BACKGROUND:The European Kidney Function Consortium (EKFC) 2021 equation to estimate GFR performs as well or better than the CKD-EPI 2009 equation in predominantly White adult European populations, with less bias and greater accuracy against measured GFR. This study explores how changing from the CKD-EPI to the EKFC equation in a large European health system may affect disease distribution, prognosis, and clinical decisions. METHODS:We studied >1.7 million adults in Stockholm undergoing routine care during 2006-2021. We compared eGFR values and reclassification across KDIGO GFR categories when changing from the CKD-EPI to EKFC equation and examined associations of eGFR and reclassification with risk for kidney failure with replacement therapy (KFRT), mortality, and major adverse cardiovascular events (MACE) using Cox models. We also modeled the impact of eGFR equation change on clinical decisions such as nephrology referral or medication eligibility/contraindication. RESULTS:EKFC yielded modestly lower eGFR values than CKD-EPI by a median (IQR) of -4.9 (-8.3 to -2.2) ml/min/1.73 m². As a result, CKD G3-G5 prevalence rose from 4.5% to 6.2%. Both equations strongly predicted KFRT, mortality, and MACE. Participants reclassified to lower eGFR categories were older; after adjustment for age, participants had similar risks of mortality and MACE to those not reclassified and a lower risk of KFRT. Changing to the EKFC equation would impact clinical decisions at low eGFR thresholds, such as nephrology referrals (22% higher), eligibility for SGLT2 is (39% higher), or contraindication for spironolactone in heart failure (26% higher). CONCLUSIONS:Adopting the EKFC equation in this Northern European health system would modestly lower eGFR estimates, increasing the prevalence of moderate/severe CKD and affecting clinical classification and decisions. eGFR by both equations strongly predicted outcomes, but individuals reclassified to a lower eGFR category by EKFC did not have consistent associations across outcomes.

BACKGROUND:Sodium-glucose cotransporter inhibitors (SGLTi) slow chronic kidney disease progression and reduce kidney failure events. Kidney transplant recipients (KTRs) remain at high risk for these outcomes. SGLTi cause an initial and sustained decline in estimated glomerular filtration rate (eGFR) and have a higher risk of urogenital infection, both of which are major concerns for KTRs. We sought to (1) assess the reversibility of eGFR changes and (2) explore safety and tolerability using sotagliflozin, a dual SGLT1/2 inhibitor. METHODS:We enrolled stable KTRs in a 16-wk open-label trial of sotagliflozin (12 wk on-drug and 4 wk off-drug) to assess the reversibility of eGFR changes. We assessed whether patient awareness of eGFR changes altered rates of withdrawal by randomizing participants to either (1) unlimited access to all study-related eGFR measurements or (2) limited access, that is, only when eGFR declined to >25% from baseline. RESULTS:Forty patients were randomized. The mean age was 56 ± 15 y; the mean baseline eGFR was 64 ± 21 mL/min/1.73 m 2 . After 1 wk, change in eGFR from baseline was -4.6 ± 6.5 mL/min/1.73 m 2 (-6.9 ± 9.5%). After washout, eGFR improved to -2.0 ± 6.3 mL/min/1.73 m 2 (-2.4 ± 11%), with 73% of patients within 10% of baseline eGFR or higher. Limited versus unlimited access to eGFR measurements did not affect protocol completion ( P  = 0.34). Sotagliflozin was generally well tolerated, but 4 patients were withdrawn due to adverse events, with none due to decline in eGFR. CONCLUSIONS:Among stable KTRs, sotagliflozin caused an initial decline in eGFR of similar magnitude to patients with chronic kidney disease, with reversibility upon withdrawal. Access to follow-up eGFR measurements did not affect study adherence.

Endothelin-1 (ET-1) is a potent vasoconstrictor and is implicated in the pathogenesis of proteinuria and progressive chronic kidney disease (CKD). With the development of ET-1 receptor antagonists, there is interest in whether higher ET-1 concentrations are associated with a greater risk of adverse cardio-kidney events among high-risk patients, e.g., established chronic kidney disease (CKD) and type 2 diabetes (T2DM). Endothelin-1 concentrations were measured in a random subset of TREAT (n = 997 patients with CKD, T2DM, and anemia) using an automated ELISA assay on the Ella analyzer (ProteinSimple). We fit unadjusted and adjusted Cox regression models to explore the association of baseline serum ET-1 (log-transformed and quartiles) with heart failure, kidney events (composite of kidney failure or doubling of serum creatinine), and cardiovascular and all-cause death. Mean age was 67 ±10 years and 56% were female. The mean eGFR was 34 ± 11 mL/min/1.73 m2; median urine protein/creatinine ratio was 0.4 [0.1, 1.7] mg/mg; median ET-1 was 2.4 [1.9, 3.0] pg/mL. During a median follow-up of 2.4 years, there were 225 kidney events, 99 heart failure events, 124 cardiovascular deaths, and 188 all-cause deaths. Each log-unit higher ET1 was associated with a higher adjusted risk of the kidney composite (HR 1.61; 95% CI 1.08, 2.39), HF (HR 2.61; 95% CI 1.42, 4.81), but not with cardiovascular death (HR 1.06; 95% CI 0.65, 1.75) or all-cause death (HR 1.33; 95% CI 0.86, 2.04). Compared with the lowest quartile, categorical analyses suggested a higher risk of kidney events, HF events, and all-cause death for the highest quartile of ET-1 (Fig. 1). Among patients with established CKD, T2DM, and anemia, higher baseline ET-1 was associated with a higher subsequent risk of kidney and heart failure and all-cause death. Whether higher ET-1 predicts responsiveness to ET-receptor antagonism warrants further investigation.

Glomerular filtration rate (GFR) estimation is a key issue in determining cancer treatment eligibility and dosing of treatments with narrow therapeutic index. Yet, little is known about the accuracy of GFR estimation among people with cancer in routine care. In a cross-sectional study including 1611 adults with cancer referred for 1837 determinations of measured GFR (mGFR), we assessed the accuracy of estimated GFR based on creatinine (eGFRcr), cystatin C (eGFRcys) and their combination (eGFRcr-cys). Accuracy was reported as percentage of patients with estimated values within 30% of mGFR; bias and precision as the median and interquartile range of eGFR-mGFR, respectively. Dosing accuracy was assessed by calculating expected dose of carboplatin for area under the curve of 5 mg/mL/min using the Calvert formula. Median age was 68 (IQI 61 to 74) years, 38.5% were female with mean mGFR 75 (SD 30) mL/min; 17% had metastatic disease. Accuracy, bias and precision were best for eGFRcr-cys. Using eGFRcr would recommend an “overdose” of carboplatin in 10–20% of participants: this was 3–4 times less common using eGFRcr-cys. eGFRcr-cys equations provide the most accurate estimates of mGFR in patients with cancer, with potential to improve dosing accuracy substantially compared to eGFRcr.

Underweight and obesity are common phenotypes in society that may affect the accuracy of estimated glomerular filtration rate (eGFR), with muscle mass affecting serum creatinine and adiposity affecting serum cystatin-C. Because eGFR equations were developed in predominantly normoweight populations, their accuracies at the extremes of the BMI spectrum are not well known. Further, individuals with these phenotypes often have body surface areas that differ from the conventional 1.73 m² used to index GFR for comparative purposes. There is a need to validate the performance of eGFR equations in people with differing BMI to inform clinical guidelines. We conducted a cross-sectional study of 4,707 adults referred for single-point plasma iohexol clearance in Stockholm, Sweden, comprising 7,503 concurrent measurements of creatinine, cystatin-C, and BMI. We calculated indexed eGFR (in ml/min/1.73 m2) and non-indexed eGFR (in ml/min) using all equations validated for use in Europe that employ creatinine (eGFRcr), cystatin-C (eGFRcys) or both (eGFRcr-cys). We assessed their performance against measured GFR (mGFR) across the spectrum of BMI with median bias, P30 accuracy, and GFR category classification accuracy. Next, we modelled the implications of filtration marker choice and non-indexed eGFR on selected examples regarding decisions of eligibility for treatment or dose-adjustment. Mean age was 57 years, 39% were female, and the median indexed and non-indexed mGFR was 59 mL/min/1.73 m² and 65 mL/min, respectively. Of the participants, 690 (9%) had underweight (BMI <20 kg/m2), 1022 (14%) had obesity class I (BMI 30–34.9 kg/m2) and 309 (4%) had obesity class II and above (BMI ≥35 kg/m2). eGFRcr equations overestimated mGFR at BMI <20 kg/m2 and ≥30 kg/m2, and eGFRcys equations underestimated eGFR at BMI ≥30 kg/m2. eGFRcr-cys equations were the least biased across the BMI range (Fig. 1A). The P30 (the percentage of estimated values within 30% of mGFR) of eGFRcr and eGFRcys equations was sub-optimal at <20 kg/m2 and ≥35 kg/m2, while eGFRcr-cys equations performed acceptably throughout the BMI range (Fig. 1B). Thus, GFR category classification accuracy was greatest for eGFRcr-cys (Fig. 1C). In theoretical modelling, using indexed eGFRcr-cys over eGFRcr across the BMI spectrum would improve the accuracy of correct eligibility for an SGLT2 inhibitor (ranging from 83%–88% vs. 71%–83% correct eligibility across BMI subgroups) as well as correct carboplatin dosing (Fig. 2A; 33%–43% vs. 19%–31% of correctly disease patients across BMI subgroups). In underweight and obese patients, using non-indexed eGFRcr-cys over indexed eGFRcr-cys resulted in improved accuracy for these treatment decisions (Fig. 2B; eligibility for SLGT2i: 78%–85% vs. 69%–82% of patients, correct dosing of carboplatin: 33%–44% vs. 17%–44% of patients). In a clinical population with ample representation of underweight and obesity, indexed eGFRcr-cys performed better than eGFRcr across the BMI range, resulting in more accuracy for determining severity of kidney disease and treatment decisions. The potential worse accuracy in drug dosing for underweight and obese patients was partially circumvented using non-indexed eGFRcr-cys.

BACKGROUND:Estimated glomerular filtration rate (eGFR) using creatinine (eGFRcr), cystatin C (eGFRcys), or both (eGFRcr-cys) is not sufficiently accurate in many settings, often due to non-glomerular filtration rate (GFR) determinants of the filtration markers. In principle, using a panel of endogenous markers (panel eGFR) could reduce the impact of non-GFR determinants of each marker, improving the accuracy of eGFR. Using global untargeted metabolomics, we previously identified 33 endogenous metabolites that correlate highly with measured GFR. METHODS:A LC-MS/MS measurement procedure was developed to quantify 11 endogenous metabolites from serum and plasma. The assay was evaluated in 99 participants with measured GFR (mGFR) from 2 research studies, including a subgroup of 51 participants with large errors in eGFRcr and large discordance between eGFRcr and eGFRcys. Performance of eGFR models using single metabolites and all metabolites (panel eGFR-11) compared to mGFR was assessed by leave-one-out cross-validated root mean square error (RMSE). RESULTS:Assay CV for single metabolites ranged from 1.1% to 6.3% over the course of 21 days. RMSE of eGFR in single metabolite models ranged from 0.184 to 0.324. RMSEs for panel eGFR-11, eGFRcr, and eGFRcr-cys were 0.195, 0.251, and 0.201, respectively, and 0.155, 0.290, and 0.203, respectively, in the subgroup with large errors and large discordance. CONCLUSIONS:A precise metabolite (LC-MS/MS) measurement procedure shows promise for more accurate GFR estimation when eGFRcr is unreliable, offering a potential new confirmatory test for GFR evaluation.

Rationale & Objective: Low muscle mass is common among older adults and associated with poor prognosis. Quantifying muscle mass is challenging in routine clinical practice. We hypothesized that glomerular filtration of creatinine (GFcr) reflects muscle mass, and previously proposed estimated GFcr (eGFcr), as a practical index of muscle mass in older adults. This study investigated whether measured GFcr (mGFcr) and eGFcr are similarly associated with the direct measure of muscle mass, the thigh total muscle lean area (TTMLA). Study Design: Cross-sectional analysis of a community-based prospective cohort. Setting & Participants: A total of 794 older adults with measured glomerular filtration rate (mGFR) and TTM LA in the AGES-Reykjavik Study. Exposure: Measured GFcr, the product of serum creatinine (Scr) and mGFR obtained using plasma iohexol clearance and eG Fcr, the product of Scr and estimated glomerular filtration rate using serum cystatin C (Scys). Outcome: TTM LA measured using computed tomography. Analytical Approach: Sex-specific Pearson's correlation and linear regression analyses using continuous and categorical mGFcr and eGFcr. Covariates included demographic, behavioral, and clinical variables, and comorbid conditions. Results: The mean age and mGFR were 80.3 +/- 4.0 (SD) years and 62.3 +/- 16.5 (SD) mL/ min/1.73 m2, respectively. The lowest sex-specific tertile of mGFcr, compared with the highest tertile, was associated with a 14.6 (95% CI, 11.5-17.6) cm2/1.73 m2 lower TTM LA in men, and a 7.9 (95% CI, 5.5-10.2) cm2/1.73 m2 lower TTM LA in women. Significant associations were observed between eGFcr and TTM LA. Correlations of eGFcr with TTM LA were generally as strong or stronger than correlations of alternative indices derived from Scr and Scys. Limitations: Residual confounding by measured and unmeasured variables. Conclusions: These findings support the validity of GFcr as an index of muscle mass among older adults and the use of eGFcr as a practical alternative to mGFcr in the clinical setting.

Background:Bariatric surgery reduces glomerular hyperfiltration in the short term and is associated with a reduced risk of glomerular filtration rate decline during long-term follow-up. Assessing surgery-induced changes in serum metabolites may be useful to understand the metabolic benefits to the kidney occurring after bariatric surgery. Methods:In a prospective, single-center research cohort of 27 adults with severe obesity who underwent bariatric surgery, we measured serum metabolites using untargeted ultrahigh performance liquid chromatography-tandem mass spectrometry and measured glomerular filtration rate (mGFR) by iohexol plasma clearance 1-3 months prior and 6 months after bariatric surgery. In generalized estimating equation (GEE) models that included age, sex, mGFR, and post-surgery terms, we examined bariatric surgery-associated changes in serum metabolites as well as associations between serum metabolites and mGFR. We used MetaboAnalyst to perform pathway analyses to determine bariatric surgery-associated metabolite pathway changes. Results:Bariatric surgery was significantly associated with changes in 223 serum metabolites after adjustment for age, sex, and mGFR at a Bonferroni-corrected p-value of 4.85 × 10-5. Following bariatric surgery, there were several pathways that were downregulated (alpha-linoleic acid and linoleic acid, methionine, tyrosine-kynurenine, and alanine-glucose metabolism pathways; raw p<0.05) or upregulated (phenylacetate, bile acid biosynthesis, taurine and hypo-taurine metabolism, porphyrin metabolism pathways; raw p<0.05), though only downregulation of alpha-linoleic acid and linoleic acid metabolism pathway was significant after correcting for multiple comparisons. Creatinine also demonstrated a significant mGFR-independent decrease following surgery. Top metabolites significantly associated with mGFR included N,N,N-trimethyl-alanyl proline betaine (TMAP), followed by creatinine, N-acetylethreonine, pseudouridine, N-acetylserine, myo-inositol, 5-methylthioribose, 5,6-dihydrouridine, erythronate, and N6-succinyladenosine. Conclusion:We confirmed several mGFR-independent metabolomic changes after bariatric surgery and also identified metabolites associated with mGFR in this setting. Further studies are needed to investigate the potential mechanistic role of identified metabolites to clarify mechanisms of obesity-related kidney disease.

BACKGROUND:Acute kidney disease (AKD) includes abnormalities of kidney function present for <90 days. Acute kidney injury (AKI) is defined as a subset of AKD, with onset within seven days. There is scant data on the rates of AKD in children and its association with outcomes. Our primary objective was to examine the rates of AKD with and without AKI and compare major adverse events (MAKE) in children in the pediatric intensive care unit (PICU). METHODS:This is a retrospective cohort study of patients ≤18 years old who were admitted to a quaternary care PICU between 2009 and 2016 using the high-density pediatric database. All patients included in the primary analysis had a known baseline serum creatinine. Patients who had a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or a history of dialysis dependence or kidney transplant were excluded. AKI and AKD were defined by Kidney Disease: Improving Global Outcomes definitions. MAKE-90 was defined as a composite outcome of death, dialysis, or persistent kidney dysfunction 90 days after PICU admission. RESULTS:Among 5,922 children included in this study, 1,199 (20.2%) had AKD, of which 1,092 (91%) had AKD with AKI and 107 (8.9%) had AKD without AKI. MAKE-90 occurred in 26% (308/1,199) of those with AKD compared to 3.6% (172/4723) without (p=<0.001). MAKE-90 occurred in 26% (279/1,092) of AKD with AKI and 27% (29/107) of AKD without AKI. After adjusting for age, sex, and illness severity, compared to patients that had no AKD, patients with AKD with AKI (aOR: 14.39, 95% CI: 11.06-18.72) and patients with AKD without AKI (aOR: 7.83, 95% CI: 4.54-13.51) had a greater odds of MAKE-90. CONCLUSIONS:More than a quarter of pediatric critically ill patients with AKD develop MAKE-90. Even in the absence of AKI, AKD is an independent risk factor for MAKE-90.

Background The presence of a low or high body mass index (BMI) in patients may influence the accuracy of eGFR. This study evaluates the performance of eGFR equations across the range of BMI. Methods This is an observational study of 4707 adults (7503 repeated observations) referred for measured GFR (mGFR) in Stockholm, Sweden. We calculated indexed eGFR (in ml/min per 1.73 m(2)) and nonindexed eGFR (in ml/min) with validated equations that use creatinine (eGFR(cr)), cystatin C (eGFR(cys)), or both (eGFR(cr-cys)). We assessed equation performance against indexed and nonindexed mGFR across categories of BMI with median bias, P-30 (the percentage of estimated values within 30% of mGFR), and classification of GFR categories, and modeled the implications of choice of filtration marker and indexing on clinical decisions regarding dose adjustment or eligibility for treatment. Results The mean age (SD) was 57 (16) years (39% female), and the median (interquartile range) indexed and nonindexed mGFR were 59 (39-79) and 65 (42-87) ml/min, respectively. In total, 9% of participants were underweight (BMI <20 kg/m(2)) and 18% were obese (BMI >= 30 kg/m(2)). For indexed and nonindexed eGFR for all equations, eGFR(cr) overestimated mGFR at BMI <20 and >= 30 kg/m(2), and eGFR(cys) underestimated mGFR at BMI >= 30 kg/m(2). eGFR(cr-cys) had the least bias, acceptable P-30, and the highest correct classification throughout the BMI range. In theoretical modeling, using indexed eGFR(cr-cys) versus eGFR(cr) would allow more accurate clinical decisions across all BMI categories. Using nonindexed versus indexed eGFR(cr-cys) led to further but smaller improvement that was not consistently related to BMI category for these decisions. Conclusions In a clinic population of northern European individuals referred for GFR measurement, indexed eGFR(cr-cys) was more accurate than indexed eGFR(cr) across the BMI spectrum. Using nonindexed eGFR(cr-cys) further improved accuracy for some treatment decisions.

PURPOSE OF REVIEW:Serum creatinine reflects both muscle mass and kidney function. Serum cystatin C has recently been recommended as an additional marker for estimating kidney function, and use of both markers together may provide an index of muscle mass. This review aims to describe the biological basis for and recent research examining the relationship of these markers to muscle mass in a range of adult populations and settings. RECENT FINDINGS:This review identified 67 studies, 50 of which had direct measures of muscle mass, and almost all found relationships between serum creatinine and cystatin C and muscle mass and related outcomes. Most studies have been performed in older adults, but similar associations were found in general populations as well as in subgroups with cancer, chronic kidney disease (CKD), and other morbid conditions. Creatinine to cystatin C ratio was the measure examined the most often, but other measures showed similar associations across studies. SUMMARY:Measures of serum creatinine and cystatin C together can be an index of muscle mass. They are simple and reliable measures that can be used in clinical practice and research. Further study is needed to determine actionable threshold values for each measure and clinical utility of testing and intervention.

In the United States, glomerular filtration rate (GFR) is commonly estimated using serum creatinine and the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for individuals older than 18 years or the 2021 Chronic Kidney Disease in Children Under 25 Study (CKiD-U25) equation for those between 1 and 25 years of age with CKD (Item S1).1,2 These equations may result in different estimated GFR (eGFR) values at 18 years and older, leading to uncertainty in assessment of severity of disease, progression rate, and clinical decisions based on level of GFR.

Rationale & Objective: beta(2)-Microglobulin (B2M) and beta-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFR(cr-cys)), but they have not been assessed in patients with cancer. Study Design: Cross-sectional analysis. Setting & Participants: Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September 2017. Exposure: CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR). Outcome: Performance of equations compared with eGFR(cr-cys) and non-GFR determinants of serum B2M and BTP (S-B2M, and S-BTP, respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (Cr-51-EDTA). Analytical Approach: Bias was defined as the median of the differences between mGFR and eGFR, and 1-P-30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P-30). Linear regression was used to assess association of clinical and laboratory variables with S-B2M, and S-BTP after adjustment for mGFR. Results: Mean age and mGFR were 58.8 +/- 13.2 SD years and 78.4 +/- 21.7 SD mL/min/1.73m(2), respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFR(cr-cys) (lesser bias and 1-P-30). Performance of 2-marker panel equations was as good as eGFR(cr-cys) (lesser bias and similar 1-P-30). S-B2M and S-BTP were not strongly influenced by cancer site. Limitations: Participants may have had better clinical performance status than the general population of patients with solid tumors. Conclusions: B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine.

Background: The commonly accepted threshold of glomerular filtration rate (GFR) to define chronic kidney disease (CKD) is less than 60 mL/min/1.73 m(2). This threshold is based partly on associations between estimated GFR (eGFR) and the frequency of adverse outcomes. The association is weaker in older adults, which has created disagreement about the appropriateness of the threshold for these persons. In addition, the studies measuring these associations included relatively few outcomes and estimated GFR on the basis of creatinine level (eGFR(cr)), which may be less accurate in older adults. Objective: To evaluate associations in older adults between eGFR(cr) versus eGFR based on creatinine and cystatin C levels (eGFR(cr-cys)) and 8 outcomes. Design: Population-based cohort study. Setting: Stockholm, Sweden, 2010 to 2019. Participants: 82 154 participants aged 65 years or older with outpatient creatinine and cystatin C testing. Measurements: Hazard ratios for all-cause mortality, cardiovascular mortality, and kidney failure with replacement therapy (KFRT); incidence rate ratios for recurrent hospitalizations, infection, myocardial infarction or stroke, heart failure, and acute kidney injury. Results: The associations between eGFR(cr-cys) and outcomes were monotonic, but most associations for eGFR(cr) were U-shaped. In addition, eGFR(cr-cys) was more strongly associated with outcomes than eGFR(cr). For example, the adjusted hazard ratios for 60 versus 80 mL/min/1.73 m(2) for all-cause mortality were 1.2 (95% CI, 1.1 to 1.3) for eGFR(cr-cys) and 1.0 (CI, 0.9 to 1.0) for eGFR(cr), and for KFRT they were 2.6 (CI, 1.2 to 5.8) and 1.4 (CI, 0.7 to 2.8), respectively. Similar findings were observed in subgroups, including those with a urinary albumin-creatinine ratio below 30 mg/g. Limitation: No GFR measurements. Conclusion: Compared with low eGFR(cr) in older patients, low eGFR(cr-cys) was more strongly associated with adverse outcomes and the associations were more uniform.