal tubular Na+ loss with compensatory hyperaldosteronism, unlikely alone in the absence of hypokalemia. 2. Partial distal tubular unresponsiveness to (A) which may improve with age and renal maturation. Measurements of (A) and (R) in infants with hyponatrenia ate necessary to distinguish pseudohypoaldosteronism from other electrolyte imbalances found in infants of low birth weight.

POSTNATAL RENAL MATURATION IN LOW BIRTH WEIGHT INFANTS

The postnatal contraction of extracellular fluid in low birth weight (LBW) infants is associated with increased solute excretion. Patterns of postnatal renal maturation were assessed with the assumption that changes in body composition are mediated in part by the developing kidney. Twenty-two appropriate for gestational age, LBW infants, (birth weight m = 1380 gms, gestational ages m=31 wks) ware studied between 12 noun and 61 days to evaluate simultaneously glomerular and tubular functional maturation. Since most LBW infants have respiratory morbidities (respiratory distress followed by chronic lung disease) the infants were grouped into: Group I, (13 infants) transient or absent respiratory morbidities and Group II, (9 infants) persistent and severe respiratory morbidities. Creatinine clearance correlated directly with postnatal age in both groups, (Group I r=0.868 p<0.001 and Group II r=0.646 p<0.01) Sodium intake did not vary significantly with age in either group. Percent fractional sodium excretion was inversely related to postnatal age, (Group I r=-0.613 p<0.01 and Group II r=-0.646 p<0.01) and no significant difference was observed between the two regression lines. Increased % fractional sodium excretion in the first 10 days of life may reflect extracellular solute losses and persistent respiratory morbidities did not alter this homeostatic regulation.

Inulin Clearance in the Newborn Infant: Relationship to Gestational and Postnatal Age

Thirty-eight healthy newborn infants with gestational ages ranging from 25 to 42 weeks were studied at 2 days to 9 weeks postnatal age to evaluate the rate of glomerular maturation after birth. Glomerular function was assessed by a constant infusion method for inulin clearance (Cin). Cin was nearly identical when measured by the traditional clearance method and by the constant infusion technique. The Cin of 22 infants 2-3 days old ranged from 0.6 to 17.9 ml/min and was directly related to gestational age (r = 0.81, P less than 0.001). For 26 infants studied at 1-9 weeks of age, Cin was directly proportional to conceptual (gestational and postnatal) age (r = 0.89, P less than 0.001), and approximated that of infants of similar gestational age studied at 2-3 days of age.

Amniotic fluid reactivity detected by somatomedin C radioreceptor assay: correlation with growth hormone, prolactin and fetal renal maturation.

Amniotic fluid was assayed by a radioreceptor assay utilizing 125I-somatomedin C and placental membranes. Growth hormone and prolactin levels were measured by radioimmunoassay at different gestational ages (8-41 weeks). Somatomedin receptor activity, growth hormone, and prolactin reached high levels during early gestation (8-26 weeks) displaying different patterns of appearance which reflect fetal serum levels of these hormones. After 26 weeks gestation all these hormones decreased in concentration. This decrease showed a strong correlation with fetal renal maturation as measured by amniotic fluid creatinine levels.

Amniotic fluid creatinine in pregnancies complicated by diabetes

Amniotic fluid (AF) creatinine concentrations, determined in 353 samples from 167 pregnancies complicated by maternal diabetes, are similar to those found at comparable gestation in uncomplicated pregnancy. Added maternal vascular disease significantly raises AF creatinine to such a degree that overestimation of fetal (renal) maturity is a clinical hazard if based solely on this parameter. Relative concentrations of creatinine in AF and maternal plasma (AF/MP ratio) are related to gestational age. Failure of AF creatinine to rise consistently on successive serial samples accompanies an increased risk of perinatal death in the pregnancy complicated by diabetes, four of five deaths in the present series following declines in this measurement.

Influence of dietary sodium intake on renal maturation in anesthetized canine puppies.

A major difference between the kidney of the newborn and the adult animal is the reduced ability of the newborn's kidney to adequately excrete an acute salt load (1-4).When anesthetized newborn dogs were given a normal saline load they excreted only 5% of the infused sodium after 2 hr of sodium infusion. Adult dogs given an equivalent infusion (per kg body wt) excreted 30 % of the sodium infused over the same period of time. Puppies excreted only 1-2% of the filtered sodium compared to 5-6% for the adult dog (5).When premature infants were accidentally given normal saline instead of distilled water in their formula they developed peripheral edema and a large weight gain (6). Infants receiving a relatively high-salt diet prior to this accidental salt load developed less edema and had a smaller weight gain than infants on a lower salt content formula. This finding lead to the speculation that different concentrations of dietary sodium intake may alter the neonatal renal response to an acute salt load and vo...

Influence of dietary Na on renal maturation in unaesthetized puppies

Influence of dietary Na on renal maturation in unaesthetized puppies

EFFECT OF GESTATIONAL AND POSTNATAL AGE ON GLOMERULAR FILTRATION RATE (GFR) ANO TUBULAR MAXIMA OF GLUCOSE TmG IN HUMAN INFANTS

Twenty-four healthy newborn infants with gestational ages ranging from 26 to 42 weeks were studied at 2 days to 9 weeks postnatal age to evaluate the rate of glomerular and tubular maturation. Glomerular function (GFR) was assessed by inulin clearance and tubular function by TmG. Birth weights of the study infants were appropriate for gestational age. The GFR of fifteen 2-3 day old infants ranges from 17 to 101 ml/min/ 1.73 m2 and is directly related to gestational age (r=0.829). The TmG of fifteen 2-3 day infants ranges from 14 to 149 mg/ min/1.73 m2 and is also directly proportional to gestational age (r=0.710). Serial studies showed extrautertne renal maturation occuring at the same rate as intrauterine. The TmG/GFR ratio did not change significantly with postnatal age (mean=l.29 ± 0.08 S.E.M. in the first 2-3 days and 1.27±0.17 S.E.M. after 3 days). These data show that the development of glomerular and tubular function in utero is consistent with morphologic maturation, and that following birth, maturational renal changes proceed in a balanced, appropriate direction.

Functional and morphologic maturation of the superficial nephrons. Relationship to total kidney function.

The functional and morphologic pattern of superficial nephron development was studied in guinea pigs ranging in age between 2 h and 38 days. Concomitent measurements of total kidney function and glomerular counts were also performed. Superficial nephron glomerular filtration rate was found to increase from 0.92 to 19.32 nl/min. The filtration rate of the entire kidney rose from 0.19 to 1.31 ml/min. During the first 15 days of life the average rate of increase in glomerular filtration rate per nephron (0.48 nl/min.day), obtained by dividing the increase in total kidney glomerular filtration rate by glomerular number, was more than twice the observed rate of increase in the superficial nephrons (0.21 nl/min.day). During the remainder of the first month, the increase in superficial nephron glomerular filtration rate (0.97 nl/min.day) was greater than the average increase for all nephrons (0.71 nl/min.day). Thus, the initial increase in total kidney glomerular filtration rate was primarily a consequence of the activity of the deep nephrons, whereas during the ensuing period the superficial nephrons appeared to be the sole contributors to the change in total kidney glomerular filtration rate.The increase in superficial nephron glomerular filtration rate was found to correlate closely with the increase in proximal tubular length. Functional glomerulotubular balance was maintained throughout the entire period of renal maturation.

Maturation of glomerular blood flow distribution in the new-born dog.

1. Glomerular blood flow distribution was studied in seventy-eight new-born mongrel dogs aged 1-40 days by measuring the distribution of radioactive labelled microspheres within the kidney.2. The microsphere technique was found to be a valid indicator of glomerular blood flow distribution for the new-born dog since (a) the spheres were completely extracted by the kidney, (b) more than 95% of the spheres were trapped in glomerular capillaries, (c) the spheres were evenly distributed within any specific region of the kidney and, (d) the spheres did not interfere with renal haemodynamics.3. Plasma flow per gram tissue to inner cortical glomeruli, relative to that to outer cortical glomeruli, the IC/OC flow ratio, was high at birth, decreased over the first 2 weeks of life and remained relatively constant thereafter. Plasma flow per gram tissue to the outer cortex increased over the whole 40 day period while that to the inner cortex decreased slightly and then increased after 2 weeks.4. The IC/OC flow ratio decreased in a curvilinear fashion as blood pressure rose with maturation. Acute increases or decreases in blood pressure in any animal produced decreases or increases, respectively, in the IC/OC flow ratio.5. There was no correlation between the IC/OC flow ratio and renal extraction of p-amino-hippurate (E(PAH)).6. There was histological evidence that glomerular differentiation persists for 2 weeks during the post-natal period in the dog. This continuing post-natal glomerulogenesis takes place only in the outer cortex.7. These results are consistent with the hypothesis that an important factor in renal maturation is a redistribution of blood flow within the kidney. As the animal matures a greater fraction of the total glomerular blood flow goes to outer cortical glomeruli. This is due partly to the continuing glomerular differentiation taking place in the outer cortical region and partly to the increasing arterial blood pressure occurring with maturation.

Birth weight, gestational age, and renal glomerular development as indices of fetal maturity

Below and up to 34 weeks' gestation in girls and 35 weeks' gestation in boys, the mean birth weights in Negroes were consistently higher than in Caucasians. Above these gestational ages, the mean birth weights of Caucasians exceeded those of Negroes. In spite of such birth weight differences, renal maturity, measured by examining the nephrogenic zone of babies who died early neonatally and were stillborn, was not significantly different in the two races within each gestational age interval. The concept that Negro fetuses mature more rapidly appears invalid. Gestational age seems to be better than birth weight as an indicator of fetal maturity if gestational age is properly recorded.

Factors affecting the maturation of glomerular filtration rate and renal plasma flow in the new-born dog.

1. The maturation of glomerular filtration rate was studied by comparison of thirty-six new-born mongrel dogs aged 1-35 days with six adult dogs.2. Under mannitol diuresis, glomerular filtration rate (GFR) rose from 0.16 ml. min(-1).g kidney(-1) at 1 day of age to 0.34 ml. min(-1).g kidney(-1) at 1 month of age. Adult GFR averaged 0.68 ml. min(-1).g(-1). There was good correlation of GFR with arterial blood pressure (r = 0.76, P < 0.001). Part of the statistical correlation of GFR with blood pressure was found to be independent of the relationship between blood pressure and age.3. Acute increases or decreases in blood pressure resulted in parallel changes in GFR in the puppies. There was no change of GFR with change of blood pressure in adult dogs. Carotid artery clamping, independent of blood pressure changes, produced increased renal vascular resistance and decreased GFR in the pups.4. Renal plasma flow (RPF) increased from 0.70 ml. min(-1).g(-1) at 1 day of age to 1.80 ml. min(-1).g(-1) at 1 month and showed good correlation with blood pressure (r = 0.67, P < 0.001). Filtration fraction (GFR/RPF) and renal vascular resistance did not vary with age in the pup and were the same as those for the adult.5. These results support the hypothesis that maturation of GFR and RPF are closely related to maturation of arterial blood pressure in the mongrel dog. The factors other than blood pressure which also affect renal maturation in the dog still need to be more clearly defined.

Maturational changes in pressure gradients for glomerular filtration.

Maturational changes in pressure gradients for glomerular filtration.

Ostnatal development of renal function: micropuncture and clearance studies in the dog.

Postnatal renal development was studied in dogs between 2 and 77 days. Single, superficial nephrons were evaluated by micropuncture, concurrently with measurements of total renal function and morphometric analyses in the same animals. Glomerular filtration rate for the entire kidney increased linearly from 0.13 ml/min per g kidney weight at 2 days to 0.91 at 77 days. Extraction of p-aminohippurate increased from about 20 to 80%, and renal plasma flow per g kidney weight, measured as Cpah/Epah, increased threefold during the same period. Filtration fraction increased to the mature value during the first half of the postnatal period studied. The clearance of urea per unit of renal mass increased with age, whereas the fraction of filtered urea reabsorbed declined during the early part of the postnatal period. The pattern of fractional urea reabsorption may be due mainly to increased medullary recycling of urea and to a rise in the reabsorption of water from the medullary collecting duct. Urine osmolality was higher than plasma from birth onward and rose with age. Osmolal equality of collecting duct fluid and medullary interstitium reflected mature vasopressin (ADH)-induced water permeability. The rise in urinary concentration was predominantly due to increasing medullary sequestration of urea. Glomerular filtration rate of the superficial nephron increased from 3.2 nl/min at 21 days, when subcapsular nephrons were uniformly patent, to 23.1 at 77 days. Despite this rise in filtered load, fractional reabsorption of sodium and water in superficial proximal tubules was constant and at the mature level from the onset of intratubular perfusion. Changes in arterial plasma protein concentration, in filtration fraction, and in the hydrostatic pressure gradient between proximal tubule and peritubular capillary may interact to maintain glomerulotubular balance. The data, together with results of an accompanying morphological study, demonstrate a sequence of coordinated changes during postnatal renal maturation.