Answer. Blood is pumped from the heart and travels through large blood vessels such as the aorta. The aorta branches into the renal arteries. After several more branchings, the blood vessels are very tiny and eventually become part of a filtering system. Unwanted molecules present in the blood come into contact with the delicate membranes of these filtering units (glomeruli) of the kidney. In healthy individuals, the metabolites of medications either cross these membranes or bypass the filters into the post-glomerular nearby vessels. From these sites, metabolites can be secreted into the kidney’s tubules.

When kidney function decreases, the burden of the metabolites of medications is greater than the kidney mass required to eliminate them. The excess buildup of these metabolites can harm the remaining kidney tissue and other tissues in the body.

Medications are designed such that some of their metabolites combine with proteins.1 A fraction remains unbound and is thus free and biologically active. In kidney failure, organic waste products also combine with proteins and thus compete with drug metabolites for the limited available binding sites. This forces more of the metabolites to remain free and unbound to protein, resulting in greater toxicity with some medications. This is true with medications such as phenytoin (Dilantin), used to treat seizures. Dilantin levels should be closely monitored in patients with impaired kidney function.

Some agents, such as non-steroidal anti-inflammatory drugs (NSAIDS), sulfa drugs, antiviral agents, ciprofloxacin and aminoglycosides and radiocontrast media can occasionally cause acute renal failure.2, 3, 4 As in any clinical conditions where the drug is excreted by the kidney or may injure the kidney if renal function is reduced, dosages of these medications should be reduced and caution should be taken.

NSAIDS are not metabolized by the kidney but by the liver. However, one of the enzymes that is inhibited by them, cyclic oxygenase, is required to maintain renal blood flow, particularly in clinical conditions such as nephrotic syndrome, severe liver disease and heart failure.5 Thus, the use of medications such as ibuprofen (Motrin), Indocin, Celebrex and Vioxx may decrease blood flow into the kidney and seriously worsen renal function.6

Other agents may accumulate in renal insufficiency and lead to adverse effects in other organ systems such as the central nervous system. This has been shown with famotidine (Pepcid).7 Digoxin (Lanoxin) is a drug that stimulates the heart. It is metabolized by the kidney and has a narrow window between therapeutic benefit and toxicity. Thus, its dose should be reduced in kidney disease.

Insulin is metabolized by the kidney. In diabetics with secondary kidney disease, it is sometimes necessary to reduce the dose of insulin to avoid hypoglycemia, an abnormal decrease of sugar in the blood, and in all situations, it is advisable to closely monitor blood sugar levels.

Potassium is a mineral that is filtered and secreted into renal tubules and excreted by the kidney. The level of serum potassium must be maintained within a narrow limit to avoid severe toxicity. Both hypokalemia, a deficiency of potassium in the blood and hyperkalemia, the presence of an abnormally high concentration of potassium in the blood can cause serious cardiac arrhythmias. In renal impairment, there is compensation so that the levels of potassium are maintained in a steady state. However, certain drugs that lead to high potassium levels, such as potassium sparing duretics (amiloride, diazide), beta blockers, converting enzyme inhibitors (lisinopril, accupril, captopril, ramipril, enalopril) angiotensin receptor blockers (losartan, telmisartan, candesartan, valsartan) and NSAIDS (Motrin, indomethacin) should be used with caution.8

Here are tips regarding the use of medications for those with impaired kidney function:

1. Always check with your doctor, even OTC medications. Drugs metabolized by the kidney require a different loading dose, maintenance dose and/or dosing interval. Your physician will need to know what your GFR rate is before making a decision.
2. Many drugs are not metabolized by the kidney, but because they cause kidney failure should be avoided, or their doseage should be reduced in patients with chronic kidney disease.
3. In many instances, drug levels should be monitored on a regular basis. The drug dosage can be adjusted based on these levels.
4. The simultaneous use of multiple medications is often necessary in patients with chronic diseases. Drug interactions may occur in these circumstances, particularly if there is underlying liver or kidney impairment. Some drugs such as coumadin may interact with food or alcohol. Other drugs may interfere with grapefruit juice.
5. Report potential side effects or changes that may lead to drug side effects. For instance, if you are on corticosteroids, let your doctor know immediately if you are running a fever or have abdominal pain. If you are on blood thinners, even aspirin, let your doctor know if you hit your head, no matter how minor the injury may seem.

Answer provided by Stephen Z. Fadem, MD, FACP, who serves as a member of AAKP’s Medical Advisory Board and the AAKP Board of Directors. Dr. Fadem is a practicing nephrologist in Houston, Texas.

References:

1. Browne TR. Pharmacokinetics of antiepileptic drugs. Neurology 1998; 51:S2-7.
2. Kodner CM, Kudrimoti A. Diagnosis and management of acute interstitial nephritis. Am Fam Physician 2003; 67:2527-34.
3. Brewster UC, Perazella MA. Acute tubulointerstitial nephritis associated with celecoxib. Nephrol Dial Transplant 2004; 19:1017-8.
4. Albright RC, Jr. Acute renal failure: a practical update. Mayo Clin Proc 2001; 76:67-74.
5. Bleumink GS, Feenstra J, Sturkenboom MC, Stricker BH. Nonsteroidal anti-inflammatory drugs and heart failure. Drugs 2003; 63:525-34.
6. Perazella MA. Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 2003; 325:349-62.
7. Yoshimoto K, Saima S, Echizen H, et al. Famotidine-associated central nervous system reactions and plasma and cerebrospinal drug concentrations in neurosurgical patients with renal failure. Clin Pharmacol Ther 1994; 55:693-700.
8. Perazella MA. Drug-induced hyperkalemia: old culprits and new offenders. Am J Med 2000; 109:307-14.

The American Association of Kidney Patients presents Ask the Doctor, an opportunity for readers to submit kidney related health questions to healthcare professionals who specialize in an area of concern. The answers are not to be construed as a diagnosis and therefore, alterations in current healthcare should not occur until the patient’s physician is consulted.

This article originally appeared in the June/July 2004 issue of Kidney Beginnings: The Magazine, Vol. 3, No. 2.

Back