Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters.

Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3-89.5% versus 76.3-78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.

Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator.

BACKGROUND: Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. METHODS: Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. RESULTS: We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. CONCLUSIONS: A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

Why pediatricians fail to diagnose hypertension: a multicenter survey.

OBJECTIVE: To elucidate why pediatricians fail to diagnose childhood hypertension, with special emphasis on the use of blood pressure (BP) reference data. We hypothesized that pediatricians frequently omit BP measurements and do not routinely relate BP measurements to reference data. STUDY DESIGN: We conducted a multicenter survey on BP measurement among 197 participants. Respondents were asked to estimate BP percentiles and classify BP readings in 12 example cases. Questionnaires were completed onsite in the presence of the researchers, without access to BP reference data. RESULTS: We found that 71% of physicians measure BP during ambulatory visits only if the child has risk factors for hypertension. After measuring BP, 65% compare the reading with reference data only if they suspect that it is elevated. Their ability to rate a reading at its true value is limited, however; 47% of the physicians classified 1 or more of the prehypertensive or hypertensive cases as normal. CONCLUSIONS: Most pediatricians do not screen for hypertension, contrary to recommendations. After obtaining a BP measurement, the majority do not compare the reading with reference standards; however, without the use of reference data, they commonly underestimate the BP percentile and potentially miss cases of childhood hypertension.

Diversity in renal function monitoring and dose modifications during treatment for childhood cancer: a call for standardization.

Despite changes in survival and drug tolerability, nephrotoxicity remains an important complication of chemotherapy. To provide cutting-edge care for children with cancer oncologist must be familiar with their nephrotoxic potential. Careful monitoring of renal function during treatment is therefore indicated. Well-defined guidelines for this are lacking. We reviewed current DCOG protocols and showed that monitoring of renal function during treatment varies widely between protocols. In some protocols recommended renal function measures are inappropriate given the chemotherapy prescribed. Advices on dose modifications in case of renal dysfunction also vary, even with comparable regimens. These differences are unwanted and call for standardization.

Early and late renal adverse effects after potentially nephrotoxic treatment for childhood cancer.

BACKGROUND: Great improvements in diagnostics and treatment for malignant disease in childhood have led to a major increase in survival. However, childhood cancer survivors (CCS) are at great risk for developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is one of these known (acute) side effects of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate impairment, proteinuria, tubulopathy and hypertension. However, evidence about the long-term effects of these treatments on renal function remains inconclusive. To reduce the number of (long-term) nephrotoxic events in CCS, it is important to know the risk of, and risk factors for, early and late renal adverse effects, so that ultimately treatment and screening protocols can be adjusted. OBJECTIVES: To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of and associated risk factors for renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with healthy controls or CCS treated without potentially nephrotoxic treatment. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2011), MEDLINE/PubMed (from 1945 to December 2011) and EMBASE/Ovid (from 1980 to December 2011). SELECTION CRITERIA: With the exception of case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment) in children and adults who were treated for a paediatric malignancy (aged 18 years or younger at diagnosis) with cisplatin, carboplatin, ifosfamide, radiation including the kidney region and/or a nephrectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction using standardised data collection forms. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: The search strategy identified 5504 studies, of which 5138 were excluded on the basis of title and/or abstract. The full-text screening of the remaining 366 articles resulted in the inclusion of 57 studies investigating the prevalence of and sometimes also risk factors for early and late renal adverse effects of treatment for childhood cancer. The 57 studies included at least 13,338 participants of interest for this study, of whom at least 6516 underwent renal function testing. The prevalence of renal adverse effects ranged from 0% to 84%. This variation may be due to diversity in included malignancies, prescribed treatments, reported outcome measurements and the methodological quality of available evidence.Chronic kidney disease/renal insufficiency (as defined by the authors of the original studies) was reported in 10 of 57 studies. The prevalence of chronic kidney disease ranged between 0.5% and 70.4% in the 10 studies and between 0.5% and 18.8% in the six studies that specifically investigated Wilms' tumour survivors treated with a unilateral nephrectomy.A decreased (estimated) glomerular filtration rate was present in 0% to 50% of all assessed survivors (32/57 studies). Total body irradiation; concomitant treatment with aminoglycosides, vancomycin, amphotericin B or cyclosporin A; older age at treatment and longer interval from therapy to follow-up were significant risk factors reported in multivariate analyses. Proteinuria was present in 0% to 84% of all survivors (17/57 studies). No study performed multivariate analysis to assess risk factors for proteinuria.Hypophosphataemia was assessed in seven studies. Reported prevalences ranged between 0% and 47.6%, but four of seven studies found a prevalence of 0%. No studies assessed risk factors for hypophosphataemia using multivariate analysis. The prevalence of impairment of tubular phosphate reabsorption was mostly higher (range 0% to 62.5%; 11/57 studies). Higher cumulative ifosfamide dose, concomitant cisplatin treatment, nephrectomy and longer follow-up duration were significant risk factors for impaired tubular phosphate reabsorption in multivariate analyses.Treatment with cisplatin and carboplatin was associated with a significantly lower serum magnesium level in multivariate analysis, and the prevalence of hypomagnesaemia ranged between 0% and 37.5% in the eight studies investigating serum magnesium.Hypertension was investigated in 24 of the 57 studies. Reported prevalences ranged from 0% to 18.2%. A higher body mass index was the only significant risk factor noted in more than one multivariate analysis. Other reported factors that significantly increased the risk of hypertension were use of total body irradiation, abdominal irradiation, acute kidney injury, unrelated or autologous stem cell donor type, growth hormone therapy and older age at screening. Previous infection with hepatitis C significantly decreased the risk of hypertension.Because of the profound heterogeneity of the studies, it was not possible to perform any meta-analysis. AUTHORS' CONCLUSIONS: The prevalence of renal adverse events after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region and/or nephrectomy ranged from 0% to 84%. With currently available evidence, it was not possible to draw any conclusions with regard to prevalence of and risk factors for renal adverse effects. Future studies should focus on adequate study design and reporting and should deploy multivariate risk factor analysis to correct for possible confounding. Until more evidence becomes available, CCS should be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.

Height-independent estimation of glomerular filtration rate in children: an alternative to the Schwartz equation.

OBJECTIVE: To compare the diagnostic performance of 2 height-independent equations used to calculate estimated glomerular filtration rate (eGFR), those of Pottel (eGFR-Pottel) and the British Columbia Children's Hospital (BCCH) (eGFR-BCCH), with the commonly used Schwartz equation (eGFR-Schwartz). STUDY DESIGN: We externally validated eGFR-Pottel and eGFR-BCCH in a well-characterized pediatric patient population (n = 152) and compared their diagnostic performance with that of eGFR-Schwartz using Bland-Altman analysis. All patients underwent glomerular filtration rate measurement using the gold standard single-injection inulin clearance method (GFR-inulin). RESULTS: Median GFR-inulin was 92.0 mL/min/1.73 m² (IQR, 76.1-107.4 mL/min/1.73 m²). Compared with GFR-inulin, the mean bias for eGFR-Schwartz was -10.1 mL/min/1.73 m(2) (95% limits of agreement [LOA], -77.5 to 57.2 mL/min/1.73 m(2)), compared with -12.3 mL/min/1.73 m² (95% LOA, -72.6 to 47.9 mL/min/1.73 m(2)) for eGFR-Pottel and -22.1 mL/min/1.73 m² (95% LOA, -105.0 to 60.8 mL/min/1.73 m(2)) for eGFR-BCCH. eGFR-Pottel showed comparable accuracy to eGFR-Schwartz, with 77% and 76% of estimates within 30% of GFR-inulin, respectively. eGFR-BCCH was less accurate than eGFR-Schwartz (66% of estimates within 30% of GFR-inulin; P < .01). CONCLUSION: The performance of eGFR-Pottel is superior to that of eGFR-BCCH and comparable with that of eGFR-Schwartz. eGFR-Pottel is a valid alternative to eGFR-Schwartz in children and could be reported by the laboratory if height data are not available.

Cystatin C more accurately detects mildly impaired renal function than creatinine in children receiving treatment for malignancy.

BACKGROUND: Monitoring of renal function is crucial in pediatric oncology. The use of creatinine to estimate glomerular filtration rate (GFR) is hampered by its dependency on muscle mass. Muscle wasting is common in children with cancer, leading to overestimation of GFR. Data on cystatin C are sparse in pediatric oncology, although this marker could be particularly useful in this population. PROCEDURE: Inulin clearance, estimated GFR using serum cystatin C according to Filler (eGFRcys) and serum creatinine according to Schwartz (eGFRcrea) were measured in 68 children with malignancy and 121 controls. We analyzed the difference between measured and estimated GFR and performance, bias and accuracy. RESULTS: Multiple linear regression analysis showed overestimation of GFR by eGFRcrea in females (B = -21.18; P = 0.001), and in patients with malignancy (B = -21.77; P = 0.014). eGFRcys overestimated GFR in females (B = -10.47; P = 0.001), but was independent of treatment for malignancy. Agreement with gold standard in detecting GFR below 90 ml/min/1.73 m(2) is better for eGFRcys (AUC 0.854) than for eGFRcrea (AUC 0.675) in the group with cancer. They performed comparably in the control group. Bland-Altman analysis showed considerable bias for eGFRcrea compared to eGFRcys (-14.3 ml/min/1.73 m(2) vs. -7.3 ml/min/1.73 m(2)). The proportion of estimates within 30% of true GFR for eGFRcrea (72.1%) was lower than for eGFRcys (82.4%) in the group with cancer. In the control group eGFRcrea (84.3%) outperformed eGFRcys (76.0%). When using the 50% limits of agreement, eGFRcys outperformed eGFRcrea in both groups. CONCLUSION: Cystatin C more accurately detects mildly impaired renal function than creatinine in children receiving treatment for malignancy.