A 65-year-old man has a history of diabetes and chronic kidney disease with baseline creatinine of 2.2 mg/dL. Despite five different antihypertensive drugs, his clinic blood pressure is 176/92 mm Hg; he has mild dyspnea on exertion and 2–3+ edema on exam. He has been taking furosemide 80 mg twice a day for 1 year now. At the clinic visit, hydrochlorothiazide 25 mg daily is added for better blood pressure control and also to treat symptoms and signs of fluid overload. Two weeks later, the patient presents to the emergency department with symptoms of weakness, anorexia, and generalized malaise. His blood pressure is now 91/58 mm Hg, and he has lost 15 kg in 2 weeks. His laboratory tests are significant for a serum creatinine of 10.8 mg/dL. What has led to the acute kidney injury? What is the reason for the weight loss? What precautions could have been taken to avoid this hospitalization?
Abnormalities in fluid volume and electrolyte composition are common and important clinical disorders. Drugs that block specific transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine volume (diuretics) have been described since antiquity, it was not until 1937 that carbonic anhydrase inhibitors were first described and not until 1957 that a much more useful and powerful diuretic agent (chlorothiazide) became available.
Technically, a “diuretic” is an agent that increases urine volume, whereas a “natriuretic” causes an increase in renal sodium excretion and an “aquaretic” increases excretion of solute-free water. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics and antidiuretic hormone antagonists (see Agents That Alter Water Excretion) are aquaretics and are not directly natriuretic; however, because they increase urine volume, diuretic is still a correct term to describe them. Most recently, an entirely new class of agents has been developed that block urea transport. These agents result in increased urine output and increased urea excretion but do not increase excretion of electrolytes. While they are technically aquaretics, they are also referred to as urearetics. These agents are not yet available for therapy but are in early investigational stages.
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), also are 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 ...