Contribution of the MDRD equation and of cystatin C for renal function estimates in cancer patients.

BACKGROUND: Serum creatinine (SCr) and Cockcroft-Gault creatinine clearance (CG CrCL) are used to estimate glomerular filtration rate (GFR). Other markers have been proposed including serum cystatin C (cysC) and the Modification of Diet in Renal Disease (MDRD) study equation. PATIENTS AND METHODS: We have compared the diagnostic performances of SCr, cysC, CG CrCL, and the MDRD equation in 144 cancer patients. For reference we used either the measured or the predicted carboplatin clearance, which is around the GFR + 25 mL/min. RESULTS: CysC was more sensitive than SCr (70.1% vs 13.4%) but was not very specific (61% for a cut-off = 0.95 mL). CysC values were higher in 40 cancer patients vs 40 healthy controls with a similar and normal mean CG CrCL (1.08 vs 0.71 mg/L; p < 0.001). CG and the MDRD equations gave similar values for Pearson's coefficient, ROC-plot AUC, and precision, except for patients with poor general status, where the MDRD equation was better (MAPE: 12.4% vs 19.6%, p < 0.001; R: 0.908 vs 0.813). CONCLUSIONS: In cancer patients, cysC is a more sensitive indicator of the glomerular filtration rate than SCr, but its diagnostic performance is lower than for CG CrCL. There may be no advantage in replacing the CG equation by the MDRD equation except for patients with severe malnutrition and/or inflammation.

Cystatin C as a new covariate to predict renal elimination of drugs: application to carboplatin.

BACKGROUND AND OBJECTIVE: The individual dosing of drugs that are mainly eliminated unchanged in the urine is made possible by assessing renal function. Most of the methods used are based on serum creatinine (SCr) levels. Cystatin C (CysC) has been proposed as an alternative endogenous marker of the glomerular filtration rate (GFR). Carboplatin is one of the drugs for which elimination is most dependent on the GFR. A prospective clinical trial including 45 patients was conducted to assess the value of serum CysC as a predictor of carboplatin clearance (CL). METHODS: The patients were receiving carboplatin as part of established protocols. Carboplatin was administered as a daily 60-minute infusion at doses ranging from 290 to 1700mg. A population pharmacokinetic analysis was performed using the nonlinear mixed effect modelling NONMEM program according to a two-compartment pharmacokinetic model. RESULTS: Data from 30 patients were used to test the relationships between carboplatin CL and morphological, biological and demographic covariates previously proposed for prediction of the GFR. The interindividual variability of carboplatin CL decreased from 31% (no covariate) to 14% by taking into account five covariates (SCr, CysC, bodyweight [BW], age and sex). Prospective evaluation of these relationships using the data from the other 15 patients confirmed that the best equation to predict carboplatin CL was based on these five covariates, with a mean absolute percentage error of 13% as an assessment of precision. NONMEM analysis of the whole dataset (n = 45 patients) was performed. The best covariate equation corresponding to the overall analysis was: CL (mL/min) = 110 x (SCr/75)-0.512 x (CysC/1.0)-0.327 x (BW/65)0.474 x (age/56)-0.387 x 0.854sex, with SCr in micromol/L, CysC in mg/L, BW in kilograms, age in years and sex = 0 if male and 1 if female. To put the value of CysC as an endogenous marker of the GFR into perspective, covariate equations without SCr were also evaluated; a better prediction was obtained by considering CysC together with age and BW (interindividual variability of 16.6% vs 23.3% for CysC alone). CONCLUSION: CysC is a marker of drug elimination that is at least as good as SCr for predicting carboplatin CL. The model based on five covariates was superior to those based on only four covariates (with BW, age and sex combined with either SCr or CysC), indicating that CysC and SCr are not completely redundant to each other. Further pharmacokinetic evaluation is needed to determine whether SCr or CysC is the better marker of renal elimination of other drugs.

Variations in the sequence and expression of the Plasmodium falciparum chloroquine resistance transporter (Pfcrt) and their relationship to chloroquine resistance in vitro.

Chloroquine has been widely used for malaria treatment and prophylaxis for several decades, but its usefulness has now declined with the emergence of chloroquine resistance. Recent studies showed that the K76T mutation in the PfCRT protein, initially associated to chloroquine-resistant parasites, is sometimes also present in susceptible parasites, suggesting that other factors control the expression of the resistance phenotype. Here, we sought new mutations in the Pfcrt gene and used real-time PCR to investigate variations in the expression level of this gene with respect to the in vitro response to chloroquine. About 40 Cambodian isolates of Plasmodium falciparum were selected on the basis of their response to chloroquine in vitro. The Pfcrt gene was characterised by amplifying and sequencing the full-length cDNA. Twelve point mutations--M74I, N75D/E, K76T, A144F, L148I, I194T, A220S, Q271E, N326S, T333S, I356T and R371I--were detected. Mutations identified at positions 144, 148, 194 and 333 had never been described before. These mutations define six distinct haplotypes, distributed heterogeneously throughout Cambodia. Only the mutations at positions 74-76, 220 and 271 were significantly associated with the in vitro response to chloroquine. Three major haplotypes--MNK/A/Q, IDT/S/E and IET/S/E--accounted for all the isolates examined. The MNK/A/Q haplotype corresponded to susceptible isolates whereas parasites with the IDT/S/E haplotype displayed an intermediate response to chloroquine and those with the IET/S/E haplotype displayed the highest IC50 values. Phylogenic analysis suggested that the IDT and IET haplotypes (positions 74-76) arose independently from the wild-type MNK sequence. We found that the expression level of Pfcrt, evaluated by real-time PCR, had no effect on the response of the parasite to the drug in vitro. Similarly, in a CQ-resistant strain short-term cultured in the presence of CQ, no change was observed in the level of transcripts. These results are discussed in light of recent finding suggesting the possible involvement of other transporters in CQ-resistance.