Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model

Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CL_cre), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters.     

Flucytosine interference with serum creatinine determinations

A patient receiving intravenous amphotericin B and oral flucytosine was found to have falsely elevated serum creatinine values. Flucytosine has been reported to interfere with serum creatinine determinations when measured by the Kodak Ektachem-700 analyzer but not when the Jaffe reaction is employed. Serum creatinine values were determined by the two methods on six serum samples obtained from this patient at various times throughout her hospitalization. Flucytosine can cause clinically significant false elevations in serum creatinine when measured by the Kodak Ektachem-700 analyzer.     

Estimation of changes in serum creatinine and creatinine clearance caused by renal transporter inhibition in healthy subjects

Creatinine is excreted into urine by glomerular filtration and renal tubular secretion through drug transporters such as organic anion transporter 2 (OAT2), organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. We aimed to investigate whether our method for estimating percentage changes in serum creatinine concentration (SCr) and creatinine clearance (CL_cre) from the baseline is applicable for studying renal transporter inhibitors. We tested 14 compounds (cimetidine, cobicistat, dolutegravir, dronedarone, DX-619, famotidine, INCB039110, nizatidine, ondansetron, pyrimethamine, rabeprazole, ranolazine, trimethoprim, and vandetanib), which were reported to cause reversible changes in SCr and/or CL_cre in healthy subjects excluding elderly. Percentage changes were estimated from the relative contributions of the forementioned transporters to CL_cre and competitive inhibition by these compounds at their maximum plasma unbound concentrations. For 7 and 9 out of these compounds, changes in SCr and/or CL_cre were estimated within 2- and 3-fold of observed values, respectively. Less than 10% changes in SCr and/or CL_cre caused by cobicistat, dolutegravir, and rabeprazole were reproduced as such by our method. These findings suggest that our method can be used to estimate changes in SCr and CL_cre caused by competitive inhibitions of renal drug transporters.     

Amphotericin B liposome-induced acrocyanosis and elevated serum creatinine

A 77-year-old male patient developed acrocyanosis and pain after treatment with amphotericin B liposome 150 mg daily intravenously for disseminated histoplasmosis, and subsequently developed elevated serum creatinine. Amphotericin B liposome was discontinued, and anisodamine was used intravenously to treat acrocyanosis and pain induced by amphotericin B liposome for 9 days and patient was cured. Naranjo adverse drug reaction probability scale score was 5, the World Health Organization-Uppsala Monitoring Centre criteria: Probable, indicating a probable adverse reaction to amphotericin B liposome.KEY WORDS: Acrocyanosis, amphotericin B liposome, histoplasmosis, impaired renal function, pain     

血肌酐值法预测地高辛个体化给药方案

在地高辛常规监测中，用血肌酐值法预测个体化药动学参数和给药方案。结果表明，８４例病人的地高辛药物动力学参数预测值为，ＣＬ７６±２１ｍｌ／（ｋｇ·ｈ），Ｖｄ７．０５±１．２０Ｌ／ｋｇ，Ｔ１／２６６±７ｈ。预测的个体化剂量为３．１±０．９μｇ／（ｋｇ·ｄ），预测的稳态血药浓度（Ｃ＿（ｓｓ））为１．２４±０．３８μｇ／Ｌ，与实测Ｃ＿（ｓｓ）１．２±０．４μｇ／Ｌ比较，差异无显著性（Ｐ＞０．０５）。     

The effect of co-trimoxazole on serum creatinine.

1 Co-trimoxazole induces a highly significant and reversible elevation of the serum creatinine level. 2 In renal-allograft patients the degree of this elevation is significantly correlated with the concentration of serum creatinine before administration of co-trimoxazole and with the concentration of non-protein-bound trimethoprim.     

冠心病患者血清肌酐分布特征及其影响因素研究

目的探讨描述冠状动脉粥样硬化性心脏病（冠心病）患者血清肌酐水平与冠状动脉病变程度及影响因素的关系。方法搜集2007年8月至2008年8月间经冠状动脉造影检查确诊为冠心病的患者482例,分析患者血清肌酐水平与其临床特征及相关危险因素间的相关性,并探讨冠状动脉病变程度对肾功能影响。结果冠心病患者血清肌酐平均水平男性（96．36±10．28）μLmol／L,女性（83．98±11．36）μmol／L,男性高于女性（P〈0．01）,其水平随着冠状动脉病变程度加重而升高,差异有统计学意义（P〈0．01）,肾功能损害发生率为11．6％。血脂异常、超重、高血压、高尿酸、糖尿病患者和有吸烟史患者的血清肌酐水平高于正常范围（P〈0．05）;高尿酸、高血压和糖尿病患者肾功能损害的现患率高于正常组（P〈0．01）。多因素分析显示,高总胆固醇、高血压、高尿酸和高空腹血糖是肾功能损害的主要影响因素,其比数比值分别为1．36、1．98、3．58和1．46（P〈0．01）。随着冠状动脉病变程度的加重与危险因素的累加,血清肌酐水平明显上升。结论冠心病患者肾功能受损与各项危险因素水平及冠脉病变程度密切相关,在冠心病临床治疗中肾功能保护是一个不容忽视的方面。     

Estimation of renal creatinine clearance in patients with unstable serum creatinine concentrations: comparison of multiple methods

The accuracy of different methods of calculating 24-hour creatinine clearance in patients with unstable renal function was compared using simulated data (based on a one-compartment pharmacokinetic model), as well as data from postrenal transplant patients. When creatinine clearance was calculated from the urinary creatinine excretion and a serum creatinine concentration, the use of the midpoint serum creatinine concentration produced the lowest degree of error. Therefore, this method is recommended for routine clinical determination of creatinine clearance in such patients. When the urinary creatinine excretion was unknown, an iteration method produced the lowest degree of error among four methods, and therefore is recommended to estimate creatinine clearance in such patients.     

Superiority of disease-specific over conventional formula in predicting creatinine clearance from serum creatinine in patients with liver cirrhosis

To determine if liver cirrhosis may influence the accuracy of formulas estimating creatinine clearance (Clcr) from serum creatinine, we compared the measured and estimated Clcr in 95 male (group A) and 47 female cirrhotic patients (group B). The Clcr values of group A and B patients were estimated with the equations obtained from 93 male (group C) and 86 female patients (group D) who were free of liver disease: the mean estimation errors (+/- SD) for the group C and D patients with the equations obtained from their own population data were 5 +/- 24% and 4 +/- 22%, respectively. However, these equations significantly (p less than 0.01) overestimated the Clcr of cirrhotic patients: the mean estimation errors for the group A and B patients were 35 +/- 43% and 14 +/- 27%, respectively. In contrast, the mean estimation errors for the group A and B patients using cirrhotic patient-specific equations obtained from their own population data were 5 +/- 33% and 3 +/- 25%, respectively. The accuracy of these disease-specific formulas was also confirmed in a prospective manner in 43 male (group E) and 21 female cirrhotic patients (group F): the mean estimation errors for the group E and F patients were 2 +/- 32% and -7 +/- 29%, respectively. We conclude that the Clcr values of cirrhotic patients, particularly male patients, may not be accurately estimated with equations of formulas deriving from liver disease-free patients, but should be estimated using their own population data.     

Elevated serum creatinine levels in three patients treated with phenacemide

Three adolescent patients with severe seizure disorders were treated with phenacemide. All three patients showed elevated serum creatinine and normal blood urea nitrogen values while on phenacemide. Simultaneous urea and creatinine clearance studies performed on each patient demonstrated normal urea clearances and decreased creatinine clearances. Inulin clearance performed in one patient was normal. The medication was discontinued in two of the patients because of co-existing neutropenia. Serum creatinine values returned to normal after phenacemide treatment was terminated. The elevation in serum creatinine values with phenacemide appears to be dose related, reversible, and unrelated to impairment of glomerular filtration.     

冠心病患者血清肌酐分布特征及其影响因素研究

Objective To observe the distribution of serum croatinine and analyze its associated influence factors in patients underwent coronary angiography. Methods Four hundred and eighty-two consecutive patients recieving coronary angiography from Aug, 2007 to Aug, 2008 at Beijing Anzhen hospital were enrolled. Results 1. The average level of serum creatinine of males (96. 36μmol/L) in male patients was significantly higher than females (83.98 μmol/L) (P < 0.01). The level of serum creatinine increased with severity of CAD (P < 0.01). The prevalence of renal dysfunction was 11.6% in this group. 2. Compared with normal people, the levels of serum creatinine were higher in groups of dyslipidemia, overweight, hypertension, hyperuricaemia, diabetes and smoking (P < 0. 05). The prevalence of renal dysfunction was higher in groups of hypercholesterolaemia, hypertension, diabetes and hyperuricaemia. 3. Hypercholesterolaemia, hypertension, diabetes and hyperuricaemia were main influencing factors of renal dysfunction, with OR 1.36, 1.98, 3.58 and 1.46 (P<0.01). 4. Level of serum creatinine increased significantly with the severity of CAD. Conclusion Gender, lipids, blood pressure, uric acid, body mess index, smoking and diabetes show influence on serum creatinine level. Hyperoholesterolaemia, hyperten-sion and hyperuricaemia are main influencing factors of renal dysfunction.     

冠心病患者血清肌酐分布特征及其影响因素研究

Objective To observe the distribution of serum croatinine and analyze its associated influence factors in patients underwent coronary angiography. Methods Four hundred and eighty-two consecutive patients recieving coronary angiography from Aug, 2007 to Aug, 2008 at Beijing Anzhen hospital were enrolled. Results 1. The average level of serum creatinine of males (96. 36μmol/L) in male patients was significantly higher than females (83.98 μmol/L) (P < 0.01). The level of serum creatinine increased with severity of CAD (P < 0.01). The prevalence of renal dysfunction was 11.6% in this group. 2. Compared with normal people, the levels of serum creatinine were higher in groups of dyslipidemia, overweight, hypertension, hyperuricaemia, diabetes and smoking (P < 0. 05). The prevalence of renal dysfunction was higher in groups of hypercholesterolaemia, hypertension, diabetes and hyperuricaemia. 3. Hypercholesterolaemia, hypertension, diabetes and hyperuricaemia were main influencing factors of renal dysfunction, with OR 1.36, 1.98, 3.58 and 1.46 (P<0.01). 4. Level of serum creatinine increased significantly with the severity of CAD. Conclusion Gender, lipids, blood pressure, uric acid, body mess index, smoking and diabetes show influence on serum creatinine level. Hyperoholesterolaemia, hyperten-sion and hyperuricaemia are main influencing factors of renal dysfunction.     

冠心病患者血清肌酐分布特征及其影响因素研究

Objective To observe the distribution of serum croatinine and analyze its associated influence factors in patients underwent coronary angiography. Methods Four hundred and eighty-two consecutive patients recieving coronary angiography from Aug, 2007 to Aug, 2008 at Beijing Anzhen hospital were enrolled. Results 1. The average level of serum creatinine of males (96. 36μmol/L) in male patients was significantly higher than females (83.98 μmol/L) (P < 0.01). The level of serum creatinine increased with severity of CAD (P < 0.01). The prevalence of renal dysfunction was 11.6% in this group. 2. Compared with normal people, the levels of serum creatinine were higher in groups of dyslipidemia, overweight, hypertension, hyperuricaemia, diabetes and smoking (P < 0. 05). The prevalence of renal dysfunction was higher in groups of hypercholesterolaemia, hypertension, diabetes and hyperuricaemia. 3. Hypercholesterolaemia, hypertension, diabetes and hyperuricaemia were main influencing factors of renal dysfunction, with OR 1.36, 1.98, 3.58 and 1.46 (P<0.01). 4. Level of serum creatinine increased significantly with the severity of CAD. Conclusion Gender, lipids, blood pressure, uric acid, body mess index, smoking and diabetes show influence on serum creatinine level. Hyperoholesterolaemia, hyperten-sion and hyperuricaemia are main influencing factors of renal dysfunction.     

冠心病患者血清肌酐分布特征及其影响因素研究

Objective To observe the distribution of serum croatinine and analyze its associated influence factors in patients underwent coronary angiography. Methods Four hundred and eighty-two consecutive patients recieving coronary angiography from Aug, 2007 to Aug, 2008 at Beijing Anzhen hospital were enrolled. Results 1. The average level of serum creatinine of males (96. 36μmol/L) in male patients was significantly higher than females (83.98 μmol/L) (P < 0.01). The level of serum creatinine increased with severity of CAD (P < 0.01). The prevalence of renal dysfunction was 11.6% in this group. 2. Compared with normal people, the levels of serum creatinine were higher in groups of dyslipidemia, overweight, hypertension, hyperuricaemia, diabetes and smoking (P < 0. 05). The prevalence of renal dysfunction was higher in groups of hypercholesterolaemia, hypertension, diabetes and hyperuricaemia. 3. Hypercholesterolaemia, hypertension, diabetes and hyperuricaemia were main influencing factors of renal dysfunction, with OR 1.36, 1.98, 3.58 and 1.46 (P<0.01). 4. Level of serum creatinine increased significantly with the severity of CAD. Conclusion Gender, lipids, blood pressure, uric acid, body mess index, smoking and diabetes show influence on serum creatinine level. Hyperoholesterolaemia, hyperten-sion and hyperuricaemia are main influencing factors of renal dysfunction.     

Prognostic value of serum cystatin C levels in cirrhotic patients with normal serum creatinine

Background/Aims

Accurate assessment of renal function in patients with liver cirrhosis is difficult and of great prognostic importance. The present study aimed to determine the prognostic significance of certain renal markers and to investigate the priority of serum cystatin C (CysC) levels on one-year mortality in cirrhotic patients.

Methods

Renal function of 45 liver cirrhotic patientss was evaluated by levels of blood urea nitrogen (BUN), serum creatinine (Cr), CysC, as well as 24-hour creatinine clearance (CCl) and estimated glomerular filtration rate obtained by Cockroft-Gault and MDRD formulas. The endpoint of the follow up was mortality within one year. Spearman’s correlation, linear regression analysis and receiver operating characteristic curves were used to investigate prognostic factors.

Results

42 men and 3 women (mean age 53.18 ± 9.71 years) were enrolled in the study. Eleven of the patients (24.4%) died as a result of liver cirrhosis within one year. In predicting mortality, levels of BUN, serum Cr and CysC showed area under the curves (AUC) values of 0.719 (95% CI, 0.539–0.899, p = 0.03), 0.726 (95% CI, 0.541–0.911, p = 0.026) and 0.770 (95% CI, 0.620–0.920, p = 0.008). Sensitivity and specificity of a CysC level of >1.3 mg/l in predicting mortality were 72% and 68%, respectively. Univariate regression analysis showed that elevated levels of CysC above the referent ones, increased the risk of one-year mortality nearly six times (p = 0.02, Exp (B) = 5.81).

Conclusions

Serum CysC could be used as a good prognostic marker in patients with cirrhosis and normal Cr levels.     

Serum cystatin C is not a better marker of creatinine or digoxin clearance than serum creatinine

AIMS: To assess whether cystatin C, a new serum marker of renal function, is a better index of creatinine or digoxin clearance than serum creatinine in older people. METHODS: Twenty-two volunteers over the age of 65 years (mean 73 +/- 5) were recruited from a healthy elderly volunteer database. None of the volunteers was taking digoxin or other medication known to interfere with digoxin kinetics or assay. Digoxin was infused at a dose of 7-10 microg kg(-1) and blood samples were taken over the following 48 h and assayed for serum digoxin. Serum cystatin C, creatinine and creatinine clearance were measured and a calculated creatinine clearance was estimated using the Cockcroft Gault formula. Digoxin clearance was calculated using a pharmacokinetic software package. All values were log transformed to normalize their distribution. RESULTS: Of the 22 volunteers enrolled into the study, 18 completed the study. Serum cystatin C ranged between 0.72 and 1.89 mg l(-1) and serum creatinine ranged from 69.6 to 153.9 micromol l(-1). Measured creatinine clearance ranged from 38 to 123 ml min(-1) and calculated creatinine clearance from 29.5 to 88.0 ml min(-1). Digoxin clearance ranged from 51.0 to 103.5 ml min(-1). Cystatin C correlated extremely well with creatinine (r=0.93, P<0.001, 95% CI 0.82, 0.97) and with creatinine clearance (r=0.67, P=0.002, 95% CI 0.3, 0.87). Neither serum cystatin C nor serum creatinine correlated with digoxin clearance (r=0.25, P=0.31, 95% CI -0.25, 0.64 and r=0.44, P=0.068, 95% CI -0.03, 0.75, respectively). Measured creatinine clearance, however, did correlate well with digoxin clearance (r=0.55, P=0.018, 95% CI 0.11, 0.81). CONCLUSIONS: Serum cystatin C and serum creatinine show very similar correlations with creatinine and digoxin clearances. Serum cystatin C does not offer any advantages in this respect. It remains to be seen whether cystatin C offers any advantage over creatinine in elderly people in other respects.