Tubular Secretion Of Creatinine Research Articles

Cancer drugs and acute kidney injury: new therapies and new challenges.

Cancer therapies continue to evolve at a rapid pace and although novel treatments, including immunotherapies and targeted therapies have allowed for substantial improvements in cancer survival, they carry associated risks of acute kidney injury (AKI). We aim to summarize the existing literature on AKI associated with the spectrum of systemic cancer treatments, including conventional chemotherapies, newer immunotherapies, and the growing number of targeted cancer therapies, which may be associated with both AKI and 'pseudo-AKI'. Conventional cytotoxic chemotherapies (e.g. cisplatin and other platinum-based agents, methotrexate, pemetrexed, ifosfamide, etc.) with well recognized nephrotoxicities (predominantly tubulointerstitial injury) remain in widespread use. Immunotherapies (e.g., immune checkpoint inhibitors and CAR-T therapies) may be associated with kidney immune-related adverse events, most often acute interstitial nephritis, and rarely, glomerular disease. Recently, multiple targeted cancer therapies have been associated with reduced renal tubular secretion of creatinine, causing elevations in serum creatinine and apparent 'pseudo-AKI'. To complicate matters further, these agents have had biopsy-proven, 'true' kidney injury attributed to them in numerous case reports. Clinicians in nephrology and oncology must be aware of the various potential kidney risks with these agents and recognize those with clinically meaningful impact on both cancer and kidney outcomes.

The Renal Protective Effect of Sickle Cell Disease-Modifying Drugs

Background Patients affected by sickle cell disease (SCD) often present with renal impairment due to the deleterious effects of polymerized red blood cells at the level of the nephron. The resulting glomerular damage leads to proteinuria as well as increased tubular secretion of creatinine, which in turn allows for the use of the urine protein:creatinine ratio (PCR) to monitor disease progression in SCD patients. Aim We aimed to evaluate the renal protective effect of various disease-modifying therapies via changes in urine PCR. Method This was a retrospective cohort study of patients with SCD (all genotyped, ≥16 years old) at UT Comprehensive Sickle Cell Center during the study period of 2019-2023. Demographics, clinical, and laboratory findings were collected and analyzed. Both the albumin:creatinine ratio (ACR) and PCR are comparable measures of kidney function. We measured PCR at our center due to test availability, and it also allowed the measurement of non-albumin urinary proteins that maybe important for prognosis. PCR was measured once or twice annually. Descriptive statistics are presented in percentages, medians, and interquartile ranges. Changes in urine PCR were calculated based on the difference in initial and recent urine PCR. A positive change means that there was improvement in the most recent urine PCR (i.e., measuring less than the initial urine PCR) or vice versa. An unpaired Student's t test was used to determine the level of significance in differences between initial and recent urine PCR for various disease-modifying drugs, with p <0.05 considered to be statistically significant. Data was analyzed using GraphPad Prism version 9.0.2. Results There was a total of 90 study participants eligible for analysis during the study period. Forty-three (47.8%) were male and 47 (52.2%) were female; the median age was 30 (IQR 24-35.3) years. The most common genotype was HbSS (81.1%), followed by HbSC (10%), and HbSB null (8.9%). Patient with sickle cell trait were excluded from this study. The majority of the patients (81.1%) received at least one treatment, and 24 (26.7%) were on combination therapy. Among the various SCD-modifying therapies, hydroxyurea was the most common therapy (64.4%) used, followed by voxelotor (13.3%), crizanlizumab (12.2%), and L-glutamine (11.1%). A detailed analysis is given in Table 1. The median initial urine PCR was 140 (IQR 90.0-242.5) mg/g. The median recent urine PCR of the study cohort was 135 mg/g (IQR 88.5-287.5), and the median change was 0 (IQR -45.0 to 43.5) mg/g. In stratifying by different disease-modifying drugs, the median change in urine PCR for hydroxyurea was -106.3 mg/g, L-glutamine 5.5 mg/g, voxelotor 19 mg/g, and crizanlizumab -22 mg/g. There was a statistically significant difference in the change in urine PCR for voxelotor and L-glutamine, compared with hydroxyurea (p=0.0361 and 0.0423, respectively) (Figure 1). Conclusion This is one of the first retrospective analyses to evaluate the renal protective effect of disease-modifying drugs at our comprehensive sickle cell center. The SCD-modifying therapies voxelotor and pharmaceutical-brand L-glutamine had the highest renal protective abilities and were associated with significant changes in urine PCR, compared with hydroxyurea. Larger studies are needed to corroborate these findings.

Kidney functional reserve and damage biomarkers in subclinical chronic kidney disease and acute kidney injury.

Significant loss of kidney function is not easily identified by serum creatinine (sCr)-based measurements. In the presence of normal sCr, decreased kidney functional reserve (KFR) may identify a significant loss of function. We evaluated KFR in experimental subclinical chronic kidney disease (sCKD) before and after brief ischemia-reperfusion injury (IRI). Using fluorescein isothiocyanate-labeled sinistrin, glomerular filtration rate (GFR) was measured transcutaneously before and after adenine-induced sCKD, and 1 and 2 wk after brief IRI, and compared with urinary kidney damage biomarkers. sCKD reduced stimulated and unstimulated GFR by ∼20% while reducing KFR by 50%. IRI reduced unstimulated GFR for 14 days, but KFR remained relatively unchanged in sCKD and transiently increased in control kidneys at 7 days. sCr increased and creatinine clearance (CrCl) decreased only immediately after IRI; sCr and CrCl correlated poorly with measured GFR except on day 1 after IRI. Heterogeneity in sCr and CrCl resulted from variation in tubular creatinine secretion. The increase in damage biomarker concentrations persisted for up to 14 days after IRI, allowing retrospective detection of sCKD before AKI by urine clusterin/urine kidney injury molecule-1 with an area under the curve of 1.0. sCr and CrCl are unreliable unless sCr is acutely elevated. Measurement of KFR and urine damage biomarker excretion detected sCKD despite normal sCr and CrCl. After IRI, the urine clusterin-to-urine kidney injury molecule-1 ratio may identify prior sCKD.NEW & NOTEWORTHY Early kidney function loss is poorly identified by serum creatinine (sCr)-based measurements. Direct kidney functional reserve (KFR) measurement before kidney injury and elevated urinary biomarkers clusterin and kidney injury molecule-1 detect subclinical chronic kidney disease (sCKD) after kidney injury despite normal range sCr and creatinine clearance. Reliance on sCr masks underlying sCKD. Acute kidney injury risk evaluation requires direct glomerular filtration rate measurement and KFR, whereas kidney damage biomarkers facilitate identification of prior subclinical injury.

Creatinine and cystatin C-based estimated glomerular filtration rate estimates of kidney function in Black people with HIV on antiretroviral therapy.

To reduce health inequalities, the creatinine-based chronic kidney disease epidemiology collaboration 2021 formula for estimated glomerular filtration rate (eGFR) is replacing the 2009 formula, which required adjustment specifically for Black individuals. We compared the 2021 and 2009 creatinine-based formulae with cystatin C-based eGFR in Black people on antiretroviral therapy (ART) with HIV RNA <200 c/ml. Cross-sectional analysis of paired serum creatinine and cystatin C measurements. Bias, imprecision, accuracy, and performance for identifying individuals with eGFR cystatin C <60 (units: ml/min per 1.73 m 2 ) were determined. The effects of ART with no, mild-moderate, or marked effect on tubular creatinine secretion on the performance of the 2021 formula was assessed. We included 362 individuals (mean age 51 years, 56% female, mean eGFR-cystatin C 88.3). Overall, the 2021 (vs. the 2009 race-adjusted) formula was less biased and had improved imprecision and accuracy compared with eGFR-cystatin C but underestimated eGFR-cystatin C in those with eGFR ≥90 and overestimated eGFR-cystatin C in those with eGFR <60. The 2021 (vs. the 2009) formula had high specificity (95% vs. 97%) and negative predictive value (97% vs. 96%), but low sensitivity (56% vs. 52%) and positive predictive value (44% vs. 54%) for identifying individuals with eGFR-cystatin C <60 ( P > 0.25). Performance at the eGFR <60 cut-off was minimally affected by ART exposure group. The CKD-EPI 2021 creatinine-based formula was better aligned with eGFR-cystatin C than the 2009 formula. eGFR-cystatin C may provide clinically useful information in Black people with eGFR <60 irrespective of ART regimen.

Characterization of the renal tubular transport of creatinine by activity-based protein profiling and transport kinetics

Serum creatinine is widely used to adjust the dosing of drugs eliminated by the kidney in patients with renal dysfunction, as it is a readily accessible indicator of kidney function. However, there are many limitations for drug dosage adjustment based on serum creatinine levels, one of which is the limited understanding of creatinine's tubular transport. Thus, we aimed to complement and advance the renal tubular transport of creatinine by activity-based protein profiling (ABPP) and transporter-overexpression technology. Renal tubular transporters were not identified via ABPP due to the low-affinity interaction between transporters and creatinine. The uptake of isotopically labeled d3-creatinine was significantly increased in OCT2-overexpressing cell lines (p<0.01), and the Km and Vmax of d3-creatinine uptake mediated by OCT2 was 3.1 mM and 408 pmol/mg protein/min, respectively. In the OCT2-overexpressing cell lines, the IC50 of creatinine for d3-creatinine uptake was 10.3 mM, and that of the OCT2 inhibitor cimetidine for d3-creatinine uptake was 99.04 μM. Different dosages of creatinine did not affect the renal excretion of d3-creatinine in mice (p>0.05), while cimetidine significantly reduced the renal excretion of d3-creatinine (p<0.01) without affecting the glomerular filtration rate. Molecular docking in silico showed that the OCT2 amino acid GLN242 could form a hydrogen bond of 2.5 Å with creatinine, and there may be a π-π interaction between TYR362 and creatinine. A site mutation experiment demonstrated that TYR362 and GLN242 were important sites for the OCT2-creatinine interaction. These results demonstrate that OCT2 mediates the renal tubular secretion of creatinine with low affinity and is a minor contributor to creatinine secretion.

Timed Creatinine Clearance and Measured Glomerular Filtration Rate in Living Kidney Donors

Assessment of predonation glomerular filtration rate (GFR) is a key aspect of the evaluation of potential living kidney donors. In the United States, measurement of donor GFR is a regulatory requirement and most commonly assessed using 24-hour timed creatinine clearance (CrCl24), despite the potential for error due to incorrectly timed urine sample collection and tubular creatinine secretion.1,2 We aimed to determine the real-world performance of CrCl24 in living donor candidates.

Evaluating Equations for Estimated Glomerular Filtration Rate (eGFR) in Patients with Sickle Cell Disease (SCD)

Background: Assessment of kidney function in sickle cell disease poses a unique dilemma, both due to the presence of hyperfiltration and the increased tubular secretion of creatinine, the metabolite most often used in eGFR assessment. In the general population, formulae utilizing serum creatinine have been developed to estimate GFR. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) have developed the most recent formulae. Until recently, the CKD-EPI-2009 creatinine-based formula has been the standard for estimating eGFR and included black race as a variable in the formula. This formula has been noted to overestimate eGFR in SCD patients, but its bias is improved when the black race variable is excluded. Among available formulae, the CKD-EPI-2012 cystatin C-based formula was shown to have the least bias in SCD patients compared to radionucleotide measured GFR but loses its accuracy when combined with creatinine. The recently developed CKD-EPI-2021 formula which excludes race as a variable is becoming the standard formula in most clinical laboratories. In this multicenter study, we sought to evaluate the agreement of various CKD-EPI formulae in SCD patents. Methods: Patients with HbSS or HbSb0 thalassemia between ages 18 and 65 years were enrolled in a prospective cohort study to assess the natural history of kidney disease in SCD. We excluded patients with bone marrow transplantation, diabetic nephropathy, cancer, connective tissue disease, other glomerular diseases, known infection with hepatitis (B or C) or HIV, and end-stage kidney disease on dialysis. Participants were enrolled during routine clinical visits at four centers. At baseline, blood samples and urine were obtained, and kidney function was assessed using each sites clinical laboratory to measure serum creatinine. Serum cystatin C was also measured at baseline using a commercially available ELISA kit. We calculated eGFR using each of the CKD-EPI formula, excluding the race variable in the CKD-EPI-2009 formula. Spearman's rank correlation coefficients were calculated for each formula compared to the others. Prevalence of CKD was assessed using the CKD-EPI-2009, CKD-EPI-2012 (cystatin C) and CKD-EPI-2021 formulae and defined as the presence of albuminuria or an eGFR ≤ 90 ml/min/1.73m2. Prevalence of CKD derived from the CKD-EPI-2012 was compared to the other two formulae using McNemar's Chi-squared test with 95% confidence intervals determined using bootstrap replications. Results: Our cohort enrolled 284 subjects with HbSS or HbSb0 thalassemia. For these analyses, 277 patients with baseline serum creatinine were included. The mean age of included subjects was 32.9 (SD ±11.5) years and 57% were female (N=158). The median eGFR of these subjects using the creatinine-based CKD-EPI-2009 formula was 123.9 (IQR 105.9, 134.0) ml/min/1.73m2. Cystatin C was available in 270 patients and had median value of 0.72 (IQR 0.59, 0.92) mg/L. Correlation between the several eGFR formulae are presented in Table 1. CKD-EPI-2009 and CKD-EPI-2021 creatinine-based formulae were very highly correlated with each other; both had similar but less correlation with the CKD-EPI-2012 cystatin C-based formula, which has been shown previously to have the least bias when compared to measured GFR. The prevalence of CKD using the creatinine-based CKD-EPI-2009 formula was 51.3% and 50.5% using the creatinine-based CKD-EPI-2021 formula. When assessed with the cystatin C-based CKD-EPI-2012 formula, CKD prevalence was higher at 55.7% (p<0.0001) than that seen with both of creatinine-based CKD-EPI formulae. Conclusions: When comparing the new CKD-EPI-2021 creatinine-based formula to the CKD-EPI-2009 formula (excluding the black race variable), eGFR calculation remains very similar in SCD patients. The CKD-EPI-2009 formula is well recognized to overestimate eGFR in SCD patients. Our data would suggest the newer formula would have similar bias. Using the cystatin C-based CKD-EPI-2012 formula, the prevalence of CKD is higher in this SCD cohort than using creatinine-based CKD-EPI formulae, although our data are limited by lack of directly measured GFR. We anticipate the newer CKD-EPI-2021 creatinine-based formula would similarly underestimate prevalence of CKD in SCD. Use of cystatin C for assessing kidney function in SCD patients should be considered, and resources should be utilized to make this measure more widely and readily available. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Levamisole causes a transient increase in plasma creatinine levels but does not affect kidney function based on cystatin C

BackgroundIn pediatric patients treated with levamisole to prevent relapses of idiopathic nephrotic syndrome (INS), a transient and non-progressive rise in creatinine levels has been observed. It has been suggested that levamisole affects tubular secretion of creatinine. However, other potential mechanisms — nephrotoxicity and interference with the analytical assay for creatinine — have never been thoroughly investigated.MethodsIn three steroid-sensitive nephrotic syndrome (SSNS) patients with elevated plasma creatinine levels, treated with levamisole 2.5 mg/kg every other day, serum cystatin C was determined. The glomerular filtration rate (GFR) was estimated using the full age spectrum for creatinine and the full age spectrum for cystatin C equations. Interference of levamisole with the enzymatic creatinine assay was tested using spare human plasma of different creatinine concentrations spiked with levamisole (4, 20, and 100 µM).ResultsThree patients who received levamisole with elevated plasma creatinine levels had normal serum cystatin C levels and corresponding estimated GFR. There was no assay interference.ConclusionLevamisole increases plasma creatinine levels, which is most probably due to impaired tubular secretion of creatinine since there was no assay interference and patients had normal eGFR based on serum cystatin C. However, interference of metabolites of levamisole could not be excluded. To monitor GFR, cystatin C in addition to creatinine should be used and be measured before and during levamisole use.

POS-387 AGREEMENT BETWEEN CREATININE AND CYSTATIN C BASED ESTIMATED GFR AMONG INDIVIDUALS WITH SICKLE CELL ANAEMIA

Better health care has resulted in increased survival of sickle cell disease (SCD) patients. Consequently, renal abnormalities are becoming a significant cause of morbidity and mortality. SCD individuals have supranormal proximal tubular function, with increased tubular secretion of creatinine, thus creatinine tends to overestimate glomerular filtration rate (GFR). Creatinine based eGFR is believed to be a late marker of nephropathy among these individuals. As such, serum cystatin C is suggested to assess renal function more accurately.

Serum Creatinine versus Corrected Cockcroft-Gault Equation According to Poggio Reference Values in Patients with Arterial Hypertension

Introduction:Serum creatinine is not enough sensitive marker for the evaluation of glomerular filtration rate (GFR). Cockcroft-Gault (CG) formula is often used to assess GFR, but it is necessary to correct original one for body surface area (BSA), adipositas, and the creatinine tubular secretion. The values of the estimated creatinine clearance and GFR are considered to Poggio reference ones according to biological parameters (age and gender). The aim of the study was to determine the difference in renal function estimation between serum creatinine and corrected CG equation according to the Poggio reference values in the arterial hypertension patients.Materials and Methods:The research included 124 patients of both gender with arterial hypertension, excluding ones with the already verified chronic kidney disease. We estimated creatinine clearance and GFR by CG method corrected for the BSA, body mass index (BMI), and the creatinine tubular secretion according to Poggio reference values.Results:There was no significant difference in both age and gender groups among patients with physiological and pathological values of the renal function determined by the serum creatinine and estimated creatinine clearance by CG equation corrected for BMI, BSA. In both age and gender groups there was significant difference among subjects with physiological and pathological values of the renal function determined by serum creatinine and estimated GFR by CG method corrected for BMI, BSA, and creatinine tubular secretion.Conclusion:There is the most striking difference in the assessment of renal function between serum creatinine and estimated GFR by CG method with three corrections (BSA, BMI, the creatinine tubular secretion). Estimated GFR by CG method with three corrections can help in the early diagnosis of renal dysfunction and optimal treatment in patients with arterial hypertension.

Effect of Prophylactic Dose of Trimethoprim-Sulfamethoxazole on Serum Creatinine in Japanese Patients With Connective Tissue Diseases.

Objectives:At normal doses of trimethoprim-sulfamethoxazole (TMP/SMX), trimethoprim inhibits tubular creatinine secretion, leading to a rapid but reversible increase in serum creatinine (SCr). Although patients with connective tissue diseases are often in the state of immunosuppression and TMP/SMX is an important prophylactic drug, clinicians often have to stop or reduce the dosage due to concerns regarding its effect on renal function. This study aimed to evaluate the effect of a prophylactic dose of TMP/SMX on SCr in Japanese patients with connective tissue diseases, the extent of SCr level elevation and the independent risk factors for creatinine elevation.Methods:A retrospective cohort study was undertaken. Participants included patients with connective tissue diseases who were treated with a prophylactic dose of TMP/SMX between 2004 and 2018. Using single and multiple regression analyses, the risk factors that affected SCr elevation were evaluated.Results:A total of 262 patients, females, n = 181; age, median (range) = 59 (19-89) years, were included. The median baseline SCr level before treatment was 0.62 (0.16-2.1) mg/dL. The median SCr elevation value was 0.07 (−0.54 to 0.84) mg/dL in 4 weeks after TMP/SMX initiation. Five (2%) participants had ⩾0.3 mg/dL SCr elevation. Multiple regression analyses, including age, baseline SCr, diuretic use, nonsteroidal anti-inflammatory drug use and diabetes mellitus, indicated that baseline SCr and advanced age were independent risk factors of SCr elevation.Conclusions:These results demonstrated that baseline SCr and advanced age were associated with SCr elevation by a prophylactic dose of TMP/SMX. However, a prophylactic dose of TMP/SMX rarely elevated the SCr level significantly. Therefore, other causes can be considered if patients show an SCr elevation ⩾0.3 mg/dL.

Tubular Secretion of Creatinine and Clinical Outcomes: The AASK Trial

Tubular Secretion of Creatinine and Clinical Outcomes: The AASK Trial

P45.12 Renal Function Change During Alectinib in ALK Rearranged Non-Small Cell Lung Cancer: A Retrospective Multicentre Analysis

The therapeutic landscape of ALK rearranged non-small cell lung cancer (NSCLC) has dramatically changed in the last few years. Several studies reported a significative reduction of creatinine-based estimated glomerular filtration rate (eGFR) during crizotinib, suggesting a direct effect on creatinine tubular secretion due to the reversibility after discontinuation, the scarce cumulative effect and the discrepancy between different methods of renal function estimation. In clinical trials serum creatinine increased in 7.2% of patients with alectinib, but it could be higher in real life population.

The Evaluation of Kidney Function in Living Kidney Donor Candidates.

Living kidney donors incur a small increased risk of ESKD, of which predonation GFR is an important determinant. As a result, kidney function assessment is central to the donor candidate evaluation and selection process. This article reviews the different methods of GFR assessment, including eGFR, creatinine clearance, and measured GFR, and the current guidelines on GFR thresholds for donor acceptance. eGFR obtained using the 2009 CKD Epidemiology Collaboration equation that, although the best of estimating estimations, tends to underestimate levels and has limited accuracy, especially near-normal GFR values. In the United States, the Organ Procurement and Transplantation Network policy on living donation mandates either measured GFR or creatinine clearance as part of the evaluation. Measured GFR is considered the gold standard, although there is some variation in performance characteristics, depending on the marker and technique used. Major limitations of creatinine clearance are dependency on accuracy of timed collection, and overestimation as a result of distal tubular creatinine secretion. GFR declines with healthy aging, and most international guidelines recommend use of age-adapted selection criteria. The 2017 Kidney Disease: Improving Global Outcomes Guideline for the Evaluation and Care of Living Kidney Donors diverges from other guidelines and recommends using absolute cutoff of <60 ml/min per 1.73m2 for exclusion and ≥90 ml/min per 1.73m2 for acceptance, and determination of candidacy with intermediate GFR on the basis of long-term ESKD risk. However, several concerns exist for this strategy, including inappropriate acceptance of younger candidates due to underestimation of risk, and exclusion of older candidates whose kidney function is in fact appropriate for age. The role of cystatin C and other newer biomarkers, and data on the effect of predonation GFR on not just ESKD risk, but also advanced CKD risk and cardiovascular outcomes are needed.

Dynamics of creatinine estimated glomerular filtration rate using one or more antiretrovirals that inhibit creatinine tubular secretion.

Cobicistat, dolutegravir and rilpivirine are all modest inhibitors of proximal tubular creatinine secretion (IPTCrS) and hence a moderate and early non-progressive creatinine estimated glomerular filtration rate (Cr-eGFR) reduction has been observed in clinical trials. Data regarding the impact of combination of those drugs on Cr-eGFR, in the clinical practice, are scarcely known. Changes in Cr-eGFR after starting darunavir/cobicistat alone or in combination with dolutegravir and/or rilpivirine were studied in a nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat. The relationship between Cr-eGFR changes over time and the use of darunavir/cobicistat alone or darunavir/cobicistat plus dolutegravir and/or rilpivirine adjusted by different HIV patient's characteristics, socio-demographics, HIV severity and use of tenofovir concomitant medication other than antiretrovirals was explored through univariate and multivariate analyses. The analysis included 725 patients. At 48 weeks, the combination of two or more IPTCrS (darunavir/cobicistat with rilpivirine and/or dolutegravir) was associated with higher decreases in Cr-eGFR [adjusted median difference (±SD) -3.5 ± 1.6 (95% CI -6.6 to -0.3), P = 0.047], and a decrease up to or higher than 15 mL/min/1.73 m2 was more frequent [adjusted OR 3.233 (95% CI 1.343-7.782), P = 0.009], with respect to darunavir/cobicistat alone. The Cr-eGFR changes between darunavir/cobicistat and darunavir/cobicistat with rilpivirine and/or dolutegravir showed more significant decreases in patients taking two or more IPTCrS at 12, 24 and 48 weeks. (ClinicalTrials.gov: NCT03042390). Concomitant use of darunavir/cobicistat plus IPTCrS dolutegravir, rilpivirine, or both produced an additive effect in the expected Cr-eGFR decrease.

Tubular Secretion of Creatinine and Risk of Kidney Failure: The Modification of Diet in Renal Disease Trial

Tubular Secretion of Creatinine and Risk of Kidney Failure: The Modification of Diet in Renal Disease Trial

Abstract 3015: Tucatinib inhibits creatinine and metformin renal tubule secretion but has no effect on renal function (GFR)

Abstract Background: Tucatinib (TUC) is a potent, highly selective investigational HER2 tyrosine kinase inhibitor in development for treatment of patients with HER2+ metastatic breast cancer (MBC). In HER2CLIMB (H2C), a pivotal study of patients with HER2+ MBC, a modest transient, reversible increase in serum creatinine (SCr) levels was observed in patients who received TUC. Similarly, in a study with healthy volunteers, SCr increased after 300 mg BID TUC and returned to baseline levels after TUC discontinuation. Clinically, SCr is used as a biomarker for glomerular filtration rate (GFR) and is routinely measured to monitor for potential renal injury. However, SCr renal elimination also depends on the kidney transporters OCT2 (uptake), MATE1 (efflux) and MATE2-K (efflux). Inhibition of OCT2 and MATE1/2-K has been associated with SCr increases in the absence of kidney damage (e.g., abemaciclib). In vitro assessments and a clinical study were performed to assess the impact of TUC on OCT2 and MATE1/2-K-mediated transport. Methods: Inhibition of OCT2, MATE1, and MATE2-K-mediated transport by TUC was estimated in transfected MDCK-II cells using creatinine and metformin (MF), a sensitive OCT2 and MATE1/2-K substrate used to quantify transport inhibition in vivo, as probe substrates. Subsequently, a single-arm drug-drug interaction study was performed in 17 healthy volunteers to evaluate the effects of TUC on MF PK. MF (850 mg, PO) was administered in the absence and presence of TUC (300 mg BID, PO). Iohexol was administered to calculate actual GFR (aGFR) in the absence and presence of TUC. Plasma (iohexol, MF and TUC) and urine (MF) samples were collected for PK analysis; drug concentrations were measured using validated LC-MS/MS methods. Serum and urine creatinine levels were also measured. Results: In MDCK II cells, TUC inhibited creatinine transport by OCT2 (IC50 = 0.107 µM) and MATE1 (IC50 = 0.086 µM) and MF transport by MATE1 (IC50 = 0.340 µM) and MATE2-K (IC50 = 0.135 µM), but not by OCT2 (IC50 = 14.7 µM). Using these IC50 values, physiologically-based pharmacokinetic (PBPK) model simulations predicted a 1.16 to 1.35-fold increase of MF exposure in the presence of TUC. Consistent with the PBPK prediction, in healthy volunteers MF exposure (AUCinf) increased ~1.4-fold and renal clearance decreased from 29.99 L/h to 17.64 L/h in the presence of TUC with no effect on MF Cmax. Iohexol clearance was unaffected in the presence of TUC indicating no change in aGFR. SCr increased in the presence of TUC and returned to baseline 8 days after TUC discontinuation. Conclusions: Together, these data demonstrate that the observed SCr increase in clinical studies with TUC is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1 and not due to an effect on kidney function. An alternative, non-creatinine-based measure of renal function should be considered for tucatinib. Citation Format: Ariel R. Topletz-Erickson, Anthony Lee, JoAl Mayor, Evelyn Rustia, Layth Abdulrasool, Luke Walker, Christopher J. Endres. Tucatinib inhibits creatinine and metformin renal tubule secretion but has no effect on renal function (GFR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3015.

P1718COMPARISON OF MEASURED GLOMERULAR FILTRATION RATE USING 24-HOUR URINE CREATININE CLEARANCE WITH 51-CHROMIUM EDTA IN A MALAYSIAN COHORT OF LIVING KIDNEY DONOR CANDIDATES

Abstract Background and Aims All living kidney donors undergo assessment of renal function by evaluation of Glomerular Filtration Rate (GFR). 51Cr-EDTA is one of the most widely used marker for measuring GFR but it is hampered by cost and laboriousness as well as not being widely available in Malaysia. Measuring 24-hour urine for creatinine clearance (Ccr) is a common alternative when exogenous filtration markers are not available. Ccr suffers from over/underestimation of measured GFR (mGFR) due to errors in urine collection and tubular secretion of creatinine. This is a study to compare the correlation of Ccr against 51Cr-EDTA in measuring GFR among the living donors in Malaysian population. Method This is a cross-sectional, single-centre study of a cohort of living kidney donor candidates from January 2007 to March 2019. All candidates who had mGFR done with both 51Cr-EDTA and Ccr in University Malaya Medical Centre were enrolled. Special consideration was taken to account for adequate urine sampling for Ccr. Clinical data was analysed for correlation, bias, precision and accuracy between Ccr and 51Cr-EDTA. Results A total of 83 living kidney donors with a mean age of 45.60 ± 11.06 years and body mass index (BMI) of 24.36 ± 4.03 were enrolled. Female comprised 74.7% of the donors while Chinese, Malay and Indian accounted for 67.5%, 20.5% and 7.2% of the donors respectively. The study group had a mean serum creatinine of 63.37 ± 16.00 umol/L with a urine volume of 2.03 ± 0.81 L (range 0.70 – 3.82). mGFR from 51Cr-EDTA was 125.56 ± 27.64 ml/min/1.73m2 (range 77.0 – 194.3) whereas calculated Ccr was 136.05 ± 36.15 ml/min/1.73m2 (range 75.32 – 280.06). The correlation coefficient between Ccr and 51Cr-EDTA is moderate (r = 0.43) (p &amp;lt; 0.01). Mean absolute bias between Ccr and 51Cr-EDTA was 10.59 ± 37.99 ml/min/1.73m2 (p &amp;lt; 0.05). The accuracy of Ccr within 30% of 51Cr-EDTA was 77.11%. Conclusion Our study showed that Ccr significantly overestimates mGFR compared to 51Cr-EDTA. However, there is a significantly moderate positive correlation between Ccr and 51Cr-EDTA. Thus, in the absence of 51Cr-EDTA, Ccr is a clinically acceptable alternative if utilized with care and understanding its limitations.

P0323REVERSIBLE RENAL FUNCTION DECLINE ASSOCIATED WITH NIRAPARIB

Abstract Background and Aims Inhibitors of poly-ADP-ribose-polymerase-1 (PARP) are prescribed for the treatment of metastatic breast and ovarian cancers. Clinical data trials suggest that niraparib may not have adverse effects on the kidney. Method We present a descriptive case series of renal function parameters of all the patients who received niraparib for maintenance treatment of recurrent ovarian cancer in a tertiary care center. Twenty patients received niraparib for the first time between april 2018 and march 2019 in the Georges Pompidou European Hospital, Paris, France. Four patients were excluded from the analysis because of lack of repeated serum creatinine (Scr) measurements during the first 4 months following niraparib introduction. Results The patients ranged in age from 51 to 82 years. All patients were women with high grade serous ovarian carcinoma. Personal medical history of hypertension was present in 68% and diabetes in 18% of patients. All patients received carboplatin and 90% received bevacizumab as maintenance treatment after first-line chemotherapy. Niraparib was introduced on average 3 years (range 2 to 9 years) after the diagnosis of cancer, at a dosage of 200 mg/day in all patients. The median Scr at baseline was 84 μmol/l (range 62 to 114 µmol/l). All patients experienced an increase in Scr level over the 3 months following niraparib introduction. The average max Scr increase was 1.35 times baseline (median Scr 117µmol/l, range 88 to 155 µmol/l, p&amp;lt;0.0001 compared to baseline values), and 3 patients (18%) developed stage 1 KDIGO Acute Kidney Injury/Disease (Scr increase &amp;gt; 1.5-2 fold baseline). None of the cases had biochemical signs of tubular or glomerular injury. Urinary creatinine clearance was higher than urinary clearance of 51Cr-EDTA, making interaction with tubular creatinine secretion unlikely. Kidney biopsy was performed in one patient who developed albuminuria. Microscopic examination identified mild tubular atrophy and interstitial fibrosis without inflammatory lesion Immunofluorescence analysis did not show immune deposits. Mesangiolysis was found in some glomeruli, typical of bevacizumab effects. Niraparib was interrupted in all but 1 patient (95%), because of haematological toxicity (n=7), tumoral progression (n=7) or gastro-intestinal toxicity (n=1). Average Scr level returned to baseline (82 µmol/l, range 62 to 107 µmol/l) over the 2 months following discontinuation. Conclusion Niraparib is associated with a systematic and significant increase in Scr (+35%) without obvious sign of tubular or glomerular injury. Renal dysfunction is mainly reversible after discontinuation. Decline of renal function under treatment may not be an incentive to stop treatment automatically. Physicians prescribing this agent should be aware of this complication.

Tubular secretion of creatinine and kidney function: an observational study

BackgroundPrior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts.MethodsTo fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time.ResultsObserved CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories.ConclusionsThese data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR.