Iothalamate Clearance Research Articles

Prospective evaluation of cystatin C in the assessment of kidney dysfunction and survival in liver transplant candidates.

Kidney dysfunction is associated with decreased survival in liver transplant (LT) candidates, yet serum creatinine (sCr) is a poor surrogate for glomerular filtration rate (GFR) in this population. Serum cystatin C (CysC) may provide a more accurate assessment of kidney function and predict outcomes. We performed a multicenter prospective cohort study of consecutive candidates for LT. CysC was obtained at LT evaluation (n = 244), and a subset underwent simultaneous I 125 -iothalamate clearance for measured GFR (mGFR) assessment (n = 137). Patients were followed to assess the need for pre-LT renal replacement therapy, simultaneous liver and kidney transplant, and survival. Estimated GFR (eGFR) based on MDRD-4, GRAIL, Royal Free Hospital Cirrhosis GFR, and the CKD-EPI equations was assessed for bias, precision, and accuracy in reference to mGFR. Receiver operator characteristic (AUROC) and competing risk survival analyses were performed. CysC more accurately discriminated mGFR than sCr at thresholds of ≤60 and ≤30mL/min/1.73m 2 with AUROC 0.92 ( p = 0.005) and 0.96 ( p =0.01), respectively. All eGFR equations overestimated GFR, especially among females ( p < 0.05). The GRAIL equation demonstrated the least bias, while CKD-EPI-cystatin C was associated with the greatest precision and lowest frequency of GFR overestimation. Among 165 recipients of LT, CysC discriminated pre-LT renal replacement therapy and the need for simultaneous liver and kidney transplant with AUROC of 0.70 and 0.85, respectively. Cumulative incidence of death, accounting for LT as a competing event, increased with CysC ( p = 0.002) but was not observed with sCr overall or among subgroups ( p = NS). CysC more accurately predicts thresholds of mGFR than sCr in candidates for LT. Elevated CysC discriminates pre-LT renal replacement therapy and simultaneous liver and kidney transplant and is strongly associated with survival in contrast with sCr. CysC is a promising tool to improve prognostication among candidates for LT.

Performance of race-neutral eGFR equations in patients with decompensated cirrhosis.

The 2021 Chronic Kidney Disease Epidemiology Collaboration equation [CKD-EPI 2021] is a race-neutral equation recently developed and rapidly implemented as a reference standard to estimate glomerular filtration rate(GFR). However, its role in cirrhosis has not been examined especially in low GFR. We analyzed the performance of CKD-EPI 2021 compared to other equations with protocol measured GFR(mGFR) in cirrhosis. We analyzed 2090 unique adult patients with cirrhosis undergoing protocol GFR measurements using iothalamate clearance from 1985-2015 when listed for liver transplantation at Baylor University in Dallas and Fort Worth, Texas. Using mGFR as a reference standard, the CKD-EPI 2021 was compared to CKD-EPI 2012, MDRD-4, MDRD-6, RFH and GRAIL overall and in certain subgroups(ascites, mGFR≤30mL/min/1.73 m2, diagnosis, MELD and gender). We examined bias(difference between eGFR and mGFR), accuracy(p30: eGFR within ±30% of mGFR) and agreement between eGFR and mGFR categories. CKD-EPI 2021 had the 2nd lowest bias across the entire range of GFR after GRAIL (6.6 vs. 4.6mL/min/1.73 m2, respectively, p<0.001). Accuracy of CKD-EPI 2021 was similar to CKD-EPI 2012 (p30=67.8% vs. 67.9%, respectively) that was higher than the other equations (p<0.001). It had a similar performance in patients with ascites, by diagnoses, MELD subgroups, by sex and in non-Black patients. However, it had a relatively higher overestimation in mGFR≤30mL/min/1.73 m2 than most equations (18.5mL/min/1.73m2, p<0.001). Specifically, 64% of patients with mGFR≤30mL/min/1.73m2 were incorrectly classified to a less severe CKD stage by CKD-EPI 2021. In Blacks, CKD-EPI 2021 underestimated eGFR by 17.9mL/min/1.73 m2 that was higher than the alternate equations except RFH (p<0.001). The novel race-neutral eGFR equation, CKD-EPI 2021, improves the GFR estimation overall but may not accurately capture true kidney function in cirrhosis specifically at low GFR. There is an urgent need for a race-neutral equation in liver disease reflecting the complexity of kidney function physiology unique to cirrhosis given implications for organ allocation and dual organ transplant.

External Validation of a Novel Multimarker GFR Estimating Equation.

Using multiple markers may improve accuracy in glomerular filtration rate (GFR) estimation. We sought to externally validate and compare the performance a novel multi-marker estimated GFR (panel eGFR) among Black and White persons using the Genetic Epidemiology Network of Arteriopathy cohort. We included 224 sex, race/ethnicity, and measured GFR (mGFR)-category-matched persons, with GFR measured using urinary clearance of iothalamate. We calculated panel eGFR using serum creatinine, valine, myo-inositol, cystatin C, age, and sex. We compared its reliability with current eGFR equations (2021 CKD-EPI creatinine [eGFR-Cr] and creatinine with cystatin C [eGFR-Cr-CysC]) using median bias, precision, and accuracy metrics. We evaluated each equation's performance in age, sex, and race subgroups. In the overall cohort, 49% were Black individuals and mean mGFR was 79 ml/min/1.73m2. Panel eGFR overestimated mGFR (bias: -2.4 ml/min/1.73m2; 95% confidence interval [CI]: -4.4, -0.7), eGFR-Cr-CysC underestimated mGFR (bias: 4.8 ml/min/1.73m2; 95% CI: 2.1, 6.7), while eGFR-Cr was unbiased (bias: 2.0 ml/min/1.73m2; 95% CI: -1.1, 4.6). All equations had comparable accuracy. Among Black males age <65 years, both eGFR-Cr (bias: 17.0 ml/min/1.73m2; 95% CI: 8.6, 23.5) and eGFR-Cr-CysC (bias: 14.5 ml/min/1.73m2; 95% CI: 6.0, 19.7) underestimated mGFR whereas panel eGFR was unbiased (bias: 1.7 ml/min/1.73m2; 95% CI: -3.4, 10.0). Metrics of accuracy for all eGFRs were acceptable in all subgroups except for panel eGFR in Black females <65 years (P30: 73.3%). Panel eGFR can be used to estimate mGFR and may have utility among Black males age <65 years where current CKD-EPI equations are biased.

Outcomes of Attenuated Dose Fludarabine and Melphalan Based Conditioning Regimen in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant for Acute Leukemia and Myelodysplastic Syndrome

Introduction: Fludarabine combined with melphalan 140 mg/m2 (FluMel140) is a commonly used reduced-intensity conditioning (RIC) regimen in patients undergoing matched related (MRD) and unrelated donor (MUD) allogeneic stem cell transplant (alloSCT). Ciurea et al Blood 2020, described outcomes of Flu 160 mg/m2 and Mel 100 mg/m2. In this study, we describe our experience of attenuated melphalan dosing 100-120 mg/m2 versus 140 mg/m2 with fludarabine 125 mg/m2 (attenuated FluMel versus regular dose FluMel). Methods: We retrospectively reviewed patients from November 2016 to April 2023 with AML, ALL or MDS undergoing alloSCT who received fludarabine and melphalan. Patients who received the lower dose of melphalan were considered to be the attenuated FluMel cohort, whereas patients receiving the melphalan 140 mg/m2 were considered to be the control cohort. Kaplan-Meier and log-rank tests were used to estimate OS. NRM and relapse incidence (RI) was calculated using competing risk analysis. R 4.2.0 (R Foundation for Statistical Computing) was used for statistical analyses. Results: A total of 134 patients [92 (68.7%) males] were evaluated. Thirty-seven (27.6%) patients received attenuated FluMel and 97 (72.4%) patients received regular dose FluMel (controls). Among the patients in the attenuated FluMel cohort, 5 (13.5%) patients also received fludarabine at doses less than 125 mg/m 2 [median 20 mg/m 2 (range 87.5-112.5 mg/m 2]. Median age at transplant was 65 years (range 30 - 76 years). The most common disease was AML [75 (56.0%) patients] ( Table 1). Patients in the attenuated FluMel group had comparable iothalamate clearance compared to control cohort (clearance &amp;lt;65 ml/min/1.73 m2: 18.9% vs. 12.4%, P = 0.52). Patients in the attenuated FluMel group had comparable rates of high/very high DRI to those in control cohort (51.4% vs. 43.3%, P = 0.91). Compared to the control cohort, patients in the attenuated FluMel group were less likely to have a matched related donor (21.6% vs. 45.4%, P = 0.02) and were more likely to receive PTCy for GVHD prophylaxis (37.8% vs. 16.5%, P = 0.02). Among the patients receiving attenuated FluMel, the median melphalan dose administered was 100 mg/m2. The median time to neutrophil engraftment was 19 days (IQR 16-21 days), and median time to platelet engraftment was 18 days (range 12-25 days). Eleven (29.7%) patients developed post-alloSCT mucositis, and 3 (8.1%) patients developed grade 3-4 mucositis. All the patients in the attenuated FluMel group achieved 100% CD33 donor chimerism at day +30 (n=35) and day +100 (n=28) after alloSCT. Similarly, 26 (74.3%, n = 35) patients achieved ≥ 95% CD3 donor chimerism at day +30 after alloSCT and 23 (82.1%, n = 28) patients achieved ≥ 95% CD3 donor chimerism at day +100 after alloSCT. Median follow-up of the entire cohort after alloSCT was 2.3 years (95% CI 2.1-2.5 years). Median follow-up was 1.5 years in the attenuated FluMel cohort and 2.5 years for the control cohort ( P&amp;lt;0.001) . Survival was similar among patients receiving attenuated FluMel vs. control cohort (2-year OS 74.7% vs. 65.0%, P = 0.28). At 2 years post-alloSCT, the attenuated FluMel and control cohort had similar non-relapse mortality (19.9% vs. 24.4%, P=0.58) and relapse (22% vs. 15.2%, P=0.51). The attenuated FluMel was not associated with an increased incidence of relapse (HR 1.36, 95% CI 0.50-3.73, P=0.55) or NRM (HR 0.74, 95% CI 0.28-1.95, P = 0.55). GVHD-free relapse free (GRFS) survival was also similar among the attenuated Flu/Mel and control cohort (1-year GRFS rate 41.1% vs. 45.6%, P = 0.8). Among the patients receiving PTCy for GVHD prophylaxis, the 2-year OS in patients receiving attenuated FluMel was higher than the control group, but it was not statistically significant (2-year OS rate: 90% vs. 55%, P=0.37, Figure 1). Compared to the control group, the attenuated FluMel group had similar rates of NRM at 100 days (10% vs. 12.5%), 1 year (NA vs. 25%) and at 2 years after alloSCT (NA vs. 25%, P=0.54). GRFS at 1 year was also similar between the attenuated FluMel and control group (68.6% vs. 43.8%, P = 0.69). Conclusion: The attenuated dosed FluMel conditioning is a safe and effective regimen for elderly patients with acute leukemia and MDS, and is non-inferior to regular dose FluMel. Among patients receiving PTCy for GVHD prophylaxis, the lower dose of melphalan was non-inferior to regular dose FluMel for survival outcomes. Larger studies are needed to confirm our findings.

B-041 Evaluation of a Nuclear Magnetic Resonance Spectroscopy-Based Method for Estimating Glomerular Filtration Rate Using Creatinine, Cystatin C, Myo-Inositol, and Valine

Abstract Background Timely and accurate monitoring of renal dysfunction is critical for patients with chronic kidney disease (CKD). Most equations currently used for estimating glomerular filtration rate (GFR) incorporate serum levels of creatinine and/or cystatin C. Here, we evaluate a recently introduced method for estimating GFR that uses nuclear magnetic resonance spectroscopy (NMR) to measure creatinine, myo-inositol, and valine in combination with cystatin C measured by immunoassay, and patient’s age and sex (eGFRNMR). Methods Serum creatinine, valine, and myo-inositol measurements were performed simultaneously by an NMR assay on a Bruker Avance III HD 600 MHz NMR instrument (Bruker Corporation, MA). Cystatin C testing was performed using an immunoturbidimetric assay (Diazyme Laboratories, CA) on a cobas 8000 analyzer (Roche Diagnostics, IN). Within-run and between-day precision studies were performed across 5 days. Method comparison was carried out by testing 86 split serum samples from adult individuals against the numares AG GFR (NMR) assay. Of the 86 samples, 20 were spiked with various concentrations of creatinine, myo-inositol, and valine to reach a wide range of GFR results. An additional method comparison study was performed against Mayo Clinic Laboratories (Rochester, MN) on 59 serum samples from adult patients that had already been tested using the same assay. Measured GFR (mGFR) was also performed on these patients by Mayo Clinic Laboratories using urinary iothalamate clearance. Results Within-run and between-day coefficients of variation (%CV) for eGFRNMR did not exceed 6%. The eGFRNMR measurement range was confirmed at 10 to 157 mL/min/1.73 m2 based on verified analytical measurement ranges of creatinine (0.28–9.8 mg/dL), myo-inositol (39–430 µmol/L), and valine (30–1250 µmol/L). Method comparison studies against both numares AG and Mayo Clinic Laboratories demonstrated excellent concordance (r2 = 0.95 and r2 = 0.97, respectively) and minimal bias (4.1% and −0.3%, respectively) with results ranging from 21 to 157 mL/min/1.73 m2. When the 59 patients who had their GFR measured were staged by their mGFR results according to the CKD classification ranges of &amp;lt;15, 15–29, 30–44, 45–59, 60–89, and ≥90 mL/min/1.73 m2, eGFRNMR showed higher classification concordance with mGFR (69%) than the CKD-EPI 2021 creatinine-cystatin C equation (63%). Conclusion Our evaluation confirms the excellent analytical and clinical performance of the recently introduced eGFRNMR assay, supporting its integration into clinical practice for improved estimation of GFR.

A-127 Bias and Precision of a NMR-based GFR Estimating Equation in Kidney Transplant Recipients

Abstract Background An accurate and reliable measurement of glomerular filtration rate (GFR) is essential to monitor for rejection and disease progression post-kidney transplantation. Measured GFR (mGFR) is the current gold standard. However, it has scarce availability at many centers and is labor intensive. Newer estimated GFR (eGFR) methods containing cystatin-C and/or other biomarkers have not been clinically validated in a post-transplant cohort. In this study, we evaluated a new NMR-based GFR (GFRNMR) equation that contains serum creatinine, cystatin C, myoinositol, and valine in post-kidney transplant recipients in a clinical routine setting. Methods Venipuncture for serum collection was performed immediately prior to mGFR measurement with urinary iothalamate clearance in 67 post-kidney transplant recipients. Serum was stored at 4°C and measured by NMR no later than four days after collection. eGFR was assessed using the following equations: i) GFRNMR, ii) CKD-EPI2021Cr (creatinine) and iii) CKD-EPI2021Cr,Cys (creatinine and cystatin-C). Bias was calculated as “eGFR—mGFR” for all equations. The Bootstrap method was employed to assess pairwise significance levels between bias distributions interquartile ranges (IQR), and P-value correction was determined with the Benjamini &amp; Hochberg method. Precision, which was defined as percentage of samples within ±30% and ±15% from the mGFR value (P30 and P15, respectively), was calculated for each equation. Pairwise comparisons were made using McNemar’s Chi-squared and Benjamini &amp; Hochberg correction. Precision was defined as the proportion of eGFR values concordant with mGFR values by CKD clinical stage. Results P30 for GFRNMR was significantly higher than CKD-EPI2021 Cr,Cys (97% vs 84%, P &amp;lt; 0.01) and higher than CKD-EPI2021 Cr (88%, P = 0.08). Similarly, P15 for GFRNMR was 63%; higher than for CKD-EPI2021 Cr (54%, P = 0.35) and CKD-EPI2021 Cr,Cys (51%, P = 0.19). Bias IQR for GFRNMR was 9.5 mL/min/1.73 m2 (median bias 2.0 mL/min/1.73 m2); significantly smaller than for CKD-EPI2021 Cr (Bias IQR 15.55 mL/min/1.73 m2, P &amp;lt; 0.05; median bias 1.47 mL/min/1.73 m2), and smaller than CKD-EPI2021 Cr,Cys (Bias IQR 14.4 mL/min/1.73 m2, P = 0.09; median bias 2.3 mL/min/1.73 m2). A broad range of medications such as immune modulators, and comorbidities such as hypertension, thyroid dysfunction, and coronary artery disease, did not interfere with GFRNMR performance. Conclusion NMR-based eGFR was less biased, more precise, and more accurate compared to creatinine and cystatin-C CKD-EPI eGFR equations in a post-kidney transplant setting. These findings suggest GFRNMR may more closely resemble mGFR in post-transplant patients and warrants further study on its potential use to improve clinical management in this patient group.

Assessing GFR With Proenkephalin

In clinical practice, kidney (dys)function is monitored through creatinine-based estimations of glomerular filtration rate (eGFR: Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Creatinine is recognized as a late and insensitive biomarker of glomerular filtration rate (GFR). The novel biomarker proenkephalin (PENK) may overcome these limitations, but no PENK-based equation for eGFR is currently available. Therefore, we developed and validated a PENK-based equation to assess GFR. In this international multicenter study in 1354 stable and critically ill patients, GFR was measured (mGFR) through iohexol or iothalamate clearance. A generalized linear model with sigmoidal nonlinear transfer function was used for equation development in the block-randomized development set. Covariates were selected in a data-driven fashion. The novel equation was assessed for bias, precision (mean ± SD), and accuracy (eGFR percentage within ±30% of mGFR, P30) in the validation set and compared with MDRD and CKD-EPI. Median mGFR was 61 [44-81] ml/min per 1.73 m2. In order of importance, PENK, creatinine, and age were included, and sex or race did not improve performance. The PENK-based equation mean ± SD bias of the mGFR was 0.5 ± 15 ml/min per 1.73 m2, significantly less compared with MDRD (8 ± 17, P< 0.001) and 2009 CKD-EPI (5 ± 17, P< 0.001), not reaching statistical significance compared with 2021 CKD-EPI (1.3 ± 16, P= 0.06). The P30 accuracy of the PENK-based equation was 83%, significantly higher compared with MDRD (68%, P< 0.001) and 2009 CKD-EPI (76%, P< 0.001), similar to 2021 CKD-EPI (80%, P= 0.13). Overall, the PENK-based equation to assess eGFR performed better than most creatinine-based equations without using sex or race.

#5465 RACE-FREE EGFR EQUATION IN KIDNEY RECIPIENTS: A DEVELOPMENT AND VALIDATION STUDY

Abstract Background and Aims To assess the performances of the current eGFR equations, including the race-free CKD-EPI-2021, in the kidney transplant population, and compare these performances to a race-free kidney-recipient-specific (KRS) GFR equation. Method We included adult kidney recipients transplanted between 01/01/2000 and 01/01/2021 in 17 academic cohorts in Europe, the USA and Australia comprising 14 transplant centres and three clinical trials. Measured GFRs (mGFR) were assessed using 51Cr-EDTA, 99Tc-DTPA, inulin, iothalamate or iohexol clearance, according to the local practice. A KRS GFR equation was developed using additive and multiplicative stepwise linear regressions and its performance was compared to those of the current GFR equations. The performances were assessed with the P30 and the correct classification of chronic kidney disease (CKD) stage metrics. Results The study included 15 489 patients, having 50 464 GFR values both measured and estimated by creatinine-based equations. Among the current GFR equations, race-free CKD-EPI-2021 equation showed the lowest performance compared with MDRD and CKD-EPI-2009 equations. We then built a race-free KRS GFR equation based on an additive model including creatinine, age, and sex. We showed that using race did not increase the performance of the equation. We found that the race-free KRS GFR equation showed significantly improved performance compared with the race-free CKD-EPI-2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). Finally, we showed that the race-free KRS GFR equation performed well in a series of kidney transplant recipient subpopulations stratified by race, sex, age, body mass index, donor type, therapeutics, creatinine and GFR measurement methods and timing. Based on these results we developed an online application that estimates GFR based on recipient age, sex and creatinine: https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/ Conclusion Using multiple, international cohorts of kidney recipients, we developed and validated a new race-free KRS GFR equation that demonstrated high accuracy and outperformed the race-free CKD-EPI-2021 equation developed in individuals with native kidneys.

#3125 EXTERNAL VALIDATION OF A NOVEL MULTIMARKER GFR ESTIMATING EQUATION

Abstract Background and Aims The use of multiple markers may improve the accuracy in glomerular filtration rate (GFR) estimation especially when the interpretation of creatinine and cystatin C is limited. We sought to externally validate a recently developed multi-marker nuclear magnetic resonance (NMR)-based estimated GFR equation (eGFR-NMR) using the biracial Genetic Epidemiology Network of Arteriopathy cohort. Method We included 224 sex, race/ethnicity, and mGFR-category-matched participants. GFR was measured using urinary clearance of iothalamate (mGFR). We calculated eGFR-NMR using serum creatinine, valine, myo-inositol, and cystatin C, age, and sex. We compared the reliability of eGFR-NMR with current eGFR equations (2021 Chronic Kidney Disease Epidemiology Collaboration equations for creatinine [eGFR-Cr] and creatinine with cystatin C [eGFR-Cr-CysC]) using median bias, precision, and accuracy metrics. In particular, we evaluated its performance in age, sex, and race subgroups. Results In the overall cohort, mean age was 63 (±8) years, 54% were females, 49% were Black individuals, and mean mGFR was 78.7 (±24.3) ml/min/1.73 m2. eGFR-NMR overestimated mGFR by 2 mL/min/1.73 m2 (95% CI, 4 to 0.7) while eGFR-Cr-CysC underestimated mGFR by −5 mL/min/1.73 m2 (95% CI, −2 to −7). All equations had acceptable accuracy metrics. When stratified by age, sex, and race, eGFR-NMR performed the best among Black males age &amp;lt;65 years compared to current equations (Figure 1). In this subgroup, eGFR-NMR was unbiased (bias, 2mL/min/1.73 m2 [95% CI, -3 to 10]) compared to substantial biases of eGFR-Cr (bias, 17 mL/min/1.73 m2 [95% CI, 9 to 24]) and eGFR-Cr-CysC (bias, 15 mL/min/1.73 m2 [95% CI, 6 to 20]). In other subgroups, measures of accuracy for eGFR-NMR, eGFR-Cr, eGFR-Cr-CysC were generally similar. Conclusion eGFR-NMR can be used to estimate mGFR and was more accurate than CKD-EPI equations among Black males age &amp;lt;65 years.

Performance of Nuclear Magnetic Resonance-Based Estimated Glomerular Filtration Rate in a Real-World Setting

An accurate estimate of glomerular filtration rate (eGFR) is essential for proper clinical management, especially in patients with kidney dysfunction. This prospective observational study evaluated the real-world performance of the nuclear magnetic resonance (NMR)-based GFRNMR equation, which combines creatinine, cystatin C, valine, and myo-inositol with age and sex. We compared GFRNMR performance to that of the 2021 CKD-EPI creatinine and creatinine-cystatin C equations (CKD-EPI2021Cr and CKD-EPI2021CrCys), using 115 fresh routine samples of patients scheduled for urinary iothalamate clearance measurement (mGFR). Median bias to mGFR of the three eGFR equations was comparably low, ranging from 0.4 to 2.0 mL/min/1.73 m2. GFRNMR outperformed the 2021 CKD-EPI equations in terms of precision (interquartile range to mGFR of 10.5 vs. 17.9 mL/min/1.73 m2 for GFRNMR vs. CKD-EPI2021CrCys; p = 0.01) and accuracy (P15, P20, and P30 of 66.1% vs. 48.7% [p = 0.007], 80.0% vs. 60.0% [p &lt; 0.001] and 95.7% vs. 86.1% [p = 0.006], respectively, for GFRNMR vs. CKD-EPI2021CrCys). Clinical parameters such as etiology, comorbidities, or medications did not significantly alter the performance of the three eGFR equations. Altogether, this study confirmed the utility of GFRNMR for accurate GFR estimation, and its potential value in routine clinical practice for improved medical care.

Estimation of Glomerular Filtration Rate in Obese Patients: Utility of a New Equation.

There is no consensus on the best equation to estimate glomerular filtration rate (eGFR) in obese patients (OP). Objective: to evaluate the performance of the current equations and the new Argentinian Equation ("AE") to estimate GFR in OP. Two validation samples were used: internal (IVS, using 10-fold cross-validation) and temporary (TVS). OP whose GFR was measured (mGFR) with clearance of iothalamate between 2007/2017 (IVS, n = 189) and 2018/2019 (TVS, n = 26) were included. To evaluate the performance of the equations we used: bias (difference between eGFR and mGFR), P30 (percentage of estimates within ±30% of mGFR), Pearson's correlation (r) and percentage of correct classification (%CC) according to the stages of CKD. The median age was 50 years. Sixty percent had grade I obesity (G1-Ob), 25.1% G2-Ob and 14.9% G3-Ob, with a wide range in mGFR (5.6-173.1 mL/min/1.73 m2). In the IVS, AE obtained a higher P30 (85.2%), r (0.86) and %CC (74.4%), with lower bias (-0.4 mL/min/1.73 m2). In the TVS, AE obtained a higher P30 (88.5%), r (0.89) and %CC (84.6%). The performance of all equations was reduced in G3-Ob, but AE was the only one that obtained a P30 > 80% in all degrees. AE obtained better overall performance to estimate GFR in OP and could be useful in this population. Conclusions from this study may not be generalizable to all populations of obese patients since they were derived from a study in a single center with a very specific ethnic mixed population.

Performance of Glomerular Filtration Rate Estimating Equations in Cancer Patients Evaluated for Chimeric Antigen Receptor T-Cell Therapy

Background: An accurate assessment of kidney function is necessary to evaluate candidates seeking chimeric antigen receptor T-cell (CAR-T) therapy.(Jain, et al, 2019, Yakoub-Agha, et al, 2019) Additionally, kidney function quantification is essential to selecting the appropriate dose for fludarabine-based lymphodepleting chemotherapy prior to CAR-T cell infusion in order to optimize outcomes.(Hirayama, et al, 2019) Treatment decisions are currently guided by a glomerular filtration rate (GFR) that is estimated using serum creatinine. However, estimated GFR (eGFR) utilizing cystatin C-based equations has been suggested to overcome the known limitations of creatinine-based eGFR in patients with cancer.(Kellum, et al, 2012, Hersh, et al, 1986) The accuracy and precision of these eGFR assessment strategies in potential CAR-T therapy recipients has not been explored, and the preferred method for quantifying GFR in this patient population remains unknown. Methods: This IRB-approved, single-center, observational study evaluated the performance of contemporary eGFR equations in any adult patient being evaluated for CAR-T therapy with a measured GFR (mGFR) by iothalamate clearance. Excluded individuals were those without a serum creatinine (SCr) and serum cystatin C (cysC) concentration performed within 14 days of the mGFR. Baseline characteristics and pertinent laboratory values were abstracted from the medical record. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, including the most recent iterations that were developed without the race parameter.(Levey, et al, 2009, Inker, et al, 2012, Inker, et al, 2021) Bias, accuracy (percentage of estimates within 10% and 30% of mGFR), and precision (SD of the difference between the eGFR and the mGFR) were assessed. The prediction of mGFR by each eGFR equation was assessed with scatterplots. Results: The 135 patients that were included had a median age of 63 (IQR: 56, 69) years and 77 (57%) were male. Two patients (1%) were African American and 123 (91%) were White. Relapsed lymphoma was the most common cancer diagnosis (n=94, 70%), followed by multiple myeloma (n=38, 28%) and acute lymphoblastic leukemia (n=3, 2%). Median mGFR was 73 ml/min/1.73m2 (IQR: 57, 92) with mGFR >60 ml/ml/1.73m2 in 95 (70%) patients. Table 1 summarizes baseline characteristics, laboratory values, and eGFR. The average absolute bias ranged from -10.1 to -0.1 ml/min/1.73m2 indicating that all equations underestimated mGFR to some degree. CKD-EPI 2021 SCr and CKD-EPI 2021 cysC+SCr had the least bias at -0.1 ml/min/1.73m2 and -4.0 ml/min/1.73m2, respectively. CKD-EPI 2021 cysC+SCr had the greatest accuracy within 10% of GFR and within 30% of mGFR. Additional bias, precision, and accuracy details of each estimating equation are summarized in table 1. The CKD-EPI 2012 cysC+SCr and the CKD-EPI 2021 cysC+SCr equations most closely correlated with mGFR in all patients (r=0.82 and 0.81, respectively). Correlation of measured glomerular filtration rate (GFR) with each of the GFR estimating equations is depicted in figure 1. Conclusion: CKD-EPI 2021 SCr and CKD-EPI 2021 cysC+SCr were the equations with the least bias. Contemporary eGFR equations had the greatest correlation with mGFR and seem acceptable when evaluating CAR-T therapy candidacy. Accuracy when dosing medications with a narrow therapeutic index, such as chemotherapy, is paramount, and all eGFR methods had limited accuracy within 10% of mGFR. Though the CKD-EPI 2021 cysC+SCr demonstrated the highest degree of accuracy within 10% of mGFR and within 30% of mGFR, iothalamate clearance should be the preferred method for kidney function assessment in patients seeking and receiving CAR-T therapy. Future research should investigate the impact of fludarabine dose selection on clinical outcomes of CAR-T recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Endorsement of the Removal of Race From GFR Estimation Equations: A Position Statement From the National Kidney Foundation Kidney Disease Outcomes Quality Initiative

An Endorsement of the Removal of Race From GFR Estimation Equations: A Position Statement From the National Kidney Foundation Kidney Disease Outcomes Quality Initiative

Standardization of serum creatinine is essential for accurate use of unbiased estimated GFR equations: evidence from three cohorts matched on renal function.

Differences in the performance of estimated glomerular filtration rate (eGFR) equations have been attributed to the mathematical form of the equations and to differences between patient demographics and measurement methods. We evaluated differences in serum creatinine (SCr) and eGFR in cohorts matched for age, sex, body mass index (BMI) and measured GFR (mGFR). White North Americans from Minnesota (n=1093) and the Chronic Renal Insufficiency Cohort (CRIC) (n=1548) and White subjects from the European Kidney Function Consortium (EKFC) cohort (n=7727) were matched for demographic patient characteristics (sex, age±3years, BMI±2.5kg/m2) and renal function (mGFR±3ml/min/1.73m2). SCr was measured with isotope dilution mass spectrometry (IDMS)-traceable assays in the Minnesota and EKFC cohorts and with non-standardized SCr assays recalculated to IDMS in the CRIC. The Minnesota cohort and CRIC shared a common method to measure GFR (renal clearance of iothalamate), while the EKFC cohort used a variety of exogenous markers and methods, all with recognized sufficient accuracy. We compared the SCr levels and eGFR predictions [for Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and EKFC equations] of patients fulfilling these matching criteria. For 305 matched individuals, mean SCr (mg/dL) was not different between the Minnesota and EKFC cohorts (females 0.83±0.20 versus 0.86±0.23, males 1.06±0.23 versus 1.12±0.37; P>.05) but significantly different from the CRIC [females 1.13±0.23 (P<.0001), males 1.42±0.31 (P<.0001)]. The CKD-EPI equations performed better than the EKFC equation in the CRIC, while the opposite was true in the Minnesota and EKFC cohorts. Significant differences in SCr concentrations between the Minnesota and EKFC cohorts versus CRIC were observed in subjects with the same level of mGFR and equal demographic characteristics and can be explained by the difference in SCr calibration.

Association of Abdominal Arterial Calcification Score with Patients' Survival and Kidney Allograft Function after Kidney Transplant.

Abdominal arterial calcification (AAC) is common among candidates for kidney transplant. The aim of this study is to correlate AAC score value with post-kidney transplant outcomes. We modified the coronary calcium score by changing the intake data points and used it to quantitate the AAC. We conducted a retrospective clinical study of all adult patients who were transplanted at our center, between 2010 and 2013, and had abdominal computed tomography scan done before transplantation. Outcomes included mortality, pulse pressure (PP) measured by 24h ambulatory blood pressure monitoring system, and kidney allograft function measured by iothalamate clearance. For each 1000 increase of AAC score value, there is an associated 1.05 increase in the risk of death (95% CI 1.02, 1.08) (p < 0.001). Overall median AAC value for all patients was 1784; Kaplan-Meier curve showed reduced survival of all-cause mortality for patients with AAC score value above median and reduced survival among patients with cardiac related mortality. The iothalamate clearance was lower among patients with total AAC score value above the median. Patients with abnormal PP (< 40 or > 60mmHg) had an elevated median AAC score value at 4319.3 (IQR 1210.4, 11097.1) compared to patients with normal PP with AAC score value at 595.9 (IQR 9.9, 2959.9) (p < 0.001). We showed an association of AAC with patients' survival and kidney allograft function after kidney transplant. The AAC score value could be used as a risk stratification when patients are considered for kidney transplant.

Quantifying Individual-Level Inaccuracy in Glomerular Filtration Rate Estimation : A Cross-Sectional Study.

Although the population-level differences between estimated glomerular filtration rate (eGFR) and measured glomerular filtration rate (mGFR) are well recognized, the magnitude and potential clinical implications of individual-level differences are unknown. To quantify the magnitude and consequences of the individual-level differences between mGFRs and eGFRs. Cross-sectional study. Four U.S. community-based epidemiologic cohort studies with mGFR. 3223 participants in 4 studies. The GFRs were measured using urinary iothalamate and plasma iohexol clearance; the eGFR was calculated from serum creatinine concentration alone (eGFRCR) and with cystatin C. All GFR results are presented as mL/min/1.73 m2. The participants' mean age was 59 years; 32% were Black, 55% were women, and the mean mGFR was 68. The population-level differences between mGFR and eGFRCR were small; the median difference (mGFR-eGFR) was -0.6 (95% CI, -1.2 to -0.2); however, the individual-level differences were large. At an eGFRCR of 60, 50% of mGFRs ranged from 52 to 67, 80% from 45 to 76, and 95% from 36 to 87. At an eGFRCR of 30, 50% of mGFRs ranged from 27 to 38, 80% from 23 to 44, and 95% from 17 to 54. Substantial disagreement in chronic kidney disease staging by mGFR and eGFRCR was present. Among those with eGFRCR of 45 to 59, 36% had mGFR greater than 60 whereas 20% had mGFR less than 45; among those with eGFRCR of 15 to 29, 30% had mGFR greater than 30 and 5% had mGFR less than 15. The eGFR based on cystatin C did not provide substantial improvement. Single measurement of mGFR and serum markers without short-term replicates. A substantial individual-level discrepancy exists between the mGFR and the eGFR. Laboratories reporting eGFR should consider including the extent of this uncertainty to avoid misinterpretation of eGFR as an mGFR replacement. National Institutes of Health.

Estimation of glomerular filtration rate for drug dosing in patients with very high or low body mass index.

An accurate estimated glomerular filtration rate (eGFR) is essential in drug dosing. This study demonstrates the limitations of indexed (ml/min/1.73 m2) and de‐indexed (ml/min) eGFR based drug dosing in patients with obesity or underweight. This systematic study aimed to determine the most appropriate approach to estimate the GFR for standardized eGFR based drug dosing in these patients. (Raw) data of 12 studies were selected to investigate the accuracy and bias of both the indexed and de‐indexed estimations of the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD‐EPI), and of the Cockcroft–Gault (CG) in patients with obesity or underweight. Accuracy was calculated as the proportion of eGFR values within 30% of the measured GFR (P30) using an inert tracer (e.g., iohexol, inulin, 51Cr‐EDTA, or iothalamate clearance). An accuracy of at least 80% was considered acceptable. GFR values estimated with the CG, MDRD, and CKD‐EPI differ significantly within a patient with obesity or underweight regardless of whether it is indexed or de‐indexed. All studies, with two exceptions, show that all three equations are inaccurate for patients with underweight or class II obesity (P30: 55%–94%). De‐indexing eGFR improves not or modestly the accuracy, and mostly remains below the 80% (P30: 62%–100%). CG was highly inaccurate in obese and underweight patients (P30: 7%–82%). Although these results show that CG is obsolete, the accuracy of MDRD and CKD‐EPI is low in patients with obesity or underweight and de‐indexing is not the solution. Better education and more accurate methods for appropriate drug dosing (e.g., measured GFR with inert tracer, therapeutic drug monitoring, or 24‐h creatinine clearance) are recommended.

Relationship of iothalamate clearance and NRM in patients receiving fludarabine and melphalan reduced-intensity conditioning

AbstractThe reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the active metabolite of fludarabine, F-ara-A, are excreted via the kidneys. Existing methods to assess clearance in this setting are based on serum creatinine, which has known limitations for glomerular filtration rate (GFR) estimation in patients with malignancy. Measured GFR (mGFR) may better predict drug dosing to mitigate toxicity and increase the chances of successful engraftment. The primary objective of this study was to assess the association between mGFR and risk for nonrelapse mortality (NRM) in patients who have undergone allogeneic HSCT receiving conditioning with fludarabine and melphalan. In the 109 included patients, mGFR <65 mL/min/1.73 m2 predicted a significantly higher rate of overall NRM (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.35; P = 04) and 1-year incidence of infection (HR, 2.63; 95% CI, 1.54-4.55; P < .001) in addition to a significantly lower 2-year survival (P = .019). Kidney function estimated via estimated GFR (eGFR) and estimated creatinine clearance did not correlate with posttransplant outcomes. These results suggest that mGFR is a promising approach for assessing clearance in patients who have undergone allogeneic HSCT and may be preferred to standard creatinine-based eGFR strategies.

Ribociclib-Induced Pseudo-Acute Kidney Injury

The combination of endocrine therapy and cyclin-dependent kinase (CDK) 4/6 inhibitors is currently one of the preferred first-line regimens for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. CDK 4/6 inhibitors can cause serum creatinine (SCr) elevation and corresponding estimated glomerular filtration rate (eGFR) reduction without affecting kidney function by inhibiting tubular secretory transporters in the kidneys—a phenomenon called pseudo-acute kidney injury (pseudo-AKI). We report a case of a 69-year old woman found to have elevated SCr while on ribociclib for treatment of metastatic breast cancer. Further evaluation with cystatin C-based eGFR and measured GFR by urinary iothalamate clearance revealed values close to her baseline Cr-based eGFR prior to initiation of treatment with ribociclib. She was therefore diagnosed with ribociclib-induced pseudo-AKI. Treatment with ribociclib was continued with steady favorable response. This case highlights that, in addition to true AKI, ribociclib can cause pseudo-AKI. Alternative methods of kidney function assessment may be necessary in patients who develop elevated SCr while on this medication to help discriminate between artifactual and true kidney function impairment. Doing so can help avoid unnecessary work-up and/or premature discontinuation of the treatment.

Clinical Impact of the Refit CKD-EPI 2021 Creatinine-Based eGFR Equation.

The National Kidney Foundation recently endorsed the refit Chronic Kidney Disease Collaboration (CKD-EPI) equation for estimated glomerular filtration rate (eGFR) using creatinine, age and sex [2021 eGFRCr(AS)] without a coefficient for race. We evaluated the impact of adopting the 2021 eGFRCr(AS) equation or a variation of the 2009 CKD-EPI eGFR equation without race [2009 CKD-EPI eGFRCr(ASR-NB)] compared to the original CKD-EPI eGFR [2009 eGFRCr(ASR)]. The studied population included patients with a clinically ordered iothalamate clearance (n = 33 889). Bias was assessed as the difference between measured and estimated GFR, P30 was defined as the percentage of estimates within 30% of measured GFR, and concordance was determined according to relevant clinical thresholds. Among Black patients, the median bias for 2009 eGFRCr(ASR), 2009 eGFRCr(ASR-NB), and 2021 eGFRCr(AS) was -1.32 mL min-1 (1.73 m2)-1 (95CI -2.46 to -0.26), -8.81 mL min-1 (1.73 m2)-1 (95CI -9.93 to -7.58), and -6.08 mL min-1 (1.73 m2)-1 (95CI -7.18 to -4.92), respectively. The median bias among non-Black patients was -0.15 m min-1 (1.73 m2)-1 (95CI -0.84 to -0.08) for 2021 eGFRcr(AS) compared to -3.09 mL min-1 (1.73 m2)-1 (95CI -3.17 to -3.03) for the 2009 eGFRCr(ASR). P30 and concordance were not significantly different in either racial group. The net reclassification improvement at a measured GFR <20 mL min-1 (1.73 m2)-1 was 6.4% (95CI 0.36 to 12.4) for Black patients and -5.1% (95CI -6.0 to -4.1) for non-Black patients using the 2021 eGFRCr(AS) equation. Overall, the change in reported eGFR was minimal. However, these changes led to significant reclassification improvements at lower eGFR, which will indirectly improve equitable access to CKD resources.