Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma

Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

peer reviewed("[en] BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.","[en] ",""

Prospects for improved glomerular filtration rate estimation based on creatinine—results from a transnational multicentre study

Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. Methods In a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation. Results 7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%. Conclusions None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated

yy Prospects for improved glomerular filtration rate estimation based on creatinine-results from a transnational multicentre study

Background: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. Methods: In a cross-sectional analysis covering the years 2003-17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund-Malmö revised equation (LMR) and the Full Age Spectrum equation. Results: 7In patients aged 18-39 years old, CKD-EPI overestimated GFR with 5.0-16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%. Conclusions: None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.status: publishe

Development and Validation of a Modified Full Age Spectrum Creatinine-Based Equation to Estimate Glomerular Filtration Rate

International audienceThe Chronic Kidney Disease in Children Study (CKiD) equation for children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults are recommended serum creatinine (SCr)-based calculations for estimating glomerular filtration rate (GFR). However, these equations, as well as their combination, have limitations, notably the problem of implausible changes in GFR during the transition from adolescence to adulthood and overestimation of GFR in young adults. The full age spectrum (FAS) equation addresses these issues but overestimates GFR when SCr levels are low

Development and Validation of a Modified Full Age Spectrum Creatinine-Based Equation to Estimate Glomerular Filtration Rate : A Cross-sectional Analysis of Pooled Data.

BACKGROUND: The Chronic Kidney Disease in Children Study (CKiD) equation for children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults are recommended serum creatinine (SCr)-based calculations for estimating glomerular filtration rate (GFR). However, these equations, as well as their combination, have limitations, notably the problem of implausible changes in GFR during the transition from adolescence to adulthood and overestimation of GFR in young adults. The full age spectrum (FAS) equation addresses these issues but overestimates GFR when SCr levels are low. OBJECTIVE: To develop and validate a modified FAS SCr-based equation combining design features of the FAS and CKD-EPI equations. DESIGN: Cross-sectional analysis with separate pooled data sets for development and validation. SETTING: Research and clinical studies (n = 13) with measured GFR available. PATIENTS: 11 251 participants in 7 studies (development and internal validation data sets) and 8378 participants in 6 studies (external validation data set). MEASUREMENTS: Clearance of an exogenous marker (reference method), SCr level, age, sex, and height were used to develop a new equation to estimate GFR. RESULTS: The new European Kidney Function Consortium (EKFC) equation is a FAS equation with low bias (-1.2 mL/min/1.73 m2 [95% CI, -2.7 to 0.0 mL/min/1.73 m2] in children and -0.9 mL/min/1.73 m2 [CI, -1.2 to -0.5 mL/min/1.73 m2] in adults) across the FAS (2 to 90 years) and SCr range (40 to 490 µmol/L [0.45 to 5.54 mg/dL]) and with fewer estimation errors exceeding 30% (6.5% [CI, 3.8% to 9.1%] in children and 3.1% [CI, 2.5% to 3.6%] in adults) compared with the CKiD and CKD-EPI equations. LIMITATION: No Black patients were included. CONCLUSION: The new EKFC equation shows improved accuracy and precision compared with commonly used equations for estimating GFR from SCr levels. PRIMARY FUNDING SOURCE: Swedish Research Council (Vetenskapsrådet).status: Published onlin

Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment

Aim: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing. Methods: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR) and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages. Results: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5-25 kg/m2, all equations performed similarly, and for BMI < 18.5 kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m2). The four more recent equations also classified mGFR stages better than CG. Conclusions: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations