Chronic kidney disease (CKD) is a worldwide public health problem affecting more than 50 million people, and more than 1 million of them are receiving kidney replacement therapy (Levey et al, 2009). The kidney is an important organ in regulating body fluids, electrolyte balance, removal of metabolic waste, and drug excretion from the body. Impairment or degeneration of kidney function affects the pharmacokinetics of drugs. Some of the more common causes of kidney failure include disease, injury, and drug intoxication. Table 21-1 lists some of the conditions that may lead to chronic or acute renal failure. Acute diseases or trauma to the kidney can cause uremia, in which glomerular filtration is impaired or reduced, leading to accumulation of excessive fluid and blood nitrogenous products in the body. Uremia generally reduces glomerular filtration and/or active secretion, which leads to a decrease in renal drug excretion resulting in a longer elimination half-life of the administered drug.
Table 21-1 Common Causes of Kidney Failure ||Download (.pdf)
Table 21-1 Common Causes of Kidney Failure
|Pyelonephritis||Inflammation and deterioration of the pyelonephrons due to infection, antigens, or other idiopathic causes.|
|Hypertension||Chronic overloading of the kidney with fluid and electrolytes may lead to kidney insufficiency.|
|Diabetes mellitus||The disturbance of sugar metabolism and acid–base balance may lead to or predispose a patient to degenerative renal disease.|
|Nephrotoxic drugs/metals||Certain drugs taken chronically may cause irreversible kidney damage—eg, the aminoglycosides, phenacetin, and heavy metals, such as mercury and lead.|
|Hypovolemia||Any condition that causes a reduction in renal blood flow will eventually lead to renal ischemia and damage.|
|Neophroallergens||Certain compounds may produce an immune type of sensitivity reaction with nephritic syndrome—eg, quartan malaria nephrotoxic serum.|
In addition to changing renal elimination directly, uremia can affect drug pharmacokinetics in unexpected ways. For example, declining renal function leads to disturbances in electrolyte and fluid balance, resulting in physiologic and metabolic changes that may alter the pharmacokinetics and pharmacodynamics of a drug. Pharmacokinetic processes such as drug distribution (including both the volume of distribution and protein binding) and elimination (including both biotransformation and renal excretion) may also be altered by renal impairment. Both therapeutic and toxic responses may be altered as a result of changes in drug sensitivity at the receptor site. Overall, uremic patients have special dosing considerations to account for such pharmacokinetic and pharmacodynamic alterations.
Uremic patients may exhibit pharmacokinetic changes in bioavailability, volume of distribution, and clearance. The oral bioavailability of a drug in severe uremia may be decreased as a result of disease-related changes in gastrointestinal motility and pH caused by nausea, vomiting, and diarrhea. Mesenteric blood flow may also be altered. However, the oral bioavailability of a drug such as propranolol (which has a high first-pass effect) may be increased in patients with renal impairment as a result of the decrease in first-pass hepatic metabolism (Bianchetti et al, 1978).