Abstract & Commentary
Comment by Allan J. Wilke, MD, Associate Professor of Family Medicine, Medical College of Ohio, Toledo, OH, and Associate Editor, Internal Medicine Alert
Synopsis: Concealed renal insufficiency is common and contributes to adverse drug reactions from hydrosoluble medications.
Source: Corsonello A, et al. Arch Intern Med. 2005;165:790-795.
Aging affects drug metabolism. the physiology behind this includes decreased liver and renal reserve, changes in body composition favoring a greater percentage of fat,1 and decreased perfusion of the liver and kidneys. Drugs that undergo a high degree of first-pass extraction have a decreased rate of metabolism.2 The glomerular filtration rate (GFR) falls by 10 mL/min/decade, resulting in a 50% decline between the ages of 30 to 80 years.3 Renal insufficiency in the elderly can be missed if we rely solely on measurement of serum creatinine (Cr). They have a smaller percentage by weight of muscle mass than young adults and inefficiently filter a lower concentration of Cr. The physiologic corollary to this is that the elderly have a smaller water mass than younger people (50% vs 60-65%, respectively). This means that the volume of distribution of hydrophilic drugs (or, as Corsonello and colleagues describe them, hydrosoluble drugs) is smaller in the elderly. The incidence of adverse drug reactions (ADRs) is higher in the elderly. Corsonello et al hypothesize that these 2 observations are linked.
The Gruppo Italiano di Farmacovigilanza nell’Anziano (GIFA) has conducted a large observational study of ADRs. They collected data between 1993 and 1998 and enrolled 17,186 hospitalized patients. After excluding patients who died during hospitalization, those on whom data were not available, and those who were not on geriatric or internal medicine services, the population was reduced to 11,687 patients.
Corsonello et al used the World Health Organization’s definition of ADR, and the patients’ physicians determined whether or not an ADR occurred. GFR was estimated by the Modification of Diet and Renal Disease Study (MDRD) formula (see Table). Corsonello et al defined 3 conditions: normal renal function (NRF, Cr < 1.2 mg/dL and GFR > 60 mL/min), concealed renal insufficiency ([CRI], Cr < 1.2 mg/dL and GFR < 60 mL/min), and overt renal insufficiency ([ORI], Cr > 1.2 mg/dL and GFR > 60 ml/min). The patients were grouped into 3 classes based on renal function. The NRF class had 7195 patients (62%); CRI, 1631 (14%); and ORI, 2861 (24%). In addition to the usual demographic measures, the other variables included body mass index (BMI), serum albumin, functional status by activities of daily living (ADL), and cognitive status.
Table: MDRD Study Formula
The percentage of patients older than 80 years was greater in the concealed and overt renal insufficiency groups than in the normal group (23% NRF, 44% CRI, 42% ORI), as were the percentage of male patients (47% NRF, 53% CRI, 64% ORI). Patients in the normal group were less dependent in ADLs, less cognitively impaired, less likely to be prescribed more that 4 medications, and less likely to have more than 4 diagnoses. They were less likely to have hypoalbuminemia, diabetes, congestive heart failure, and hypertension.
During hospitalization, 941 patients (8.0%) had an ADR. Significant risk factors for ADRs included age older than 65 years, female gender, hypoalbuminemia, having more than 4 diagnoses, taking more than 4 medications, having a length of stay in excess of 14 days, and having ORI (but not CRI). When the ADRs were grouped by hydrosolubility, age was associated with hydrosoluble drugs and female gender with non-hydrosoluble drugs, and the other risk factors appeared with statistically equivalent frequencies. ADRs to non-hydrosoluble drugs were not associated with renal function. Patients afflicted with an ADR to a hydrosoluble drug were more likely to have CRI (odds ratio, 1.61) or ORI (odds ratio, 2.02).
Hydrosoluble drugs accounted for 301 of 941 ADRs. The hydrosoluble drugs most likely to cause an ADR (and the reaction) were diuretics (hypokalemia), digitalis (bradycardia), angiotensin-converting enzyme inhibitors (hypotension), and hypoglycemic agents (hypoglycemia).
Comment
GIFA previously published results of a study showing that ADRs were responsible for 3.4% of all hospital admissions and that the greatest risk factor was the number of medications taken.4 This study also points to polypharmacy as an ADR risk factor. Polypharmacy probably results from drug-drug interactions,5 often with the same drugs implicated in this study. Although several other risk factors were identified, only polypharmacy and hypoalbuminemia are potentially modifiable. Faced with this, what should clinicians do? Calculating GFR on all elderly patients is a necessary first step. Fully one patient in 7 in this population had CRI. If you don’t look for it, you won’t see it. (If you are unable to perform MDRD calculations in your head, get a medical calculator. I use MedMath, a Palm OS program, available as a component of Epocrates® or as a free stand-alone download.6 A Pocket PC version7 from the National Kidney Foundation or Epocrates® and an on-line calculator8 from the National Kidney Disease Education Program, an initiative of the National Institutes of Health, are available for free.) Patients with NRF comprised 62% of the population, but suffered only 55% of the ADRs. In patients with ORI or CRI or who are hypoalbuminemic, a review of all medications (but especially hydrosoluble ones) with an eye to reducing the number or dosage of drugs to a bare minimum is good geriatric medicine. Although there is no evidence for this, switching from a hydrosoluble drug to an equivalent non-hydrosoluble one may reduce the occurrence of ADRs. Intuitively, correcting hypoalbuminemia seems reasonable, but there is no evidence for this, either.
Some factors that may have skewed these results are the exclusion of patients who died and the physician’s judgment when deciding whether an ADR had occurred. What prevented physicians from not recognizing, ignoring, or not reporting an ADR when it occurred? All could have reduced the number of ADRs identified. Another thing to keep in mind is hydrosolubility is not an all-or-nothing proposition. Finally, Corsonello et al did not distinguish between ADRs based on the severity of the reaction.
References
1. Fulop T Jr, et al. Gerontology. 1985;31:6-14.
2. Turnheim K. Exp Gerontol. 2003;38:843-853.
3. Luckey AE, Parsa CJ. Arch Surg. 2003;138:1055-1060.
4. Onder G, et al. J Am Geriatr Soc. 2002;50: 1962-1968.
5. Juurlink DN, et al. JAMA. 2003;289:1652-1658.
6. www.smi-web.stanford.edu. Accessed May 8, 2005.
7. www.kidney.org/professionals/kdoqi/cap.cfm. Accessed May 8, 2005.
8. www.nkdep.nih.gov/professionals/gfr_calculators/mdrd.htm. Accessed May 8, 2005.
Concealed renal insufficiency is common and contributes to adverse drug reactions from hydrosoluble medications.
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