Neonatal hyperglycaemia, as usually defined (a whole blood glucose of >7 mmol/L), is common in the first week of life in babies born more than 12 weeks early. However, a review of a cohort of all such births in the north of England suggests that significant glycosuria is uncommon, and that there is no threat of an osmotic diuresis until the urine contains 2% glucose (by which time the blood glucose level almost always exceeds 15 mmol/L). The current statistical or epidemiological definition of hyperglycaemia (derived from data on term babies) needs to be replaced, for clinical purposes, by a more operationally relevant definition.

The past decade has seen enormous progress in understanding the renal regulation of salt and water homeostasis. Most of the key transporters have been cloned, and their physiological importance has been revealed from studies of children with inherited diseases and from mutagenesis studies on a cellular level. We are beginning to understand the complexity with which the activity of these transporters is regulated by hormones. Studies on experimental animals have uniformly shown that the majority of renal salt and water transporters undergo profound changes in the postnatal period. There is generally a robust increase in the number of transporters expressed in a single tubular cell. Many of the transporters also shift their expression from one isoform to another with a somewhat different function. The short-term regulation of salt and water transporters, the key to a well-functioning homeostatic system, is often blunted in the early postnatal period. Taken together, these findings explain some phenomena well known in infants. The low urinary concentrating capacity can, for example, be at least partially attributed to immaturity of the expression of water channels, sodium losses in preterm infants to low expression of the energy generator for salt transport, Na(+),K(+)-ATPase, and the disposition to acidosis to immaturity of the Na(+)/H(+)exchanger. We propose that further studies on how these transporters are regulated will lead to the improved prevention and treatment of salt water balance disorders in infants.

Adequacy of glucose infusion may be monitored via the glycosuria levels, as there is a relationship between glycemia and glycosuria regulated by the renal glucose threshold. In the neonatal period, however, this relationship is not so clear.

To evaluate the occurrence of glycosuria in preferm infants submitted to glucose infusion and to verify the relationship between glycosuria and blood glucose level.

Accuracy study.

Neonatal intensive care unit of General Maternity Hospital.

40 Preterm newborns receiving glucose infusion.

511 concomitant determinations of glycemia and glycosuria were performed. These 511 pairs were divided into stable and unstable, according to the clinical status of the newborn at the time of data collection, and they were studied in relation to the gestational age, birth weight and glucose infusion rate.

The results revealed a greater frequency of glycosuria in gestational age < or = 30 weeks, birth weight < 1500 g and glucose infusion rate > 6 mg/kg/min. Eight (25.8%) episodes of positive glycosuria occurred in the absence of hyperglycemia, indicating only a moderate concordance between them.

Glycosuria alone is an unreliable marker of blood glucose concentration and adequacy of glucose infusion rate. It is therefore necessary to monitor blood glucose levels in infants submitted to continuous glucose infusion.

Renal function was assessed in 40 children during the acute illness and after recovery from falciparum malaria. Creatinine clearance was significantly lower during the acute illness than after recovery. Six of 18 children with impaired creatinine clearance (< 50 ml/min/1.73 m2) had evidence of acute tubular dysfunction. Hyponatraemia occurred in 12.5% during the acute phase. Fractional sodium excretion was raised in 27% during the acute illness and continuing sodium wastage occurred in 17% after recovery. Plasma potassium was significantly higher and fractional potassium excretion (FeK) significantly lower during the acute illness than after recovery. There was a positive correlation between FeNa and FeK both during and after recovery from the illness but they did not exactly mirror each other in every individual. Urine sodium:potassium ratios were similar during and after recovery from the illness and was related to FeNa. Fractional glucose excretion was zero. Mild proteinuria occurred in 40% during the acute illness but were not related to creatinine clearance, body temperature at presentation, or peripheral parasite density. Proteinuria was absent after recovery. Acute intrinsic renal impairment occurs during apparently 'uncomplicated' falciparum malaria in children.

Reference values for tubular transport of sodium, phosphate, glucose and amino acids are generally based on inulin or creatinine short-term clearances, which are difficult to obtain in children. Hence, quantitative assessment of tubular transport capacities is rarely performed. For a simplified procedure, reference values for fractional sodium excretion, phosphate reabsorption related to glomerular filtration rate, percent glucose and percent amino acid reabsorption were established in 62 children from spot urine and simultaneously obtained blood samples. Sodium excretion, and glucose and amino acid reabsorption were significantly lower in infants than children, whereas phosphate reabsorption decreased during the first year of life. Results using the proposed protocol and those obtained from timed urine specimens correlated well; the phenomenon of renal adaptation during childhood could equally well be demonstrated. Renal tubular dysfunction can be diagnosed without timed urine specimens.

Renal glucose excretion was measured on 239 occasions in a sample of 36 infants of 25.5-33 weeks' gestation, birth weight 720-2000 g, between the ages of 0.5 and 32 days. Glucose was invariably present in urine from the first day. Fractional glucose excretion varied widely from 0.1% to 90% of filtered glucose and glucose excretion rate was up to 15.5 mmol/kg/day and was higher in the most immature infants, especially below 28 weeks' gestation. The highest values were in association with hyperglycaemia between 5 and 15 days but there was no consistent plasma glucose threshold with frequent glucose spillage at normal blood glucose concentrations. There was some correlation with sodium excretion in the first week suggesting that in the absence of hyperglycaemia with a normal filtered glucose load, glucose excretion is caused by proximal tubular immaturity.

Normal urine contains small amounts of glucose, called basal glucosuria, and other carbohydrates. Increased amounts of glucose beyond the basal excretion rates i.e. frank glucosuria, reflect reduced activity of tubular glucose reabsorption. Clinically, there are two conditions which are known to appear with a primary disturbance of epithelial glucose transport: intestinal glucose-galactose malabsorption and benign familial renal glucosuria. In the latter, both the renal threshold for glucose and maximal tubular glucose reabsorption are diminished. The degree of glucosuria is variable; the most severe defect demonstrates minimal glucose threshold values and extremely low levels of maximal glucose reabsorption (type 0). The moderate and mild types show variable reductions of both functional parameters. It is questionable whether these should be subdivided into type A and type B glucosurias. Data in the literature reveal that two distinct entities do not exist, but that there is instead a continuous transition from low to normal values. The defect is transmitted genetically, either in an autosomal dominant or autosomal recessive manner. It seems plausible that the different defects might be produced either by mutations on different gene loci, or by multiple alleles of the same gene locus that determines the synthesis of the glucose carrier.

Glomerulotubular balance for beta-2-microglobulin (beta 2M) in the human kidney has been reported to occur after 34 weeks conceptional age (CA), and fractional tubular reabsorption of beta 2M (T beta 2M) has been suggested as a useful index of renal tubular maturation. To confirm and extend these observations to include still less mature infants, renal handling of beta 2M was investigated during timed-urine collections with corresponding blood samples obtained from 57 infants with CA of 26 to 43 weeks and postnatal ages (PNA) 0.2 to 12 days (study 1); 18 infants were studied a second time 5 to 17 days later (study 2). GFR was measured by endogenous creatinine clearance (CCr). T beta 2M and fractional reabsorption of sodium (TNa) were calculated. Results indicated that while both increased with CA, T beta 2M (r = -0.69, P less than 0.0001) and TNa (r = -0.79, P less than 0.0001) varied inversely with fractional urine flow rate (V/CCr). Moreover, an inverse relationship between changes in T beta 2M and V/CCr was observed in the same infant between study 1 and study 2 (r = -0.47, P less than 0.05). These data suggest that the renal handling of beta 2M in the human neonate is influenced by physiologic variables that are independent of CA, and thus T beta 2M may not be a reliable predictor of renal tubular maturation in the human neonate.

Glomerular filtration rate and urine flow were measured in 40 babies of 26 to 40 weeks' gestation without the need for accurately timed collections of urine by infusing inulin continuously for greater than or equal to 24 hours. Estimates of GFR and urine flow were similar to those obtained when timed specimens of urine were also collected, the coefficient of variation being only 6.1% (22 studies). Although the plasma inulin concentration 80 minutes after a bolus and continuous infusion changed only slowly, it still closely reflected the size of the bolus dose (eight studies, P less than 0.001) and did not correlate with GFR (P = 0.48) as previously claimed. The GFR measured over two hours with a single injection of inulin correlated poorly with values recorded after a continuous 24-hour infusion of inulin (n = 5, P greater than 0.1). The agreement was closer (P less than 0.1) and the values lower (P less than 0.02) when the single-injection studies were extended to five hours. The half-life of inulin in the plasma of preterm babies was 4.3 +/- 0.8 hours (14 estimations in nine babies). This is longer than in adults because babies have a low GFR and a relatively large extracellular fluid compartment. The duration of some renal function test protocols needs to be extended because the long half-life leads to slower changes in plasma concentrations of test substances cleared by the kidney, and delayed equilibration.

The development of glomerular and tubular function was studied in preterm and fullterm infants of varying gestational and postnatal age. The results indicate that glomerular functional development precedes tubular functional development until the 34th postmenstrual week. After the 34th week the tubular transport capacity seems to be more vulnerable than the glomerular filtration rate in states of disease. The release of a postulated renal vasoconstriction could account for the rapid changes in renal function after birth. The purpose of such a vasoconstriction could be to protect the tubules from an overload.

In the neonate kidney the glomerular filtration rate is generally depressed both in absolute terms and when calculated per gram kidney weight. Micropuncture studies have revealed that this phenomenon is due, not to changes in the driving pressures or the hydraulic conductivity of the glomerular capillary membrane, but to a retarded glomerular blood flow. A retarded flow will thus mean a steep rise in the protein concentration in parallel to the filtration of the protein-free filtrate. The corresponding steep rise of the colloid osmotic pressure will then induce cessation of the filtration in the distal parts of the glomerular capillary. In dehydrated states this phenomenon will be even more aggravated. An extracellular volume expansion with saline induces relaxation of the two arterioles with subsequent rise in the glomerular blood flow. The rise in the colloid osmotic pressure along the capillary is then less and the filtration can proceed along the whole of the glomerulus. Accordingly the glomerular filtration rate will be increased, reaching figures typical of the mature kidney.

The developmental aspects of the renal uptake of 3-OH-3-CH3-glutaric acid (HMG) was examined using isolated renal tubules prepared from both newborn and adult rats and isolated renal brush border membranes vesicles from adult rats. The accumulation of 70 microM HMG by both newborn and adult tubules reached a steady state and achieved a distribution ratio (DR) of 4.9 and 6.5, respectively; decreased DR's at higher substrate concentrations suggest concentration-dependent uptake. Lineweaver-Burk analysis of the 5 min calculated velocities of HMG uptake by newborn and adult tubules indicate a single transport system with the same apparent Km of 0.2 mM in both age groups. The Vmax in adult rats was twofold greater than in newborn (0.95 versus 0.44 mM/1/5 min). The carrier system for HMG is assumed to be distinct from those of amino acids and sugars because tubule uptake of HMG is not affected by the presence of alpha-NH2-isobutyric acid and alpha-methyl-D-glucoside. Sodium maleate and acetoacetate significantly decreased HMG uptake in tubules of both age groups. HMG uptake by isolated renal brush border membrane vesicles from adult rats suggests that uptake is both carrier-mediated and Na+-dependent. These observations are consistent with renal tubular HMG uptake by an energy-dependent, carrier-mediated system.

Young rats (20-24 days) and adult rats (40-45 days) were studied during hydropenia and volume expansion with regard to glomerular filtration rate (GFR) and the determinants of GFR. During hydropenia, GFR and renal blood flow (RBF) were significantly lower in younger than in adult rats both in absolute terms and when related to bodyweight. Equivalent degrees of volume expansion (6% of b.wt.) resulted in a much more pronounced increase in GFR and RBF in younger than in older rats. This suggests that the high renal vascular resistance in hydropenic young rats is primarily due to vasoconstriction. The relationship between the filtration rate of superficial nephrons and the total GFR was the same in hydropenic and volume expanded rats in both age groups. The tubular stop flow pressure, the calculated hydrostatic glomerular capillary pressure and ultrafiltration pressure in the afferent part of the glomerular capillaries was slightly lower in hydropenic young rats than in hydropenic adult rats. The pressures did not rise after volume expansion. It is concluded that the marked increase in GFR in volume expanded young rats is mainly due to increased renal plasma flow.

The urinary excretion and proximal tubular reabsorption of beta-2-microglobulin was studied in 17 healthy newborn infants in relation to gestational and post-natal age. The effect of IRDS and non-conjugated hyperbilirubinemia on the tubular reabsorption of the protein was evaluated in 10 IRDS infants and 14 infants with non-conjugated hyperbilirubinemia. The urinary excretion of beta-2-microglobulin was determined under standardized conditions. When GFR was determined, the single injection clearance method was used. The filtered load of beta-2-microglobulin was found to increase with increasing gestational age. This was due to a rise in plasma beta-2-microglobulin concentration as well as to a rise in the GFR. Although the smallest filtered load was recorded in infants with a mean GA of 32.4 weeks, these infants had a lower fractional reabsorption of the protein (88%) than infants with a mean GA of 35.0 weeks or more (98%). In infants with a GA of 35 weeks or more a glomerulo-tubular balance for beta-2-microglobulin apparently was established. In these infants the filtered load of beta-2-microglobulin increased rapidly during the first days of life. This was paralleled by an increase in the reabsorptive capacity for the protein. In infants with IRDS and in infants with non-conjugated hyperbilirubinemia the fractional reabsorption of beta-2-microglobulin was lower than in control infants of a corresponding gestational and postnatal age. This indicates, that in the neonatal period, the proximal tubular transporting capacity is more vulnerable than the glomerular filtration rate in states of hypoxia and hyperbilirubinemia.

Standard values were established for urinary excretion and clearance of uric acid in 95 normal, nonhospitalized children. We found that urinary uric acid excretion and serum uric values increase throughout childhood; that in early childhood, fractional excretion and clearance of uric acid are higher than adult norms; and that despite an increasing filtered load of uric acid, there is a progressive decrease in fractional excretion and clearance of uric acid with advancing age. Some tubular maturational change, either decreasing secretion or increasing reabsorption, must account for the progressive decline in fractional excretion and clearance of uric acid.

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.

This chapter has sought to gather together the background information on systems controlling homoeostasis of salt and water and their clinical derangement. The temptation to adopt an all-embracing approach to the management of these problems is strong but such an approach is difficult to achieve and indeed dangerous. The circumstances of each sick infant are unique and plans for treatment must be individually tailored and flexible, dependent upon clinical and biochemical progress. Future developments in this field are likely to involve further understanding of renal and hormonal control of fluid and electrolyte and it might be expected that as new methods of management emerge they will be accompanied by their own peculiar risks of inducing secondary homoeostatic disturbances. With regard to infant feeding each advance appears to underline the desirability of breast feeding and support current moves toward provision of low solute feeds for those who are artificially fed. Paediatricians should be vocal in their advocation of breast feeding and ensure that the major principles of salt and water handling are understood by all who work with small infants. An extra scoop of powdered milk can be more of a poison than a food.