Approach to the patient with salt-wasting tubulopathies

Sodium is the main ion of the extracellular compartments, and it is through control of sodium reabsorption that the kidneys maintain volume homoeostasis and systemic blood pressure. The amount of sodium that is first filtered by the glomerulus and then reabsorbed in the tubule is quite staggering: assuming a glomerular filtration rate of 100 mL/min and a serum sodium concentration of 140 mmol/L, an average-sized person filters about 20,000 mmol of sodium per day, equivalent to the amount in 1.2 kg of cooking salt. In the steady state, the amount of sodium excreted is equal to the amount ingested. An average Western diet contains about 8–10 g of salt per day; a low-salt diet may be around 2 g per day. Under physiological conditions, the tubules reabsorb about 99% of filtered sodium. This enormous task is accomplished by a combination of distinct and sequentially oriented sodium or sodium-coupled transport systems along the nephron and the concerted and parallel action of some of these systems within the kidney. These are described, along with the consequences of disorders of the processes. A diagnostic approach to salt-losing states such as Fanconi, Bartter Gitelman and other syndromes, and hypoaldosteronism, is described.

The molecular logic of sodium-coupled neurotransmitter transporters

Synaptic transmission at chemical synapses requires the removal of neurotransmitter from extracellular spaces. At synapses in the central nervous system, this is accomplished by sodium-coupled transport proteins, integral membrane proteins that thermodynamically couple the uptake of neurotransmitter to the uptake of sodium and, in some cases, the uptake and export of additional ions. Recent X-ray crystallographic studies have revealed the architecture of the two major families of neurotransmitter transporters and, together with additional biochemical and biophysical studies, have provided insights into mechanisms of ion coupling, substrate uptake, and inhibition of transport.

Electrophysiology of sodium-coupled transport in proximal renal tubules

Effects of sodium-coupled transport on intracellular electrolytes and electrical properties of proximal renal tubule cells are described in this review. Simultaneous with addition of substrate for sodium-coupled transport to luminal perfusates, both cell membranes depolarize. The luminal cell membrane depolarizes due to opening of sodium-cotransport pathways. The depolarization of the peritubular cell membrane during sodium-coupled transport is primarily due to a circular current reentering the lumen via the paracellular pathway. The depolarization leads to a transient decrease of basolateral potassium conductance that in turn amplifies the depolarization. However, within 5-10 min of continued exposure to substrate, potassium conductance increases again, and peritubular cell membrane repolarizes. During depolarization the driving force of peritubular bicarbonate exit is reduced. As a result net alkalinization of the cell prevails despite an increase of intracellular sodium activity, which reduces the driving force for the sodium-hydrogen ion exchanger and would thus have been expected to acidify the cell. No evidence is obtained for regulatory inhibition of sodium-coupled transport by intracellular sodium or calcium. Rather, luminal cotransport is altered by the change of driving forces.