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Background: Children with overweight and obesity are at risk for developing chronic kidney disease (CKD). During lifestyle adjustment, the first step in the treatment of childhood obesity, body proportions are likely to change. The aim of this study was to examine how lifestyle intervention affects creatinine-based kidney function estimation in children with overweight and obesity., Methods: This longitudinal lifestyle intervention study included 614 children with overweight and obesity (mean age 12.17 ± 3.28 years, 53.6% female, mean BMI z-score 3.32 ± 0.75). Loss to follow-up was present: 305, 146, 70, 26, and 10 children were included after 1, 2, 3, 4, and 5 (about yearly) follow-up visits, respectively. Serum creatinine (SCr) was rescaled using Q-age and Q-height polynomials., Results: At baseline, 95-97% of the children had a SCr/Q-height and SCr/Q-age in the normal reference range [0.67-1.33]. SCr/Q significantly increased each (about yearly) follow-up visit, and linear mixed regression analyses demonstrated slopes between 0.01 and 0.04 (corresponding with eGFR FAS reduction of 1.1-4.1 mL/min/1.73 m 2 ) per visit. BMI z-score reduced in both sexes and this reduction was significantly higher in males. No correlation between change in rescaled SCr and BMI z-score reduction could be demonstrated., Conclusions: Rescaled serum creatinine (SCr/Q) slightly increases during multidiscipline lifestyle intervention in this cohort of children with overweight and obesity. This effect seems to be independent from change in BMI z-score. Whether this minor decrease in estimated kidney function has clinical consequences in the long term remains to be seen in trials with a longer follow-up period., Clinical Trial Registration: ClinicalTrial.gov; Registration Number: NCT02091544., (© 2024. The Author(s).)

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., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: New equations to estimate glomerular filtration rate based on creatinine (eGFRcr), cystatin C (eGFRcys) or both (eGFRcr-cys) have been developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the European Kidney Function Consortium (EKFC). There is a need to evaluate the performance of these equations in diverse European settings to inform implementation decisions, especially among people with key comorbid conditions., Methods: We performed a cross-sectional study including 6174 adults referred for single-point plasma clearance of iohexol in Stockholm, Sweden, with 9579 concurrent measurements of creatinine and cystatin C. We assessed the performance of the CKD-EPI 2009/2012/2021, EKFC 2021/2023, revised Lund-Malmö (RLM) 2011 and Caucasian, Asian, Pediatric and Adult (CAPA) 2014 equations against measured GFR (mGFR)., Results: Mean age was 56 years, median mGFR was 62 mL/min/1.73 m2 and 40% were female. Comorbid conditions were common: cardiovascular disease (30%), liver disease (28%), diabetes (26%) and cancer (26%). All eGFRcr-cys equations had small bias and P30 (the percentage of estimated values within 30% of mGFR) close to 90%, and performed better than eGFRcr or eGFRcys equations. Among eGFRcr equations, CKD-EPI 2009 and CKD-EPI 2021 showed larger bias and lower P30 than EKFC 2021 and RLM. There were no meaningful differences in performance across eGFRcys equations. Findings were consistent across comorbid conditions, and eGFRcr-cys equations showed good performance in patients with liver disease, cancer and heart failure., Conclusions: In conclusion, eGFRcr-cys equations performed best, with minimal variation among equations in this Swedish cohort. The lower performance of CKD-EPI eGFRcr equations compared with EKFC and RLM may reflect differences in population characteristics and mGFR methods. Implementing eGFRcr equations will require a trade-off between accuracy and uniformity across regions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Serum creatinine and serum cystatin C are the most widely used renal biomarkers for calculating the estimated glomerular filtration rate (eGFR), which is used to estimate the severity of kidney damage. In this review, we present the basic characteristics of these biomarkers, their advantages and disadvantages, some basic history, and current laboratory measurement practices with state-of-the-art methodology. Their clinical utility is described in terms of normal reference intervals, graphically presented with age-dependent reference intervals, and their use in eGFR equations.

Estimating glomerular filtration rate (GFR) is important in daily practice to assess kidney function and adapting the best clinical care of patients with and without chronic kidney disease. The new creatinine-based European Kidney Function Consortium (EKFC) equation is used to estimate GFR. This equation was developed and validated mainly in European individuals and based on a rescaled creatinine, with the rescaling factor (Q-value) defined as the median normal value of serum creatinine in a given population. The validation was limited in Non-Black Americans and absent in Black Americans. Here, our cross-sectional analysis included 12,854 participants from nine studies encompassing large numbers of both non-Black and Black Americans with measured GFR by clearance of an exogenous marker (reference method), serum creatinine, age, sex, and self-reported race available. Two strategies were considered with population-specific Q-values in Black and non-Black men and women (EKFC PS ) or a race-free Q-value (EKFC RF ). In the whole population, only the EKFC PS equation showed no statistical median bias (0.14, 95% confidence interval [-0.07; 0.35] mL/min/1.73m 2 ), and the bias for the EKFC RF (0.74, [0.51; 0.94] mL/min/1.73m 2 ) was closer to zero than that for the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021 ) equation (1.22, [0.99; 1.47]) mL/min/1.73m 2 ]. The percentage of estimated GFR within 30% of measured GFR was similar for CKD-EPI 2021 (79.2% [78.5%; 79.9%]) and EKFC RF (80.1% [79.4%; 80.7%]), but improved for the EKFC PS equation (81.1% [80.5%; 81.8%]). Thus, our EKFC equations can be used to estimate GFR in the United States incorporating either self-reported race or unknown race at the patient's discretion per hospital registration records., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Precise determination of circulating parathyroid hormone (PTH) concentration is crucial to diagnose and manage various disease conditions, including the chronic kidney disease-mineral and bone disorder. However, the lack of standardization in PTH assays is challenging for clinicians, potentially leading to medical errors because the different assays do not provide equivalent results and use different reference ranges. Here, we aimed to evaluate the impact of recalibrating PTH immunoassays by means of a recently developed LC-MS/MS method as the reference. Utilizing a large panel of pooled plasma samples with PTH concentrations determined by the LC-MS/MS method calibrated with the World Health Organization (WHO) 95/646 International Standard, five PTH immunoassays were recalibrated. The robustness of this standardization was evaluated over time using different sets of samples. The recalibration successfully reduced inter-assay variability with harmonization of PTH measurements across different assays. By recalibrating the assays based on the WHO 95/646 International Standard, we demonstrated the feasibility for standardizing PTH measurement results and adopting common reference ranges for PTH assays, facilitating a more consistent interpretation of PTH values. The recalibration process aligns PTH results obtained from various immunoassays with the LC-MS/MS method, providing more consistent and reliable measurements. Thus, establishing true standardization across all PTH assays is crucial to ensure consistent interpretation and clinical decision-making., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The new European Kidney Function Consortium (EKFC) creatinine-based equation has been developed to be applicable over the entire age range (from 2 to 100 years) without any loss of performance in young adults and without loss of continuity in estimating glomerular filtration rate (GFR) between adolescents and adults. This goal is obtained by better taking into account the relationship between serum creatinine (SCr) and age in the estimating GFR model. This is accomplished by rescaling SCr, namely, dividing SCr by so-called Q value which is the median normal value of SCr concentration in a given healthy population. The better performance of the EKFC equation, compared to the current equations, has been shown in large European and African cohorts. Such good results are also suggested in cohorts from China, including in the current issue of Nephron. The good performance of the EKFC equation is observed, especially when the authors used a specific Q value for their populations notwithstanding GFR was measured by a controversial method. Using a population-specific Q value could make the EFKC equation universally applicable., (© 2023 S. Karger AG, Basel.)

Finerenone, a new nonsteroidal mineralocorticoid receptor antagonist, showed a significant reduction in a primary composite renal outcome in FIDELIO-DKD and a significant reduction in a primary composite cardiovascular outcome in FIGARO-DKD in patients with type 2 diabetes (T2D) and a chronic kidney disease (CKD). In a subsequent analysis that combined these two clinical trials (FIDELITY), the reduction becomes statistically significant when compared to placebo for both outcomes, with a hazard ratio of 0.86 (95 % confidence interval 0.78-0.95; P = 0.0018) for the cardiovascular outcome and 0.77 (0.67-0.88; P = 0.0002) for the renal outcome. Furthermore, all renal events occurred less frequently with finerenone than with placebo, including the progression to end-stage CKD independently of the baseline levels of glomerular filtration rate and albuminuria and regardless of associated medications (including gliflozins). The safety profile was excellent. However, a significant increase in serum potassium level was observed. Even if it is less pronounced than the increase usually seen with spironolactone, the risk of hyperkalemia requires some caution regarding both patient selection and monitoring. Finerenone (Kerendia®) is indicated in the treatment of CKD with albuminuria in adult patients with T2D. In Belgium, it is reimbursed with conditions in combination with a renin-angiotensin blocker.

Objectives: Chronic kidney disease (CKD) is a global health issue, ranking as the third leading cause of death worldwide. CKD diagnosis and management depend on clinical laboratory tests, necessitating consistency for precise patient care. Global harmonization of CKD testing through clinical practice guidelines (CPGs) is recommended. Prior to CPG development, assessing the current CKD testing landscape is crucial. In 2022, the European Federation of Laboratory Medicine (EFLM) conducted an online survey among European laboratories associated with EFLM, evaluating CKD testing practices, including new glomerular filtration rate (GFR) estimation methods. This report summarizes the 2022 survey findings and offers recommendations for improving CKD test standardization., Methods: An online survey was conducted in November 2022 using a questionnaire hosted on LimeSurvey sent to European laboratories affiliated with the EFLM. The survey results were recorded in Excel files and analysed., Results: The results highlight significant discrepancies among countries in unit expression, methods, cystatin C use, and GFR calculation equations. Additionally, limited attention to pediatric renal biology specifics, varied proteinuria and albuminuria result expressions, and limited awareness of GFR measurement methods through iohexol clearance are noted., Conclusions: In an effort to enhance the standardization of crucial biomarkers utilized in nephrology for evaluating renal function and diagnosing kidney injuries, the EFLM Task Group on CKD suggests nine practical recommendations tailored for European laboratories. The group is confident that implementing these measures will minimize result expression discrepancies, ultimately leading to enhanced patient care., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: To make glomerular filtration rate (GFR) estimating equations applicable across populations with different creatinine generation by using rescaled serum creatinine (sCr/Q) where sCr represents the individual creatinine level and Q the average creatinine value in healthy persons of the same population., Methods: GFR measurements (mGFR, plasma clearance of 51 Cr-EDTA) were conducted in 964 adult Black Europeans. We established the re-expressed Lund-Malmö revised equation (r-LMR) by replacing serum creatinine (sCr) with rescaled creatinine sCr/Q. We evaluated the r-LMR equation based on Q-values of White Europeans (r-LMR Q-white ; Q-values females: 62 μmol/L, males: 80 μmol/L) and Black Europeans (r-LMR Q-Black ; Q-values females: 65 μmol/L, males: 90 μmol/L), and the European Kidney Function Consortium equation (EKFC Q-White and EKFC Q-Black ) regarding bias, precision (interquartile range, IQR) and accuracy (percentage of estimates within ±10 % [P 10 ] and ±30 % [P 30 ] of mGFR)., Results: Median bias of r-LMR Q-White /r-LMR Q-Black /EKFC Q-White /EKFC Q-Black were -9.1/-4.5/-6.3/-0.9 mL/min/1.73 m 2 , IQR 14.7/14.5/14.5/15.6 mL/min/1.73 m 2 , P 10 25.1 %/34.8 %/30.3 %/37.2 % and P 30 74.2 %/84.1 %/80.6 %/83.6 %. The improvement of bias and accuracy when using proper Q-values was most pronounced in men. Similar improvements were obtained above and below mGFR 60 mL/min/1.73 m 2 and at various age and BMI intervals, except for BMI<20 kg/m 2 where bias increased, and accuracy decreased., Conclusions: GFR estimating equations may be re-expressed to include rescaled creatinine (sCr/Q) and used across populations with different creatinine generation if population-specific average creatinine concentrations (Q-values) for healthy persons are established., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Sodium-glucose cotransporter type 2 inhibitors (SGLT2is or gliflozins) are now considered as a therapeutic breakthrough in clinical practice, not only for the management of type 2 diabetes (T2D), but also for the treatment of heart failure and chronic renal disease. Patients with T2D are exposed to a higher risk of atheromatic lesions, heart failure and renal insufficiency, all complications that can be reduced by a gliflozin as shown in several placebo- controlled randomised trials in at high risk patients. Unexpectedly, such cardio-renal protection has also been observed among non-diabetic patients with heart failure (both with reduced and preserved ejection fraction) or with chronic kidney disease (especially with albuminuria). Because of these properties, SGLT2is now occupy a privileged place in diabetology, cardiology and nephrology. However, they are still slow to settle in primary care practice, even in high risk patients who should benefit, an underuse possibly due at least partially to quite complex reimbursement criteria in Belgium.

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.

Background: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown., Methods: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex., Results: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone., Conclusions: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.)., (Copyright © 2023 Massachusetts Medical Society.)

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.)

The inhibition of the renin-angiotensin system represents the first preventive treatment of the chronic kidney disease (CKD), especially in presence of albuminuria. Recently, sodium-glucose cotransporter type 2 inhibitors (SGLT2i, gliflozins) demonstrated a nephroprotective effect, first in patients with type 2 diabetes at cardiovascular risk, then in diabetic patients with CKD assessed by a reduction of the glomerular filtration rate (GFR) and albuminuria (CREDENCE with canagliflozin), and finally in patients with CKD and albuminuria, with or without diabetes (DAPA-CKD with dapagliflozin). EMPA-KIDNEY study compared the effects of empagliflozin 10 mg/day versus placebo in patients with CKD, with or without diabetes. In comparison with the two previous renal studies, this clinical trial randomised patients with a lower GFR (78 % of patients with GFR inferior to 45 mL/min/1.73 m²) and a lower level of albuminuria (20 % of patients without pathological albuminuria). EMPA-KIDNEY demonstrated a reduction by 28 % (p inferior to 0.001) of the primary composite outcome (progression of CKD or cardiovascular death) and of several renal endpoints, including the shift to terminal CKD (-33 %), independently of the presence of diabetes, and with a tolerance profile comparable to what is already known. EMPA-KIDNEY results reinforce the use of SGLT2is, in general, and of empagliflozin, in particular, in a broader population with CKD and, thus, the indication of this pharmacological class in nephrology in combination with inhibitors of the renin-angiotensin system.

Background: Whether the new chronic kidney disease-epidemiology (CKD-EPI) equation without the race variable remains accurate enough for glomerular filtration rate (GFR) estimation in non-US kidney transplant recipients (KTRs) is unclear. We sought to compare the predictive performance between this equation and the classical CKD-EPI equation in a French cohort of KTRs. We also evaluated the performance of the European Kidney Function Consortium (EKFC) equation, an estimate that has proved very accurate in nontransplant patients and that does not include race variable., Methods: We retrospectively selected 489 KTRs for whom GFR was measured by inulin clearance. Performances of GFR equations were compared according to median bias, imprecision, and accuracy within 30% (P30) and 20% (P20). Differences in P20/P30 were tested using the exact McNemar test., Results: Although the 4 equations exhibited a similar level of imprecision, the bias of the new CKD-EPI equation was +5.5 (4.0; 6.6) mL/min/1.73 m², much higher than the bias of the classical CKD-EPI, EKFC, and Modified Diet in Renal Diseases (MDRD) equation (2.4 [1.7;3.5], 2.2 [1.1;3.1], and -0.5 [-1.5; 1.0] mL/min/1.73 m², respectively). The new CKD-EPI equation was significantly less accurate with a P30 of 68.3% as compared with 74.2%, 75.3%, and 77.1% for the classical CKD-EPI, EKFC, and MDRD equation, respectively. The EKFC equation outperformed both versions of the CKD-EPI equation in terms of P20., Conclusions: The new CKD-EPI equation is suboptimal for the care and follow-up of European transplanted patients. The EKFC equation shows at least a similar performance to the MDRD and the classical CKD-EPI equation. Further validation of the EKFC equation in KTRs from a diverse ethnic background is needed., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The EFLM recommends not to implement the race-free Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation in European laboratories and to keep the 2009 version of the CKD-EPI equation, without applying a race correction factor. This recommendation is completely in line with a recent Editorial published by the European Renal Association who has also proposed to change to a novel equation only when it has considerably better performance, trying to reach global consensus before implementing such a new glomerular filtration rate (GFR) estimation equation. In Europe, this equation could be for instance the new European Kidney Function Consortium (EKFC) equation, which is population-specific, developed from European cohorts and accurate from infants to the older old. Beyond serum creatinine, the estimating equations based on cystatin C will probably gain in popularity, especially because cystatin C seems independent of race. Finally, we must keep in mind that all GFR equations remain an estimation of GFR, especially rough at the individual level. Measuring GFR with a reference method, such as iohexol clearance, remains indicated in specific patients and/or specific situations, and here also, the role of the clinical laboratories is central and should still evolve positively in the future., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Background: The Chronic Kidney Disease in children (CKiD) equation to estimate glomerular filtration rate eGFR = k × Ht / SCr (Ht = height in cm, SCr = serum creatinine in mg/dL), with fixed k = 0.413, has recently been optimized by introducing age/sex dependent k-values valid for young children up to young adults (the CKiD Under 25 years (CKiDU25) equation). Although the CKiD equation was designed for children with chronic kidney disease (CKD), this equation found common use both clinically and in research, and also in children without CKD. This report aims to evaluate properties of CKiD and CKiDU25 in healthy children and adolescents., Method: Sex-specific metadata (height and creatinine) for healthy children were obtained from national growth curves and creatinine versus age curves. These data were used to calculate average CKiD and CKiDU25 values for each year of age and compare them against age-independent measured GFR of 107 mL/min/1.73 m 2 ., Results: The CKiD estimations show a steep decline with age (1.5 mL/min/1.73 m 2 /year in females and 2.0 mL/min/1.73 m 2 /year in males) over the entire age range (2-20 years) and large differences between adolescent males and females. Due to the age/sex specific k-values, the CKiDU25 equation solves this age-decline artifact of the CKiD equation. However, CKiDU25 still shows a systematic higher estimation of about 10% in healthy males compared to females over the entire age range., Conclusion: Although the CKiDU25 shows major improvements compared to the CKiD equation, as the unexpected age decline has been removed, a systematic difference is still observed between healthy males and females., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Finerenone is a new mineralocorticoid receptor antagonist with a different structure, volume of distribution and half-life compared to spironolactone. This drug has been tested in two large, randomized trials including diabetic patients with chronic kidney disease (in terms of glomerular filtration rate and albuminuria) and already treated by renin-angiotensin system blockade. Results are positive on hard renal- and cardiac endpoints. Risk of hyperkalaemia is higher than with placebo but is considered as acceptable. An open question that will be tested in further studies is the role of finerenone in the context of a treatment by gliflozins, drugs that also showed cardiorenal protection., Competing Interests: Pierre Delanaye et Sophie de Seigneux déclarent des conflits d’intérêts avec AstraZeneca et Bayer.

Introduction: Chronic kidney disease (CKD) affects > 10% of the population but not all CKD patients require referral to a nephrologist. Various recommendations for referral to nephrologists are proposed worldwide. We examined the profile of French patients consulting a nephrologist for the first time and compared these characteristics with the recommendations of the International Kidney Disease: Improving Global Outcomes (KDIGO), the French "Haute Autorité de Santé" (HAS), and the Canadian Kidney Failure Risk Equation (KFRE)., Methods: University Hospital electronic medical records were used to study patients referred for consultation with a nephrologist for the first time from 2016 to 2018. Patient characteristics (age, sex, diabetic status, estimated glomerular filtration rate (eGFR) and urine protein-to-creatinine ratio (PCR), etiology reported by the nephrologist) and 1-year patient follow-up were analyzed and compared with the KDIGO, HAS and Canadian-KFRE recommendations for referral to a nephrologist. The stages were defined according to the KDIGO classification, based upon kidney function and proteinuria.  RESULTS: The 1,547 included patients had a median age of 71 [61-79] years with 56% males and 37% with diabetes. The main nephropathies were vascular (40%) and glomerular (20%). The KDIGO classification revealed 30%, 47%, 19%, 4% stages G1-2 to G5, and 50%, 22%, 28% stages A1-A3, respectively. According to KDIGO, HAS and KFRE scores, nephrologist referral was indicated for 42%, 57% and 80% of patients respectively, with poor agreement between recommendations. Furthermore, we observed 890 (57%) patients with an eGFR> 30 ml/min and  a urine protein to creatinine ratio 0.5 g/g, mostly aged over 65 years (67%); 40% were diabetic, and 57% had a eGFR > 45 ml/min/1.73m 2 , 56% were diagnosed as vascular nephropathy and 11% with unknown nephropathy., Conclusion: These results underline the importance of better identifying patients for referral to a nephrologist and informing general practitioners. Other referral criteria (age and etiology of the nephropathy) are debatable., (© 2021. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Objectives: Severity of chronic kidney disease is defined by glomerular filtration rate (GFR) and albuminuria (ACR) by the KDIGO and are related to cardiovascular outcomes and end-stage-kidney-failure. However, proteinuria (PCR) is more often available than ACR in records. Recently, equations were developed to estimate ACR from PCR. We investigated their performances in our population., Methods: In the academic medical hospital of Liège, we retrospectively analysed same day measurement of ACR and PCR and staged them according to the KDIGO A1-A2-A3 categories. Analyser Roche Cobas (R) gathered 2,633 urinalysis (May 2018-May 2019) and analyser Abbott Alinity (A) 2,386 urinalysis (May 2019-March 2020). We compared the KDIGO staging of mACR and eACR obtained from Weaver's and Sumida's equations., Results: Median age was 63 [52;71]/64 [53;72] years old, 43/42% were female; 78/74% had diabetes; proportion of mACR-A1 was 65.6%/64.2%, A2 was 25.5%/25.5% and A3 was 8.8%/10.3% (Method R/A, respectively). Both equations gave similar distribution of KDIGO staging of eACR. Overall agreements were higher than 88% regardless of the analyser or of the equation. Performances in between equations were equivalent according to the multi-level AUC (multinomial logistic regression model)., Conclusions: Good concordance was observed between mACR and eACR regardless of the equation or of the analyser. No patient with an A3-measured ACR was estimated within the KDIGO A1 category. Though ACR should be measured when clinically needed, it may be reasonably estimated from the PCR through these equations, for epidemiologic retrospective studies or research purposes., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

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.)

Kidney lifespan is a patient-oriented outcome that provides much needed context for understanding chronic kidney disease (CKD). Nephron endowment, age-associated decline in nephron number, kidney injury history and the intrinsic capacity of nephrons to adapt to haemodynamic and metabolic overload vary widely within the population. Defining percentiles of kidney function might therefore help to predict individual kidney lifespan and distinguish healthy ageing from progressive forms of CKD. In response to nephron loss, the remaining nephrons undergo functional and structural adaptations to meet the ongoing haemodynamic and metabolic demands of the organism. When these changes are no longer sufficient to maintain kidney cell homeostasis, remnant nephron demise occurs and CKD progression ensues. An individual's trajectory of glomerular filtration rate and albuminuria reflects the extent of nephron loss and adaptation of the remaining nephrons. Nephron overload represents the final common pathway of CKD progression and is largely independent of upstream disease mechanisms. Thus, interventions that efficiently attenuate nephron overload in early disease stages can protect remnant kidney cells and nephrons, and delay CKD progression. This Review provides a conceptual framework for individualized diagnosis, monitoring and treatment of CKD with the goal of maximizing kidney lifespan., (© 2021. Springer Nature Limited.)

Introduction: Sodium-glucose co-transporter type 2 inhibitors (SGLT2is) were developed as glucose-lowering agents for the management of type 2 diabetes (T2D). Unexpectedly, they showed a significant reduction in hospitalization for heart failure and hard renal outcomes in patients with and without T2D. Underlying mechanisms remain a matter of debate., Areas Covered: We summarize the protective renal effects of SGLT2is in patients with cardiovascular disease, chronic kidney disease (CKD, especially with albuminuria) or heart failure; a description of the safety of SGLT2is, with a special focus on the risk/benefit balance in people with stage 3 CKD; a comprehensive discussion of mechanisms that could explain nephro-protection; a reappraisal of the positioning of SGLT2is in recent international guidelines., Expert Opinion: Several mechanisms could contribute to improved renal prognosis with SGLT2is, among which a reduction in intraglomerular pressure by restoring the tubuloglomerular feedback, a diuretic effect that contributes to lower albuminuria and renal decongestion, especially if fluid overload is present, a reduction in renal oxygen consumption, an improvement of heart failure status with less cardiorenal syndrome and a lower risk of acute renal injury. All these effects may be mutually not exclusive, and their respective contribution may differ according to patient characteristics.

Purpose of Review: There is currently a heated debate ongoing whether or not to use the race coefficient for black people in the Modification of Diet in Renal Diseases and Chronic Kidney Disease Epidemiology-equation. The use of the race coefficient is thought by several American authors as a source of discrimination., Recent Findings: It has recently been shown that the race coefficient is inaccurate in European and African black people. Therefore, it seems that the race correction is more a correction for black Americans, rather than for black in general. This 'correction' at the glomerular filtration rate (GFR)-level has been criticized, as it is misleading, and should be abandoned, as it has not been shown that GFR is different between black and white people. However, as differences in creatinine generation between black and white people might exist, a correction or adjustment, different for black and white people, at the creatinine level might be required, very similar to the different scaling of creatinine for males and females., Summary: The current debate on the race coefficient is particularly difficult because of the absence of good scientific data in black subjects and there lies the real discrimination in our opinion. We therefore call for future dedicated studies, both in Europe and USA., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The CKD-EPI creatinine-based estimation equation for glomerular filtration rate (GFR) cannot be used in children, overestimates GFR in young adults, and its combination with the KDIGO recommended pediatric CKiD (Schwartz bedside) equation causes implausible increases in estimated GFR when switching from pediatric to adult care. By establishing sex-specific creatinine growth curves for children and young adults, creatinine levels of children and young adults below age 40 years were adjusted with 40 as assigned age and applied in the CKD-EPI equation. Validation was performed in 4005 children (2-17 years) and 3309 young adults (18-39 years) using metrics based on bias, precision, and accuracy including percentage of estimates within 30% (P 30 ) of measured GFR (mGFR). Comparisons were made with the CKiD and Schwartz-Lyon equations in children. CKD-EPI with age-adjusted creatinine instead of actual age and creatinine led to extensive improvements in bias, precision, and accuracy at all ages, in both sexes and at all levels of mGFR. At mGFR below and above 75 mL/min/1.73m 2 , the P 30 increased from 12% to 75% and 33% to 88% in children, respectively, and from 56% to 73% and 83% to 92% in young adults, respectively. In children adjusted CKD-EPI was more accurate than CKiD, especially above mGFR 75 mL/min/1.73m 2 (P30 88% vs. 82%), while Schwartz-Lyon was more accurate than adjusted CKD-EPI at mGFR below 75 mL/min/1.73m 2 (P30 81% vs. 75%). Thus, the proposed strategy based on age-adjusted creatinine in children and young adults makes the CKD-EPI equation applicable across the full spectrum of age and kidney function., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Identifying people with HIV (PWH) at risk for chronic kidney disease, cardiovascular events, and death is crucial. We evaluated biomarkers to predict all-cause mortality and cardiovascular events, and measured glomerular filtration rate (mGFR) slope., Methods: Biomarkers were measured at enrollment. Baseline and 5-year mGFR were measured by plasma iohexol clearance. Outcomes were a composite criterion of all-cause mortality and/or cardiovascular events, and mGFR slope., Results: Of 168 subjects, 146 (87.4%) had undetectable HIV load. Median follow-up was 59.1 months (interquartile range, 56.2-62.1). At baseline, mean age was 49.5 years (± 9.8) and mean mGFR 98.9 mL/min/1.73m2 (± 20.6). Seventeen deaths and 10 cardiovascular events occurred during 5-year follow-up. Baseline mGFR was not associated with mortality/cardiovascular events. In multivariable analysis, cystatin C (hazard ratio [HR], 5.978; 95% confidence interval [CI], 2.774-12.88; P < .0001) and urine albumin to creatinine ratio (uACR) at inclusion (HR, 1.002; 95% CI, 1.001-1.004; P < .001) were associated with mortality/cardiovascular events. Area under receiver operating curve of cystatin C was 0.67 (95% CI, .55-.79) for mortality/cardiovascular event prediction. Biomarkers were not associated with GFR slope., Conclusions: uACR and cystatin C predict all-cause mortality and/or cardiovascular events in PWH independently of mGFR., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Sodium-glucose cotransporter type 2 inhibitors (iSGLT2 or gliflozins) exert their antidiabetic action through a specific renal mechanism, by inhibiting tubular glucose reabsorption. These agents have proven their efficacy to reduce major cardiovascular events and hospitalisation for heart failure, but also the progression of chronic kidney disease (CKD), in patients with type 2 diabetes (T2DM) at high risk, independently of glucose control. While the glucose-lowering effect of iSGLT2 is decreasing with the decline of estimated glomerular filtration rate (eGFR), both cardiovascular and renal protections remain present until an eGFR as low as 30 ml/min/1,73 m². These effects were demonstrated in several meta-analyses and in two trials specifically dedicated to renal outcomes in patients with CKD and macroalbuminuria : CREDENCE with canagliflozin and Dapa-CKD with dapagliflozin. In addition, Dapa-CKD showed similar positive results whatever the presence or absence of T2DM. Safety profile of SGLT2is among patients with CKD is good and similar to that of patients with normal renal function. These favourable findings led to a privileged place of SGLT2i in recent international guidelines promoted by diabetologists, cardiologists and nephrologists. Current restrictive criteria for the prescription and reimbursement of SGLT2i in Belgium according to eGFR level (initiation only if eGFR superior to 60 and interruption if eGFR inferior to 45 ml/min/1.73 m²) should be enlarged very soon owing to convincing results of published controlled trials.

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure and function proven to be chronic. The prevalence of CKD in the majority of studies is 10%-16%, neglecting the chronicity character. Jonsson et al., in a nationwide study defining CKD adhering strictly to Kidney Disease: Improving Global Outcomes (KDIGO) criteria, found a clearly lower prevalence of CKD (6%). This indicated that to obtain a correct CKD prevalence, one should start by correctly applying the KDIGO guidelines., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

In chronic kidney disease (CKD) patients, the dosage of many medications should be adapted according to the glomerular filtration rate (GFR). GFR estimation is obtained by using creatinine-based equations. Many different equations have been proposed in the literature, and they don't systematically lead to the same result in terms of drug dosage. There is an ongoing debate to determine which equations should be recommended, with the Cockcroft equation on one side and the MDRD (« Modified Diet in Renal Diseases ») or CKD-EPI (« Chronic Kidney Disease Epidemiology ») on the other side. The last two equations are especially used by nephrologists whereas the Cockcroft is still considered by geriatrists and pharmacologists. In the current article, we discuss the pro/cons from both sides, and propose recommendation for the clinical practice., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Chronic kidney disease (CKD) impairs the quality of life and increases the risk for cardiovascular morbimortality. Intensive research is conducted in order to slow down CKD development and progression. During the past decade, a better understanding of the pathophysiological mechanisms of glomerular diseases has highlighted the benefits of rituximab. Progresses have also been made in the understanding of the mechanisms of autosomal polycystic kidney disease, the most frequent inherited kidney disease. These observations led to the discovery and validation of tolvaptan, a blocker of the V2 receptor of the antidiuretic hormone as an innovative treatment. Type 2 diabetic disease is the leading cause worldwide of endstage kidney disease and dialysis. The development of new drugs, such as the gliflozins (inhibiting the sodium glucose reabsorption in the proximal tubule), has contributed to an improvement in the management of the cardiovascular and renal risks especially reducing congestive heart failure rate. Another important progress in nephrology since the beginning of the new century concerns a more precise estimation of the kidney function, which allows to better evaluate the slope of CKD progression and test the influence of different therapeutic approaches aiming at correcting anemia, hyperkalemia, metabolic acidosis and disturbances of calcium and phosphate. The present review summarizes all of these major advances in the field of CKD diagnosis and treatment, and envisions the future of nephrology for the next decade.

Sclerostin is sometimes presented as a promising biomarker in assessing bone health both in the general population and chronic kidney disease patients. However, it is still unclear whether it has any true added value compared to existing bone biomarkers in predicting bone turnover and/or bone density in chronic kidney disease patients. A wealth of papers has been published to evaluate the association between sclerostin and vascular calcifications development or even as prognostic biomarker for mortality, but often with conflicting results. Standardization and harmonization of analytical techniques is a prerequisite to advance clinical knowledge in sclerostin., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Of the glomerular, tubular and endocrine functions of the kidney, nephrologists have mostly focused their attention on the glomerular functions-albuminuria and glomerular filtration rate (GFR)-to grade the severity of chronic kidney disease (CKD). Although both albuminuria and GFR are associated with renal and cardiovascular morbidity and mortality, the utility of measured GFR (mGFR) has been questioned. GFR when measured adequately is the most precise measure of glomerular function and can be useful to individualize therapy among patients with CKD. In situations where estimated GFR is known to provide imprecise estimates of glomerular function, for example, sarcopenia and advanced cirrhosis, the measurement of GFR may be especially important. We discuss several clinical situations where mGFR can potentially influence the quality of life or complications of therapy because of interventions based on imperfect knowledge of GFR. We reason that although large databases may not detect the benefits of mGFR at the population level, precision medicine requires that therapy be individualized based on the best estimate of GFR that can be obtained particularly when the risk of harm is increased. The recent standardization of mGFRs is a step in the right direction and may help in treating the individual patient with CKD with a lower risk of complications and a better quality of life. We call for research in these subgroups of patients where it is clinically felt that mGFR is useful for clinical decision-making., (Published by Oxford University Press on behalf of ERA-EDTA 2018. This work is written by US Government employees and is in the public domain in the US.)

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable., (Copyright © 2019 by the American Society of Nephrology.)

Glomerular filtration rate (GFR) is the best index for kidney function; however, the applicability of GFR estimating equations in sub-Saharan African populations remains unclear. In a cross-sectional study of adults living in Kinshasa, Democratic Republic of Congo (n=210) and Abidjan, Ivory Coast (n=284), we evaluated the performance of creatinine and cystatin C-based equations using plasma clearance of iohexol as the reference standard. The race coefficient did not improve the performance of creatinine-based GFR estimates; in fact, both the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology (CKD-EPI) equations performed better without the race coefficient in participants with GFR ≥60 mL/min/1.73m 2 . The CKD-EPI and Full Age Spectrum (FAS) equations were unbiased and had similar precision (SD of 17.9 versus 19 mL/min/1.73 m 2 ) and accuracy within 30% (P30, 86.7% versus 87.4%) in participants with GFR ≥60 mL/min/1.73m 2 . Both equations performed poorly in the subgroup with measured GFR < 60 mL/min/1.73m 2 (n=80), but the FAS equation had smaller bias (-4.8 mL/min/1.73m 2 versus -7.7 mL/min/1.73m 2 for CKD-EPI) and higher P30 (56.3% versus 31.3% for CKD-EPI). The corresponding equations including cystatin C alone or in combination with creatinine had similar performance. In a sub-Saharan African population, adjustment for race did not improve the performance of GFR estimating equations. The creatinine-based FAS and CKD-EPI equations performed reasonably well and were comparable when GFR was ≥ 60 mL/min/1.73m 2 . Cystatin C did not improve performance. The FAS equation may be preferable when GFR is < 60 mL/min/1.73m 2 , but this should be confirmed in larger studies., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The current Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend the use of the bedside creatinine-based Chronic Kidney Disease in Children (CKiD) equation to estimate glomerular filtration rate (GFR) in children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in adults. However, this approach causes implausible changes in estimated GFR (eGFR) at the transition from pediatric to adult care. We investigated the performance of the KDIGO strategy and various creatinine-based eGFR equations in a cross-sectional dataset of 5,764 subjects (age 10-30 years), using directly measured GFR (mGFR) as reference. We also evaluated longitudinal GFR slopes in 136 subjects who transitioned to adult care. Implausible changes in eGFR resulted from the large overestimation (bias=+21 mL/min/1.73m 2 ) and poor precision of the CKD-EPI equation in the 18-20 year age group, compared to CKiD in the 16-18 year age group (bias=-2.7 mL/min/1.73m 2 ), resulting in a mean change of 23 mL/min/1.73m 2 at the transition to adult care. Averaging the CKiD and CKD-EPI estimates in young adults only partially mitigated this issue. The Full Age Spectrum equation (with and without height), the Lund-Malmö Revised equation, and an age-dependent weighted average of CKiD and CKD-EPI resulted in much smaller changes in eGFR at the transition (change of 0.6, -2.1, -0.9 and -1.8 mL/min/1.73m 2 , respectively). The longitudinal analysis revealed a significant difference in average GFR slope between mGFR and the KDIGO strategy (-2.2 vs. +2.9 mL/min/1.73 m 2 /year), which was not observed with the other approaches. These results suggest that the KDIGO recommendation for GFR estimation at the pediatric-adult care transition should be revisited., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The prevalence of chronic kidney disease (CKD) clearly depends on its definition, and the definition used most often is the one proposed by the Kidney Disease: Improving Global Outcomes guidelines in 2012: 'CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health.' Abnormality of kidney function is a glomerular filtration rate (GFR) <60 mL/min/1.73 m2, and the most frequently used marker of kidney damage is the presence of albuminuria [albumin excretion rate >30 mg/24 h or albumin/creatinine ratio (ACR) >30 mg/g (or 3 mg/mmol)]. However, two major aspects of this definition could explain why CKD prevalence is, in our view, overstated in most epidemiological studies. First, the fixed threshold at 60 mL/min/1.73 m2 is questionable because normal GFR decreases with age. This and the profound consequence it has on CKD epidemiology will be illustrated. The second aspect of the definition is the criterion of chronicity, which is ignored by the vast majority of epidemiological studies. In other words, confirming CKD (low GFR and/or high ACR) is mandatory. Indeed, a large proportion of subjects with a low first GFR level has a normal GFR level when tested a second time. The prevalence of CKD may hence, in fact, be considerably lower although still neither negligible nor irrelevant., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)