Streamlined intraoperative brain tumor classification and molecular subtyping in stereotactic biopsies using stimulated Raman histology and deep learning.

PURPOSE: Recent artificial intelligence (AI) algorithms aided intraoperative decision-making via stimulated Raman histology (SRH) during craniotomy. This study assesses deep-learning algorithms for rapid intraoperative diagnosis from SRH images in small stereotactic-guided brain biopsies. It defines a minimum tissue sample size threshold to ensure diagnostic accuracy. EXPERIMENTAL DESIGN: A prospective single-center study examined 121 SRH images from 84 patients with unclear intracranial lesions undergoing stereotactic brain biopsy. Unprocessed, label-free samples were imaged with a portable fiber-laser Raman scattering microscope. Three deep-learning models were tested to (I) identify tumorous/non-tumorous tissue as qualitative biopsy control, (II) subclassify into high-grade glioma (CNS WHO grade 4), diffuse low-grade glioma (CNS WHO grade 2-3), metastases, lymphoma, or gliosis, and (III) molecularly subtype IDH- and 1p/19q-status of adult-type diffuse gliomas. Model predictions were evaluated against frozen section analysis and final neuropathological diagnoses. RESULTS: The first model identified tumorous/non-tumorous tissue with 91.7% accuracy. Sample size on slides impacted accuracy in brain tumor subclassification (81.6%, κ=0.72 frozen section; 73.9%, κ=0.61 second model), with SRH being smaller than H&E (4.1±2.5mm² vs 16.7±8.2mm², p<0.001). SRH images with over 140 high-quality patches and a mean squeezed sample of 5.26mm² yielded 89.5% accuracy in subclassification and 93.9% in molecular subtyping of adult-type diffuse gliomas. CONCLUSIONS: AI-based SRH image analysis is non-inferior to frozen section analysis in detecting and subclassifying brain tumors during small stereotactic-guided biopsies once a critical squeezed sample size is reached. Beyond frozen section analysis, it enables valid molecular glioma subtyping, allowing faster treatment decisions in the future. Refinement is needed for long-term application.

Which is the best glomerular filtration marker: Creatinine, cystatin C or both?

BACKGROUND: The glomerular filtration rate (GFR) is estimated by the serum or plasma concentration of creatinine and/or cystatin C using equations that include demographic data. The equations worldwide most widely used are those of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) consortium and updated in 2021 to remove the Afro-American racial correction factor. In 2021 and then in 2023, the European Kidney Function Consortium also developed equations based on creatinine and cystatin C, usable across the full age spectrum, and constructed by including the Q value (i.e. the median creatinine or cystatin C in healthy men and women, which is customizable for specific populations). METHODS: The aim of this narrative review is to examine the strengths and weaknesses of each biomarker. RESULTS: Both biomarkers have non-GFR determinants, namely muscle mass, protein intake and tubular secretion for creatinine; dysthyroidism and systemic corticosteroids for cystatin C, as well as other more debated determinants (diabetes, obesity, proteinuria, inflammatory syndrome). These non-GFR determinants are the reason why no equation based on a single endogenous biomarker has an accuracy within 30% greater than 90% over the entire age spectrum (in at least one patient in 10, estimated GFR is at least 30% higher or at least 30% lower than the measured GFR). CONCLUSION: Equations combining the two biomarkers provide a better estimate of GFR, particularly in the subgroup of patients whose estimates based on each of the biomarkers are highly discordant. These patients must also be identified as being at increased risk of morbidity, particularly cardiovascular, and mortality.

Diabetic status and the performances of creatinine- and cystatin C-based eGFR equations.

BACKGROUND AND HYPOTHESIS: The estimation of glomerular filtration rate (GFR) is one main tool to detect renal disease. The most used biomarker remains serum creatinine and the European Kidney Function Consortium (EKFCcrea) equation is the most validated in Europe. More recently, cystatin C, has been proposed. We studied the performances of the EKFC equations in a large cohort of subjects according to their diabetic status. METHODS: Four cohorts from the EKFC dataset were retrospectively considered in which the diabetic status was available. GFR was measured by plasma clearances (mGFR) (iohexol or 51Cr-EDTA). The performance of the equations was assessed by calculating bias, precision (IQR) and P30 (percentage of eGFR-values within ± 30% of mGFR). RESULTS: In the whole population (n = 6 158), median [IQR] age was 61 [47;72] years, with 45.8% women. Mean mGFR was 60 [39;82] mL/min/1.73m². Compared to non-diabetic individuals (n = 5 124), diabetic patients (n = 1 034) were older, more frequently male, heavier, and had lower mGFR. The performance of the EKFCcys equation was similar to EKFCcrea, but the EKFCcrea+cys had better P30 than the single-biomarker equations. P30 values were substantially lower in diabetic patients than in non-diabetic but, according to a matched analysis, this is mainly explained by the difference in GFR levels between the two populations, not by diabetic status. CONCLUSION: We showed that equation combining creatinine and cystatin C present a better performance. If accuracy of equations seems better in non-diabetic than in diabetic individuals, it is more due to differences in GFR levels than to the diabetic status.

Kidney biopsy for the diagnosis and treatment of kidney diseases. Recommendations from the French speaking Society of Nephrology (SFNDT) and French National Authority for Health (HAS) 2022

Kidney Biopsy (KB) is a crucial diagnostic tool in the field of renal diseases and is routinely performed in nephrology departments. A previous survey conducted by the Société Francophone de Néphrologie Dialyse Transplantation (SFNDT) revealed significant disparities in clinical practices, sometimes conflicting with the existing literature and recently published recommendations. In response, the SFNDT wished to promote the development of best practice guidelines, under the auspices of the French National Authority for Health (HAS), to establish a standardized framework for performing kidney biopsies in France.

La biopsie rénale (BR) est un outil diagnostique crucial dans le domaine des maladies rénales et est pratiquée en routine dans les services de néphrologie. Une précédente enquête menée par la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a révélé d'importantes disparités dans les pratiques cliniques, parfois en contradiction avec la littérature existante et les recommandations récemment publiées. En réponse, la SFNDT a souhaité promouvoir l'élaboration de recommandations de bonnes pratiques, sous l'égide de la Haute Autorité de santé (HAS), afin d'établir un cadre standardisé pour la réalisation des biopsies rénales en France.

Glomerular Filtration Rate Estimation in Adults: Myths and Promises.

BACKGROUND: In daily practice, glomerular filtration rate (GFR) is estimated with equations including renal biomarkers. Among these biomarkers, serum creatinine remains the most used. However, there are many limitations with serum creatinine, which we will discuss in the current review. We will also discuss how creatinine-based equations have been developed and what we can expect from them in terms of performance to estimate GFR. SUMMARY: Different creatinine-based equations have been proposed. We will show the advantages of the recent European Kidney Function Consortium equation. This equation can be used in children and adults. This equation can also be used with some flexibility in different populations. KEY MESSAGES: GFR is estimated by creatinine-based equations, but the most important for nephrologists is probably to know the limitations of these equations.

Glomerular Filtration Rate Measured Based on Iomeprol Clearance Assessed at CT Urography in Living Kidney Donor Candidates.

Background Estimating glomerular filtration rate (GFR) from serum creatinine can be inaccurate, and current procedures for measuring GFR are time-consuming and cumbersome. Purpose To develop a method for measuring GFR based on iomeprol clearance assessed at CT urography in kidney donor candidates and compare this with iohexol clearance (reference standard for measuring GFR). Materials and Methods This cross-sectional retrospective study included data from kidney donor candidates who underwent both iohexol clearance and CT urography between July 2016 and October 2022. CT-measured GFR was calculated as the iomeprol excretion rate in the urinary system between arterial and excretory phases (Hounsfield units times milliliters per minute) divided by a surrogate for serum iomeprol concentration in the aorta at the midpoint (in Hounsfield units). Performance of CT-measured GFR was assessed with use of mean bias (mean difference between CT-measured GFR and iohexol clearance), precision (the distance between quartile 1 and quartile 3 of the bias [quartile 3 minus quartile 1], with a small value indicating high precision), and accuracy (percentage of CT-measured GFR values falling within 10%, 20%, and 30% of iohexol clearance values). Intraobserver agreement was assessed for 30 randomly selected individuals with the Lin concordance correlation coefficient. Results A total of 75 kidney donor candidates were included (mean age, 51 years ± 13 [SD]; 45 female). The CT-measured GFR was unbiased (1.1 mL/min/1.73 m2 [95% CI: -1.9, 4.1]) and highly precise (16.2 mL/min/1.73 m2 [quartiles 1 to 3, -6.6 to 9.6]). The accuracy of CT-measured GFR within 10%, 20%, and 30% was 61.3% (95% CI: 50.3, 72.4), 88.0% (95% CI: 80.7, 95.4), and 100%, respectively. Concordance between CT-based GFR measurements taken 2 months apart was almost perfect (correlation coefficient, 0.99 [95% CI: 0.98, 0.99]). Conclusion In living kidney donors, GFR measured based on iomeprol clearance assessed at CT urography showed good agreement with GFR measured based on iohexol clearance. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Davenport in this issue.

Diagnostic standard: assessing glomerular filtration rate.

Creatinine-based estimated GFR (eGFR) is imprecise at individual level, due to non-GFR-related serum creatinine determinants, including atypical muscle mass. Cystatin C has the advantage of being independent on muscle mass, a feature that led to the development of race- and sex-free equations. Yet, cystatin C-based equations do not perform better than creatinine-based equations to estimate GFR, unless both variables are included together. The new race-free Chronic Kidney Disease Epidemiology (CKD-EPI) equation, had slight opposite biases between Black and Non-Black subjects in USA, but performs poorer than that the previous version in European populations. The European Kidney Function Consortium (EKFC) equation developed in 2021 can be used both in children and adults, is more accurate in young and old adults, and is applicable to non-white European populations, by rescaling the Q factor, i.e. population median creatinine, in a potentially universal way. A sex- and race-free cystatin C-based EKFC, with the same mathematical design, has also be defined. New developments in the field of GFR estimation would be standardization of cystatin C assays, development of creatinine-based eGFR equations that would incorporate muscle mass data, implementation of new endogenous biomarkers, and the use of artificial intelligence. Standardization of different GFR measurement methods would also be a future challenge, as well as new technologies for measuring GFR. Future research is also needed on discrepancies between cystatin C and creatinine, which is associated with high risk of adverse events: standardize the definition of discrepancy, and understand its determinants.

MSL2 ensures biallelic gene expression in mammals.

In diploid organisms, biallelic gene expression enables the production of adequate levels of mRNA1,2. This is essential for haploinsufficient genes, which require biallelic expression for optimal function to prevent the onset of developmental disorders1,3. Whether and how a biallelic or monoallelic state is determined in a cell-type-specific manner at individual loci remains unclear. MSL2 is known for dosage compensation of the male X chromosome in flies. Here we identify a role of MSL2 in regulating allelic expression in mammals. Allele-specific bulk and single-cell analyses in mouse neural progenitor cells revealed that, in addition to the targets showing biallelic downregulation, a class of genes transitions from biallelic to monoallelic expression after MSL2 loss. Many of these genes are haploinsufficient. In the absence of MSL2, one allele remains active, retaining active histone modifications and transcription factor binding, whereas the other allele is silenced, exhibiting loss of promoter-enhancer contacts and the acquisition of DNA methylation. Msl2-knockout mice show perinatal lethality and heterogeneous phenotypes during embryonic development, supporting a role for MSL2 in regulating gene dosage. The role of MSL2 in preserving biallelic expression of specific dosage-sensitive genes sets the stage for further investigation of other factors that are involved in allelic dosage compensation in mammalian cells, with considerable implications for human disease.

New and old GFR equations: a European perspective.

Glomerular filtration rate (GFR) is estimated in clinical practice from equations based on the serum concentration of endogenous biomarkers and demographic data. The 2009 creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI2009) was recommended worldwide until 2021, when it was recalibrated to remove the African-American race factor. The CKD-EPI2009 and CKD-EPIcr2021 equations overestimate GFR of adults aged 18-30 years, with a strong overestimation in estimated GFR (eGFR) at age 18 years. CKD-EPICr2021 does not perform better than CKD-EPI2009 in US population, overestimating GFR in non-Black subjects, and underestimating it in Black subjects with the same magnitude. CKD-EPICr2021 performed worse than the CKD-EPI2009 in White Europeans, and provides no or limited performance gains in Black European and Black African populations. The European Kidney Function Consortium (EKFC) equation, which incorporates median normal value of serum creatinine in healthy population, overcomes the limitations of the CKD-EPI equations: it provides a continuity of eGFR at the transition between pediatric and adult care, and performs reasonably well in diverse populations, assuming dedicated scaling of serum creatinine (Q) values is used. The new EKFC equation based on cystatin C (EKFCCC) shares the same mathematical construction, namely, it incorporates the median cystatin C value in the general population, which is independent of sex and ethnicity. EKFCCC is therefore a sex-free and race-free equation, which performs better than the CKD-EPI equation based on cystatin C. Despite advances in the field of GFR estimation, no equation is perfectly accurate, and GFR measurement by exogenous tracer clearance is still required in specific populations and/or specific clinical situations.

Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells.

Members of the NSL histone acetyltransferase complex are involved in multiorgan developmental syndromes. While the NSL complex is known for its importance in early development, its role in fully differentiated cells remains enigmatic. Using a kidney-specific model, we discovered that deletion of NSL complex members KANSL2 or KANSL3 in postmitotic podocytes led to catastrophic kidney dysfunction. Systematic comparison of two primary differentiated cell types reveals the NSL complex as a master regulator of intraciliary transport genes in both dividing and nondividing cells. NSL complex ablation led to loss of cilia and impaired sonic hedgehog pathway in ciliated fibroblasts. By contrast, nonciliated podocytes responded with altered microtubule dynamics and obliterated podocyte functions. Finally, overexpression of wild-type but not a double zinc finger (ZF-ZF) domain mutant of KANSL2 rescued the transcriptional defects, revealing a critical function of this domain in NSL complex assembly and function. Thus, the NSL complex exhibits bifurcation of functions to enable diversity of specialized outcomes in differentiated cells.

Development and validation of a new equation based on plasma creatinine and muscle mass assessed by CT scan to estimate glomerular filtration rate: a cross-sectional study.

Background: Inter-individual variations of non-glomerular filtration rate (GFR) determinants of serum creatinine, such as muscle mass, account for the imperfect performance of estimated GFR (eGFR) equations. We aimed to develop an equation based on creatinine and total lumbar muscle cross-sectional area measured by unenhanced computed tomography scan at the third lumbar vertebra. Methods: The muscle mass-based eGFR (MMB-eGFR) equation was developed in 118 kidney donor candidates (iohexol clearance) using linear regression. Validation cohorts included 114 healthy subjects from another center (51Cr-EDTA clearance, validation population 1), 55 patients with chronic diseases (iohexol, validation population 2), and 60 patients with highly discordant creatinine and cystatin C-based eGFR, thus presumed to have atypical non-GFR determinants of creatinine (51Cr-EDTA, validation population 3). Mean bias was the mean difference between eGFR and measured GFR, precision the standard deviation (SD) of the bias, and accuracy the percentage of eGFR values falling within 20% and 30% of measured GFR. Results: In validation population 1, performance of MMB-eGFR was not different from those of CKD-EPICr2009 and CKD-EPICr2021. In validation population 2, MMB-eGFR was unbiased and displayed better precision than CKD-EPICr2009, CKD-EPICr2021 and EKFC (SD of the biases: 13.1 vs 16.5, 16.8 and 15.9 mL/min/1.73 m2). In validation population 3, MMB-eGFR had better precision and accuracy {accuracy within 30%: 75.0% [95% confidence interval (CI) 64.0-86.0] vs 51.5% (95% CI 39.0-64.3) for CKD-EPICr2009, 43.3% (95% CI 31.0-55.9) for CKD-EPICr2021, and 53.3% (95% CI 40.7-66.0) for EKFC}. Difference in bias between Black and white subjects was -2.1 mL/min/1.73 m2 (95% CI -7.2 to 3.0), vs -8.4 mL/min/1.73 m2 (95% CI -13.2 to -3.6) for CKD-EPICr2021. Conclusion: MMB-eGFR displayed better performances than equations based on demographics, and could be applied to subjects of various ethnic backgrounds.

New developments and future prospects in the field of glomerular filtration rate estimation / Actualités et perspectives dans l'estimation du débit de filtration glomérulaire

Glomerular filtration rate (GFR) is estimated from equations based on serum or plasma concentrations of endogenous markers (creatinine and/or cystatin C), and demographic data (age, sex, ± ethnicity). These equations are accurate at the population level, but often inaccurate at the individual level. The creatinine-based Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation published in 2009 (CKD-EPIcr-2009), and the CKD-EPI equation published in 2012 based on creatinine and cystatin C, were recalibrated in 2021 to remove their dedicated race correction factors for black American subjects. All creatinine-based CKD-EPI equations overestimate true GFR in subjects younger than 30 years. The Full Age Spectrum (FAS) equation, applicable across the entire age spectrum (pediatrics to old age), solved this problem, but remained suboptimal at low GFR values. The European Kidney Function Consortium (EKFC) equation published in 2021 was an improvement of the FAS equation, which also includes the Q factor (median creatinine in the general population). EKFC is applicable across the age spectrum and is efficient at low and normal GFR values. The new creatinine-based CKD-EPI equation (CKD-EPIcr-2021) underestimates GFR in Black Americans and overestimates it in non-Black Americans. In European and African subjects, CKD-EPIcr-2021 overestimates true GFR and should not be adopted. The EKFC equation, which performs well in this population, also performs well in European Black subjects and in African subjects, provided dedicated Q factors are used.

Le débit de filtration glomérulaire (DFG) est estimé à partir d'équations prenant en compte la concentration sérique ou plasmatique de marqueurs endogènes (créatinine et/ou cystatine C) et des données démographiques (âge, sexe, ± origine ethnique). Ces équations sont justes à l'échelle populationnelle, mais fréquemment inexactes à l'échelle individuelle. L'équation Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI), basée sur la créatinine, publiée en 2009 (CKD-EPIcr-2009), et l'équation CKD-EPI de 2012, basée sur la créatinine et la cystatine C, ont été recalibrées en 2021 afin d'éliminer leurs facteurs correctifs ethniques dédiés aux sujets Noirs américains. Toutes les équations CKD-EPI basées sur la créatinine surévaluent le DFG réel chez les sujets de moins de 30 ans. L'équation Full Age Spectrum (FAS), applicable sur tout le spectre d'âge (de la pédiatrie au grand âge), résolvait ce problème, mais restait suboptimale aux valeurs basses de DFG. L'équation European Kidney Function Consortium (EKFC) publiée en 2021 est une amélioration de l'équation FAS, qui inclut également le facteur Q (créatinine médiane en population générale). Elle est applicable sur tout le spectre d'âge, et performante aux valeurs basses et normales de DFG. La nouvelle équation CKD-EPI basée sur la créatinine (CKD-EPIcr-2021) sous-évalue le DFG chez les sujets Noirs américains et le surévalue chez les non-Noirs américains. Chez les sujets européens et africains, CKD-EPIcr-2021 surévalue le DFG réel et ne doit pas être adoptée. L'équation EKFC, qui est performante dans cette population, l'est aussi chez les sujets européens Noirs et les Africains, à condition d'utiliser des facteurs Q dédiés.

Natural course and determinants of short-term kidney function decline in hereditary transthyretin amyloidosis: a French observational study.

Data regarding renal involvement in patients with hereditary transthyretin (ATTRv) amyloidosis are scarce and the natural course of chronic kidney disease (CKD) in this population remains unclear. This observational study, including adult patients diagnosed with ATTRv amyloidosis at the French Reference Centre for Cardiac Amyloidosis, investigated renal function outcome and its determinants. Multivariable logistic regression models identified factors associated with CKD at baseline. Determinants of the change in estimated glomerular filtration rate (eGFR) over 24 months of follow-up were assessed with a multivariable linear mixed-effects model. In total, 232 patients (78 women [34%], mean age: 64 years) with ATTRv amyloidosis were classified on the basis of their TTR variants: ATTRV122I (37%), ATTRV30M (29%), and other variants (34%). Median baseline eGFR was 78 ml/min/1.73 m2. Seventy-two patients (31%) had an eGFR below 60 ml/min/1.73m2 and 27/137 patients (20%) had significant proteinuria (urine protein/creatinine ratio ≥30 mg/mmol). Renal biopsy, performed in four cases, found typical Congo red-positive and TTR-labelled amyloid deposits in all cases. Older age (OR 1.07, p < .001) and a prior history of hypertension (OR 2.09, p = .04) were associated with a higher prevalence of CKD at baseline, whereas higher left ventricular global longitudinal strain (LVGLS) (OR 0.83, p < .001) was associated with a lower prevalence. The estimated change in eGFR was -7.12 [-9.61, -4.63] and -8.21 [-10.81, -5.60] ml/min/1.73 m2 after 12 and 24 months of follow-up, respectively. eGFR decline was independently associated with older age ((67-74], coefficient= -14.35 mL/min/1.73 m2, p < .01, >74, coefficient = -22.93 mL/min/1.73 m2, p < .001, versus <56), ATTRV122I (coefficient = -17.17 mL/min/1.73m2, p < .01, versus ATTRV30M) and LVGLS (coefficient = 1.22, p < .01). These data suggest that CKD is a common finding in patients with ATTRv amyloidosis, and that eGFR decline is rapid during the first year of evaluation. Older age, lower LVGLS and ATTRV122I were associated with a worse renal outcome. Further studies are now needed to evaluate effects of new targeted therapies on long term renal function.

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

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.

Determination of the Tool-Chip Contact Length for the Cutting Processes.

The thermomechanical interaction of the tool with the chip in the most loaded secondary cutting zone depends on the contact length of the tool rake face with the chip. Experimental studies of the dependency of the contact length on the cutting speed, the undeformed chip thickness, and the tool rake angle, performed by the optical method, are used for comparison with the contact length obtained by the FE modeling of the orthogonal cutting process. To determine the parameters of the constitutive Johnson-Cook equation, which serves as a material model of the FE cutting model that has a predominant influence on the contact length, a software-implemented algorithm was developed. This algorithm is based on determining the generalized parameters of the constitutive equation through finding the intersection of these parameter sets. The plurality intersection of the parameter sets of the constitutive equation is determined by means of the design of experiments and refined by subsequent multiple iterations. The comparison of the contact length values, obtained by simulating the cutting process using the generalized parameters of the constitutive equation as a material model with their experimental values, does not exceed 12% for a wide range of cutting speeds and depths of cut, as well as for the tool rake angle.