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Objectives: To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA:nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function., Methods: Eighty adolescents were studied at baseline [mean (SD) age 14.2 (1.5) years; mean diabetes duration 6.7 (3.0) years] and followed up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR (qPCR)., Results: Overall, 4.2% of participants had diabetic kidney disease (DKD) at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73m2) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration and HbA1c [hyperfiltration -1.46 (3.07) mL/min/1.73 m2/year vs non-hyperfiltration -0.51 (2.48) mL/min/1.73m2/year, P=0.02]. Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73m2/year) compared to those without hyperfiltration [OR 14.11, 95% CI (2.30-86.60), P=0.004]. Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modelling., Conclusion: Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after ∼9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

In clinical practice, the glomerular filtration rate (GFR), a measurement of kidney functioning, is normally calculated using equations, such as the European Kidney Function Consortium (EKFC) equation. Despite being the most general equation, EKFC, just like previously proposed approaches, can still struggle to achieve satisfactory performance, limiting its clinical applicability. As a possible solution, recently machine learning (ML) has been investigated to improve GFR prediction, nonetheless the literature still lacks a general and multi-center study. Using a dataset with 19,629 patients from 13 cohorts, we investigate if ML can improve GFR prediction in comparison to EKFC. More specifically, we compare diverse ML methods, which were allowed to use age, sex, serum creatinine, cystatin C, height, weight and BMI as features, in internal and external cohorts against EKFC. The results show that the most performing ML method, random forest (RF), and EKFC are very competitive where RF and EKFC achieved respectively P10 and P30 values of 0.45 (95% CI 0.44;0.46) and 0.89 (95% CI 0.88;0.90), whereas EKFC yielded 0.44 (95% CI 0.43; 0.44) and 0.89 (95% CI 0.88; 0.90), considering the entire cohort. Small differences were, however, observed in patients younger than 12 years where RF slightly outperformed EKFC., (© 2024. The Author(s).)

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS., Objectives: Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies., Design: A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline ( n  = 1167) and their ability to detect change over 3 years ( n  = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components ( n  = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs ( n  = 875)., Setting: Primary, secondary and tertiary care., Participants: Adults (≥ 18 years) with stage 3 chronic kidney disease., Interventions: Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations., Main Outcome Measures: Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated., Results: Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior ( p  < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate., Limitations: Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target., Future Work: Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken., Conclusions: Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease., Trial Registration: This trial is registered as ISRCTN42955626., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

Glycogen storage disease type Ib (GSD Ib, biallelic variants in SLC37A4) is a rare disorder of glycogen metabolism complicated by neutropenia/neutrophil dysfunction. Since 2019, the SGLT2-inhibitor empagliflozin has provided a mechanism-based treatment option for the symptoms caused by neutropenia/neutrophil dysfunction (e.g. mucosal lesions, inflammatory bowel disease). Because of the rarity of GSD Ib, the published evidence on safety and efficacy of empagliflozin is still limited and does not allow to develop evidence-based guidelines. Here, an international group of experts provides 14 best practice consensus treatment recommendations based on expert practice and review of the published evidence. We recommend to start empagliflozin in all GSD Ib individuals with clinical or laboratory signs related to neutropenia/neutrophil dysfunction with a dose of 0.3-0.4 mg/kg/d given as a single dose in the morning. Treatment can be started in an outpatient setting. The dose should be adapted to the weight and in case of inadequate clinical treatment response or side effects. We strongly recommend to pause empagliflozin immediately in case of threatening dehydration and before planned longer surgeries. Discontinuation of G-CSF therapy should be attempted in all individuals. If available, 1,5-AG should be monitored. Individuals who have previously not tolerated starches should be encouraged to make a new attempt to introduce starch in their diet after initiation of empagliflozin treatment. We advise to monitor certain safety and efficacy parameters and recommend continuous, alternatively frequent glucose measurements during the introduction of empagliflozin. We provide specific recommendations for special circumstances like pregnancy and liver transplantation., Competing Interests: Declaration of competing interest All authors with exception of ELC, JlF, PH and SKU received accommodation support by Sophie's Hope Foundation. All authors report no conflict of interest related to this study. TGJD declares that he has confidentiality agreements with third parties. In the past 36 months, there have been consultation agreements (with Danone, Ultragenyx Pharmaceutical Inc, ModernaTX Inc., and Beam Therapeutics), contracts for financial research support for investigator-initiated research (NCT04311307) and sponsor-initiated research (NCT03517085, NCT03970278, NCT05139316, and NCT05196165), honoraria for lectures or presentations (by MEDTalks, Prelum, and Danone), and participations in a Data Safety Monitoring Board (NCT05095727) and Advisory Boards (Ultragenyx Pharmaceutical Inc, ModernaTX Inc., and Beam Therapeutics). For all private-public relationships, all contracts are via UMCG Contract Research Desk and all payments are to UMCG. ND declares that he is a director and minority shareholder in SpOtOn Clinical Diagnostics Ltd. KMS declares that in the last 36 months there were consultancy agreements with BioMarin, Chiesi, Takeda, Sanofi, Amicus and Immusoft Corporation. SCG declares that over the last 3 years in the area of inherited metabolic diseases she has received accommodation support from Nutricia Metabolics, honoraria for lectures from Vitaflo and Ultragenyx, and that she is an advisory board member of Ultragenyx. JL and BS declare no conflict of interest. Funding to Sophie's Hope Foundation and curegsd1b.org is by individual donors, rather than pharmaceutical or medical food industry. ELC declares no conflict of interest. C.D. Nina la Guerrera (www.ninalaguerrera.org) is a small size non-for-profit platform, whose main sources of funding are by individual donors from sectors that have no interest in biomedical research. HM declares that over the last 3 years in the area of inherited metabolic diseases she has received accommodation support from Vitaflo. honoraria for lectures from Vitaflo and Nutricia and served as a paid consultant for Ultragenyx. SBW declares that over the last 3 years in the area of inherited metabolic diseases she has received accommodation support from Nutricia Metabolics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Given limited data regarding the involvement of disadvantaged groups in paediatric diabetes clinical trials, this study aimed to evaluate the socioeconomic representativeness of participants recruited into a multinational clinical trial in relation to regional and national type 1 diabetes reference populations., Methods: Retrospective, cross-sectional evaluation of a subset of adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) participants from Australia (n = 144), Canada (n = 312) and the UK (n = 173). Validated national measures of deprivation were used: the Index of Relative Socioeconomic Disadvantage (IRSD) 2016 (Australia), the Material Resources (MR) dimension of the Canadian Marginalisation index 2016 (Canada) and the Index of Multiple Deprivation (IMD) 2015 (UK). Representativeness was assessed by comparing the AdDIT cohort's distribution of deprivation quintiles with that of the local paediatric type 1 diabetes population (regional), and the broader type 1 diabetes population for which the trial's intervention was targeted (national)., Results: Recruited study cohorts from each country had higher proportions of participants with higher SES, and significant underrepresentation of lower SES, in relation to their national references. The socioeconomic make-up in Australia mirrored that of the regional population (p = 0.99). For Canada, the 2nd least deprived (p = 0.001) and the most deprived quintiles (p < 0.001) were over- and under-represented relative to the regional reference, while the UK featured higher regional and national SES bias with over-representation and under-representation from the least-deprived and most-deprived quintiles (p < 0.0001)., Conclusions: Significant national differences in trial participation of low SES participants were observed, highlighting limitations in access to clinical research and the importance of reporting sociodemographic representation in diabetes clinical trials., Trial Registration: NCT01581476. Registered on 20 April 2012., (© 2023. The Author(s).)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Objectives: During 2020, the UK's Department of Health and Social Care (DHSC) established the Moonshot programme to fund various diagnostic approaches for the detection of SARS-CoV-2, the pathogen behind the COVID-19 pandemic. Mass spectrometry was one of the technologies proposed to increase testing capacity., Methods: Moonshot funded a multi-phase development programme, bringing together experts from academia, industry and the NHS to develop a state-of-the-art targeted protein assay utilising enrichment and liquid chromatography tandem mass spectrometry (LC-MS/MS) to capture and detect low levels of tryptic peptides derived from SARS-CoV-2 virus. The assay relies on detection of target peptides, ADETQALPQRK (ADE) and AYNVTQAFGR (AYN), derived from the nucleocapsid protein of SARS-CoV-2, measurement of which allowed the specific, sensitive, and robust detection of the virus from nasopharyngeal (NP) swabs. The diagnostic sensitivity and specificity of LC-MS/MS was compared with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) via a prospective study., Results: Analysis of NP swabs (n=361) with a median RT-qPCR quantification cycle (Cq) of 27 (range 16.7-39.1) demonstrated diagnostic sensitivity of 92.4% (87.4-95.5), specificity of 97.4% (94.0-98.9) and near total concordance with RT-qPCR (Cohen's Kappa 0.90). Excluding Cq>32 samples, sensitivity was 97.9% (94.1-99.3), specificity 97.4% (94.0-98.9) and Cohen's Kappa 0.95., Conclusions: This unique collaboration between academia, industry and the NHS enabled development, translation, and validation of a SARS-CoV-2 method in NP swabs to be achieved in 5 months. This pilot provides a model and pipeline for future accelerated development and implementation of LC-MS/MS protein/peptide assays into the routine clinical laboratory., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma., Results: We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort., Conclusion: We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research., (© 2022. The Author(s).)

Aims/hypothesis: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control., Methods: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log 10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA 1c , BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable., Results: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA 1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk., Conclusions/interpretation: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies., Trial Registration: isrctn.org ISRCTN91419926., (© 2022. The Author(s).)

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/m 2 , all equations performed similarly, and for BMI < 18.5 kg/m 2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m 2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m 2 ). 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., (© 2021 British Pharmacological Society.)

Early detection of CKD using point of care creatinine and eGFR testing improves patient management outcomes. We undertook a field study to evaluate the use of a whole blood creatinine/eGFR device to screen a rural Nicaraguan population to determine the variability between creatinine methods and specimen types. All specimens including capillary and venous dried blood spots (DBS) were tested with an isotope dilution liquid chromatography mass spectrometry (ID-LCMS) gold standard method. This is to our knowledge the first time a capillary whole blood (POC) method has been directly compared to the gold standard IDMS method, through the novel approach of using dried blood spots. Capillary and venous whole blood specimens were obtained and tested directly with the BCMS method, and then, DBS samples were prepared. Venous plasma specimens were tested using three laboratory analyzer creatinine methods. DBS were sent to the site performing ID-LCMS. Control samples were also prepared to assess the stability of shipment and storage of DBS. The ID-LCMS method was aligned using primary and secondary standards. Sixty-six (66) patients participated in the study, and the CKD prevalence rate was 7.8%. While all creatinine methods showed a good correlation to ID-LCMS, there was a positive bias (mean absolute bias range: 0.21-0.63 mg/dL). All methods used were 100% sensitive, but specificity varied from 62.7 to 94.9% with PPV ranging from 25 to 62.5%. A correction factor was used to align the values from each method to ID-LCMS which improved the specificity of each method. This study used a unique DBS approach to align capillary whole blood creatinine to ID-LCMS. To ensure reliability of BCMS for identifying screened patients with CKD, it is important to establish IDMS traceability and alignment prior to undertaking CKD studies., (© 2022. The Author(s).)

Prospective biomarker studies can be used to identify biomarkers predictive of disease onset. However, if serum biomarkers are measured years after their collection, the storage conditions might affect analyte concentrations. Few data exists concerning which metabolites and proteins are affected by storage at - 20 °C vs - 80 °C. Our objectives were to document analytes affected by storage of serum samples at - 20 °C vs - 80 °C, and to identify those indicative of the storage temperature. We utilized liquid chromatography tandem mass spectrometry and Luminex to quantify 300 analytes from serum samples of 16 Finnish individuals with type 1 diabetes, with split-aliquot samples stored at - 80 °C and - 20 °C for a median of 4.2 years. Results were validated in 315 Finnish and 916 Scottish individuals with type 1 diabetes, stored at - 20 °C and at - 80 °C, respectively. After quality control, we analysed 193 metabolites and proteins of which 120 were apparently unaffected and 15 clearly susceptible to storage at - 20 °C vs - 80 °C. Further, we identified serum glutamate/glutamine ratio greater than 0.20 as a biomarker of storage at - 20 °C vs - 80 °C. The results provide a catalogue of analytes unaffected and affected by storage at - 20 °C vs - 80 °C and biomarkers indicative of sub-optimal storage., (© 2022. The Author(s).)