Pathophysiology and management of hyponatremia and hypernatremia in the neonate

Development of renal function and tubular transport

The fetal kidney begins to function around the 10th to 11th week of gestation. Although the kidney has its full complement of glomeruli at term, the function of the neonatal kidney continues to undergo development in its ability to filter the blood (glomerular filtration rate [GFR]) and modify the filtered fluid (tubular function). ^,

The GFR of a term neonate is only 30% of the normal adult rate when factored for body surface area. The GFR in preterm infants is significantly lower than that of term infants. The GFR increases during the first 12–18 months of life when it becomes approximately the same as the adult when factored for body surface area. The glomerular ultrafiltrate is then modified by the renal tubules to eventually form the final urine. The tubules reabsorb solutes including sodium, bicarbonate, glucose, and amino acids and secrete a number of solutes including potassium, acid and ammonium. The excretion rate of the primary nitrogenous waste product, urea, is determined by the GFR, which obligates a high filtration rate to excrete urea so the neonate can remain in nitrogen balance. The renal tubules then reabsorb a large amount of sodium and fluid to remain in balance.

Proximal tubule sodium transport

In the proximal tubule, the key transporter for luminal sodium entry is the sodium-hydrogen exchanger ( Fig. 7.1 ). ^, The primary isoform of this transporter in the adult kidney is sodium-hydrogen exchanger-3 NHE3. ^, By linking the sodium entry to proton secretion, this transporter will increase the intracellular pH of the proximal tubule cell so there will be a gradient for sodium and bicarbonate exit through its basolateral membrane via the sodium-bicarbonate cotransporter, (NBC).

In the luminal fluid of the proximal tubule, the proton combines with the filtered bicarbonate to form carbonic acid that is then converted to water and carbon dioxide in the presence of carbonic anhydrase. Once the water and carbon dioxide enter the cell, they are converted back to carbonic acid that ionizes into a proton and bicarbonate. The proton can then be secreted and the bicarbonate is transported through the basolateral membrane and into the bloodstream.

Because the processes involved in the reabsorption of bicarbonate have finite rates, the entire process exhibits saturation kinetics and has a transport maximum. When the filtered load of bicarbonate is below the transport maximum, all the filtered bicarbonate will be reabsorbed. If the filtered load exceeds the transport maximum, some of the filtered bicarbonate will be excreted. Because bicarbonate is an anion, it must be excreted with a cation such as sodium or potassium leading to volume depletion due to sodium loss and also to hypokalemia.

Other sodium-coupled transporters on the luminal membrane include the sodium-glucose cotransporters (SGLT1 and SGLT2), sodium-phosphate cotransporter (NaPi2a), and sodium-amino acid cotransporters. (The transport of amino acids is very complex and is beyond the scope of this chapter. Please see Broer ^, for further details.) These cotransporters account for only a small portion of the sodium that is reabsorbed but are responsible for reabsorbing almost the entire filtered load of glucose and amino acids. The amount of phosphate that is reabsorbed is dependent on the diet and comprises a very wide range of the filtered load. Thus, there is almost no glucose or amino acids in the final urine, but there can be a considerable amount of phosphate, depending on the dietary intake of phosphate.

Active, transcellular transport of sodium chloride occurs via the action of parallel transporters, NHE3 and the chloride-hydroxyl exchanger ( Fig. 7.1 ). ^{, ,} As discussed previously, the sodium-hydrogen exchanger raises the intracellular pH of the proximal tubule. This leads to a pH gradient that can be used to exchange intracellular base (hydroxyl ions) for luminal chloride ions. The hydrogen ion that is secreted combines with the hydroxyl ion to form water, and the sodium and chloride exit the cell via the basolateral membrane and into the bloodstream.

The actions of these transporters for the reabsorption of bicarbonate, glucose, and amino acids in the early proximal tubule will cause the luminal fluid in the distal portion of the proximal tubule to have a low bicarbonate concentration and a high chloride concentration ( Fig. 7.2 ). This chloride concentration gradient is then used to reabsorb NaCl and water by passive paracellular transport. The rate of reabsorption in this part of the nephron is dependent on the chloride concentration gradient that was generated as well as the paracellular permeability to chloride.

Claudins, intercellular junction proteins, determine the paracellular permeability of the proximal tubule. As will be discussed in the development of proximal tubule transport, the expression of these claudins changes during development and has a direct impact on the rate of transport of sodium chloride.

Development of proximal tubule sodium reabsorption

The plasma bicarbonate concentration of neonates is lower than that of older children and adults. Direct measurement of the epithelial permeability to bicarbonate demonstrated a lower permeability in neonatal compared with adult rabbit proximal tubules. Thus, lower active transport of bicarbonate in the neonatal tubule is the cause of the lower serum bicarbonate level in the neonate.

As the proximal tubule matures, the components of bicarbonate transport increase. Development of the Na-K ATPase activity parallels that of the basolateral surface area and provides the required energy for the secondary active secretion of protons through the luminal membrane. This increase in the Na-K-ATPase provides the necessary energy for transporting bicarbonate as well as other filtered solutes such as glucose, phosphate and amino acids.

The development of the luminal sodium hydrogen exchanger is more complex. The primary isoform in the adult kidney is NHE3. ^, Although the expression of NHE3 in neonatal rabbit proximal tubules is very low, the measured sodium-hydrogen exchange activity could not be explained by the negligible amount of NHE3 expressed. ^, The isoform responsible for this exchange activity in the neonatal tubules is NHE8. This isoform is also expressed in adult proximal tubules but is in intracellular compartments, whereas in the neonatal tubules it is in the luminal membrane. This is evidence for an isoform switch for the luminal sodium-proton exchanger throughout development.

Developmental expression of NHE3 and NHE8 is under hormonal control. Glucocorticoids stimulate the expression of NHE3 ^, and also decrease the luminal expression of NHE8 and are one of the primary regulators of the development of transport of bicarbonate and sodium in the proximal tubule.

Although thyroid hormone has some effect on the maturational changes in the expression of NHE3 and NHE8, it has more significant effects on the paracellular transport of sodium chloride. ^, Proximal straight tubules from hypothyroid neonatal rabbits have a very low chloride permeability. Proximal straight tubules from hypothyroid animals that were treated with thyroid hormone have a chloride permeability that was not different from control animals. Thus, the passive, paracellular transport in the proximal tubule also undergoes significant changes that appear to be affected by thyroid hormone.

Claudins 6, 9, and 13 have high expression in the neonatal tubules but not in the adult tubules. ^, These claudins were subsequently shown in a cell culture model to have effects on chloride permeability. Thus, the mechanism of sodium chloride transport in the late proximal tubule has significant maturational changes that are stimulated in part by thyroid hormone.

Proximal tubule water permeability

The proximal tubule reabsorbs the bulk of the filtered load of sodium, chloride, and water in an isotonic fashion. The osmolality of the luminal fluid throughout the proximal tubule does not differ much from the osmolality of the blood. This isotonicity is maintained because of the high expression of aquaporin 1 (AQP1), the membrane water channel, in the luminal and basolateral membranes of the adult proximal tubule. ^, This high water permeability allows for the osmotic movement of water with the small solute concentration gradient generated by the active transport of sodium and other solutes.

Expression of AQP1 in the proximal tubule of the neonatal rabbit kidney is much lower than that of the adult proximal tubule. In addition, water permeability measurements of vesicles made from proximal tubule luminal and basolateral membranes showed that the water permeability of these membranes is much lower in the neonatal tissue than the adult kidney tissue. ^, Thus, it appears that the water permeability of the neonatal proximal tubule should be much lower than the adult. However, direct measurements in isolated perfused rabbit proximal tubules showed that there is no difference in the water permeability between tubules from neonatal rabbits and adult rabbits. This is explained by the fact that the intracellular compartment in the neonatal tubules is much smaller than that of the adult tubules and provides less resistance to the movement of water through the epithelium. Thus, although the expression of AQP1 is lower in the neonatal proximal tubule, the epithelial water permeability remains high enough so that water could be reabsorbed with the solutes.

Thin descending and thin ascending loops of henle

Although transport of salt and water in the thin descending and ascending portions of the loop of Henle is primarily passive in nature, it is complex and its contribution to the medullary hypertonicity is incompletely understood. The osmolality of the medullary interstitium is higher than that of the luminal fluid so there is an osmotic gradient for water reabsorption as the thin descending limb goes further into the medulla. Some, but not all, of the thin descending limbs of Henle express AQP1 so there is high water permeability in these segments. As water is reabsorbed, solute in the lumen becomes more concentrated so that when the fluid begins to ascend to the cortex, there is a gradient for passive sodium reabsorption from the lumen of the thin ascending limb of the loop of Henle.

The developing fetus has only short thin limbs of Henle. Shortly before birth, they begin to form the long loops of Henle that will eventually contribute to medullary hypertonicity. The molecular signals controlling this process have only recently been studied. ^, Defects in this process could contribute to the medullary hypoplasia seen in many forms of renal dysplasia.

Thick ascending limb of henle

The thick ascending limb of Henle (TAL) actively transports sodium from the luminal fluid to the bloodstream in a way that also causes many other ions to be reabsorbed as well ( Fig. 7.3 ). ^, The primary active transporter is the Na-K-ATPase located in the basolateral membrane of the cell that maintains a very low intracellular sodium concentration. The luminal sodium-potassium-2-chloride cotransporter (NKCC2) utilizes this sodium concentration gradient to transport sodium, potassium, and two chloride ions into the cell. This transporter is electroneutral and does not directly affect the luminal membrane electric potential.

Potassium enters the thick ascending limb cells through both the basolateral membrane (via the Na-K-ATPase) and the luminal membrane (via NKCC2). Both membranes have potassium channels, known as renal outer medullary K channels (ROMK), for the recycling of potassium ions. Because of the luminal potassium recycling, there is a lumen positive electric potential that leads to passive paracellular reabsorption of many cations including sodium, potassium, calcium, and magnesium. Thus, inhibition of transport of NKCC2 with loop diuretics such as furosemide and bumetanide results in increased excretion of not only sodium and potassium but also calcium and magnesium.

The thick ascending limb has no water channels on its luminal membrane but has AQP1 in the basolateral membrane so that the cell volume can respond to changes in interstitial osmolality. In addition, the lipid composition of the luminal membrane is such that the water permeability is extremely low. As solute is actively reabsorbed from the lumen, the osmolality of the luminal fluid decreases and free water is generated. Thus, the thick ascending limb is considered part of the diluting segment of the nephron. Although neonatal transport of sodium chloride in the TAL is only about 20% of that of the adult TAL the normal newborn is still able to dilute its urine and avoid hyponatremia.

Distal convoluted tubule

The distal convoluted tubule (DCT) continues reabsorbing sodium by an active mechanism driven by the Na-K-ATPase located on the basolateral membrane ( Fig. 7.4 ). ^, Sodium can then enter the cell down its electrochemical gradient through the luminal sodium-chloride cotransporter (NCC). The membranes of the DCT are similar to those of the TAL in that they have very low water permeability. This allows the DCT to continue to remove solute from the lumen, leaving behind the water, which will continue to dilute the tubular fluid and create free water. The TAL and DCT are collectively known as the diluting segment.