Utility, or not, of estimates of glomerular filtration rate in modifying drug dosage, with particular reference to enoxaparin

A reduced clearance of some drugs in renal failure is a problem, particularly with drugs that are excreted by the kidney substantially unmetabolised and also have significant toxicity and a low therapeutic ratio. The problem is compounded by the significant inaccuracy of estimated glomerular filtration rate (eGFR). The aim was to develop general recommendations to reduce the risk of drug toxicity in renal failure, with particular reference to enoxaparin. The substantial inaccuracies in eGFR (eGFR in 32% of patients is different from measured GFR by 20-30%) are compounded when using a dichotomous decision tree (renal failure or not). As the eGFR approaches the GFR decision boundary, for classification as renal failure or not, misclassification approaches 50%. Recommendations, when patients are at risk, include the following: acknowledge inaccuracies of eGFR, particularly in anthropometrically diverse populations; measure drug levels wherever possible; realise that drug levels after early doses relate more to volume of distribution, rather than renal function, allowing time for modification of the drug dose; where accurate urine collection is feasible, use creatinine clearance as an estimate of GFR; and use eGFR as a (more) continuous, rather than dichotomous, variable to adjust dosage, exampled by enoxaparin.     

Magnitude of underascertainment of impaired kidney function in older adults with normal serum creatinine

OBJECTIVES: To estimate in a community-dwelling elderly population the magnitude of renal function misclassification, occurring when persons with normal serum creatinine have reduced glomerular filtration rate (GFR), and to describe the participant characteristics related to misclassification. DESIGN: Cross-sectional. SETTING: Population-based study of older Italian people. PARTICIPANTS: Six hundred sixty participants aged 65 to 92 with normal serum creatinine. MEASUREMENTS: GFR was estimated using the Cockcroft-Gault equation and creatinine clearance (CrCl) calculated from 24-hour urine collection. RESULTS: In participants with normal serum creatinine, 39% and 25% had moderate renal function impairment (GFR<60 mL/min) according to the Cockcroft-Gault equation and CrCl calculation, respectively. Prevalence of moderate renal impairment in those aged 65 to 74, 75 to 84, and 85 and older was 18.6%, 58.3%, and 96.8%, respectively (P for trend <.001) according to the Cockcroft-Gault equation, and 15%, 35.7%, and 58.7%, respectively (P for trend <.001) based on the CrCl calculation. In addition, female sex (P<.001) and normal or underweight (P<.05) were factors associated with high risk of misclassification. CONCLUSION: Serum creatinine alone is one of the most widely used methods of assessing renal function in clinical practice despite its well-known poor correlation with GFR. A large proportion of older persons with impaired renal function are not diagnosed if clinicians rely solely on normal serum creatinine as evidence of normal renal function. Opportunities may be missed for slowing progression of kidney disease, managing comorbidities and complications related to renal impairment, and adjusting drug dosage for renal function.     

The effect of impaired renal function on the pharmacokinetics of metoprolol after single administration of a 14/190 metoprolol OROS system

Renal function is known to sometimes have a significant effect on the pharmacokinetics of drugs or drug metabolites, which are eliminated in appreciable amounts by the kidneys. For this reason, we conducted a study to compare the plasma concentration profiles of metoprolol and its metabolite, alpha-hydroxymetoprolol (OH-metoprolol), in healthy volunteers and in renally impaired patients. Following a single oral dose of a 14/190 metoprolol OROS (oral osmotic) tablet, plasma metoprolol profiles were shown to be similar for both subject groups. However, in renally impaired patients, renal clearance of OH-metoprolol was reduced and mean plasma levels of OH-metoprolol were increased approximately two- to threefold in comparison with healthy volunteers. The accumulation of OH-metoprolol in plasma, however, is unlikely to contribute to the beta-blocking effect of metoprolol, since OH-metoprolol possesses only one tenth the activity of its parent compound.     

重症心力衰竭合并肾功能不全40例联合药物治疗的远期疗效

目的 :观察重症心力衰竭合并肾功能不全患者联合用药的远期疗效。方法 :对 4 0例重症心力衰竭合并肾功能不全的患者 ,根据个体差异逐渐调整地高辛、依那普利、美托洛尔、氢氯噻嗪、螺内酯的用药剂量 ,长期随访观察两年。结果 :对重症心力衰竭合并肾功能不全患者长期联合用药治疗 ,随访显示 ,心功能明显改善 (P <0 .0 0 1) ,未加重肾功能损害 (P >0 .0 5 ) ,病死率下降。结论 :重症心力衰竭合并肾功能不全的患者 ,长期联合用药治疗 ,并根据血清肌酐清除率及地高辛浓度调整用药剂量 ,可有效改善心功能 ,不加重肾功能损害 ,并提高了生存质量     

Renal Considerations in Geriatric Patients With Heart Disease

Renal and electrolyte complications occur commonly in elderly patients with heart disease. Renal function declines with age. A seemingly normal serum creatinine level in the geriatric patient often represents a creatinine clearance of 60 ml/min or less. It is important to measure or estimate the creatinine clearance in an older patient with a borderline high or elevated serum creatinine level before administering renally excreted drugs. The Cockcroft and Gault formula is recommended for estimating the creatinine clearance in such patients. Impaired renal function can also predispose to drug-induced hyperkalemia in geriatric patients; the most common offending drugs are potassium chloride supplements, potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, digoxin, and nonsteroidal anti-inflammatory drugs. Elderly patients should be evaluated for renal artery stenosis if they have worsening of previously stable hypertension, new-onset hypertension, or progressive renal impairment on angiotensin-converting enzyme inhibitors. Risk factors and management guidelines for radiocontrast nephropathy in the elderly are also discussed.     

Elevated blood urea nitrogen level as a predictor of mortality in patients admitted for decompensated heart failure

BACKGROUND: Hospitalization for decompensated heart failure is associated with high mortality after discharge. In heart failure, renal function involves both cardiovascular and hemodynamic properties. We studied the relation between renal dysfunction and mortality in patients admitted for decompensated heart failure. METHODS: The prognostic importance of four measures of renal function-blood urea nitrogen, serum creatinine, blood urea nitrogen/creatinine ratio, and estimated creatinine clearance-was evaluated in 541 patients (mean [+/- SD] age, 63 +/- 14 years; 377 men [70%]) with a previous diagnosis of heart failure (96% with New York Heart Association class III or IV symptoms) who were admitted for clinical decompensation. RESULTS: During a mean follow-up of 343 +/- 185 days, 177 patients (33%) died. In multivariable Cox regression models, the risk of all-cause mortality increased with each quartile of blood urea nitrogen, with an adjusted relative risk of 2.3 in patients in the upper compared with the lower quartiles (95% confidence interval [CI]: 1.3 to 4.1; P = 0.005). Creatinine and estimated creatinine clearance were not significant predictors of mortality after adjustment for other covariates. Blood urea nitrogen/creatinine ratio yielded similar prognostic information as blood urea nitrogen (adjusted relative risk = 2.3; 95% CI: 1.4 to 3.8; P = 0.0007 for patients in the upper compared with the lower quartiles). CONCLUSION: Blood urea nitrogen is a simple clinical variable that provides useful prognostic information in patients admitted for decompensated heart failure. In this setting, elevated blood urea nitrogen levels probably reflect the cumulative effects of hemodynamic and neurohormonal alterations that result in renal hypoperfusion.     

The aging liver: structural and functional changes and their consequences for drug treatment in old age

BACKGROUND/OBJECTIVE: Numerous age-related changes in hepatic structure and function have been described, although liver function seems to be quite well maintained in old age. Few consistent and reproducible observations and a lack of correlation between structural and functional data characterize the present state of our knowledge. In contrast to renal clearance, no equally reliable method exists to estimate hepatic drug clearance. The contribution of age to altered drug clearance in the elderly is difficult to assess as drug interactions, numbers and types of drugs taken at a time, underlying disease and increased interindividual variability are superimposed to the aging process. METHODS: A comprehensive computer-assisted search of the literature. RESULTS: A decline in liver volume and blood flow and a reduction in in vitro and in vivo metabolic capacity have been shown in older subjects, and the physiologic basis of reduced hepatic drug clearance in this age group. CONCLUSIONS: After decades of research into the matter, the old and well-known aphorism "start lower--go slower" is valid more than ever in the field of geriatric prescribing. Not only renally excreted drugs but also substances which are metabolized and excreted by the liver should be used at a starting dose which is 30-40% smaller than the average dose used in middle-aged adults.     

Concealed renal failure and adverse drug reactions in older patients with type 2 diabetes mellitus

BACKGROUND: In elderly patients serum creatinine may be normal despite decreased glomerular filtration rate (GFR). The aim of this study was to evaluate the prevalence of this "concealed" renal failure, i.e., renal failure with normal serum creatinine levels, in elderly diabetic patients, and to verify whether it is a risk factor for adverse drug reactions (ADR) to hydrosoluble drugs. METHODS: We used data on 2257 hospitalized patients with type 2 diabetes mellitus enrolled in the Gruppo Italiano di Farmacovigilanza nell'Anziano study. On the basis of serum creatinine and calculated GFR, patients were grouped as follows: normal renal function (normal serum creatinine levels and normal GFR), concealed (normal serum creatinine levels and reduced GFR), or overt (increased creatinine levels and reduced GFR) renal failure. GFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation. The outcome of the study was the incidence of ADR to hydrosoluble drugs during the hospital stay. The relationship between renal function and ADR was evaluated using Cox regression analysis including potential confounders. RESULTS: Concealed renal failure was observed in 363 (16.1%) of patients studied. Patients with concealed or overt renal failure were older, had more frequently cognitive impairment and polypharmacy, and had lower serum albumin levels than did those with normal renal function. Both concealed (hazard ratio = 1.90; 95% confidence interval, 1.04-3.48; p =.036) and overt (hazard ratio = 2.23; 95% confidence interval, 1.40-3.55; p =.001) renal failure were significantly associated with ADR to hydrosoluble drugs. The use of more than four drugs also qualified as an independent risk factor for ADRs to hydrosoluble drugs during hospital stay. CONCLUSIONS: Older diabetic patients should be systematically screened to ascertain the presence of concealed renal failure in an attempt to optimize the pharmacological treatment and reduce the risk of ADRs.     

Concealed renal insufficiency and adverse drug reactions in elderly hospitalized patients

BACKGROUND: Adverse drug reactions (ADRs) are common causes of in-hospital complications for elderly people. The purpose of the present study is to verify whether concealed renal insufficiency, that is, reduction of the estimated glomerular filtration rate (GFR) in people with normal serum creatinine levels, is a risk factor for ADRs in elderly hospitalized patients. METHODS: We used data on 11,687 hospitalized patients enrolled in the Gruppo Italiano di Farmacovigilanza nell'Anziano study. The outcomes of the study were any ADR, ADR to hydrosoluble drugs, and ADR to any other drug during the hospital stay. We compared 3 groups: normal renal function (normal serum creatinine levels and normal estimated GFRs), concealed (normal serum creatinine levels and reduced estimated GFRs), or overt (increased creatinine levels and reduced estimated GFRs) renal insufficiency. The relationship between renal function and ADR was evaluated using contingency tables and multiple regression analysis including potential confounders. RESULTS: Concealed renal insufficiency was detected in 1631 (13.9%) patients and was frequently associated with male sex and poor nutritional status. Hydrosoluble drugs were responsible for 301 of the 941 recorded ADRs. After adjusting for potential confounders, both concealed (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.15-1.25) and overt (OR, 2.02; 95% CI, 1.54-2.65) renal failure were associated with ADR to hydrosoluble drugs, but not with ADR to other drugs (OR, 0.83 [95% CI, 0.65-1.08], and OR, 1.01 [95%CI, 0.83-1.23], respectively). CONCLUSION: Older hospitalized patients frequently have impaired renal function despite normal serum creatinine levels and are exposed to an increased risk of ADRs to hydrosoluble drugs.     

Pitfalls of using estimations of glomerular filtration rate in an intensive care population

Background: Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing. Aims: Recently, an estimation of GFR (eGFR) was suggested as a method of estimating GFR. How well this formula predicts GFR in unwell patients with normal initial serum creatinine concentrations has not been examined. Methods: The accuracy of the eGFR (before and after adjustment for actual body surface area (BSA)) was compared with measured and with estimated creatinine clearance using the Cockcroft Gault (CG) formula adjusted for total and lean body weight. Results: A total of 237 observations was recorded in 47 subjects. These were initially analysed independently, and then using the first observation only. Overall the mean difference between measured creatinine clearance and eGFR was ?12 mL/min (95% confidence interval (CI) ?20 to ?3), between measured creatinine clearance and CG +17 mL/min (95% CI 9–24), between measured creatinine clearance and CG adjusted for ideal body weight +12 mL/min (95% CI 4–21) and between measured creatinine clearance and eGFR ‘unadjusted’ for BSA 5 mL/min (95% CI ?2–13). Conclusions: Using either eGFR or CG formulae to estimate renal function in ICU subjects with normal serum creatinine concentrations is inaccurate. Although correcting for BSA improves the eGFR, this requirement to measure height and weight removes a major attraction for its use. We suggest that eGFR should not be automatically calculated in the ICU setting.     

Cardiac drugs: adjusting their use in aging patients

Reduced drug metabolism, both renal and hepatic, occurs with aging. Algorithms for dose adjustments of renally excreted drugs are available, but dose adjustments must be empiric for drugs which undergo hepatic metabolism. Decreased drug clearance in combination with potentially increased sensitivity to drugs in the elderly means that, as a general rule, drug dosages should be reduced as the age of the patient increases. The frequent need for multi-drug therapy may also lead to adverse effects in the elderly compared with younger cardiac patients. Managing the geriatric patient requires careful drug monitoring and a heightened awareness of the potential for adverse drug effects.     

Prediction of cardiovascular outcome by estimated glomerular filtration rate and estimated creatinine clearance in the high-risk hypertension population of the VALUE trial

BACKGROUND: Reduced renal function is predictive of poor cardiovascular outcomes but the predictive value of different measures of renal function is uncertain. METHODS: We compared the value of estimated creatinine clearance, using the Cockcroft-Gault formula, with that of estimated glomerular filtration rate (GFR), using the Modification of Diet in Renal Disease (MDRD) formula, as predictors of cardiovascular outcome in 15 245 high-risk hypertensive participants in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. For the primary end-point, the three secondary end-points and for all-cause death, outcomes were compared for individuals with baseline estimated creatinine clearance and estimated GFR < 60 ml/min and > or = 60 ml/min using hazard ratios and 95% confidence intervals. Coronary heart disease, left ventricular hypertrophy, age, sex and treatment effects were included as covariates in the model. RESULTS: For each end-point considered, the risk in individuals with poor renal function at baseline was greater than in those with better renal function. Estimated creatinine clearance (Cockcroft-Gault) was significantly predictive only of all-cause death [hazard ratio = 1.223, 95% confidence interval (CI) = 1.076-1.390; P = 0.0021] whereas estimated GFR was predictive of all outcomes except stroke. Hazard ratios (95% CIs) for estimated GFR were: primary cardiac end-point, 1.497 (1.332-1.682), P < 0.0001; myocardial infarction, 1.501 (1.254-1.796), P < 0.0001; congestive heart failure, 1.699 (1.435-2.013), P < 0.0001; stroke, 1.152 (0.952-1.394) P = 0.1452; and all-cause death, 1.231 (1.098-1.380), P = 0.0004. CONCLUSION: These results indicate that estimated glomerular filtration rate calculated with the MDRD formula is more informative than estimated creatinine clearance (Cockcroft-Gault) in the prediction of cardiovascular outcomes.     

Fenoldopam in critically ill patients with early renal dysfunction. A crossover study

Background: Acute kidney injury is a frequent problem among many critically ill patients, commonly in the context of multiple organ failure and decreased renal perfusion. Its presence conveys a poor prognosis. Currently, effective therapeutic interventions are limited and dopaminergic agonists have been suggested as an option to prevent further damage. Methods: We performed a randomized, double‐blinded, prospective crossover study in 17 patients admitted to our trauma intensive care unit (ICU) with evidence of impaired renal function. Patients were randomized to a 24‐h intravenous infusion of low‐dose fenoldopam or placebo. When the infusion of fenoldopam or placebo was completed, patients underwent a 24‐h “washout” period in which no study intervention was performed. This sequence was repeated in each patient with the opposite agent, so each patient served as his own control. Four‐hour creatinine collections were taken during the last 4 h of each infusion and washout periods to determine creatinine clearance changes during and after the administration of the study drug. Results: The creatinine clearance was higher with fenoldopam infusion than with placebo infusion (P= 0.045). The FENa was not significantly different. Conclusions: Our study showed that low‐dose Fenoldopam increases creatinine clearance in the critically ill with renal insufficiency. Fenoldopam may be a useful drug in ICU patients with early renal dysfunction.     

Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*)

Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor with a primarily non‐renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM). Methods: Linagliptin pharmacokinetics was studied under single‐dose and steady‐state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end‐stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM). Results: Renal excretion of unchanged linagliptin was <7% in all groups. Under single‐dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration–time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20–60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady‐state AUC and C_max values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half‐life of linagliptin ranged from 14–15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r² = 0.18) was seen between creatinine clearance and steady‐state exposure. Conclusions: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.     

Clinical significance of renal function in hypertensive patients at high risk: results from the INSIGHT trial

BACKGROUND: Increasing evidence suggests renal involvement in hypertension-related cardiovascular and cerebrovascular complications. To assess this role of renal function in more detail, we studied the evolution of renal function and the relationship of renal function with mortality and morbidity in the Intervention as a Goal in Hypertension Treatment (INSIGHT) study. METHODS: The INSIGHT study was a double-blind, randomized, multicenter trial in patients with hypertension and at least 1 additional cardiovascular risk factor. Treatment consisted of nifedipine gastrointestinal therapeutic system, 30 mg/d, or hydrochlorothiazide-amiloride (25 mg/d of hydrochlorothiazide and 2.5 mg/d of amiloride hydrochloride). Primary outcome was a composite of cardiovascular death, myocardial infarction, heart failure, and stroke. Renal function was assessed by measuring creatinine clearance, serum creatinine level, and serum uric acid level and by the presence of proteinuria. RESULTS: Creatinine clearance fell more in nifedipine recipients than in hydrochlorothiazide-amiloride recipients. Renal insufficiency developed in 2% of nifedipine recipients and 5% of hydrochlorothiazide-amiloride recipients. Primary outcomes occurred in 15% of patients with increased serum creatinine levels and 6% of patients with normal levels (odds ratio [OR] 2.89; 95% confidence interval [CI], 1.92-4.36; P<.001). Primary outcomes were more likely in patients with low creatinine clearance (<60 mL/min) than in those with higher clearances (9% vs 5%, respectively [OR, 1.51, 95%CI, 1.22-1.88; P<.001]). CONCLUSIONS: Renal function is an important predictor of risk in hypertensive patients at high risk. Antihypertensive treatment with a long-acting dihydropyridine calcium channel blocker may better preserve renal function than would treatment with diuretics.     

Prognostic significance of creatinine clearance rate in patients with heart failure and normal serum creatinine

Kidney failure is an important prognostic factor in patients with heart failure. Renal function is usually evaluated by measuring the serum creatinine level. However, a normal creatinine level can mask established kidney failure. We investigated the prognostic significance of the estimated creatinine clearance rate (Cockcroft formula) in 235 patients with heart failure and a normal serum creatinine level. The two-year mortality rate was significantly higher in patients who had established kidney disease (i.e., a creatinine clearance rate <60 mL/min) than in those who did not (35.1% vs. 10.1%, P<.001). Even when only patients without established kidney failure were analyzed, the creatinine clearance rate had prognostic significance (rate > or = 90 mL/min, mortality 3.2%; rate 89-60 mL/min, mortality 13.9%; P=.02). On Cox regression analysis, which included age, sex, heart failure etiology, left ventricular ejection fraction, diabetes and hypertension, the creatinine clearance rate remained an independent predictor of mortality.     

Renal function in newly diagnosed multiple myeloma — A demographic study of 1353 patients

This study describes the occurrence of renal failure among 1353 newly diagnosed cases of multiple myeloma. Renal function was evaluated by serum creatinine concentration in 1353 cases, 31% of whom had renal failure at the time of diagnosis. In 1206 cases an estimation of creatinine clearance was made. When renal failure was defined by using creatinine clearance estimation, 49% had renal failure at the time of diagnosis. Renal failure was present in 24% of patients with an M component of IgG-, 31% of IgA- and 100% of IgD-type. 52% of patients with light chain disease had renal failure. The frequency of renal failure was similar in lambda-and kappa-light chain disease. Patients with a high excretion of Bence Jones protein in the urine (> 10 g/24 h) had renal failure significantly more often than patients with lower excretion. Renal failure was related to advanced disease; 41% of patients with stage III (Durie-Salmon) disease had renal failure. Renal failure was found in 45% of patients with hypercalcaemia. When estimated creatinine clearance was used as a predictor of renal function, the same trends were found as mentioned above. In addition, the proportion of patients with renal failure was found to increase with advancing age.