The kidneys play a major role in maintaining K⁺ balance. Two-thirds of the filtered K⁺ are reabsorbed in the proximal tubule and 20% in the ascending limb of loop of Henle. The regulation of K⁺ excretion occurs via the secretion of K⁺ in the distal tubule and collecting duct. When the dietary intake of K⁺ is too large, K⁺ excretion can exceed the K⁺ filtered load. Three major factors control the rate of distal K⁺ secretion: (a) the activity of the Na⁺, K⁺-ATPase; (b) the electrochemical gradient for K⁺ across the apical membrane; and (c) the permeability of the apical membrane to K⁺. The excretion of K⁺ is regulated by the plasma K⁺ concentration, the acid–base balance, aldosterone, and AVP.

Seventy percent of the filtered Ca²⁺ is reabsorbed in the proximal tubule, 20% in the thick ascending limb of loop of Henle, 9% in the distal tubule, and 1% in the collecting duct. In the proximal tubule, Ca²⁺ enters the apical membrane by diffusing through a paracellular route or Ca²⁺ channels, down the electrochemical gradient created by the primary and secondary active transport of Ca²⁺ out of the basolateral membrane (Ca²⁺-ATPase; Na⁺-Ca²⁺ antiport). Reabsorption of Ca²⁺ in the ascending limb is largely passive down the electrochemical gradient created by the active reabsorption of Na⁺. The reabsorption of Na⁺ and Ca²⁺ changes in parallel in both the proximal and the thick ascending limb of loop of Henle. This accounts for the occurrence of parallel changes in Ca²⁺ and Na⁺ excretion. In the distal tubule the reabsorption of Ca²⁺ is entirely active and independent from that of Na⁺. The renal excretion of Ca²⁺ is regulated by parathyroid hormone, calcitriol, and calcitonin (1).

The proximal tubule reabsorbs 80% of the filtered load of Pi and the distal tubule 10%. The remaining 10% is excreted in the urine. Pi enters the apical membrane by a 2Na⁺–Pi symporter and exits the cell across the basolateral membrane by a Pi–anion antiporter. The excretion of Pi is mainly regulated by parathyroid hormone. Extracellular fluid (ECF) volume expansion decreases the reabsorption of Pi. Other factors depressing the reabsorption of Pi include metabolic acidosis and the glucocorticoids (1).

Angiotensin II stimulates proximal Na⁺ and water reabsorption by increasing the apical Na⁺/H⁺ exchange. It is an important secretagogue for aldosterone. By acting on the zona glomerulosa of the adrenal cortex to release aldosterone, it indirectly favors distal Na⁺ reabsorption. Angiotensin II release is activated by a decrease in extracellular fluid volume and renal perfusion.

Aldosterone stimulates the distal reabsorption of Na⁺ by increasing the permeability of the collecting tubule luminal membrane to Na⁺. Aldosterone also favors the secretion of K⁺ and H⁺ and increases the reabsorption of Cl^–. Aldosterone stimulates the Na⁺, K⁺-ATPase and the production of ATP. The secretion of aldosterone by the adrenal cortex is stimulated by angiotensin II, hyperkalemia, and severe hyponatremia.

The heart produces two natriuretic peptides: the ANP stored in the atrial myocytes and the brain natriuretic peptide (BNP) stored in the ventricular myocytes. Both peptides are released when the heart dilates. The kidneys produce a related natriuretic peptide termed urodilatin. In general, the natriuretic peptides antagonize the actions of the renin–angiotensin–aldosterone system. The 28-amino acids peptide is released when atrial stretch receptors sense an increase in the effective circulating volume. ANP stimulates the excretion of Na⁺ by (a) increasing GFR via vasodilatation of the afferent arterioles; (b) inhibiting renin release and the secretion of aldosterone; (c) inhibiting the Na⁺, K⁺-ATPase in the inner medullary collecting duct, and (d) closing the epithelial Na⁺ channels.

The prostaglandins, synthesized by the cyclooxygenases in the renal cortex, the medullary interstitium, and the collecting duct epithelial cells, increase Na⁺ excretion. They do it by increasing GFR and by inhibiting Na⁺ reabsorption in the collecting duct.

Norepinephrine and epinephrine released from sympathetic nerves and the adrenal medulla, respectively, stimulate Na⁺ reabsorption in the proximal tubule, the thick ascending limb of the loop of Henle, the distal tubule, and the collecting duct.

Dopamine, synthesized by proximal tubular cells and dopaminergic nerves, increases the excretion of Na⁺ by inhibiting Na⁺ proximal reabsorption.

Water following Na⁺ passively, its reabsorption is increased by all the factors that stimulate Na⁺ reabsorption. The hormone that really regulates water balance is AVP, a nonapeptide with a molecular weight of 1,099 daltons.

Three types of receptors mediate the actions of AVP. V_1A receptors are located on vascular smooth muscle and mediate vasoconstriction. V_1B receptors are present in the anterior pituitary gland and mediate the release of adrenocorticotropic hormone. The V₂ receptors are located in the renal distal tubule and collecting duct. AVP binding to the V₂ receptors leads to activation of an adenylyl cyclase with subsequent rise in intracellular cyclic AMP. This second messenger mediates the translocation of intracellular vesicles containing the water channel aquaporin-2 into the apical plasma membrane (3) and increases the transcription of aquaporin 2 (AQP-2). AVP-regulated AQP-2 shuttling is the primary determinant for water permeability of the collecting duct and, consequently, for the antidiuresis. In addition, AVP stimulates Na⁺–K⁺–2Cl^– cotransport in the ascending limb of loop of Henle via V₂ receptors.

The release of AVP is rapid, its plasma half-life is short (10 to 15 minutes), thus allowing a fine regulation of the plasma osmolality. Small changes in P_osm (±3 mOsm per kg H₂ O) activate or inhibit AVP release. Osmoreceptors, located in the supraoptic nucleus of the hypothalamus, regulate the release of AVP. Volo- and baroreceptors also affect AVP release. Because of the greater sensitivity of the osmoreceptors, their influence predominates when changes in osmolality and plasma volume are moderate. When large changes in plasma volume occur, however, the influence of the volo- and baroreceptors predominates over that of the osmoreceptors, leading to “inappropriate” secretion of AVP, with consequent water retention and hemodilution. Nonosmotic stimulation or inhibition of AVP release occurs as a consequence of drugs (nicotine, morphine, barbiturates), pain, and respiratory or cerebral distress (1).

NaCl, the major osmotically active solute in ECF, determines its volume. The balance between the intake and the
renal excretion of Na⁺ thus regulates ECF volume, and as a consequence cardiac output and blood pressure. Long-term changes in Na⁺ excretion are regulated by aldosterone. More rapid changes in Na⁺ excretion are achieved by changes in GFR and/or by various intrarenal hormones that regulate Na⁺ reabsorption.

ECF volume is closely related to plasma volume. Alterations in plasma volume are sensed both on the venous and on the arterial side of the circulation. Arterial sensors perceive the adequacy of blood flow in the arterial circuit, a parameter coined as effective circulating volume. This volume is also sensed by baroreceptors located in the juxtaglomerular apparatus of the kidney. A decrease in renal perfusion pressure activates the renin–angiotensin–aldosterone system. Changes in the effective circulating volume activate other intrarenal hormones that modulate Na⁺ reabsorption either directly by an action on tubular transport or indirectly by changes in GFR (1).

The plasma osmolality is maintained within narrow limits. A 2% to 3% increase in P_osm stimulates the osmoreceptors with the consequent release of AVP, leading to the reabsorption of free water in the collecting duct. Urine flow rate decreases and the osmolality of the urine increases. The opposite happens when P_osm decreases by 2% to 3%. The concentration of urine can vary from 40 to 1,400 mOsm per kg H₂ O, depending on whether AVP is completely absent or maximally stimulated. Concentration of the urine requires the presence of a hypertonic medullary interstitium. Impaired NaCl transport in the thick ascending limb of loop of Henle or defective countercurrent multiplier mechanisms results in a decrease in maximal urine osmolality (1).

Salt and water retention with edema formation can occur as a primary event or as a consequence of reduced effective circulating volume with secondary hyperaldosteronism. The use of diuretics can be lifesaving when Na retention is associated with an expansion of the ECF volume. It may on the contrary further compromise the situation when sodium
retention occurs in response to homeostatic mechanisms mobilized to defend the circulating volume. The use of diuretics therefore requires careful monitoring of the patient’s hemodynamic states and an understanding of his or her underlying condition (6,13).

Arterial hypertension may be secondary to salt retention and expansion of the ECF volume. Na⁺ retention may be directly related to excessive synthesis of aldosterone in primary hyperaldosteronism. In the renal vascular form of hypertension, increased formation of angiotensin II elevates the blood pressure by inducing vasoconstriction and by stimulating sodium reabsorption. In essential hypertension, the retention of Na⁺ is not obvious. It has been recently hypothesized that impaired extrusion of Na⁺ out of the cells, secondary to defective Na⁺/Ca²⁺ counter transport could lead to an increase in intracellular Ca²⁺ with consequent increased vascular contractility (17). By leading to ECF volume contraction, diuretics decrease the blood pressure. They are often used as first-line drugs in the treatment of arterial hypertension (18,19). In adults, low-dose diuretics (hydrochlorothiazide 12.5 mg; torasemide 2.5 mg) constitute effective one-daily monopharmacotherapies for mild-to-moderate uncomplicated essential hypertension (17).

Diuretics can be used in various situations associated with dyselectrolytemia. They can increase K⁺ excretion in hyperkalemic states (loop diuretics, thiazides), increase calcium excretion in hypercalcemia (loop diuretics), or decrease the rate of calcium excretion in hypercalciuric states (thiazides). Increased HCO₃^– excretion can be achieved by the acetazolamide, whereas increased H⁺ excretion can be stimulated by loop diuretics.

This condition is characterized by the resistance of the collecting duct to the action of ADH. It can be due either to a X-linked congenital defect in the V2 receptors or to an autosomal recessive mutation in the aquaporin-2 molecule. The patient with diabetes insipidus excretes large amounts of dilute urine. The thiazides can reduce the extracellular space volume by impairing sodium distal reabsorption and increasing NaCl excretion. This decrease in ECF volume stimulates proximal salt and water retention, thus eventually leading to reduced urine flow rate. Prolonged treatment with hydrochlorothiazide–amiloride appears to be more effective and better tolerated than with just hydrochlorothiazide. Such treatment is as efficacious as the association hydrochlorothiazide–indomethacin, with fewer severe side effects (20).

Because they have been shown to variably increase total renal blood flow, loop diuretics are often administered to patients with oliguric renal insufficiency, in the hope of
promoting diuresis and improving GFR and renal perfusion (31). Although diuretic administration may convert oliguric ARF to nonoliguric ARF, there is no evidence that this treatment can ameliorate renal function or improve the outcome of patients with ARF (21).

Diuretics such as acetazolamide, furosemide, or hydro-chlorothiazide can be used to test distal tubular acidification or distal sodium reabsorption defects.

Dopamine, a naturally occurring catecholamine, acts on the specific dopaminergic receptors DA₁ and DA₂, and also activates the α- and the β-adrenoreceptors. Dopamine may improve renal function by (a) increasing cardiac output through stimulation of the β-adrenergic receptors, (b) increasing blood pressure by inotropic and vasoactive mechanisms, (c) increasing renal perfusion via stimulation of the dopamine receptors in the renal vessels, and (d) directly inhibiting sodium reabsorption (22). The beneficial effects of low-dose dopamine in oliguric states are variable and, when present, modest. Because of a great overlap in the response to dopamine and significant individual variation, no dose is clearly only a beneficial renal dose (23). Even at low doses, dopamine may increase cardiac contractility and systemic vascular resistance and produce tachycardia, arrhythmia, tissue necrosis, and digital gangrene (24). Dopamine also blunts hypoxic ventilatory drive and may increase pulmonary shunt fraction in critically ill patients. Until efficacy and safety are demonstrated in control prospective studies, the use of dopamine as a renal protective agent remains questionable (25). The price of the modest improvement in urine output and sodium excretion with dopamine may be too high.