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Background and Hypothesis: Measurement of glomerular filtration rate (GFR) is subject to inaccurate urine collection. Clearances of d-serine and d-asparagine, rare enantiomers of amino acids, are the measures of GFR since they are almost free of tubular secretion and reabsorption. We hypothesize that d-serine and d-asparagine can accurately determine urine volume and GFR., Methods: This cross-sectional observational study included 209 living kidney transplant donors and recipients for whom GFR was measured using the clearance of inulin. Assuming that urine excretions of d-serine and d-asparagine are constant and using urine levels of d-serine and d-asparagine from each urine collection, an equation for estimated urine volume (eUV) was established. Based on the eUV, the abnormal urine volume was replaced with an estimate with which the GFR was re-evaluated., Result: Clearances of d-serine and d-asparagine were minor in proportional biases when compared with that of creatinine. Using 627 urine collection, the equation for eUV (mL/min) was established as 21.88/urine d-Ser (0.40 + 0.20 × log10(urine d-Asn)). Using eUV, we identified 20 instances where urine collection volumes varied significantly from the estimated values. After replacement with eUV, measured GFR (mGFR) was corrected to adjusted mGFR, which was within approximately 20 mL/min/1.73m2 of the mGFR., Conclusion: d-Serine and d-asparagine are nearly completely excreted in urine after glomerular filtration, enabling the estimation of urine volume and correct mGFR. Besides reflecting GFR, d-serine and d-asparagine can be used to estimate urine volume. By applying the eUV method, mGFR determined using clearance methods becomes more accurate., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Cardiovascular disease, kidney health, and metabolic disease (CKM) syndrome is associated with significant morbidity and mortality, particularly from congestive heart failure (CHF). Guidelines recommend measurement of cardiac troponin (cTn) to identify subclinical heart failure (HF) in diabetics/CKM. However, appropriate thresholds and the impact from routine screening have not been elucidated., Methods: cTnI was assessed using the Abbott high sensitivity (hs)-cTnI assay in outpatients with physician-ordered hemoglobin A1c (Hb A1c) and associated with cardiac comorbidities/diagnoses, demographics, and estimated glomerular filtration rate (eGFR). Risk thresholds used in CKM staging guidelines of >10 and >12 ng/L for females and males, respectively, were used. Multivariate logistic regression was applied. hs-cTnI was assessed in a high-fat-diet induced murine model of obesity and diabetes., Results: Of 1304 patients, 8.0% females and 15.7% males had cTnI concentrations above the risk thresholds. Thirty-one (4.2%) females and 23 (4.1%) males had cTnI above the sex-specific 99% upper reference limit. A correlation between hs-cTnI and Hb A1c (R = 0.2) and eGFR (R = -0.5) was observed. hs-cTnI concentrations increased stepwise based on A1C of <5.7% (median = 1.5, IQR:1.3-1.8), 5.7%-6.4% (2.1, 2.0-2.4), 6.5%-8.0% (2.8, 2.5-3.2), and >8% (2.8, 2.2-4.3). Male sex (P < 0.001), eGFR (P < 0.001), and CHF (P = 0.004) predicted elevated hs-cTnI. Obese and diabetic mice had increased hs-cTnI (7.3 ng/L, 4.2-10.4) relative to chow-fed mice (2.6 ng/L, 1.3-3.8)., Conclusion: A high proportion of outpatients with diabetes meet criteria for subclinical HF using hs-cTnI measurements. Glucose control is independently associated with elevated cTnI, a finding replicated in a murine model of metabolic syndrome., (© Association for Diagnostics & Laboratory Medicine 2024. 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.)

Background: Sex- and population-specific 99th percentiles of high-sensitivity cardiac troponin (hs-cTn) are recommended in guidelines although the evidence for a clinical utility is sparse. The DANSPOT trial will investigate the clinical effect of sex- and population-specific 99th percentiles of cTn. We report the 99th percentiles derived from this trial and their dependency on kidney function., Methods: We used samples from healthy Danish blood donors and measured hemoglobin A1c, N-terminal pro-brain natriuretic peptide and creatinine, and calculated an estimated glomerular filtration rate (eGFR). We compared 2 cutoffs for the eGFR of healthy participants (60 vs 90 mL/min/1.73 m2). The cTn assays investigated were Siemens Atellica and Dimension Vista hs-cTnI, Abbott hs-cTnI, and Roche hs-cTnT., Results: A total of 2287 participants were sampled, of which 71 (3.1%) were excluded due to a history of heart disease (n = 4), insufficient material (n = 7), or a screening biomarker (n = 60). Of the remaining 2216 participants, 1325 (59.8%) had an eGFR ≥90 mL/min/1.73 m2. Compared to a cutoff of 60 mL/min/1.73 m2 for eGFR, using 90 mL/min/1.73 m2 resulted in lower 99th percentiles for females; Siemens Vista (46 vs 70 ng/L), Abbott (14 vs 18 ng/L), and Roche cTnT (10 vs 13 ng/L), and decreased the number of measurements above the manufacturers' 99th percentiles for all assays., Conclusions: We present reference values for 4 cTn assays for eGFR cutoffs of 60 and 90 mL/min/1.73 m2. These cutoffs differ based on the eGFR threshold for inclusion indicating that any chosen cutoff is also valuable with moderately reduced kidney function., (© Association for Diagnostics & Laboratory Medicine 2024. 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.)

Background: To examine the agreement of different calculated estimated glomerular filtration rate (eGFR) formulas and measured creatinine clearance (CrCI) at the primary diagnosis of muscle-invasive bladder cancer (MIBC)., Materials and Methods: We performed a multicenter analysis of patients with MIBC, treated with cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), or with RC alone, between 2011 and 2021. Baseline eGFR was computed using 4 calculated serum equations including Cockcroft-Gault (CG), MDRD, CKD-EPI 2009, and race-free CKD-EPI 2021. To examine the association between calculated eGFR and measured CrCI, subgroup analyses were performed among patients in whom measured 24-hour urine CrCl was determined. Cisplatin-ineligibility was defined as CrCI and/or eGFR < 60 mL/minute per 1.73 m2., Results: Of 956 patients, 30.0%, 33.3%, 31.9%, and 27.7% were found to be cisplatin-ineligible by the CG, MDRD, CKD-EPI, and race-free CKD-EPI equations (P = .052). The concordance between calculated eGFR formulas was rated substantial (Cohen's kappa (k): 0.66-0.95). Among the subgroup (n = 245) with measured CrCl, 37 (15.1%) patients had a CrCI less than 60 mL/minute. Concordance between measured CrCl and calculated eGFR was poor (ĸ: 0.29-0.40). All calculated eGFR formulas markedly underestimated the measured CrCI. Specifically, 78%-87.5% of patients with a calculated eGFR between 40 and 59 mL/minute exhibited a measured CrCI ≥ 60 mL/minute., Conclusions: Comparing calculated eGFR formulas, similar percentages of patients with MIBC were deemed cisplatin-ineligible. However, a significant number of patients could be upgraded by being cisplatin-fit based on measured CrCI, particularly when the calculated eGFR was falling within the gray range of 40-59 mL/minute., (© The Author(s) 2024. Published by Oxford University Press.)

Objectives: Despite the well-established association between prediabetes and hyperuricaemia, knowledge about serum urate (SU) trends during the prediabetic phase is limited. Therefore, we aimed to assess the longitudinal changes of SU in individuals with prediabetes., Methods: Individuals with prediabetes, defined by initial haemoglobin A1c (HbA1c) levels between 5.7% and 6.4%, were identified using electronic health records from an academic health system (2007-2022). We required at least one SU test before and after the prediabetes diagnosis. The primary outcome was the longitudinal SU trends during the follow-up period, estimated with a multivariable mixed-effects model. Patients were censored at diabetes onset. Marginal effects of covariates on SU changes were estimated. Subsequent analyses examined SU variations in subgroups stratified by age, sex, BMI, HbA1c, estimated glomerular filtration rate and metformin use., Results: Out of 25 526 individuals with prediabetes, 1521 met the SU cohort requirements, contributing to 6832 SU observations. At baseline, median age was 63 years and 40% were female. Median values were SU 6.3 mg/dl, HbA1c 5.9% and BMI 30 kg/m2. Median follow-up was 7.4 years. Older age, male sex, greater BMI and higher HbA1c were significant predictors of increased longitudinal SU levels. Individuals with a BMI ≥30 kg/m2 exhibited higher SU levels compared with those with lower BMI values., Conclusion: Among individuals with prediabetes, several baseline variables were significant predictors of increased SU levels over time. These longitudinal trends in SU, support the potential for early intervention during the prediabetic phase, possibly reducing the risk of gout., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: A low-protein diet (LPD) is recommended to patients with advanced chronic kidney disease (CKD), whereas geriatric guidelines recommend a higher amount of protein. The aim of this study was to evaluate the safety of LPD treatment in older adults with advanced CKD., Methods: The EQUAL study is a prospective, observational study including patients ≥65 years of age with an incident estimated glomerular filtration rate <20 ml/min/1.73 m2 in six European countries with follow-up through 6 years. Nutritional status was assessed by a 7-point subjective global assessment (SGA) every 3-6 months. Prescribed diet (g protein/kg of bodyweight) was recorded on every study visit; measured protein intake was available in three countries. Time to death and decline in nutritional status (SGA decrease of ≥2 points) were analysed using marginal structural models with dynamic inverse probability of treatment and censoring weights., Results: Of 1738 adults (631 prescribed LPD at any point during follow-up), there were 1319 with repeated SGA measurements, of which 267 (20%) decreased in SGA ≥2 points and 565 (32.5%) who died. There was no difference in survival or decrease in nutritional status for patients prescribed a LPD ≤0.8 g/kg ideal bodyweight {odds ratio [OR] for mortality 1.15 [95% confidence interval (CI) 0.86-1.55)] and OR for decrease in SGA 1.11 [95% CI 0.74-1.66]} in the adjusted models. In patients prescribed a LPD <0.6 g/kg ideal bodyweight, the results were similar. There was a significant interaction with LPD and older age >75 years, lower SGA and higher comorbidity burden for both mortality and nutritional status decline., Conclusions: In older adults with CKD approaching end-stage kidney disease, a traditional LPD prescribed and monitored according to routine clinical practice in Europe appears to be safe., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background and Hypothesis: It remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants., Methods: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2) and albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses., Results: Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD, and 9% albuminuria), albuminuria was independently associated with covert infarcts [adjusted OR, 1.55 (1.00-2.38); P = 0.049] and incident MCI and dementia [adjusted hazard ratio (HR), 1.68 (1.18-2.41); P = 0.005 and 1.71, (1.11-2.64); P = 0.015, respectively]. CKD was not associated with CSVD markers but was associated with a higher risk of incident dementia [HR, 1.53 (1.02-2.29); P = 0.041]. While albuminuria was predictive of the Alzheimer's disease subtype [adjusted HR = 1.68, (1.03-2.74); P = 0.04), CKD was predictive of vascular dementia [adjusted HR, 2.78 (1.16-6.68); P = 0.023]., Conclusions: Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond BP-related injury., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Accurate estimation of glomerular filtration rate (GFR) is crucial in living kidney donation. While most estimated GFR (eGFR) equations are based on plasma creatinine, its levels are strongly influenced by muscle mass. Application of cystatin C (cysC)-based estimates before donation may improve both estimation of current GFR and prediction of post-donation GFR., Methods: We assessed the performance of Chronic Kidney Disease Epidemiology Collaboration equations based on creatinine (eGFRcreat-2009, eGFRcreat-2021), cysC (eGFRCysC-2012) or both (eGFRcombined-2012, eGFRcombined-2021) for estimating pre- and post-donation (mGFR) GFR in 486 living kidney donors. We subsequently focused on a subgroup of individuals with high/low muscle mass (25% highest/lowest 24-hour urinary creatinine excretion, sex stratified and height indexed)., Results: Pre-donation eGFRcombined-2012 and eGFRcombined-2021 showed the strongest associations with pre- and post-donation mGFR. Pre-donation eGFRcombined-2021 was most accurate for estimating both pre-donation (bias 0.01 ± 11.9 ml/min/1.73 m2) and post-donation mGFR (bias 1.3 ± 8.5 ml/min/1.73 m2). In donors with high/low muscle mass, cysC-based equations (with or without creatinine) performed better compared with equations based on only creatinine., Conclusions: Combined eGFR equations yielded a better estimate of pre- and post-donation mGFR compared with estimates based on creatinine or cysC only. The added value of cysC seems particularly pronounced in donors with high or low muscle mass., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: The concept of residual kidney function (RKF) is exclusively based upon urine volume and small solute clearance, making RKF challenging to assess in clinical practice. The aim of this study was to test the technical feasibility of obtaining usable sodium magnetic resonance imaging (23Na-MRI) kidney images in hemodialysis (HD) participants., Methods: We conducted an exploratory prospective study to quantify the cortico-medullary sodium gradient in 17 healthy volunteers and 21 HD participants. Participants fasted for 8 h prior to their study visit. Urine samples were collected to measure urinary osmolarity, before MRI. Proton and sodium pictures were merged; regions of interest were delineated for the medulla and cortex when feasible. In cases where cortex could not be identified, we considered the corticomedullary gradient (CMG) to be no longer present, resulting in a medulla-to-cortex ratio of 1., Results: Median (interquartile range) fasting medulla-to-cortex ratio was significantly higher 1.56 (1.5-1.61) in healthy volunteers compared with HD patients 1.22 (1.13-1.3), P < .0001. Medulla to cortex ratio and median urinary osmolarity were correlated (r = 0.87, P < .0001) in the whole population. We found a significant association between HD vintage and medulla-to-cortex ratio, whereas we did not find any association with urine volume. Sodium signal intensity distribution within healthy kidney describes two different peaks relating to well defined cortex and medulla, whereas HD participants displays only a single peak indicative of the markedly lower sodium concentration., Limitations: This study is only exploratory, with a modest number of patients., Conclusions: The application of kidney 23Na-MRI to the study of RKF in patients receiving maintenance HD is practical and provides a previously unavailable ability to interrogate the function of remnant tubular function.Clinical Trial Registration: NCT05014178., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: People with chronic kidney disease (CKD) have increased incidence and mortality of most cancer types. We hypothesized that the odds of presenting with advanced cancer may vary according to differences in estimated glomerular filtration rate (eGFR), that this could contribute to increased all-cause mortality and that sex differences may exist., Methods: Data were from Secure Anonymised Information Linkage Databank, including people with de novo cancer diagnosis (2011-17) and two kidney function tests within 2 years prior to diagnosis to determine baseline eGFR (mL/min/1.73 m2). Logistic regression models determined the odds of presenting with advanced cancer by baseline eGFR. Cox proportional hazards models tested associations between baseline eGFRCr and all-cause mortality., Results: eGFR <30 was associated with higher odds of presenting with advanced cancer of prostate, breast and female genital organs, but not other cancer sites. Compared with eGFR >75-90, eGFR <30 was associated with greater hazards of all-cause mortality in both sexes, but the association was stronger in females [female: hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.56-1.88; male versus female comparison: HR 0.88, 95% CI 0.78-0.99]., Conclusions: Lower or higher eGFR was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites, but was associated with reduced survival. A stronger association with all-cause mortality in females compared with males with eGFR <30 is concerning and warrants further scrutiny., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Purpose: The objective of this study was to evaluate the impact of a pharmacist consult service on rates of hypoglycemia in adult inpatients with renal dysfunction receiving antidiabetic medications., Methods: This was a single-center, institutional review board-approved, quasi-experimental, 2-phase prospective study. Adult inpatients admitted within 48 to 96 hours of hospitalization with a creatine clearance of less than 30 mL/min or estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 and an active antidiabetic medication order were included. Patients located in a critical care unit or with a previous or planned transplantation were excluded. Each phase was conducted over 4 months. The primary endpoint was the change in the incidence of hypoglycemic episodes (blood glucose [BG] of <70 mg/dL) per 100 patient days when comparing the cohorts. Secondary endpoints included the incidence of recurrent and severe (BG of <40 mg/dL) episodes of hypoglycemia per 100 patient days, occurrence of a BG concentration of higher than 300 mg/dL, and length of stay., Results: Overall, 150 patients were included in the retrospective preimplementation phase and 172 were included in the prospective postimplementation phase. In the postimplementation group, there was a significant decrease in the rate of hypoglycemia per 100 patient days when compared to the retrospective group (5.8 vs 9.0; incidence rate ratio, 1.55; 95% confidence interval, 1.2-2.0; P < 0.05). There was no difference in secondary endpoints between the groups., Conclusion: The implementation of a pharmacy consult service resulted in lower rates of hypoglycemic events, which supports pharmacist involvement to prevent hypoglycemia in this at-risk population. Additional studies involving pharmacists working under collaborative practice agreements may reinforce the results., (© American Society of Health-System Pharmacists 2024. 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.)

Background: Cardiovascular disease prevalence remains high among chronic kidney disease (CKD) patients. Mechanisms and treatments to improve prognosis remain of paramount important and imaging biomarkers of left ventricular myocardial structure and function have better defined the phenotype of renal cardiomyopathy. The left atrial function and right heart remain are less well reported in CKD. This study used cardiac MRI to assess the interplay of left atrial and right ventricular function., Methods: In a cross-sectional study, we examined 58 CKD patients (Group I: stages 2-3, n = 25; Group II: stages 4-5, n = 33). Additionally, 26 age-matched healthy controls were included. Comprehensive CMR protocols (1.5T) were employed, encompassing cine imaging, native T1 and T2 mapping, and tissue tracking strain analysis. LV, RV, and LA structure, function, and strain parameters were assessed., Results: Compared to healthy controls, both groups I and II exhibited impaired RV and LA function. RVEDVi and RVESVi showed significant increases in both groups I and II (p < 0.001). All LV, RV, and LA strain parameters were reduced in the patient groups (all p < 0.001). In the univariate binary logistic regression, several parameters, including age, blood pressure, RV volumes and LV/RV strain were found to have a statistically significant association with CKD. In a multivariable model adjusted for other confounders, RV GLS and left atrial strain remained as independent significant predictors., Conclusions: RV size, LA strain and volume assessed by CMR serve as markers of RV and LA cardiac dysfunction in CKD patients with preserved LVEF. Greater attention should be given to RV and LA dysfunction for early identification of cardiac dysfunction in CKD patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Immunoglobulin A (IgA) vasculitis nephritis (IgAVN) is the most common secondary IgA nephropathy (IgAN). Urinary C4d have been identified associated with the development and progression in primary IgAN; however, its role in kidney disease progression of IgAVN is still unclear., Methods: This study enrolled 139 patients with IgAVN, 18 healthy subjects, 23 focal segmental glomerulosclerosis patients and 38 IgAN patients. Urinary C4d levels at kidney biopsy were measured using enzyme-linked immunosorbent assay. The association between urinary C4d/creatinine and kidney disease progression event, defined as 40% estimated glomerular filtration rate decline or end-stage kidney disease, was assessed using Cox proportional hazards models and restricted cubic splines., Results: The levels of urinary C4d/creatinine (Cr) in IgAVN and IgAN patients were higher than in healthy controls. Higher levels of urinary C4d/Cr were associated with higher proteinuria and severe Oxford C lesions, and glomerular C4d deposition. After a median follow-up of 52.79 months, 18 (12.95%) participants reached composite kidney disease progression event. The risk of kidney disease progression event was higher with higher levels of Ln(urinary C4d/Cr). After adjustment for clinical data, higher levels of urinary C4d/Cr were associated with kidney disease progression in IgAVN [per Ln-transformed urinary C4d/Cr, hazard ratio 1.573, 95% confidence interval (CI) 1.101-2.245; P = .013]. Compared with the lower C4d/Cr group, the hazard ratio was 5.539 (95% CI 1.135-27.035; P = .034) for the higher levels group., Conclusions: Higher levels of urinary C4d/Cr were associated with kidney disease progression event in patients with IgAVN., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: In primary aldosteronism (PA), aldosterone could affect glomerular hemodynamics by elevating renal vascular resistance and glomerular capillary pressure. However, the relationship between plasma aldosterone concentrations (PAC) and glomerular hemodynamics including efferent arteriolar resistance (Re), and afferent arteriolar resistance (Ra) in humans is still unclear. The aim of this study was to investigate the relationships of PAC with intraglomerular hemodynamic parameters in patients with PA., Methods: An observational study of glomerular hemodynamics was performed using simultaneous measurements of plasma clearance of para-aminohippurate and inulin (Cin; glomerular filtration rate (GFR)) in 17 patients with PA. Kidney function was evaluated by Cin, estimated GFR based on serum creatine (eGFRcre) and serum cystatin C (eGFRcys) and creatine clearance (Ccr). Intraglomerular hemodynamic parameters, including Re, Ra, and intraglomerular hydrostatic pressure (Pglo) were calculated using Gomez's formulae., Results: In the 17 PA cases, PAC was significantly correlated with Cin (rho = 0.752, P = 0.001) and eGFRcys (rho = 0.567, P = 0.018), but was not correlated with eGFRcre and Ccr. PAC was also significantly correlated with Pglo, Re, and urinary protein/day (rho = 0.775, P = 0.0004, rho = 0.625, P = 0.009, and rho = 0.625, P = 0.007, respectively). Multivariable regression analysis showed that PAC was significantly associated with Cin and Re. In comparing aldosterone-producing adenoma (APA) and non-APA cases, Cin was significantly elevated in APA (P = 0.037), whereas eGFRcre, eGFRcys, and Ccr were not. Re tended to be higher in APA (P = 0.064)., Conclusions: These results suggest high aldosterone causes glomerular hyperfiltration by constricting Re. Cin, but not eGFRcre and Ccr, may be useful for evaluating kidney function in PA., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. 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.)

Inflammatory bowel disease [IBD] is associated with various immune-mediated disorders including spondylarthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and uveitis. Chronic kidney disease [CKD] is defined by a reduction in kidney function (estimated glomerular filtration rate [eGFR] less than 60 ml/min/1.73m2] and/or damage markers that are present for at least 3 months, regardless of the aetiology. Case reports and cohort studies suggest that IBD is associated with CKD. The extent and magnitude of a potential association is unknown. A comprehensive search was conducted in EMBASE, MEDLINE, Web of Science, the Cochrane database, and SCOPUS. Two separate reviewers were involved in the process of article selection and evaluation. Odds ratios were calculated in those papers with a comparison between an IBD population and a non-IBD control population, the Mantel Haenszel test was employed, using a random effect model. The systematic review was registered in PROSPERO [RD42023381927]. A total of 54 articles was included in the systematic review. Of these, eight articles included data on prevalence of CKD in IBD patients [n = 102 230] vs healthy populations [n = 762 430]. Of these, diagnosis of CKD was based on International Classification of Diseases [ICD] codes in five studies vs on eGFR in three studies. The overall odds ratio of developing CKD in the IBD population is 1.59, [95% CI 1.31-1.93], without any difference between studies using diagnostic coding (odds ratio [OR] 1.70, 95% CI 1.33-2.19] vs diagnosis based on eGFR [OR 1.36, 95% CI 1.33-1.64]. IBD is associated with a clinically meaningful increased CKD prevalence. We provide recommendations on diagnostic evaluation, as well as suggestions for future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. 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.)

Background: The objective of this study was to compare The Binding Site's Freelite on Optilite and Diazyme's Kappa/Lambda free light chains (K/L FLC) on Abbott Architect c8000 with healthy and renal insufficient populations and to evaluate their respective reference intervals for serum free light chains (sFLCs)., Methods: Two hundred sixty serum samples were measured for creatinine and sFLCs by both assays and a subset by immunofixation electrophoresis. Verification of manufacturer-defined reference intervals was assessed., Results: Kappa free light chains (KFLC) showed excellent correlation of 0.998 R2 with a slope of 0.73. For Lambda free light chains (LFLC), an acceptable correlation of 0.953 R2 was found with a slope of 1.50 as well as a skewness-based difference with a -12.70 intercept. Healthy estimated glomerular filtration rate (eGFR) ≥60 reference interval verification of central 95% could not be confirmed for either Freelite or Diazyme although LFLC was much closer than KFLC for both assays with Freelite KFLC recovering only 37% of values within reference interval claims. The K/L FLC ratio did not meet 100% claim for both Freelite (91%) and Diazyme (95%) among those with eGFR ≥60. Samples with eGFR ≤59 had increasingly higher levels of KFLC and LFLC for both assays. When comparing worsening eGFR status, Freelite recovered increasingly higher ratios while Diazyme recovered increasingly lower ratios., Conclusions: Healthy reference intervals could not be verified for either Freelite or Diazyme. Renal reference intervals for Freelite are currently warranted while they are not recommended for Diazyme. The differences between these 2 assays can be minimized by standardization efforts such as recalibration., (© Association for Diagnostics & Laboratory Medicine 2024. 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.)

Objective: Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation., Design: Prospective randomized controlled trial. ClinicalTrials.gov: NCT00522028., Setting: Eight Scandinavian referral centers., Participants: From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses., Intervention: Seventy patients were randomized to PTX and 80 to observation without intervention (OBS)., Measures: e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide., Results: No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years., Limitations: Secondary analyses of a randomized controlled trial., Conclusion: PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective., Competing Interests: Conflict of interest: none., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Introduction: Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear., Methods: We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimated glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy or death due to kidney disease) in EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure., Results: In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid and urine albumin-to-creatinine ratio mediated 79.4%, 33.2% and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%) and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis., Conclusions: Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Kidney involvement is common in anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) and the prognosis is determined by the severity of kidney damage. This study focused on long-term kidney outcomes, defining possible risk factors and comparing the performance of three different histological classifications to predict outcomes for patients with AAV., Methods: The dataset included 848 patients with newly diagnosed AAV who participated in seven randomized controlled trials (RCTs) (1995-2012). Follow-up information was obtained from questionnaires sent to the principal investigators of the original RCTs., Results: The cumulative incidence of end-stage kidney disease (ESKD) at 5 and 10 years was 17% and 22%, respectively. Patients who developed ESKD had reduced patient survival compared with those with preserved kidney function (hazard ratio 2.8, P < .001). Comparing patients with AAV and kidney involvement with a matched general population, patients with AAV had poor survival outcomes, even in early stages of chronic kidney disease. The main cause of death was infection followed by cardiovascular disease in patients developing ESKD and malignancy in those who did not. Some 34% of patients with initial need for dialysis recovered kidney function after treatment. Thirty-five out of 175 in need of kidney replacement therapy (KRT) during follow-up received a kidney transplant with good outcome; there was 86% patient survival at 10 years.In the subcohort of 214 patients with available kidney biopsies, three scoring systems were tested: the Berden classification, the Renal Risk Score and the Mayo Clinic Score. The scores highlighted the importance of normal glomeruli and severe glomerulosclerosis on kidney survival (P < .001 and P = .001, respectively). The Renal Risk Score demonstrated a moderate prediction of kidney survival (area under the curve 0.79; standard error 0.03, 95% confidence interval 0.71-0.83)., Conclusions: Early diagnosis of AAV is extremely important. Even milder forms of kidney involvement have an impact on the prognosis. Patients in need of KRT had the lowest survival rates, but kidney transplantation has shown favorable outcomes for eligible AAV patients. The three histologic scoring systems were all identified as independent prognostic factors for kidney outcome., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Clinical variability among individuals with heterozygous pathogenic/likely pathogenic (P/LP) variants in the COL4A3/COL4A4 genes (also called autosomal dominant Alport syndrome or COL4A3/COL4A4-related disorder) is huge; many individuals are asymptomatic or show microhematuria, while others may develop proteinuria and chronic kidney disease (CKD). The prevalence of simple kidney cysts (KC) in the general population varies according to age, and patients with advanced CKD are prone to have them. A possible association between heterozygous COL4A3, COL4A4 and COL4A5 P/LP variants and KC has been described in small cohorts. The presence of KC in a multicenter cohort of individuals with heterozygous P/LP variants in the COL4A3/COL4A4 genes is assessed in this study., Methods: We evaluated the presence of KC by ultrasound in 157 individuals with P/LP variants in COL4A3 (40.7%) or COL4A4 (53.5%) without kidney replacement therapy. The association between presence of KC and age, proteinuria, estimated glomerular filtration rate (eGFR) and causative gene was analyzed. Prevalence of KC was compared with historical case series in the general population., Results: Half of the individuals with P/LP variants in COL4A3/COL4A4 showed KC, which is a significantly higher percentage than in the general population. Only 3.8% (6/157) had cystic nephromegaly. Age and eGFR showed an association with the presence of KC (P < .001). No association was found between KC and proteinuria, sex or causative gene., Conclusions: Individuals with COL4A3/COL4A4 P/LP variants are prone to develop KC more frequently than the general population, and their presence is related to age and to eGFR. Neither proteinuria, sex nor the causative gene influences the presence of KC in these individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

We are currently facing a pandemic of physical inactivity that might contribute to the growing prevalence of chronic kidney disease (CKD). Here, we summarize currently available evidence on the association between physical activity and CKD, and also review the effects of exercise intervention in affected patients. Physical activity/exercise might act as a polypill against CKD, preventing its development or even exerting beneficial effects once it is established (i.e. improvements in patients' physical fitness and cardiovascular risk, as well as in kidney function). Exercise benefits are also found at advanced CKD stages or in patients under hemodialysis. The biological mechanisms behind the clinical evidence are also discussed. An active lifestyle appears as a cornerstone in CKD prevention and management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Creatinine-based equations are the most used to estimate glomerular filtration rate (eGFR). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), the re-expressed Lund-Malmö Revised (r-LMR) and the European Kidney Function Consortium (EKFC) equations are the most validated. The EKFC and r-LMR equations have been suggested to have better performances in young adults, but this is debated., Methods: We collected data (GFR) measured by clearance of an exogenous marker (reference method), serum creatinine, age and sex from 2366 young adults (aged between 18 and 25 years) both from Europe and the USA., Results: In the European cohorts ( n  = 1892), the bias (in mL/min/1.73 m²) was systematically better for the EKFC and r-LMR equations compared with the CKD-EPI equation [2.28, 95% confidence interval (1.59; 2.91), -2.50 (-3.85; -1.76), 17.41 (16.49; 18.47), respectively]. The percentage of estimated GFR within 30% of measured GFR (P30) was also better for EKFC and r-LMR equations compared with the CKD-EPI equation [84.4% (82.8; 86.0), 87.2% (85.7; 88.7) and 65.4% (63.3; 67.6), respectively]. In the US cohorts ( n  = 474), the bias for the EKFC and r-LMR equations was better than for the CKD-EPI equation in the non-Black population [0.97 (-1.69; 3.06), -2.62 (-5.14; -1.43) and 7.74 (5.97; 9.63), respectively], whereas the bias was similar in Black US individuals. P30 results were not different between the three equations in US cohorts. Analyses in sub-populations confirmed these results, except in individuals with high GFR levels (GFR ≥120 mL/min/1.73 m²) for whom the CKD-EPI equation might have a lower bias., Conclusions: We demonstrated that both the EKFC and r-LMR creatinine-based equations have a better performance than the CKD-EPI equation in a young population. The only exception might be in patients with hyperfiltration., Competing Interests: P.D. reports consulting fees from Nephrolyx and is a member of the CKJ Editorial Board., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a new cystic fibrosis transmembrane conductance regulator (CFTR) modulator that has transformed the respiratory prognosis of people with cystic fibrosis (pwCF). However, its impact on other organs such as the kidneys, where CFTR is expressed, remains unclear. Since pwCF are risk of both kidney disease and urolithiasis, we aimed to study the potential effects of ETI on renal function, volume status, and risk factors for urolithiasis., Methods: This prospective, observational, single-center, before-after cohort study, involved adult pwCF eligible for ETI. The changes in plasma and urinary profiles were assessed by comparing renal function (using 2021 CKD-EPI creatinine and 2021 CKD-EPI creatinine-cystatin C formulas), volume status (using aldosterone/renin ratio and blood pressure), and risk factors for urolithiasis, at the time of ETI introduction (M0) and 7 months after (M7)., Results: Nineteen pwCF were included. No significant change in renal function was observed between M0 and M7 (2021 CKD-EPI creatinine : 105.5 ml/min/1.73 m² at M0 vs. 103.3 ml/min/1.73 m² at M7; P  = .17). There was a significant reduction in aldosterone level (370.3 pmol/l at M0 vs. 232.4 pmol/l at M7; P  = .02) and aldosterone/renin ratio (33.6 at M0 vs. 21.8 at M7; P  = .03). Among the risk factors for urolithiasis, a significant reduction in magnesuria level was found (4.6 mmol/d at M0 vs. 3.8 mmol/d at M7; P  = .01)., Conclusion: These findings suggest that ETI seem to have no short-term impact on the renal function of adult pwCF and appears to correct secondary hyperaldosteronism due to excessive sweat losses. Further investigations are needed to determine the potential impact of decreased magnesuria observed under ETI therapy on the risk of urolithiasis., Competing Interests: D.F. has received speaker fees or travel support from AstraZeneca, Astellas, Lilly and Fresenius Kabi. I.D. declares an activity as a clinical trial investigator for Vertex and acknowledges having received support for conference travel from Viatris. L.K. having received grants from Fresenius Kabi, Nestlé, Lallemand, AstraZeneca and consultancy or speaker fees or travel support from AstraZeneca, Lilly, Baxter, Bayer, and Fresenius Kabi. P.G., E.N.-C., Q.R., R.N.-J., and S.P. declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Context: Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD); however, factors associated with CKD are unknown., Objective: We aimed to identify the factors associated with CKD and assess the effect of adrenalectomy on kidney function in patients with NFA or MACS., Methods: A single-center cohort study of patients with NFA and MACS, 1999 to 2020, was conducted. MACS was diagnosed based on post dexamethasone suppression test (DST) cortisol greater than or equal to 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and postadrenalectomy delta eGFR., Results: Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 mL/min/1.73 m2; P < .001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, postadrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow-up. Factors associated with increased eGFR were younger age, lower preadrenalectomy eGFR, and longer follow-up period., Conclusion: DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Patients with both MACS and NFA demonstrate an increase in eGFR post adrenalectomy, especially younger patients with lower eGFR pre adrenalectomy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: C4d mesangial deposition, a hallmark of lectin pathway activation in immunoglobulin A nephropathy (IgAN), has been shown to be associated with risk of kidney failure. To date, the relationship between urinary C4d and renal outcome remain unelucidated., Methods: A total of 508 patients with biopsy-proven IgAN were enrolled in this study, whose baseline urine samples at the time of biopsy were collected and the levels of urinary C4d were quantified by enzyme-linked immunosorbent assay. The time-averaged C4d (TA-C4d) and the change in proteinuria were measured in sequential urine samples obtained from IgAN patients. The kidney progression event was defined as a 50% estimated glomerular filtration rate (eGFR) decline or end-stage kidney disease or death., Results: After a median follow-up of 36 months, 70 (13.8%) of the participants reached the kidney progression event. Higher levels of urinary C4d/Ucr were found to be associated with decreased eGFR, massive proteinuria, lower serum albumin levels, hypertension, and severe Oxford E and T scores. Upon adjusting for traditional risk factors (including demographics, eGFR, proteinuria, hypertension, Oxford pathologic score and immunosuppressive therapy), elevated levels of urinary C4d/Ucr were independently associated with an increased risk of chronic kidney disease progression [adjusted hazard ratio (HR) per standard deviation increment of log-transformed C4d/Ucr: 1.46; 95% CI 1.04-2.06; P = .030]. In reference to the low C4d group, the risk of poor renal outcome increased for the high C4d group (adjusted HR 1.93; 95% CI 1.05-3.54; P = .033). Additionally, a low baseline C4d level was independently associated with a favorable proteinuria response to immunosuppressive therapy at 3 months (adjusted relative risk 2.20; 95% CI 1.04-4.63, P = .038)., Conclusion: The urinary C4d, serving as a non-invasive biomarker, is associated with the progression of IgAN and holds the potential to predict proteinuria response in this disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: To explore the association between the differences between cystatin C- and creatinine-based estimated glomerular filtration rate (eGFRdiff), and the risk of mortality and cardiovascular (CV) events in individuals with diabetes., Methods: Three prospective cohorts analyzed data from adults with diabetes from the Incident, Development, and Prognosis of Diabetic Kidney Disease (INDEED) study (2016-17 to 2020) in China, the National Health Nutrition Examination Survey (NHANES, 1999-2004 to 2019) in the USA and UK Biobank (UKB, 2006-10 to 2022) in the UK. Baseline eGFRdiff was calculated using both absolute difference between cystatin C- and creatinine-based calculations (eGFRabdiff), and the ratio between them (eGFRrediff). Cox proportional hazards regression models were used to investigate the association between eGFRdiff and outcomes including all-cause mortality and incident CV events., Results: A total of 8129 individuals from INDEED (aged 60.7 ± 10.0 years), 1634 from NHANES (aged 62.5 ± 14.4 years) and 29 358 from UKB (aged 59.4 ± 7.3 years) were included. At baseline, 43.6%, 32.4% and 42.1% of participants in INDEED, NHANES and UKB, respectively, had an eGFRabdiff value ≥15 mL/min/1.73 m2. During a median follow-up of 3.8 years for INDEED, 15.2 years for NHANES and 13.5 years for UKB, a total of 430, 936 and 6143 deaths and a total of 481, 183 and 5583 CV events occurred, respectively. Each 1-standard deviation higher baseline eGFRabdiff was independently associated with a lower risk of all-cause mortality and CV events, with hazard ratios of 0.77 and 0.82 in INDEED, 0.70 and 0.68 in NHANES, and 0.66 and 0.78 in UKB. Similar results were observed for eGFRrediff., Conclusions: eGFRdiff represents a marker of adverse events for diabetes among general population. Monitoring both eGFRcys and eGFRcr yields additional prognostic information and has clinical utility in identifying high-risk individuals for mortality and CV events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy., Methods: Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up., Results: The median follow-up was 3.7 years (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up., Conclusion: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The global burden of chronic kidney disease (CKD) is high and increasing. Early diagnosis and intervention are key to improve outcomes. Single-nephron glomerular hyperfiltration is an early pathophysiologic manifestation of CKD that may result in absolute glomerular hyperfiltration, i.e. a high glomerular filtration rate (GFR), or be associated with normal or low GFR because of nephron loss (relative glomerular hyperfiltration). Even though compensatory glomerular hyperfiltration may contribute to maintain kidney function after the loss of kidney mass, the associated increased glomerular capillary pressure and glomerular and podocyte size drive podocyte loss, albuminuria and proximal tubular overload, contributing to CKD progression. In this regard, all kidney protective drugs in clinical use so far, from renin-angiotensin system blockers to mineralocorticoid receptor blockers to sodium-glucose co-transporter 2 inhibitors to tolvaptan, induce an early dip in glomerular filtration that is thought to represent reversal of hyperfiltration. As glomerular hyperfiltration may be present early in the course of kidney disease, its recognition may provide an effective intervention window that may predate current criteria based on high albuminuria or loss of GFR. Nevertheless, there is no diagnostic method with high sensitivity and specificity to identify single-nephron glomerular hyperfiltration, except when it leads to obvious absolute glomerular hyperfiltration, as observed in the early stages of diabetic kidney disease when nephron mass is still preserved. We now review the concept of glomerular hyperfiltration as an indicator of CKD risk, including definitions, challenges in diagnosis and evaluation, underlying pathophysiological mechanisms, potential therapeutic approaches and unanswered questions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Autosomal dominant Alport Syndrome (ADAS), also known as thin basement membrane disease (TBMD), is caused by pathogenic variants in the COL4A3 and COL4A4 genes. A cystic phenotype has been described in some patients with TBMD, but no genetic studies have been performed. We conducted a genetic and radiologic investigation in a cohort of ADAS patients to analyze the prevalence of multicystic kidney disease (MKD) and its association with chronic kidney disease (CKD)., Methods: This was a retrospective single-center cohort study. Thirty-one patients showing pathogenic or likely pathogenic variants in COL4A3 or COL4A4 from a cohort of 79 patients with persistent microscopic hematuria were included. Mean follow-up was 9.4 ± 9.6 years. The primary objective of the study was to determine the prevalence of MKD in the cohort of ADAS patients. Secondary objectives were to determine risk factors associated with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 at the time of genetic and radiologic evaluation and to investigate the coexistence of other genetic abnormalities associated with familial hematuria and cystic kidney disease., Results: MKD was found in 16 patients (52%). Mean number of cysts per kidney was 12.7 ± 5.5. No genetic abnormalities were found in a panel of 101 other genes related to familial hematuria, focal segmental glomerulosclerosis and cystic kidney disease. A greater number of patients with MKD had an eGFR <45 mL/min/1.73 m2 (63% vs 7%, P = .006) and more advanced CKD than patients without MKD. The annual rate of eGFR decline was greater in patients with MKD: -1.8 vs 0.06 mL/min/1.73 m2/year (P = .009). By multivariable linear regression analysis, the main determinants of eGFR change per year were time-averaged proteinuria (P = .002) and MKD (P = .02)., Conclusion: MKD is commonly found in ADAS and is associated with a worse kidney outcome. No pathogenic variants were found in genes other than COL4A3/COL4A4., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Identifying the biomarkers associated with new-onset glomerular filtration rate (GFR) decrease in an initially healthy population could offer a better understanding of kidney function decline and help improving patient management., Methods: Here we described the proteomic and transcriptomic footprints associated with new-onset kidney function decline in an initially healthy and well-characterized population with a 20-year follow-up. This study was based on 1087 individuals from the familial longitudinal Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) cohort who attended both visit 1 (from 1993 to 1995) and visit 4 (from 2011 to 2016). New-onset kidney function decline was approached both in quantitative (GFR slope for each individual) and qualitative (defined as a decrease in GFR of >15 ml/min/1.7 m 2 ) ways. We analysed associations of 445 proteins measured both at visit 1 and visit 4 using Olink Proseek ® panels and 119 765 genes expressions measured at visit 4 with GFR decline. Associations were assessed using multivariable models. The Bonferroni correction was applied., Results: We found several proteins (including PLC, placental growth factor (PGF), members of the tumour necrosis factor receptor superfamily), genes (including CCL18, SESN3 ), and a newly discovered miRNA-mRNA pair (MIR1205-DNAJC6) to be independently associated with new-onset kidney function decline. Complex network analysis highlighted both extracellular matrix and cardiovascular remodelling (since visit 1) as well as inflammation (at visit 4) as key features of early GFR decrease., Conclusions: These findings lay the foundation to further assess whether the proteins and genes herein identified may represent potential biomarkers or therapeutic targets to prevent renal function impairment., Competing Interests: The authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Context: Type 2 diabetes (T2D) is the major contributor to chronic kidney disease and end-stage kidney disease (ESKD). The influence of trimethylamine N-oxide (TMAO) on kidney outcomes in T2D remains unclear., Objective: To examine the association between fasting serum TMAO levels and adverse kidney outcomes in patients with T2D., Methods: Between October 2016 and June 2020, patients with T2D were recruited and monitored every 3 months until December 2021. Serum TMAO levels were assessed using liquid chromatography-mass spectrometry. The primary kidney outcomes were doubling of serum creatinine levels or progression to ESKD necessitating dialysis; the secondary kidney outcome was a rapid 30% decline in estimated glomerular filtration rate within 2 years. All-cause mortality was also evaluated., Results: Among the 440 enrolled patients with T2D, those in the highest serum TMAO tertile (≥0.88 μM) were older, had a longer diabetes duration, elevated blood urea nitrogen, and lower estimated glomerular filtration rate. Over a median follow-up period of 4 years, 26 patients (5.9%) had a doubling of serum creatinine level or progression to ESKD. After propensity score weighting, the patients in the highest serum TMAO tertile had a 6.45-fold increase in the risk of doubling of serum creatinine levels or progression to ESKD and 5.86-fold elevated risk of rapid decline in kidney function compared with those in the lowest tertile. Additionally, the stepwise increase in serum TMAO was associated with all-cause mortality., Conclusion: Patients with T2D with elevated circulating TMAO levels are at higher risk of doubling serum creatinine, progressing to ESKD, and mortality. TMAO is a potential biomarker for kidney function progression and mortality in patients with T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear., Methods: The association between baseline glycated hemoglobin (HbA1c) and rates of estimated glomerular filtration rate (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial and 2378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of eGFR decline were also evaluated in PERL., Results: A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (-0.87 and -0.27 mL/min/1.73 m2/year per Hba1c unit increment, P < .0001 and P = .0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (P for interaction <.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe rather than moderate albuminuria (+1.13 vs + 0.26 mL/min/1.73 m2/year, P = .01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline., Conclusion: In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of glomerular filtration rate decline after DKD onset, especially in persons with severe albuminuria., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In 2022, the National Kidney Foundation's Laboratory Engagement Working Group (NKF-WG) released recommendations for clinical implementation of the race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 estimated glomerular filtration rate (eGFR) equation.This study examined laboratory communications during CKD-EPI 2021 implementation including communication methods and delivery, content inclusion, and alignment with stakeholder inclusion as defined by the NKF-WG., Methods: An anonymous web-based survey was distributed to members of ADLM (AACC) and the American Society for Clinical Laboratory Science (ASCLS) in November 2022 to solicit laboratory directors of CLIA-licensed clinical laboratories in the United States. Seventeen questions covering topics related to implementation of CKD-EPI 2021, stakeholder inclusion, methods and timing of communications delivery, and content inclusion were surveyed., Results: All participating laboratories (n = 28) reported including physicians/advanced practitioners in implementation communications, while only 10.7% reported inclusion of patients. When reporting on methods of communication, 81.5% (n = 27) of respondents reported using multiple methods of communication with providers and 88.8% issued provider communications prior to implementation. In contrast, when patient communications were delivered, 87.5% (n = 8) issued these communications exclusively after CKD-EPI 2021 implementation and the majority (6 of 8) reported using only one method of communication during delivery. When reporting on content inclusion, 64.3% (n = 28) of laboratories reported including concerns regarding previous race-based eGFR equations in communications with physicians/advanced practitioners, while only 16.7% (n = 18) of those who included this information did so with patients., Conclusions: Participants reported limited engagement in CKD-EPI 2021 laboratory-to-patient implementation communications as well as limited inclusion of additional stakeholder groups, as defined in the NKF-WG recommendations. Laboratories utilized multiple communication methods and deliveries in physician/advanced practitioner communications; however, this strategy was not replicated when engaging with additional NKF-WG stakeholder groups., (© Association for Diagnostics & Laboratory Medicine 2024. 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.)

Background: The accurate assessment of kidney function is vital for the early detection of kidney damage. The estimated glomerular filtration rate GFR (eGFR) from serum cystatin C (CysC) and creatinine-based equations are commonly used in clinical practice as an alternative to the invasive measured glomerular filtration rate (mGFR), which is the usually accepted overall best index of kidney function in health and disease. Recently the CKiD under 25 (CkiD U25) equations have been shown to perform well in children and young adults with chronic kidney disease (CKD). In this focused report, we evaluated the performance of the CkiD U25 equations alongside 3 non-race-corrected (NRC) eGFR equations commonly used in pediatrics in our cohort., Methods: mGFR measured following the intravenous injection of tracer Tc-99mDTPA was retrospectively compared with eGFR from these equations in 57 patients (6 months to 22 years) from different races/ethnicities. Ordinary least squares regression analyses were used to assess correlation between the mGFRs and eGFRs., Results: The average mGFR for this cohort was 84.1 mL/min/1.73 m2. The NRC creatinine equations overestimated eGFR across all groups, with the lowest bias for CKiD U25-creatinine (22.59 mL/min/1.73 m2). The best correlations to mGFR, P30, and lowest biases were the CKiD U25-CysC (0.6281, 80.7%, 3.72 mL/min/1.73 m2) and Schwartz CysC (0.6372, 77.2%, -4.68 mL/min/1.73 m2)., Conclusions: Overall, both CKiD U25-CysC and Schwartz CysC provide a good estimation of mGFR with the CKiD U25-CysC having the overall best performance compared to mGFR in our study., (© Association for Diagnostics & Laboratory Medicine 2024. 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.)

Background: Chronic kidney disease (CKD) is a growing global health concern. Identifying individuals in routine clinical care with new-onset CKD at high risk of rapid progression of the disease is imperative to guide allocation of prophylactic interventions, but community-based data are limited. We aimed to examine the risk of rapid progression, kidney failure, hospitalization and death among adults with incident CKD stage G3 and to clarify the association between predefined risk markers and rapid CKD progression., Methods: Using plasma creatinine measurements for the entire Danish population from both hospitals and primary care, we conducted a nationwide, population-based cohort study, including adults in Denmark with incident CKD stage G3 in 2017-2020. We estimated 3-year risks of rapid progression (defined by a confirmed decline in estimated glomerular filtration rate of ≥5 mL/min/1.73 m2/year), kidney failure, all-cause hospitalization and death. To examine risk markers, we constructed a heat map showing the risk of rapid progression based on predefined markers: albuminuria, sex, diabetes and hypertension/cardiovascular disease., Results: Among 133 443 individuals with incident CKD stage G3, the 3-year risk of rapid progression was 14.6% [95% confidence interval (CI) 14.4-14.8]. The 3-year risks of kidney failure, hospitalization and death were 0.3% (95% CI 0.3-0.4), 53.3% (95% CI 53.0-53.6) and 18.1% (95% CI 17.9-18.4), respectively. In the heat map, the 3-year risk of rapid progression ranged from 7% in females without albuminuria, hypertension/cardiovascular disease or diabetes, to 46%-47% in males and females with severe albuminuria, diabetes and hypertension/cardiovascular disease., Conclusion: This population-based study shows that CKD stage G3 is associated with considerable morbidity in a community-based setting and underscores the need for optimized prophylactic interventions among such patients. Moreover, our data highlight the potential of using easily accessible markers in routine clinical care to identify individuals who are at high risk of rapid progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) have disproportionately high levels of fibroblast growth factor 23 (FGF-23) for their chronic kidney disease stage, however only a subgroup develops kidney phosphate wasting. We assessed factors associated with phosphate wasting and hypothesize that it identifies patients with more severe disease and predicts disease progression., Methods: We included 604 patients with ADPKD from a multicenter prospective observational cohort (DIPAK; Developing Intervention Strategies to Halt Progression of Autosomal Dominant Polycystic Kidney Disease) in four university medical centers in the Netherlands. We measured parathyroid hormone (PTH) and total plasma FGF-23 levels, and calculated the ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) with <0.8 mmol/L defined as kidney phosphate wasting. We analysed the association of TmP/GFR with estimated GFR (eGFR) decline over time and the risk for a composite kidney outcome (≥30% eGFR decline, kidney failure or kidney replacement therapy)., Results: In our cohort (age 48 ± 12 years, 39% male, eGFR 63 ± 28 mL/min/1.73 m2), 59% of patients had phosphate wasting. Male sex [coefficient -0.2, 95% confidence interval (CI) -0.2; -0.1], eGFR (0.002, 95% CI 0.001; 0.004), FGF-23 (0.1, 95% CI 0.03; 0.2), PTH (-0.2, 95% CI -0.3; -0.06) and copeptin (-0.08, 95% CI -0.1; -0.08) were associated with TmP/GFR. Corrected for PTH, FGF-23 and eGFR, every 0.1 mmol/L decrease in TmP/GFR was associated with a greater eGFR decline of 0.2 mL/min/1.73 m2/year (95% CI 0.01; 0.3) and an increased hazard ratio of 1.09 (95% CI 1.01; 1.18) of the composite kidney outcome., Conclusion: Our study shows that in patients with ADPKD, phosphate wasting is prevalent and associated with more rapid disease progression. Phosphate wasting may be a consequence of early proximal tubular dysfunction and insufficient suppression of PTH., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Mental health problems, particularly anxiety and depression, are common in patients with chronic kidney disease (CKD) and negatively impact quality of life, treatment adherence and mortality. However, the degree to which mental health and addiction services are utilized by those with CKD is unknown. We examined the history of mental health and addiction service use of individuals across levels of kidney function., Methods: We performed a population-based cross-sectional study using linked healthcare databases from Ontario, Canada from 2009 to 2017. We abstracted the prevalence of individuals with mental health and addiction service use within the previous 3 years across levels of kidney function [estimated glomerular filtration rate (eGFR) ≥60, 45 to <60, 30 to <45, 15 to <30, <15 ml/min/1.73 m2 and maintenance dialysis]. We calculated prevalence ratios (PRs) to compare prevalence across kidney function strata, while adjusting for age, sex, year of cohort entry, urban versus rural location, area-level marginalization and Charlson comorbidity index., Results: Of 5 956 589 adults, 9% (n = 534 605) had an eGFR <60 ml/min/1.73 m2 or were receiving maintenance dialysis. Fewer individuals with an eGFR <60 ml/min/1.73 m2 had a history of any mental health and addiction service utilization (crude prevalence range 28-31%) compared with individuals with an eGFR ≥60 ml/min/1.73 m2 (35%). Compared with an eGFR ≥60 ml/min/1.73 m2, the lowest prevalence of individuals with any mental health and addiction service utilization was among those with an eGFR of 15 to <30 ml/min/1.73 m2 {adjusted PR 0.86 [95% confidence interval (CI) 0.85 to 0.88]}, an eGFR <15 ml/min/1.73 m2 [adjusted PR 0.81 (95% CI 0.76-0.86)] and those receiving maintenance dialysis [adjusted PR 0.83 (95% CI 0.81-0.84)]. Less use of outpatient services accounted for differences in service utilization., Conclusions: Mental health and addiction service utilization is common but less so in individuals with advanced CKD in Ontario, Canada., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Creatinine-based estimated glomerular filtration rate (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 of 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 for estimating GFR unless both variables are included together. The new race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation had slight opposite biases between Black and non-Black subjects in the USA, but has poorer performance than that the previous version in European populations. The European Kidney Function Consortium (EKFC) equation developed in 2021 can be used in both 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 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 into discrepancies between cystatin C and creatinine, which is associated with high risk of adverse events: we need to standardize the definition of discrepancy and understand its determinants., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective(s): Chronic kidney disease (CKD) is an insidious disease that requires early nephroprotective measures to delay progression to end-stage kidney disease. The objective of this study was to describe the management of patients with CKD in primary care, including clinical and biological monitoring and prescribed treatments. A retrospective, single-centre study was conducted on adult patients who were treated in the Maison de Neufchâtel (France) between 2012 and 2017 at least once a year. The inclusion criteria were 2 estimated glomerular filtration rate (eGFR) measurements <60 mL/min more than 3 months apart. Two subgroups were constituted according to whether CKD was coded in the electronic medical records (EMRs)., Results: A total of 291 (6.7%, CI95% 5.9-7.4) patients with CKD were included. The mean eGFR was 51.0 ± 16.4 mL/min. Hypertension was the most frequent health problem reported (n = 93, 32%). Nephrotective agents were prescribed in 194 (66.7%) patients, non-steroidal anti-inflammatory drugs (NSAIDs) in 22 (8%) patients, and proton-pump inhibitors (PPIs) in 147 (47%) patients. CKD coding in EMRs was associated with dosage of natraemia (n = 34, 100%, P < 0.01), albuminuria (n = 20, 58%, P < 0.01), vitamin D (n = 14, 41%, P < 0.001), and phosphorus (n = 11, 32%, P < 0.001). Eighty-one patients (31.5%) with low eGFR without an entered code for CKD were prescribed an albuminuria dosage. Clinical monitoring could not be analysed due to poor coding., Conclusion: This pilot study reinforces the hypothesis that CKD is underscreened and undermanaged. More systematic coding of medical information in EMRs and further studies on medical centre databases should improve primary care practices., (© The Author(s) 2023. Published by Oxford University Press. 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.)

Over the past decade, several observational studies and case series have provided evidence suggesting a connection between glomerular diseases and the development of malignancies, with an estimated risk ranging from 5 to 11%. These malignancies include solid organ tumours as well as haematologic malignancies such as lymphoma and leukaemia. However, these risk estimates are subject to several sources of bias, including unmeasured confounding from inadequate exploration of risk factors, inclusion of glomerular disease cases that were potentially secondary to an underlying malignancy, misclassification of glomerular disease type and ascertainment bias arising from an increased likelihood of physician encounters compared with the general population. Consequently, population-based studies that accurately evaluate the cancer risk in glomerular disease populations are lacking. While it is speculated that long-term use of immunosuppressive medications and glomerular disease activity measured by proteinuria and estimated glomerular filtration rate may be associated with cancer risk in patients with glomerular disease, the independent role of these risk factors remains largely unknown. The presence of these knowledge gaps could lead to a lack of awareness of cancer as a potential chronic complication of glomerular disease, underutilization of routine screening practices in clinical care that allow early diagnosis and treatment of malignancies and underrecognition of modifiable risk factors to decrease the risk of de novo malignancies over time. This review summarizes the current evidence on the risk of cancer in patients with glomerular diseases, explores the limitations of prior studies and discusses methodological challenges and potential solutions for obtaining accurate estimates of cancer risk and identifying modifiable risk factors unique to GN populations., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)