D W Cockcroft, M H Gault
Prediction of creatinine clearance from serum creatinine.
Nephron. 1976;16(1):31-41.
Abstract/Text
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
堀尾勝：GFR推定法.腎機能（GFR）・尿タンパク測定の手引. P81-91, 日本腎臓学会編, 東京医学社, 2009.
Revised equations for estimated GFR from serum creatinine in Japan.
Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.ajkd.2008.12.034. Epub 2009 Apr 1.
Abstract/Text
D Du Bois, E F Du Bois
A formula to estimate the approximate surface area if height and weight be known. 1916.
Nutrition. 1989 Sep-Oct;5(5):303-11; discussion 312-3.
Abstract/Text
日本腎臓病薬物療法学会 編：腎臓病薬物療法ガイドブック 腎臓病薬物療法専門・認定薬剤師テキスト第2版．じほう、2022.
Kosuke Doki, Sibylle Neuhoff, Amin Rostami-Hodjegan, Masato Homma
Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling.
CPT Pharmacometrics Syst Pharmacol. 2019 Feb;8(2):118-126. doi: 10.1002/psp4.12382.
Abstract/Text
Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or coadministration of a P-glycoprotein inhibitor. Because the combined effects of drug-drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P-glycoprotein inhibitors is empirical at its best. We conducted virtual drug-drug interactions studies between DABE and the P-glycoprotein inhibitor verapamil in RI populations using physiologically based pharmacokinetic modeling. The developed physiologically based pharmacokinetic model for DABE and dabigatran was used to predict trough dabigatran concentrations in the presence and absence of verapamil in virtual RI populations. The population-based physiologically based pharmacokinetic model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as drug-drug interactions in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies.
© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
Giusti DL, Hayton WL: Dosage regimen adjustment. Drug Intel. Clin. Pharmacy 7: 1973; 382,.
平田純生, 和泉 智, 古久保 拓 編：改訂3版 透析患者への投薬ガイドブック．じほう、2017.
日本腎臓病薬物療法学会 編：腎機能別薬剤投与量POCKET BOOK第4版．じほう、2022.
Emily Hart, Terry E Dunn, Steven Feuerstein, David M Jacobs
Proton Pump Inhibitors and Risk of Acute and Chronic Kidney Disease: A Retrospective Cohort Study.
Pharmacotherapy. 2019 Apr;39(4):443-453. doi: 10.1002/phar.2235. Epub 2019 Mar 21.
Abstract/Text
BACKGROUND: Proton pump inhibitors (PPIs) have been linked to acute kidney injury (AKI) and chronic kidney disease (CKD); however, current evidence has only been evaluated in a small number of studies with short follow-up periods. This study examined the association between PPI use and risk of incident AKI and CKD in a large population-based health maintenance organization (HMO) cohort.
METHODS: Patients aged 18 years or older, without evidence of preexisting renal disease, started on PPI therapy, and those continuously enrolled for at least 12 months between July 1993 and September 2008 were identified in an HMO database. Incidences of AKI and CKD were defined using documented International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes or a glomerular filtration rate less than 60 ml/min/1.73 m2 after initiation of PPI therapy. Patients with AKI were followed for up to 90 days (cohort 1), and patients with CKD required at least 1 year of follow-up (cohort 2). Multivariable logistic regression analyses were used to adjust for differences in demographics (excluding race), comorbidities, and medication use between groups.
RESULTS: In 93,335 patients in the AKI cohort, 16,593 of whom were exposed to PPIs, the incidence rate of AKI was higher in the PPI group than nonusers (36.4 vs 3.54 per 1000 person-years, p<0.0001, respectively). In adjusted models, PPI exposure was associated with an increased risk of AKI (adjusted odds ratio [aOR] 4.35, 95% confidence interval [CI] 3.14-6.04, p<0.0001). In 84,600 patients in the CKD cohort, 14,514 of whom were exposed to PPIs, the incidence rate of CKD was higher in the PPI group than nonusers (34.3 vs 8.75 per 1000 person-years, p<0.0001, respectively). In adjusted models, PPIs were associated with a higher risk of CKD compared with controls (aOR 1.20, 95% CI 1.12-1.28, p<0.0001). Associations between PPI use and AKI and CKD persisted in propensity score-matched analyses.
CONCLUSION: The use of PPIs is associated with an increased risk of incident AKI and CKD. This relationship could have a considerable public health impact; therefore, health care provider education and deprescribing initiatives will be necessary to raise awareness and reduce health care burden.
© 2019 Pharmacotherapy Publications, Inc.
古久保拓, 他: 短期間経口投与でAcyclovir中毒をきたした透析症例.臨床薬理33: 277-279, 2002.
Y W Lam, S Banerji, C Hatfield, R L Talbert
Principles of drug administration in renal insufficiency.
Clin Pharmacokinet. 1997 Jan;32(1):30-57. doi: 10.2165/00003088-199732010-00002.
Abstract/Text
Normal renal function is important for the excretion and metabolism of many drugs. Renal diseases which affect glomerular blood flow and filtration, tubular secretion, reabsorption and renal parenchymal mass alter drug clearances and lead to the need for alterations in dosage regimens to optimise therapeutic outcome and minimise the risk of toxicity. Renal disease is increasing and the cost of care has risen progressively over the past decade. Part of these costs is related to inappropriate drug therapy and excessive drug use. Although there are a variety of methods for evaluating the various aspects of renal function, the most practical and commonly used clinical measure of renal function is estimated creatinine clearance (CLCR) as a marker for glomerular filtration. This is useful since alterations in drug clearance are proportional to alterations in CLCR, and this relationship is used as the basis for changing doses and dosage intervals for drugs which are largely renally excreted. Two populations, neonates and the elderly, are at risk of inappropriate drug dosage due to physiological changes in renal function. Estimated CLCR may not be the best method of evaluating renal function in these patients, and dosage regimens should be carefully considered. Renal insufficiency and concurrent drug therapy used in these populations can either increase or decrease drug absorption, depending on the particular agent. Drug distribution may be altered in renal insufficiency due to pH-dependent protein binding and reduced protein (primarily albumin) levels. Interestingly, renal disease may affect hepatic as well as renal drug metabolism; the exact mechanisms for these changes are not well understood. The most important quantitative pharmacokinetic change is excretion. Glomerular filtration and tubular process may both be affected but not to the same extent, and the type of renal disease may differentially affect filtration and excretion. Drug removal by dialysis is dependent on a number of factors, including the characteristics of a particular drug and the type of dialysis and equipment used. Therapeutic outcomes may be evaluated using end-points such as plasma concentrations, patient outcomes such as reduction in fever or negative cultures, and system-wide changes such as drug-use or laboratory-use patterns.
Shuler C, t al: "Prescribing drugs in renal disease. Management of the patient with renal failure. " Brenner ＆ Rector’s The Kidney. 5th ed. Brenner B. M. ed. Philadelphia, W.B. Saunders Company., p.2653-2702, 1996.
J W Cheng, S L Charland, L M Shaw, S Kobrin, S Goldfarb, E J Stanek, S A Spinler
Is the volume of distribution of digoxin reduced in patients with renal dysfunction? Determining digoxin pharmacokinetics by fluorescence polarization immunoassay.
Pharmacotherapy. 1997 May-Jun;17(3):584-90.
Abstract/Text
STUDY OBJECTIVE: To determine digoxin pharmacokinetics in subjects with different degrees of renal function using fluorescence polarization immunoassay (FPIA), which is associated with less interference from digoxin-like immunoreactive substances (DLIS) than radioimmunoassay.
SETTING: University hospital clinical research center.
PARTICIPANTS: Eighteen subjects (mean age 44 yrs) with different degrees of renal function: group 1, creatinine clearance (Clcr) below 10 ml/minute; group 2, Clcr 10-50 ml/minute; and group 3, Clcr greater than 50 ml/minute (6 patients in each group).
INTERVENTION: Over 5-7 days, 15 serum samples were collected after a single intravenous dose of digoxin 7 or 10 micrograms/kg actual body weight (WT) for serum concentration measurements by FPIA. Two-compartment pharmacokinetic parameters (zero-time intercept of the concentration-time curve of the initial distribution phase [A], zero-time intercept of the concentration-time curve of the terminal elimination phase [B], initial distribution phase constant [alpha], terminal elimination rate constant [beta], volume of distribution in the central compartment [Vc] and at steady state [Vss], total body clearance [Cl], mean residence time [MRT], area under the concentration-time curve [AUC]) were determined using a nonlinear least squares regression program.
MEASUREMENTS AND MAIN RESULTS: No significant differences were found among groups for A, B, alpha, beta, beta-half-life Vc/WT, MRT, AUC, and Cl/WT. Significant differences were observed in Vss/WT (4.8 +/- 1.0, 6.6 +/- 0.5, 6.4 +/- 0.7 L/kg) between group 1 versus group 2 and group 1 versus group 3 (p < 0.01). Measured Clcr was correlated with Cl (r2 = 0.40, p < 0.01), Cl/WT (r2 = 0.29, p < 0.05), Vss (r2 = 0.35, p = 0.01), and Vss/WT (r2 = 0.24, p < 0.05).
CONCLUSION: This study confirmed that Vss is smaller in patients with chronic renal failure (Clcr < 10 ml/min) than those without chronic renal failure. Therefore, previous recommendations that lower digoxin loading doses should be administered in patients with renal failure are applicable to digoxin serum concentration monitoring using FPIA.
R W Jelliffe
An improved method of digoxin therapy.
Ann Intern Med. 1968 Oct;69(4):703-17. doi: 10.7326/0003-4819-69-4-703.
Abstract/Text
W J Jusko, M Weintraub
Myocardial distribution of digoxin and renal function.
Clin Pharmacol Ther. 1974 Sep;16(3):449-54. doi: 10.1002/cpt1974163part1449.
Abstract/Text
M M Reidenberg, M Affrime
Influence of disease on binding of drugs to plasma proteins.
Ann N Y Acad Sci. 1973 Nov 26;226:115-26. doi: 10.1111/j.1749-6632.1973.tb20474.x.
Abstract/Text
Belpaire FM, et al. : Influence of continuous ambulatory peritoneal dialysis on serum α1-acid glycoprotein concentration and drug binding. Eur J Pharmacol 35: 339-343, 1988.
D B Haughey, C J Kraft, G R Matzke, W F Keane, C E Halstenson
Protein binding of disopyramide and elevated alpha-1-acid glycoprotein concentrations in serum obtained from dialysis patients and renal transplant recipients.
Am J Nephrol. 1985;5(1):35-9.
Abstract/Text
A rapid ultrafiltration technique was used to measure the free (unbound) fraction of disopyramide in serum obtained from 14 normal volunteers, 6 chronic hemodialysis patients, and 10 renal transplant recipients. The disopyramide-free fraction varied more than tenfold at a corresponding total (free plus bound) serum disopyramide concentration of 3 micrograms/ml and was related to the concentration of an acute-phase protein, alpha-1-acid glycoprotein (AAG), in patient serum. Moreover, disopyramide-free fraction values were nearly twofold lower than normal in serum specimens obtained from those renal patients and transplant recipients with corresponding AAG serum concentrations greater than 100 mg/100 ml. AAG concentrations varied tenfold in patient serum and were on average nearly three times higher than AAG concentrations in normal volunteer serum. These findings suggested that the free fraction of disopyramide and possibly other drugs which bind extensively to AAG may be lower, and the interpatient variability in drug binding may be much more pronounced in serum obtained from hemodialysis patients and transplant recipients than previously recognized.
T Arima, Y Motoyama, K Nagata, T Kondo
Serum glycoproteins in the liver diseases. II. Radioimmunoassay of alpha-1 acid glycoprotein.
Gastroenterol Jpn. 1976;11(4):307-12.
Abstract/Text
A radioimmunoassay for human alpha1-acid glycoprotein has been developed. 97.8% of 125I-alpha1-acid glycoprotein prepared for the assay were immunoprecipitable with specific anti-sera against the protein. alpha1-acid glycoprotein concentration in sera from normal adults was found to range between 70 and 114 mg/100 ml, with a mean of 93. Fulminant hepatitis, liver cirrhosis or chronic active hepatitis with sublobular necrosis caused a significant lowering of alpha1-acid glycoprotein concentration. Sera obtained from patients with acute hepatitis in convalescence, chronic inactive hepatitis or primary biliary cirrhosis gave normal concentration of the glycoprotein.
A O Iyun, G T Tucker
Antipyrine kinetics in Nigerian women in chronic renal failure.
Afr J Med Med Sci. 1982 Mar;11(1):7-9.
Abstract/Text
Antipyrine was given orally to five patients with Chronic renal failure and nine normal subjects. Plasma antipyrine levels were measured by high pressure liquid chromatography method, the plasma half-life of the drug was determined and used as an index of drug oxidation. The mean (+/- s.d.) plasma antipyrine half-life in patients with chronic renal failure (7.8 +/- 2.6 h) was significantly shorter than in normal subjects (13.1 +/- 2.3 h) (P less than 0.001). There was no significant difference in the volume of distribution but there was a significant difference in the clearance in ml.kg-1h-1 (P less than 0.001). The results suggest that oxidation of antipyrine by hepatic microsomal enzymes is increased in patients with chronic renal failure. The role of this in the apparent resistance among our patients to antihypertensive agents needs further study.
N Weyer, T Kröplin, L Fricke, H Iven
Human thiopurine S-methyltransferase activity in uremia and after renal transplantation.
Eur J Clin Pharmacol. 2001 May;57(2):129-36. doi: 10.1007/s002280100287.
Abstract/Text
UNLABELLED: In addition to cyclosporin and steroids, azathioprine is frequently used for immunosuppression after renal transplantation. Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs. A genetic polymorphism was shown with 1 in 300 homozygous for a TPMT deficiency. These subjects carry the risk of severe myelosuppression when treated with azathioprine.
OBJECTIVE: To investigate the influence of hemodialysis on TPMP activity in uremic patients and the effect of azathioprine treatment on enzyme activity.
METHODS: The assay for measurement of TPMT activity in packed red blood cells is based on a non-radioactive conversion of 6-thioguanine to 6-methylthioguanine. In 251 patients, TPMT activity was determined before and after a 4-h period of hemodialysis. In 49 patients (26 on azathioprine, 23 on mycophenolate mofetil as control group), TPMT activity was regularly determined during the first 120 days after renal transplantation.
RESULTS: TPMT activity is elevated in red blood cells of uremic patients before hemodialysis when compared with TPMT activity after hemodialysis. The latter is comparable to the activity in healthy subjects. In patients treated with azathioprine, the TPMT activity showed a slow increase that declined to pre-treatment values when azathioprine was withdrawn. This could not be observed in patients treated with mycophenolate mofetil.
CONCLUSIONS: In uremic patients, TPMT activity is activated by some uremic factors that are removed by hemodialysis. In contrast to what has been observed before, dialysis shifted the TPMT activity close to that of a healthy control group. In patients treated with azathioprine after renal transplantation, the observed increase of TPMT activity could possibly be the result of enzyme induction.
Thomas D Nolin, Kofi Appiah, Scott A Kendrick, Phuong Le, Ellen McMonagle, Jonathan Himmelfarb
Hemodialysis acutely improves hepatic CYP3A4 metabolic activity.
J Am Soc Nephrol. 2006 Sep;17(9):2363-7. doi: 10.1681/ASN.2006060610. Epub 2006 Aug 9.
Abstract/Text
The uremic syndrome remains poorly understood despite the widespread availability of dialysis for almost four decades. To date, assessment of the biologic activity of uremic toxins has focused primarily on in vitro effects, rather than on specific biochemical pathways or enzymatic activity in vivo. The activity of cytochrome P450 (CYP) 3A4, the most important enzyme in human drug metabolism, is decreased in uremia. The purpose of this study was to assess the effect of hemodialysis and hence varying concentrations of uremic toxins on CYP3A4 activity using the 14C-erythromycin breath test and the traditional phenotypic trait measure, 20-min 14CO2 flux. CYP3A4 activity increased by 27% postdialysis (P = 0.002 compared with predialysis) and was significantly inversely related to plasma blood urea nitrogen concentration (rs= -0.50, P = 0.012), but not to several middle molecules. This is the first study in humans characterizing uremia as a state in which hepatic CYP3A4 activity is acutely improved by hemodialysis.
T P Gibson
Renal disease and drug metabolism: an overview.
Am J Kidney Dis. 1986 Jul;8(1):7-17. doi: 10.1016/s0272-6386(86)80148-2.
Abstract/Text
Renal disease will perturb the disposition of drugs that primarily depend upon renal excretory function for elimination. While changes in drug half-life (T1/2) are often cited as evidence of altered drug disposition, it must be remembered that T1/2 is a dependent variable whose magnitude varies directly with volume of distribution (Vd) and indirectly with total body clearance (ClT). ClT is the one term that succinctly describes drug elimination. ClT is defined as the sum of the renal (ClR) and nonrenal (ClNR), or metabolic, clearances of a drug. Renal failure has been shown to alter the hepatic microsomal mixed-function oxidase system of drug metabolizing enzymes. Therefore, in end-stage renal failure, the potential exists for the modification of the disposition of drugs whose elimination is primarily hepatic. The kidneys themselves contain many of the enzymes important in hepatic drug metabolism. Drugs such as morphine, paracetamol, and p-aminobenzoic acid are metabolized in the kidney and experimental renal disease has been shown to reduce drug metabolism in the diseased kidney compared with the contralateral normal kidney. Renal disease, then, has the potential to alter not only the renal clearance of unchanged drug but also may substantially modify the metabolic transformation of drugs in both the liver and the kidneys. It can no longer be assumed that the pharmacokinetics of drugs that are disposed mainly by metabolism will be unaltered in renal failure.
T P Gibson, A J Atkinson, E Matusik, L D Nelson, W A Briggs
Kinetics of procainamide and N-acetylprocainamide in renal failure.
Kidney Int. 1977 Dec;12(6):422-9. doi: 10.1038/ki.1977.133.
Abstract/Text
Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.
Judith Naud, Josée Michaud, Caroline Boisvert, Karine Desbiens, Francois A Leblond, Andrew Mitchell, Christine Jones, Alain Bonnardeaux, Vincent Pichette
Down-regulation of intestinal drug transporters in chronic renal failure in rats.
J Pharmacol Exp Ther. 2007 Mar;320(3):978-85. doi: 10.1124/jpet.106.112631. Epub 2006 Nov 29.
Abstract/Text
Chronic renal failure (CRF) is associated with an increased bioavailability of drugs by a poorly understood mechanism. One hypothesis is a reduction in the elimination of drugs by the intestine, i.e., drug elimination mediated by protein membrane transporters such as P-glycoprotein (Pgp) and multidrug-resistance-related protein (MRP) 2. The present study aimed to investigate the repercussions of CRF on intestinal transporters involved in drug absorption [organic anion-transportingpolypeptide (Oatp)] and those implicated in drug extrusion (Pgp and MRP2). Pgp, MRP2, MRP3, Oatp2, and Oatp3 protein expression and Pgp, MRP2, and Oatp3 mRNA expression were assessed in the intestine of CRF (induced by five-sixth nephrectomy) and control rats. Pgp and MRP2 activities were measured using the everted gut technique. Rat enterocytes and Caco-2 cells were incubated with sera from control and CRF rats to characterize the mechanism of transporters' down-regulation. Protein expression of Pgp, MRP2, and MRP3 were reduced by more than 40% (p < 0.01) in CRF rats, whereas Oatp2 and Oatp3 expression remained unchanged. There was no difference in the mRNA levels assessed by real-time polymerase chain reaction. Pgp and MRP2 activities were decreased by 30 and 25%, respectively, in CRF rats compared with control (p < 0.05). Uremic sera induced a reduction in protein expression and in activity of drug transporters compared with control sera. Our results demonstrate that CRF in rats is associated with a decrease in intestinal Pgp and MRP2 protein expression and function secondarily to serum uremic factors. This reduction could explain the increased bioavailability of drugs in CRF.
S-M Huang, R Temple, S Xiao, L Zhang, L J Lesko
When to conduct a renal impairment study during drug development: US Food and Drug Administration perspective.
Clin Pharmacol Ther. 2009 Nov;86(5):475-9. doi: 10.1038/clpt.2009.190.
Abstract/Text
To optimize drug therapy for individuals, it is critical to understand how various intrinsic (e.g., age, gender, race, genetics, organ impairment) and extrinsic factors (e.g., diet, smoking, concomitantly administered drugs) affect drug exposure and response.(1) Up to now, it has been far easier to discover effects on exposure caused by these factors, and the US Food and Drug Administration (FDA) has published several guidance documents with recommendations on how to evaluate these factors during drug development.
L Dettli
Drug dosage in renal disease.
Clin Pharmacokinet. 1976;1(2):126-34. doi: 10.2165/00003088-197601020-00004.
Abstract/Text
Based on the well known linear relationship between the overall drug elimination rate constant and the endogenous creatinine clearance, it is shown how individual drug elimination parameters in patients with renal disease can be estimated from the patient's creatinine clearance or serum creatinine concentration. By means of a simple nomogram the elimination rate fraction is determined which describes the elimination rate of the drug as a fraction of its normal elimination rate constant. Based on the estimated elimination rate fraction the dosage regimen in the patient with renal disease is individually modified according to pharmacokinetic principles. At present the described method can be used with 45 different drugs.
栫幸宏, 他 : 経口インフルエンザウイルス治療薬リン酸オルセタミビルの薬理作用および体内動態. 化学療法の領域17（1）103-111, 2001.
平田純生, 他: 血液透析による薬物除去率に影響する要因. 透析会誌37: 1893-1900, 2004.
Motoki Urata, Yuki Narita, Masaki Fukunaga, Daisuke Kadowaki, Sumio Hirata
Simple Formula for Predicting Drug Removal Rates During Hemodialysis.
Ther Apher Dial. 2018 Oct;22(5):485-493. doi: 10.1111/1744-9987.12675. Epub 2018 Jul 10.
Abstract/Text
The present study sought to derive a simple formula for predicting the drug removal rates during hemodialysis. We examined the relationship between drug removal rates during hemodialysis and the molecular weights or pharmacokinetic parameters of injectable drugs (N = 90) obtained from pharmaceutical interview forms in Japan. Stepwise multiple regression analysis with the removal rate by hemodialysis as the objective variable adjusted for molecular weight or pharmacokinetic parameters as explanatory variables, showed that the logarithm of molecular weight (B = -18.87), the protein binding rate (B = -0.40), and the fraction of the unchanged drug excreted into the urine/volume of distribution (B = 0.05) were significantly and independently associated with drug removal rate by hemodialysis (α = 90.78, adjusted R2 = 0.64, P = 2.2e-16 ). Our data demonstrated that molecular weight, protein binding rate, and volume of distribution were important factors affecting drug removal during hemodialysis, and that our simple regression equation could be used to predict the drug removal rate during hemodialysis.
© 2018 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.
Marina Murakami, Yuki Narita, Motoki Urata, Misato Ichigi, Sakura Nakatani, Yuki Kondo, Yoichi Ishitsuka, Tetsumi Irie, Sumio Hirata
Improved Formula for Predicting Hemodialyzability of Intravenous and Oral Drugs.
Blood Purif. 2021;50(6):865-875. doi: 10.1159/000513152. Epub 2021 Mar 9.
Abstract/Text
BACKGROUND: The rate of drug removal by hemodialysis needs to be considered when designing drug dosage regimens for patients on hemodialysis. We previously developed a simplified equation to predict the removal rates of intravenously administered drugs by hemodialysis. Here, we addressed shortcomings of this equation and developed a more accurate equation that can also predict the removal rates of orally administered drugs.
METHODS: A total of 70 drugs with known pharmacokinetic and physical parameters and drug removal rates that were measured during hemodialysis in clinical cases were randomly assigned at a 4:1 ratio to a training data group or a test data group. A prediction equation was developed by performing stepwise multiple regression analyses using the training data (i.e., the removal rate by hemodialysis) as the objective variable and pharmacokinetic parameters as the explanatory variables. The equation was validated using the test data.
RESULTS: Multiple regression analyses revealed that molecular weight (MW), protein binding rate, and fraction excreted unchanged in urine relative to the volume of distribution (Vd) were independently correlated with the drug clearance rate (adjusted coefficient of determination, 0.83; p = 2.2e-16). The following equation was obtained: drug removal rate by hemodialysis (%) = -17.32 × [log (MW)] - 0.39 × [protein binding rate (%)] + 0.06 × [fraction excreted unchanged in urine (%)/Vd (L/kg)] + 83.34. Validation of the equation using the test data showed a very high correlation between predicted and measured reduction rate (R = 0.93, p = 1.87e-6). Mean error was -3.34 (95% confidence interval: -10.03, 3.35), mean absolute error was 9.59, and root mean square error was 16.48.
CONCLUSION: The modified equation derived in this study using pharmacokinetic and physical parameters as variables precisely predicted the removal rates of both intravenous and oral drugs by hemodialysis.
© 2021 S. Karger AG, Basel.
Konstantinos Makris, Loukia Spanou
Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes.
Clin Biochem Rev. 2016 May;37(2):85-98.
Abstract/Text
Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI.
Moeko Tsutsuura, Hiromu Moriyama, Nana Kojima, Yuki Mizukami, Sho Tashiro, Sumika Osa, Yuki Enoki, Kazuaki Taguchi, Kazutaka Oda, Satoshi Fujii, Yoshiko Takahashi, Yukihiro Hamada, Toshimi Kimura, Yoshio Takesue, Kazuaki Matsumoto
The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.
BMC Infect Dis. 2021 Feb 6;21(1):153. doi: 10.1186/s12879-021-05858-6. Epub 2021 Feb 6.
Abstract/Text
BACKGROUND: This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety.
METHODS: We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47-0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15-20 μg/mL (OR 2.39, 95% CI 1.78-3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18-0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13-3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28-1.01); however, it was not significant in the analysis of mortality.
CONCLUSIONS: We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.
Todd A Miano, Sean Hennessy, Wei Yang, Thomas G Dunn, Ariel R Weisman, Oluwatosin Oniyide, Roseline S Agyekum, Alexandra P Turner, Caroline A G Ittner, Brian J Anderson, F Perry Wilson, Raymond Townsend, John P Reilly, Heather M Giannini, Christopher V Cosgriff, Tiffanie K Jones, Nuala J Meyer, Michael G S Shashaty
Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study.
Intensive Care Med. 2022 Sep;48(9):1144-1155. doi: 10.1007/s00134-022-06811-0. Epub 2022 Jul 14.
Abstract/Text
PURPOSE: Although dozens of studies have associated vancomycin + piperacillin-tazobactam with increased acute kidney injury (AKI) risk, it is unclear whether the association represents true injury or a pseudotoxicity characterized by isolated effects on creatinine secretion. We tested this hypothesis by contrasting changes in creatinine concentration after antibiotic initiation with changes in cystatin C concentration, a kidney biomarker unaffected by tubular secretion.
METHODS: We included patients enrolled in the Molecular Epidemiology of SepsiS in the ICU (MESSI) prospective cohort who were treated for ≥ 48 h with vancomycin + piperacillin-tazobactam or vancomycin + cefepime. Kidney function biomarkers [creatinine, cystatin C, and blood urea nitrogen (BUN)] were measured before antibiotic treatment and at day two after initiation. Creatinine-defined AKI and dialysis were examined through day-14, and mortality through day-30. Inverse probability of treatment weighting was used to adjust for confounding. Multiple imputation was used to impute missing baseline covariates.
RESULTS: The study included 739 patients (vancomycin + piperacillin-tazobactam n = 297, vancomycin + cefepime n = 442), of whom 192 had cystatin C measurements. Vancomycin + piperacillin-tazobactam was associated with a higher percentage increase of creatinine at day-two 8.04% (95% CI 1.21, 15.34) and higher incidence of creatinine-defined AKI: rate ratio (RR) 1.34 (95% CI 1.01, 1.78). In contrast, vancomycin + piperacillin-tazobactam was not associated with change in alternative biomarkers: cystatin C: - 5.63% (95% CI - 18.19, 8.86); BUN: - 4.51% (95% CI - 12.83, 4.59); or clinical outcomes: dialysis: RR 0.63 (95% CI 0.31, 1.29); mortality: RR 1.05 (95%CI 0.79, 1.41).
CONCLUSIONS: Vancomycin + piperacillin-tazobactam was associated with creatinine-defined AKI, but not changes in alternative kidney biomarkers, dialysis, or mortality, supporting the hypothesis that vancomycin + piperacillin-tazobactam effects on creatinine represent pseudotoxicity.
© 2022. The Author(s).
Dulce Maria Calvo, Luis Carlos Saiz, Leire Leache, Maria Concepción Celaya, Marta Gutiérrez-Valencia, Alvaro Alonso, Juan Erviti, Natalia Alzueta, Amaya Echeverría, Javier Garjón, Carmen Fontela, Lorea Sanz, Maria Teresa Acín, Maria Loreto Fernández, Nerea Gómez
Effect of the combination of diuretics, renin-angiotensin-aldosterone system inhibitors, and non-steroidal anti-inflammatory drugs or metamizole (triple whammy) on hospitalisation due to acute kidney injury: A nested case-control study.
Pharmacoepidemiol Drug Saf. 2023 Aug;32(8):898-909. doi: 10.1002/pds.5621. Epub 2023 Apr 5.
Abstract/Text
PURPOSE: Concomitant use of diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs) or metamizole, known as 'triple whammy' (TW), has been associated with an increased risk of acute kidney injury (AKI). Nevertheless, there is still uncertainty on its impact in hospitalisation and mortality. The aim of the study was to analyse the association between exposure to TW and the risk of hospitalisation for AKI, all-cause mortality and the need for renal replacement therapy (RRT).
METHODS: A case-control study nested in a cohort of adults exposed to at least one diuretic or RAAS inhibitor between 2009 and 2018 was carried out within the Pharmacoepidemiological Research Database for Public Health Systems (BIFAP). Patients hospitalised for AKI between 2010 and 2018 (cases) were matched with up to 10 patients of the same age, sex and region of Spain who had not been hospitalised for AKI as of the date of hospitalisation for AKI of the matching case (controls). The association between TW exposure versus non-exposure to TW and outcome variables was analysed using logistic regression models.
RESULTS: A total of 480 537 participants (44 756 cases and 435 781 controls) were included (mean age: 79 years). The risk of hospitalisation for AKI was significantly higher amongst those exposed to TW [adjusted odds ratio (aOR) 1.36, 95% confidence interval (95%CI) 1.32-1.40], being higher with current (aOR 1.60, 95%CI 1.52-1.69) and prolonged exposure (aOR 1.65, 95%CI 1.55-1.75). No significant association was found with the need of RRT. Unexpectedly, mortality was lower in those exposed to TW (aOR 0.81, 95%CI 0.71-0.93), which may be influenced by other causes.
CONCLUSION: Vigilance should be increased when diuretics, RAAS inhibitors, and NSAIDs or metamizole are used concomitantly, especially in patients at risk such as elderly patients.
© 2023 John Wiley & Sons Ltd.
Yuki Kunitsu, Daiki Hira, Aya Morikochi, Tomohiro Ueda, Tetsuichiro Isono, Shin-Ya Morita, Tomohiro Terada
Time until onset of acute kidney injury by combination therapy with "Triple Whammy" drugs obtained from Japanese Adverse Drug Event Report database.
PLoS One. 2022;17(2):e0263682. doi: 10.1371/journal.pone.0263682. Epub 2022 Feb 9.
Abstract/Text
Acute kidney injury (AKI) associated with "Triple Whammy" drug therapy consisting of renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported. There have been no reports investigating "Triple Whammy" drug therapy and the time to AKI onset using adverse drug events report databases. The aim of this study was to determine the relationship between the time to AKI onset and treatment with "Triple Whammy" drug therapy. We analyzed AKI cases registered in the Japanese Adverse Drug Event Report database. The data were analyzed using the Kaplan-Meier approach, generalized Wilcoxon tests, and Weibull distribution. AKI was reported in 18,415 cases, of which 7,466 cases used Triple Whammy drugs. All combinations of Triple Whammy drugs were associated with significantly higher odds ratios for reporting AKI. In Weibull analysis, AKI onset was early for most combination patterns of Triple Whammy drugs. The Kaplan-Meier approach showed that the treatment duration to AKI onset was much shorter in cases using NSAIDs; median onsets, 8 days for triple combination, 7 days for NSAIDs added to renin-angiotensin system inhibitors, 9 days for NSAIDs added to diuretics, 6 days for diuretics added to NSAIDs, and 9 days for NSAIDs alone. AKI associated with Triple Whammy drugs is likely to occur in the early stages of treatment, especially with concomitant NSAIDs. Patients should be monitored for the occurrence of AKI within the first 2 weeks.
Tobias Dreischulte, Daniel R Morales, Samira Bell, Bruce Guthrie
Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury.
Kidney Int. 2015 Aug;88(2):396-403. doi: 10.1038/ki.2015.101. Epub 2015 Apr 15.
Abstract/Text
Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI) when used in triple combination with renin-angiotensin system inhibitors and diuretics, but previous research reported that NSAIDs in dual combinations with either renin-angiotensin system inhibitors or diuretics alone were not. However, earlier studies relied on hospital coding to define AKI, which may underestimate true risk. This nested case-control study characterized the risk of community-acquired AKI associated with NSAID use among 78,379 users of renin-angiotensin system inhibitors and/or diuretics, where AKI was defined as a 50% or greater increase in creatinine from baseline. The AKI incidence was 68/10,000 person-years. The relative increase in AKI risk was similar for NSAID use in both triple (adjusted rate ratio 1.64 (95% CI 1.25-2.14)) and dual combinations with either renin-angiotensin system inhibitors (1.60 (1.18-2.17)) or diuretics (1.64 (1.17-2.29)). However, the absolute increase in AKI risk was higher for NSAIDs used in triple versus dual combinations with renin-angiotensin system inhibitors or diuretics alone (numbers needed to harm for 1 year treatment with NSAID of 158 vs. over 300). AKI risk was highest among users of loop diuretic/aldosterone antagonist combinations, in those over 75 years of age, and in those with renal impairment. Thus, the nephrotoxic potential of both dual and triple combinations of NSAIDs with renin-angiotensin system inhibitors and/or diuretics yields a higher incidence of AKI than previously thought.
Su Hooi Teo, Ngiap Chuan Tan, Jason Chon Jun Choo, Jia Liang Kwek, Hanis Bte Abdul Kadir, Yong Mong Bee, Huijun Huang, Manish Kaushik, Andrew Teck Wee Ang, Cynthia Ciwei Lim
Non-steroidal anti-inflammatory drugs in chronic kidney disease and risk of acute adverse kidney events according to route of administration.
Int Urol Nephrol. 2023 Mar;55(3):679-686. doi: 10.1007/s11255-022-03344-9. Epub 2022 Sep 5.
Abstract/Text
BACKGROUND: Topical non-steroidal anti-inflammatory drugs (NSAIDs) have lower risks for cardiovascular disease and gastrointestinal adverse effects compared to oral NSAIDs, but there are little data regarding their kidney risks in chronic kidney disease (CKD). We evaluated the risk of adverse acute kidney outcomes in CKD according to route of NSAID administration.
METHODS: Retrospective cohort study of adults with CKD (eGFR less than 60 ml/min/1.73 m2) who received prescriptions between 2015 and 2017 from a major healthcare cluster in Singapore. The adverse acute kidney outcomes were acute kidney injury (AKI) and need for nephrology specialist consult within 30 days.
RESULTS: Among 6298 adults with CKD (mean age 72.1 ± 13.3 years and eGFR 41.9 ± 12.2 ml/min/1.73 m2), systemic and topical NSAIDs were prescribed in 16.7% and 32.0%, respectively. Incident AKI (any severity), KDIGO Stage 2 or 3 AKI, and need for nephrology specialist consult occurred in 16.7%, 2.6%, and 10.6% of the study cohort, respectively. After adjusting for age, diabetes, recent cardiovascular hospitalization, baseline eGFR, RAAS blocker and diuretic, systemic NSAIDs, and topical NSAIDs, compared with the no-NSAID group, were independently associated with incident AKI [adjusted OR 1.77 (95% CI 1.46-2.15) and 1.38 (1.18-1.63), respectively]. Moderate and severe AKI (adjusted OR 1.68, 95% CI 1.09-2.58, p = 0.02) and need for nephrology consults (adjusted OR 1.41, 95% CI 1.09-1.82, p = 0.008) were also increased in systemic NSAIDs.
CONCLUSION: Among adults with CKD, both systemic and topical NSAIDs were independently associated with acute adverse kidney outcomes.
© 2022. The Author(s), under exclusive licence to Springer Nature B.V.
