This chapter is divided into three sections. The first section covers major renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15–1, Table 15–1). Several autacoids, which exert multiple, complex effects on renal physiology (adenosine, prostaglandins, and urodilatin, a renal autacoid closely related to atrial natriuretic peptide), are also discussed. The second section describes the pharmacology of diuretic agents. Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (vaptans, or vasopressin antagonists). The physiology of each nephron segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. The third section of the chapter describes the clinical applications of diuretics.
Sodium bicarbonate (NaHCO3), sodium chloride (NaCl), glucose, amino acids, and other organic solutes are reabsorbed via specific transport systems in the early proximal tubule
Glomerulus tubule Proximal straight tubule Cortex Outer medulla Diuretics1 Acetazolamide/canagliflozin 2 Osmotic agents (mannitol, urearetics) 3 Loop agents (eg, furosemide) 4 Thiazides 5 Aldosterone antagonists 6 ADH antagonists Adenosine 2Thin descending limb H2O H2O H2O (+ADH) Inner medulla Loop of Henle Thin ascending limb Thick ascending limb Na+ K+ K+ 2Cl– Ca2+ Mg2+ convoluted tubule (+PTH) (+aldosterone) 124356277777
FIGURE 15–1 Tubule transport systems and sites of action of diuretics. ADH, antidiuretic hormone; PTH, parathyroid hormone.
(proximal convoluted tubule, PCT). Potassium ions (K+) are reabsorbed via the paracellular pathway. Water is reabsorbed passively, through both a transcellular pathway (mediated by a specific water channel, aquaporin-1 [AQP1]) and a paracellular pathway (likely mediated by claudin-2). Importantly, the water permeability of the PCT is very high, and hence, the osmolality of proximal tubular fluid is maintained at a nearly constant level, and the gradient from the tubule lumen to surrounding interstitium is very small. As tubule fluid is processed along the length of the proximal tubule, the luminal concentrations of most solutes decrease relative to the concentration of inulin, an experimental marker that is filtered but neither secreted nor absorbed by renal tubules. Approximately 66% of filtered sodium ions (Na+), 85% of the NaHCO3, 65% of the K+, 60% of the water, and virtually all of the filtered glucose and amino acids are reabsorbed by the proximal tubule in normal humans.