Hypertension Drugs Plus NSAIDs May Injure Kidneys

Acute kidney injury (AKI) — a serious disorder that can lead to hospitalization, dialysis and death — has a number of causes, including various drugs. Elderly patients with hypertension, diabetes, congestive heart failure or chronic kidney disease are particularly susceptible to drug-induced kidney injury.

A recent British Medical Journal (BMJ) study suggests that an increased risk of AKI is associated with combining nonsteroidal anti-inflammatory drugs (NSAIDs) with two antihypertensive drugs: a diuretic plus either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB). The risk was found to be highest during the first 30 days of starting an NSAID in patients who also are already taking a diuretic plus an ACE inhibitor or an ARB.

These findings are particularly relevant to patients with hypertension, diabetes, congestive heart failure or chronic kidney disease, because such patients are routinely treated with diuretics, ACE inhibitors and ARBs.

Overview of acute kidney injury

The kidneys are vital organs that perform numerous functions, each critical to sustaining life. The most important function of the kidneys is to filter out of the blood waste products from normal body metabolism and excrete them into the urine. The kidneys also precisely regulate the amount of water in the body and the concentration of electrolytes such as sodium, potassium, calcium and chloride.

When AKI occurs, the rate at which the kidneys filter metabolic waste products from the blood suddenly decreases. In addition, the processes for controlling fluid and electrolytes are disrupted. Patients with early or mild AKI usually have no symptoms, and the disorder can be detected only by blood tests that measure kidney function. Patients with more severe AKI may experience loss of appetite, nausea, vomiting, fatigue, weakness, swelling (edema), shortness of breath and high blood pressure.

NSAIDs and the kidneys

NSAIDs are used to treat the inflammation, pain and fever associated with a wide variety of acute and chronic conditions. They are frequently used to treat the most common form of arthritis in the elderly: osteoarthritis, or degenerative joint disease.

NSAIDs can adversely impact the kidneys by blocking the production of special hormone-like substances known as prostaglandins. These compounds control blood flow to the filters within the kidneys.

In healthy people, production of prostaglandins in the kidneys is minimal, so the use of NSAIDs by such individuals has little impact on kidney function. However, in people who have lost excessive amounts of body fluid (as sometimes happens in those taking diuretics), have congestive heart failure or chronic kidney disease, or take ACE inhibitors or ARBs, increased production of prostaglandins in the kidneys plays an important role in maintaining near-normal blood flow to the filters of the kidneys, where waste products are removed from the blood. Therefore, in such patients, use of NSAIDs can seriously impair kidney function.

BMJ study overview

The study was done by researchers in Canada and published on Jan. 8, 2013. The researchers used computerized medical and pharmacy records for adult patients seen by general practitioners in the U.K. to assess the risk of developing AKI after exposure to antihypertensive drugs — in particular, diuretics, ACE inhibitors and ARBs — combined with NSAIDs. The study was well-designed, with many features to minimize the possibility of study bias.

The medical records for the study were stored in the Clinical Practice Research Datalink (CPRD), which was established in 1987 and is the largest computerized database in the world of medical records from primary care patients. From these records, the researchers identified a group of 487,372 adult patients who were prescribed drugs for hypertension (diuretics, ACE inhibitors, ARBs, calcium channel blockers, beta blockers or alpha blockers) between January 1997 and December 2008. The patients had been followed for at least one year before receiving their first prescription for any hypertension drugs. The researchers excluded patients with a history of any cancer, kidney disease, hepatitis, autoimmune disease, traumatic injury, HIV infection or drug abuse. Patients were followed until one of the following occurred: They were admitted to the hospital for the first time for AKI, they developed one of the above-listed diseases or disorders for which patients were initially excluded from the study, or they died. The average total length of patient follow-up was 5.9 years.

From the population of patients meeting their inclusion criteria, the researchers identified all patients who were hospitalized for AKI for the first time. (These patients are referred to as “cases.”) To be counted as a case, AKI had to be the primary diagnosis leading to the hospitalization. The research team identified 2,215 cases and compared them to a randomly selected control group of 21,993 patients without AKI who were matched to the cases by age, sex and duration of follow-up. For all cases and control-group members, they obtained information on all the drugs prescribed between entry into the study and the date on which a case developed AKI.

BMJ study findings

The overall incidence rate of AKI in the study population was low: 7 cases per 10,000 people per year.

The researchers first evaluated the risk of developing AKI in current users of a double-therapy combination. (“Double therapy” was defined as using an NSAID plus one of the following hypertension drugs: a diuretic, an ACE inhibitor or an ARB. For the purposes of this study, “current users” were defined as those patients whose supply of the most recent prescriptions for the drugs of interest overlapped within the 90-day period before a case patient was diagnosed with AKI.)

After adjusting for multiple factors that might predispose patients to kidney disease, such as the presence of diabetes and hypertension severity, the researchers found that there was no increased risk of AKI in current users of double-therapy combinations. In other words, current users of a diuretic plus an NSAID did not have an increased risk of AKI compared with current users of diuretics who were not using NSAIDs. Likewise, current users of double therapy with either an ACE inhibitor or an ARB with an NSAID did not have an increased risk of AKI compared with patients taking an ACE inhibitor or an ARB without an NSAID.

However, patients currently using a triple-therapy combination — a diuretic, an ACE inhibitor or an ARB, and an NSAID — did have a 31 percent greater risk of developing AKI in comparison with current users of a diuretic plus an ACE inhibitor or an ARB without an NSAID. On further analysis, the researchers found that the increased risk of AKI was highest during the first 30 days of exposure to the triple-drug regimen, an increased risk of 82 percent. With increasing duration of exposure to the triple-drug regimen, the risk of AKI progressively decreased until there was no increased risk seen after more than 90 days of use.

Study implications

In general, observational studies like the BMJ study, showing an association between the use of a particular drug (or drug combination) and a specific adverse event, don’t unequivocally prove that the drug causes the adverse event. However, given the known physiologic effects that diuretics, ACE inhibitors, ARBs and NSAIDs have on the kidneys, it is biologically highly plausible that treatment with a combination of three of these drugs could cause AKI.

The December 2012 issue of Worst Pills, Best Pills News warned readers against combining an ACE inhibitor with an ARB because such drug combinations fail to provide additional benefit but do cause a higher rate of several life-threatening side effects compared with therapy using only one of these medications.

In the case of drug regimens combining a diuretic plus an ACE inhibitor or ARB with an NSAID, we are not advising that such combinations never be used. There certainly are patients who have one disease or disorder for which a diuretic plus an ACE inhibitor or ARB is indicated (for example, hypertension or heart failure) and another disease for which an NSAID is indicated (for example, severe osteoarthritis or other inflammatory condition).

However, physicians prescribing, and patients taking, such combinations of drugs need to be aware of the potential for AKI and be vigilant for signs and symptoms of this disorder. Patients who already have underlying kidney disease or other risk factors for  developing AKI should try to avoid these combinations whenever possible. For example, kidney disease patients taking an ACE inhibitor and a diuretic should try acetaminophen (TYLENOL) instead of an NSAID for pain relief or fever management.

For patients with kidney disease who take a diuretic and an ACE inhibitor or ARB and require treatment with an NSAID, the duration of NSAID use should be limited to the shortest time necessary. Since the first 30 days of triple therapy may be the riskiest time for developing AKI, blood tests monitoring kidney function should be done prior to starting the NSAID, then every one to two weeks for the first month and periodically thereafter.