Evaluation of applying drug dose adjustment by physicians in patients with renal impairment

Abstract

Objective

To determine whether appropriate dose adjustment was taken into account or not by the physicians when prescribing drugs in patients with renal impairment.

Design

A retrospective chart review was performed and included 98 adult in-patients, diagnosed with renal impairment based on clinical evaluation and laboratory data, in King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, who was admitted to the hospital from September 2005 to January 2011. Data of the patients were noted and recorded including baseline demographics, clinical data, laboratory data, renal state, treatment data and medications.

Results

The initial number of the patients was reduced to 80 where a total of 502 drugs were investigated in the present study with an average of six drugs per patient. Of these 502 studied drugs, 196 (39%) required dose adjustment where 92 (46.9%) were adjusted and 104 (53.1%) were not adjusted. It was found also that most of the drugs requiring dose adjustment were antibiotics (39.8%).

Conclusion

The current study confirms that physicians still do not take into account sufficiently patients’ renal function when prescribing drugs. Continuous medical education and collaboration with clinical pharmacist should be encouraged for quality improvement in patients with renal impairment.

1. Introduction

Kidney is the major organ for maintaining homeostasis of fluid and electrolytes and, in particular, plays an important role in the disposition of many drugs. Chronic kidney disease (CKD) is divided into five stages (Table 1) (Hartmann et al., 2010). It is important to know whether a patient is suffering from renal insufficiency (CKD stages 2 through 5) and, if so, at what stage, because nearly half of all drugs or their metabolites are excreted by the kidneys, and 30% of all adverse effects of medication have a renal cause or a renal effect (Corsonello et al., 2005). Therefore, the patients with renal dysfunction must be closely monitored for the drugs that require modifications of dosages or frequencies to prevent adverse effects (Preston et al., 1995).

Table 1.

The severity of renal insufficiency and stages of chronic kidney disease (CKD) (Hartmann et al., 2010).

CKD stage	GFR (mL/min)	Renal insufficiency
1	120–90	Non
2	90–60	Mild
3	60–30	Intermediate
4	30–15	Severe
5	15–0	Preterminal, requires dialysis

The high prevalence of renal failure and the large number of drugs with renal elimination or potential nephrotoxicity suggest that physicians should consider renal function when prescribing (Reed and Sabatini, 1986; Liano et al., 1996; Hunt et al., 1998). The few studies that have assessed drug prescribing in renal impairment showed that adjustments were rarely applied by the physicians (Cantu et al., 1992; Wong and Jones, 1998). The current study was designed to assess the prevalence of proper applying dose adjustment by the physicians in patients with renal impairment in the university hospital in Jeddah, Saudi Arabia.

2. Methods

A retrospective chart review was performed at the male/female medical ward in King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia on adult patients who was admitted to the hospital from September 2005 to January 2011. The study was done after approval from KAUH review board and it was conducted to assess applying dose adjustment by the physicians in patients with impaired renal function.

The study was carried out on patients diagnosed with renal impairment based on clinical evaluation and laboratory data. All patients with associated conditions as hypertension, diabetes mellitus or other diseases or patients with kidney transplant were enrolled in the study. The initial study group of 98 was reduced to 80 as a result of insufficient recorded data available in 17 patients and the transfer of one patient to another hospital. Data of the patients were noted and recorded including baseline demographics, clinical data, laboratory data (including serum creatinine and creatinine clearance), renal state (including degree of renal impairment and dialysis), treatment data and medications (including drugs, dosages, concomitant drugs and dose adjustment). Data of the study were analyzed descriptively.

Creatinine clearance (CrCl) was calculated using the Cockroft–Gault equation (Cockroft and Gault, 1976):

$$\text{Male}:\text{CrCl}=(140-\text{age})\text{x}\text{weight}/(72\text{x serum creatinine})$$

$$\text{Female}:\text{CrCl}=(140-\text{age})\text{x}\text{weight}\text{x}0.85/(72\text{x serum creatinine})$$

If the actual body weight of the patient was more than 120% of the ideal body weight (IBW), the weight would be adjusted by the formula listed as follows and be plugged into the Cockroft–Gault equation.

$$\text{IBW for male adults}:\text{IBW}(\text{kg})=(\text{height}(\text{cm})-80)\text{x}0.7$$

$$\text{IBW for female adults}:\text{IBW}(\text{kg})=(\text{height}(\text{cm})-70)\text{x}0.6$$

$$\text{Dosing weight}=(\text{actual body weight}-\text{IBW})\text{x}0.4+\text{IBW.}$$

3. Results

A total of 502 drugs in 80 patients were investigated in the current study with an average of six drugs per patient. The mean age of these patients was 60 years with 55% male and 45% female. All patients have associated diseases with the highest percent having multiple diseases including hypertension, diabetes and other diseases (40%) and 5% of patients were renally transplanted. The highest number of patients was in stage 3 (4%) (Table 2).

Table 2.

Baseline characteristics of patients with chronic kidney disease (CKD) (n = 80).

Characteristics	n (%)
Sex
–Male –Female	44 (55)
	36 (45)
Median age	60
Associated diseases
–CKD + hypertension –CKD + diabetes –CKD + hypertension + diabetes –CKD + hypertension + diabetes + other diseases –CKD + other diseases rather than hypertension or diabetes –Patients with renal transplant	10 (12.5)
	2 (2.5)
	20 (25)
	32 (40)
	12 (15)
	4 (5)
Degree of CKD
–Stage 2 –Stage 3 –Stage 4 –Stage 5	16 (20)
	32 (40)
	22 (27.5)
	10 (12.5)

Of these 502 studied drugs, 196 (39%) required dose adjustment where 92 (46.9%) were adjusted and 104 (53.1%) were not adjusted (Fig. 1). The current results showed also that most of the drugs requiring dose adjustment were antibiotics (39.8%). Vancomycin was frequently given and ranked the highest among antibiotics being recommended for renal dosing adjustment. Besides, ranitidine, atenolol and furosemide were also the highest among all drugs recommended for renal dosing adjustment (Table 3).

Figure 1.

Adjusted and non-adjusted drugs in patients with renal impairment.

Table 3.

Non-adjusted drugs in patients with renal impairment.

Drug (n= 196)	Non-adjusted n (%)
Analgesics
–Tramadol (4)	0 (0)
Antacid
–Ranitidine (14)	12 (86)
Antimicrobials
–Amikacin (8) –Ampicillin (2) –Augmentin (6) –Ceftazidime (8) –Cefuroxime (4) –Ciprofloxacin (10) –Co-trimazole (2) –Imipenem (8) –Meropenem (8) –Tazocin (8) –Vancomycin (12) –Fluconazole (2)	0 (0)
	0 (0)
	6 (100)
	8 (100)
	0 (0)
	0 (0)
	2 (100)
	8 (100)
	8 (100)
	0 (0)
	12 (100)
	0 (0)
Antidiabetcs
–Glibincamide (2) –Gliclazide (2) –Metformin (4)	2 (100)
	0 (0)
	0 (0)
Antiemetics
–Domperidone (2) –Metoclopramide (4)	0 (0)
	4 (100)
Antigout
–Allopurinol (4) –Colchicine (4)	2 (50)
	4 (100)
Cardiovascular drugs
–Aspirin (16) –Atenolol (10) –Digoxin (4) –Enalapril (2) –Bisoprolol (4)	4 (25)
	10 (100)
	4 (100)
	0 (0)
	2 (50)
Diuretics
–Furosemide (30) –Hydrochlorothiazide (6)	10 (34)
	6 (100)
Immunosuppressants
–Mycophenolate (6)	0 (0)

4. Discussion

Many drugs are extensively excreted by the kidney, and therefore, they will accumulate in patients with poor renal function and cause profound adverse effects (Livornese et al., 2004). For these drugs, dosage adjustment according to renal function is indicated in order to avoid overdosage and iatrogenic risk of renal impairment or its aggravation (Alkhuniazi and Schrier, 1996). Physicians should pay careful attention when considering drug therapies with active or toxic metabolites that can accumulate and contribute to exaggerated pharmacologic effects or adverse drug reactions in patients with chronic kidney disease (Munar and Singh, 2007). It should also be noted that product information sheets often have only crude dosing guidelines for renal impairment and sometimes specifically exclude patients with renal impairment, usually because these patients were excluded from the primary studies (Doogue and Polasek, 2011).

The current study showed that 53.1% of the drugs that require adjustment were not adjusted by the physicians’ orders. In a similar study conducted in a public hospital in Paris, France, Salomon et al., 2003, found that 34% of the ordered medications by the physicians were inappropriate. Several explanations may be elucidated for this lack of dose adjustment. These include physicians’ underestimation of the consequences of mild renal impairment in terms of subsequent iatrogenic risks or their poor knowledge of the medications requiring adjustment in renal impairment (Dryer, 1977). Although used in daily practice, serum creatinine level is often inappropriate to assess actual renal function and leads to underestimation of renal impairment, particularly in elderly. The assessment of creatinine clearance with Cockroft–Gault equation, taking into account patient’s weight, age and serum creatinine provides an accurate assessment of renal function (Cockroft and Gault, 1976). Another explanation is that physicians do not calculate creatinine clearance and underestimate the necessity of adjusting medication dosage.

The present study showed also that most of the drugs requiring dose adjustment were antibiotics especially vancomycin. This finding was in accordance with that found by Hou et al., 2011, in Taiwan, with gentamicin as the most ranked antibiotics.

It is important to realize that the necessary dose adjustment could be calculated proportionally to the changed elimination rate (and thus inversely proportionally to the half-life). Either the dose of a drug must be reduced in inverse proportion to the half-life, or else the interval between doses must be prolonged proportionally to the half-life (Aronoff, 1999). If, for example, the half-life of a drug is five times longer because of renal insufficiency, its dose should be reduced to 20% of the normal dose (1/5 = 0.20). If the dose is thus reciprocally lowered and the interval between doses is unchanged, then the area under the curve will be the same as in the normal case, but with higher trough values which are what is customarily measured in drug monitoring. This can easily lead physicians unfamiliar with the relevant pharmacokinetics to draw false conclusions and then reduce the dose of the drug still further, e.g., in the case of vancomycin. In order to achieve effective levels in patients with renal failure, the trough values of vancomycin should lie between 10 and 15 mg/L (Hartmann et al., 2010).

Beside patient outcome improvement with dose adjustment, we can also benefit from cost saving medication. As an example, if vancomycin 500 mg/vial that was highly ranked in the current study was adjusted from one vial every 12 h to one vial once daily; hence, one vial will be saved every day.

The main limitation of the present study was that it was a retrospective study lacking the direct contact and observation of the patients, and some data about the patients and dialytic state were not included in all files. Moreover, the study was performed only in one hospital, so, a large multicenter study may be needed in the future.

5. Conclusion

The current study showed that physicians still do not pay enough attention to the need of dose adjustment for most drugs in patients with renal impairment. Continuous medical education of the physicians and collaboration with clinical pharmacist is an important issue for quality improvement regarding renally impaired patients.

6. Competing interests

None.