Glomerular filtration rate measurement during platinum treatment for urothelial carcinoma: optimal methods for clinical practice.

BACKGROUND: We assessed the accuracy of four estimated glomerular filtration rate (eGFR) methods: MDRD, Cockcroft-Gault, CKD-EPI, and Wright. METHOD: The four methods were compared to measure GFR (mGFR) in patients with urothelial urinary tract cancer (T2-T4bNxMx) receiving platinum-based chemotherapy at Rigshospitalet, Copenhagen, from January 2019 to December 2021. Using standardized assays, creatinine values were measured, and mGFR was determined using Technetium-99 m diethylenetriaminepentaacetic acid (Tc-99 m-DTPA) or Cr-51-ethylenediaminetetraacetic acid (Cr-51-EDTA) plasma clearance. Patients (n = 146) with both mGFR and corresponding creatinine values available were included (n = 345 measurements). RESULTS: The CKD-EPI method consistently demonstrated superior accuracy, with the lowest Total Deviation Index of 21.8% at baseline and 22.9% for all measurements compared to Wright (23.4% /24.1%), MDRD (26.2%/25.5%), and Cockcroft-Gault (25.x%/25.1%). Bland Altman Limits of agreement (LOA) ranged from - 32 ml/min (Cockcroft-Gault) to + 33 ml/min (MDRD), with CKD-EPI showing the narrowest LOA (- 27 ml/min to + 24 ml/min and lowest bias (0.3 ml/min). Establishing an eGFR threshold at 85 ml/min-considering both the lower limit of agreement (LOA) and the minimum cisplatin limit at 60 ml/min-allows for the safe omission of mGFR in 30% of patients in this cohort. CONCLUSION: CKD-EPI equation emerged as the most suitable for estimating kidney function in this patient group although not meeting benchmark criteria. We recommend its use for initial assessment and ongoing monitoring, and suggest mGFR for patients with a CKD-EPI estimated GFR below 85 ml/min. This approach could reduce costs and decrease laboratory time for 30% of our UC patients.

Self-reported Race, Serum Creatinine, Cystatin C, and GFR in Children and Young Adults With Pediatric Kidney Diseases: A Report From the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Recent reassessment of the use of race in estimated glomerular filtration rate (eGFR) in adults has instigated questions about the role of race in eGFR expressions for children. Little research has examined the associations of self-reported race with measured GFR (mGFR) adjusting for serum creatinine or cystatin C in children and young adults with chronic kidney disease (CKD). This study examined these associations and evaluated the performance of the previously published "U25" (under the age of 25 years) eGFR equations in a large cohort of children and young adults with CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Kidney Disease in Children (CKiD) study including 190 Black and 675 non-Black participants contributing 473 and 1,897 annual person-visits, respectively. EXPOSURE: Self- or parental-reported race (Black, non-Black). Adjustment for serum creatinine or cystatin C, body size, and socioeconomic status. OUTCOME: mGFR based on iohexol clearance. ANALYTICAL APPROACH: Linear regression with generalized estimating equations, stratified by age (<6, 6-12, 12-18, and ≥18 years) incorporating serum creatinine or serum cystatin C. Contrasting performance in different self-reported racial groups of the U25 eGFR equations. RESULTS: Self-reported Black race was significantly associated with 12.8% higher mGFR among children in regression models including serum creatinine. Self-reported Black race was significantly associated with 3.5% lower mGFR after adjustment for cystatin C overall but was not significant for those over 12 years. The results were similar after adjustment for body size and socioeconomic factors. The average of creatinine- and cystatin C-based U25 equations was unbiased by self-reported race groups. LIMITATIONS: Small number of children < 6 years; lean body mass was estimated. CONCLUSIONS: Differences in the creatinine-mGFR relationship by self-reported race were observed in children and young adults with CKD and were consistent with findings in adults. Smaller and opposite differences were observed for the cystatin C-mGFR relationship, especially in the younger age group. We recommend inclusion of children for future investigations of biomarkers to estimate GFR. Importantly, for GFR estimation among those under 25 years of age, the average of the new U25 creatinine and cystatin C equations without race coefficients yields unbiased estimates of mGFR.

Measurement and Estimation of GFR for Use in Clinical Practice: Core Curriculum 2021.

Assessment of glomerular filtration rate (GFR) is fundamental to clinical practice, public health, and research. The kidney has several critical functions; GFR is used as an overall assessment of these kidney functions. GFR is used to diagnose, stage, and manage chronic kidney disease (CKD); ascertain the prognosis for chronic kidney disease-related events and mortality; and determine drug dosages. GFR is the rate at which the glomerulus filters plasma to produce an ultrafiltrate and can be assessed from clearance or serum levels of filtration markers. Clearance measurements using exogenous filtration markers are difficult to perform in routine clinical practice, so GFR is more commonly estimated through equations based on serum concentrations of endogenous filtration markers, most commonly creatinine. These GFR estimates are reasonably accurate, but optimal care for patients may require a confirmatory test for a more accurate GFR assessment. Confirmatory tests currently available include cystatin C-based equations, urinary or plasma clearance of exogenous filtration markers, or urinary clearance of creatinine. Appreciation of the concept of GFR and methods for optimal assessment in routine practice or special circumstances, and their strengths and limitations, are critical in making judicious use of the available tools.

Evaluating chronic kidney disease in rural South Africa: comparing estimated glomerular filtration rate using point-of-care creatinine to iohexol measured GFR.

OBJECTIVES: The prevalence of chronic kidney disease is rising rapidly in low- and middle-income countries. Serum creatinine and estimation of glomerular filtration rate (GFR) are critical diagnostic tools, yet access to centralised laboratory services remains limited in primary care resource-limited settings. The aim of this study was to evaluate point-of-care (POC) technologies for serum creatinine measurement and to compare their performance to a gold standard measurement using iohexol measured GFR (mGFR). METHODS: POC creatinine was measured using iSTAT® and StatSensor® devices in capillary and venous whole blood, and laboratory creatinine was measured using the compensated kinetic Jaffe method in 670 participants from a rural area in South Africa. GFR estimating equations Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease (CKD-EPI and MDRD) for POC and laboratory creatinine were compared to iohexol mGFR. RESULTS: Calculated GFR for laboratory and POC creatinine measurements overestimated GFR (positive bias of 1.9-34.1 mL/min/1.73 m2). However, all POC devices had less positive bias than the laboratory Jaffe method (1.9-14.7 vs. 34.1 for MDRD, and 8.4-19.9 vs. 28.6 for CKD-EPI). Accuracy within 30% of mGFR ranged from 0.56 to 0.72 for POC devices and from 0.36 to 0.43 for the laboratory Jaffe method. POC devices showed wider imprecision with coefficients of variation ranging from 4.6 to 10.2% compared to 3.5% for the laboratory Jaffe method. CONCLUSIONS: POC estimated GFR (eGFR) showed improved performance over laboratory Jaffe eGFR, however POC devices suffered from imprecision and large bias. The laboratory Jaffe method performed poorly, highlighting the need for laboratories to move to enzymatic methods to measure creatinine.

The correlation between kidney volume and measured glomerular filtration rate in an Asian ADPKD population: a prospective cohort study.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder that leads to end stage renal disease (ESRD). Cyst expansion in ADPKD is strongly associated with the decline in renal function. However, the correlation between total kidney volume (TKV) and glomerular filtration rate (GFR) at an early stage has not been well demonstrated. There is growing evidence that utilization of estimated GFR (eGFR) may induce misleading information in a population with near normal renal function. Therefore, a more accurate method is essential. METHODS: A prospective cohort of ADPKD patients was conducted with clinical data and laboratory collection. Measured GFR (mGFR) was assessed by iohexol plasma clearance method using ultra performance liquid chromatography. eGFR was calculated using the CKD-EPI equation. Kidney volumes were evaluated using MRI imaging protocol. RESULTS: Thirty two patients completed the study. The mean age was 56 years old. The mean initial mGFR was 83.8 mL/min/1.73m2. The mean change in mGFR per year was -2.99 mL/min/1.73m2/year. The mean initial height-adjusted TKV (htTKV) was 681.0 mL/m. The mean percentage change in htTKV per year (%ΔhtTKV/y) was 4.77 %/year. mGFR had a better association with clinical parameters than eGFR. Initial mGFR was significantly and inversely correlated with initial htTKV and age. The percentage change in mGFR per year was significantly and inversely correlated with the %ΔhtTKV/y and 24-hr urine albumin. The %ΔhtTKV/y was significantly correlated with initial htTKV. CONCLUSIONS: Our studies demonstrated that mGFR using iohexol is a more reliable and accurate method than eGFR for evaluating GFR changes in the early stages of ADPKD patients. There is a strong inverse correlation between kidney volume and mGFR in an Asian ADPKD population. The initial htTKV is a good predictor of kidney volume progression. The %ΔhtTKV/y is a good early surrogate marker for the decline in renal function. 24-hr urine albumin is also a good indicator for renal progression.

Fasting Urinary Osmolality, CKD Progression, and Mortality: A Prospective Observational Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) characterized by decreased glomerular filtration rate (GFR) is often accompanied by various degrees of impaired tubular function in the cortex and medulla. Assessment of tubular function may therefore be useful in establishing the severity of kidney disease and identifying those at greater risk for CKD progression. We explored reductions in urinary concentrating ability, a well-known feature of CKD, as a risk factor for GFR decline and end-stage renal disease (ESRD). STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 2,084 adult patients with CKD stages 1 to 4 from the French NephroTest Cohort Study. PREDICTOR: Fasting urinary osmolality measured using delta cryoscopy. OUTCOMES: ESRD, mortality before ESRD, and measured GFR (mGFR) assessed using 51Cr-EDTA renal clearance. ANALYTICAL APPROACH: Cause-specific hazards models were fit to estimate crude and adjusted associations of urinary osmolality with ESRD and death before ESRD. Linear mixed models with random intercepts were fit to evaluate the association of urinary osmolality with slope of decline in mGFR. RESULTS: At baseline, mean age was 58.7±15.2 (SD) years with a median mGFR of 40.2 (IQR, 29.1-54.5) mL/min/1.73m2 and a median fasting urinary osmolality of 502.7±151.7mOsm/kg H2O. Baseline fasting urinary osmolality was strongly associated with mGFR (R=0.54; P < 0.001). 380 ESRD events and 225 deaths before ESRD occurred during a median follow-up of 5.9 (IQR, 3.8-8.2) years. Patients with lower baseline fasting urinary osmolality had higher adjusted risk for ESRD but not for mortality (HRs of 1.97 [95% CI, 1.26-3.08] and 0.99 [95% CI, 0.68-1.44], respectively, for the lowest vs highest tertile). Based on a mixed linear model adjusted for baseline mGFR and clinical characteristics, patients in the lowest tertile of baseline urinary osmolality had a steeper decline in kidney function (-4.9% ± 0.9% per year; P < 0.001) compared with patients in the highest tertile. LIMITATIONS: Fasting was self-reported. CONCLUSIONS: Fasting urinary osmolality may be a useful tool, in addition to GFR and albuminuria, for assessing nonglomerular damage in patients with CKD who are at higher risk for CKD progression.

Pre-dialysis decline of measured glomerular filtration rate but not serum creatinine-based estimated glomerular filtration rate is a risk factor for mortality on dialysis.

Background: Monitoring of renal function is important in patients with chronic kidney disease progressing towards end-stage renal failure, both for timing the start of renal replacement therapy and for determining the prognosis on dialysis. Thus far, studies on associations between estimated glomerular filtration rate (eGFR) measurements in the pre-dialysis stage and mortality on dialysis have shown no or even inverse relations, which may result from the poor validity of serum creatinine-based estimation equations for renal function in pre-dialysis patients. As decline in renal function may be better reflected by the mean of the measured creatinine and urea clearance based on 24-h urine collections (mGFR by C Cr-U ), we hypothesize that in patients with low kidney function, a fast mGFR decline is a risk factor for mortality on dialysis, in contrast to a fast eGFR decline. Methods: For 197 individuals, included from the multicentre NECOSAD cohort, pre-dialysis annual decline of mGFR and eGFR was estimated with linear regression, and classified according to KDOQI as fast (>4 mL/min/1.73 m 2 /year) or slow (≤4 mL/min/1.73 m 2 /year). Cox regression was used to adjust for potential confounders. Results: Patients with a fast mGFR decline had an increased risk of mortality on dialysis: crude hazard ratio (HR) 1.84 (95% confidence interval: 1.13-2.98), adjusted HR 1.94 (1.11-3.36). In contrast, no association was found between a fast eGFR decline in the pre-dialysis phase and mortality on dialysis: crude HR 1.20 (0.75-1.89), adjusted HR 1.14 (0.67-1.94). Conclusions: This study demonstrates the importance of mGFR decline (by C Cr-U ) as opposed to eGFR decline in patients with low kidney function, and gives incentive for repeated mGFR measurements in patients on pre-dialysis care.

Discordance Between Iothalamate and Iohexol Urinary Clearances.

BACKGROUND: Iothalamate and iohexol are contrast agents that have supplanted inulin for the measurement of glomerular filtration rate (GFR) in clinical practice. Previous studies have noted possible differences in renal handling of these 2 agents, but clarity about the differences has been lacking. STUDY DESIGN: Study of diagnostic test accuracy. SETTING & PARTICIPANTS: 150 participants with a wide range of GFRs were studied in an outpatient clinical laboratory facility. INDEX TESTS: Simultaneous urinary clearances of iothalamate, iohexol, and creatinine. REFERENCE TEST: None. OUTCOME: Relative differences between the urinary clearances. Iohexol and iothalamate in plasma and urine were assayed concurrently by a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. RESULTS: Mean iohexol, iothalamate, and creatinine clearances were 52±28 (SD), 60±34, and 74±40 mL/min/1.73 m(2), respectively. The proportional bias of iohexol to iothalamate urinary clearance was 0.85 (95% CI, 0.83-0.88) and was proportional across the GFR range. The mean proportional bias of iohexol clearance compared with creatinine clearance is 1.27 (95% CI, 1.20-1.34), whereas that of iothalamate clearance compared with creatinine clearance is 1.09 (95% CI, 1.03-1.15). LIMITATIONS: Lack of reference standard. CONCLUSIONS: This study reveals a significant and consistent difference between urinary clearances of iothalamate and iohexol. Comparison of studies reporting renal clearance measurements using iohexol versus iothalamate must account for this observed bias.

Midlife Blood Pressure and Late-Life GFR and Albuminuria: An Elderly General Population Cohort.

BACKGROUND: Chronic kidney disease (CKD) is common in the elderly, but the cause is often not identifiable. Some posit that age-related reductions in glomerular filtration rate (GFR) and increases in albuminuria are normal, whereas others suggest that they are a consequence of vascular disease. STUDY DESIGN: Cross-sectional analysis of a substudy of a prospective cohort. SETTING & PARTICIPANTS: AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study. PREDICTOR: Exposure to higher blood pressure in midlife. OUTCOMES & MEASUREMENTS: Measured GFR using plasma clearance of iohexol and urine albumin-creatinine ratio. RESULTS: GFR was measured in 805 participants with mean age in midlife and late life of 51.0±5.8 and 80.8±4.0 (SD) years, respectively. Mean measured GFR was 62.4±16.5 mL/min/1.73 m(2) and median albuminuria was 8.0 (IQR, 5.4-16.5) mg/g. Higher midlife systolic and diastolic blood pressures were associated with lower later-life GFRs. Associations persisted after adjustment. Higher midlife systolic and diastolic blood pressures were also associated with higher albumin-creatinine ratios, and associations remained significant even after adjustment. LIMITATIONS: This is a study of survivors, and people who agreed to participate in this study were healthier than those who refused. Blood pressure may encompass effects of the other risk factors. Results may not be generalizable to populations of other races. We were not able to adjust for measured GFR or albuminuria at the midlife visit. CONCLUSIONS: Factors other than advanced age may account for the high prevalence of CKD in the elderly. Midlife factors are potential contributing factors to late-life kidney disease. Further studies are needed to identify and treat midlife modifiable factors to prevent the development of CKD.

Feasibility and reliability of measured glomerular filtration rate with [I125]-iothalamate among young adults with mild-to-moderate cerebral palsy.

Objective: Despite the need, measuring glomerular filtration rate (mGFR) is not routinely performed for adults with cerebral palsy (CP), possibly due to unknown feasibility given the secondary complications of CP. This study aimed to assess the feasibility and reliability of mGFR and explore factors associated with eGFR-mGFR discordance among young adults with mild-to-moderate CP. Methods: This single-center, cross-sectional study included 18- to 40-year-olds with CP gross motor function classification system (GMFCS) I-III. The participants were excluded if they were pregnant/lactating, had cognitive impairments, or had contraindications to mGFR. A routine clinical protocol for mGFR and eGFR was used. mGFR feasibility was assessed based on the number of participants who completed testing. mGFR reliability was assessed using the coefficient of variation (CV) across the four 30 min intervals. The association between age, sex, and GMFCS and the percentage of eGFR-mGFR discordance was assessed. Results: Of the 19 participants enrolled, 18 completed the testing [mean age (SD), 29.9 (7.4) years, n = 10 female participants, n = 10/3/5 for GMFCS I/II/III] and most (n = 15) of the participants had an mGFR >90 mL/min; 14 participants (77.8%) had a CV <20%, 2 had a CV between 20 and 25%, and 2 had a CV >50%. eGFR overestimated mGFR by a median (interquartile range) of approximately 17.5% (2-38%); the full range of mis-estimation was -20.5 to 174.3%. Increasing age and GMFCS levels exhibited notable, but weak-to-modest, associations with a larger eGFR-mGFR discordance. Discussion: Obtaining mGFR was feasible and reasonably reliable within this small sample. eGFR overestimated mGFR by a notable amount, which may be associated with patient-level factors.

Determination of glomerular filtration rate "en passant" after high doses of iohexol for computed tomography in intensive care medicine-a proof of concept.

Accurate assessment of renal function is of great clinical and scientific importance, as it is an important pharmacokinetic covariate of pivotal drugs. The iohexol clearance is nearly identical to the glomerular filtration rate, but its determination usually requires an intravenous injection and therefore bears intrinsic risks. This motivates to showcase an "en passant" approach to quantification of renal function without additional risk or blood sampling beyond routine care using real-world data. We enrolled 37 intensive care patients who received high doses of iohexol for computed tomography imaging, and quantified series of iohexol plasma concentrations by high-performance liquid chromatography (HPLC-UV). Iohexol clearance was derived by both log-linear regression and nonlinear least squares fitting and compared to glomerular filtration rate estimated by the CKD-EPI-2021 formulas. Nonlinear fitting not only turned out to be more accurate but also more robust in handling the irregularly timed data points. Concordance of iohexol clearance against estimations based on both creatinine and cystatin C showed a slightly higher bias (-3.44 mL/min/1.73 m2) compared to estimations based on creatinine alone (-0.76 mL/min/1.73 m2), but considerably narrower limits of agreement (±42.8 vs. 56 mL/min/1.73 m2) and higher Lin's correlation (0.84 vs. 0.72). In summary, we have demonstrated the feasibility and performance of the "en passant" variant of the iohexol method in intensive care medicine and described a working protocol for its application in clinical practice and pharmacologic studies.

Comparison of Renal Functions Evaluated by Measured Glomerular Filtration Rate in Patients Treated With Cisplatin, Carboplatin, and Oxaliplatin.

INTRODUCTION: In cancer chemotherapy platinum drugs do cause damage to the normal cells and as a result, many physiological functions are derailed. Renal function as measured by measured glomerular filtration rate (mGFR) plays a large role in drug dosing on the basis of the maximum tolerated dose, which is the highest dose that may be administered without unacceptable toxicity, to maximize anticancer efficacy. OBJECTIVE: The objective of the study was to compare the toxic effect of platinum drugs on renal function as measured by mGFR in patients with malignancy and to study the difference in the magnitude of nephrotoxicity by these drugs. METHODOLOGY: The study was conducted in the Department of Physiology in close collaboration with the Department of Radiotherapy at a tertiary care centre in Western Rajasthan, India. 150 patients suffering from different malignances undergoing treatment with cisplatin, carboplatin, and oxaliplatin were examined for their renal function as measured by mGFR using 99mTc-diethylene triamine pentaacetic acid (99mTc-DTPA) and were compared with 50 subjects of control group. RESULTS:  In the cisplatin group there was a gradual fall of GFR from 85.49 ml/min/1.73sqm to 58.09ml/min/1.73sqm at cycle II. In the carboplatin group it was 84.86ml/min/1.73sqm at baseline whereas cycle II was 75.5 ml/min/1.73sqm with SD ± 16.49. mGFR fell significantly (p<0.0001) in cisplatin and carboplatin groups but not in the cohort of patients who received oxaliplatin. The GFR reduction continued from the baseline to cycle I and then cycle II in cisplatin and carboplatin groups. CONCLUSION: Nephrotoxicity is a major side effect of platin drugs and further studies should be done to establish their optimal dose in relation to renal function and minimize toxicity by trying various cytoprotective agents.

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 < 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.

Hearing loss in fabry disease: A 16 year follow-up study of the Danish nationwide cohort.

Background: Fabry disease (FD) is a lysosomal storage disorder resulting in systemic accumulation of globotriaosylceramide (Gb3) causing multi-organ dysfunction. The audiologic involvement in FD has been neglected in previous studies; while not a lethal aspect of the disease, hearing loss can have a significantly negative impact on quality of life. Objective: To investigate hearing loss from baseline through 16 years follow-up of the Danish FD cohort and to compare audiometric data to other clinical variables. Methods: Data was collected prospectively and assessed retrospectively during a period of 16 years from 83 patients (age: 9-72 years; sex: 29 males and 54 females). 55 patients underwent treatment. Air conduction thresholds was assessed at six frequencies between 0.25 and 8 kHz bilaterally. Data was analyzed using multilinear models. Results: Mean follow-up period for patients undergoing a FD specific treatment was 7.8 years (0-12.8 years, SD 3.8 years, n = 55). Hearing thresholds for FD patients deviated from healthy individuals at all frequencies for both sexes (p < 0.001). Males had more profound hearing loss than females at high frequencies (4,8 kHz) (p = 0.025). There was no improvement in hearing with treatment (p = 0.343♂, p = 0.256♀). No associations between hearing loss and measured glomerular filtration rate, left ventricular wall thickness or cerebral white matter lesions were found. Lower plasma Gb3 concentration correlated with better hearing (p = 0.046) in males. Conclusion: Our findings demonstrated significant hearing loss in FD patients compared to audiologically healthy individuals at all frequencies, and no change in hearing during treatment. Lower plasma Gb3 concentrations correlated with better hearing in males.

Measurement of glomerular filtration rate using endogenous d-serine clearance in living kidney transplant donors and recipients.

BACKGROUND: Endogenous molecules that provide an unbiased and a precise evaluation of kidney function are still necessary. We explored the potential of clearance of d-serine, a rare enantiomer of serine and a biomarker of kidney function, as a measure of glomerular filtration rate (GFR). METHODS: This was a cross-sectional observational study of 200 living kidney transplant donors and recipients enrolled between July 2019 and December 2020 in a single Japanese center, for whom GFR was measured by clearance of inulin (C-in). Clearance of d-serine (C-dSer) was calculated based on blood and urine levels of d-serine, as measured by two-dimensional high-performance liquid chromatography. Analytical performance was assessed by calculating biases. Utilizing data from 129 participants, we developed equations for C-in based on C-dSer and C-cre using a linear regression model, and the performance was validated in 68 participants. FINDINGS: The means of C-in and C-dSer were 66.7 and 55.7 mL/min/1.73 m2 of body surface area, respectively, in the entire cohort. C-dSer underestimated C-in with a proportional bias of 22.0% (95% confidence interval, 14.2-29.8%) and a constant bias of -1.24 (-5.78-3.31), whereas the proportional bias was minor to that of C-cre (34.6% [31.1-38.2%] and 2.47 (-1.18-6.13) for proportional and constant bias, respectively). Combination of C-dSer and C-cre measured C-in with an equation of 0.391 × C-dSer + 0.418 × C-cre + 3.852, which reduced the proportional bias (6.5% [-0.2-13.1%] and -4.30 [-8.87-0.28] for proportional and constant bias, respectively). In the validation dataset, this equation performed well with median absolute residual of 3.5 [2.3-4.8], and high ratio of agreement (ratios of 30% and 15% different from C-in [P30 and P15] of 98.5 [91.4-100] and 89.7 [80.0-95.2], respectively). INTERPRETATION: The smaller proportional bias compared to that of C-cre is an advantage of C-dSer as a measure of C-in. Combinational measurement of d-serine and creatinine, two endogenous molecules, has the potential to serve as a measure of GFR with precision and minor biases and can support important clinical decisions. FUNDING: Japan Society for the Promotion of Science (JSPS, grant number 17H04188), Japan Agency of Medical Research and Development (AMED, JP20gm5010001), Osaka Kidney Bank (OKF19-0010), Shiseido Co., Ltd and KAGAMI Inc.

Cystatin C, a Controversial Biomarker in Hypothyroid Patients under Levothyroxine Therapy: THYRenal, a Pilot Cohort Observational Study.

BACKGROUND: Cystatin C (Cys-C) is recognized as one of the most reliable renal function parameters in the general population, although it might be biased by thyroid status. Herein, we tested Cys-C and conventional renal parameters in a cohort of hypothyroid patients treated with Levothyroxine. METHODS: Eighty-four hypothyroid patients were recruited and subgrouped according to their serum thyroid-stimulating hormone (TSH) values as a paradigm for therapeutic targeting (n = 54, optimal TSH range = 0.5-2 µIU/mL; n = 30, TSH > 2µIU/mL). Serum Cys-C, creatinine, measured and estimated glomerular filtration rates (mGFR and eGFR) were assessed. Results-mGFR and eGFR were comparable among the two subgroups, whereas Cys-C was significantly higher in patients with suboptimal TSH values (>2 µIU/mL) (p < 0.0001). TSH significantly correlated with Cys-C in the overall patient group, and in the subgroup with TSH above the target value (>2 µIU/mL). Out of 20 patients with abnormal Cys-C, 19 had suboptimal TSH levels. Receiver operating characteristic (ROC) analysis indicated Cys-C as a moderately accurate diagnostic tool (AUC = 0.871) to assess Levothyroxine replacement efficacy in hypothyroid patients (63% sensitivity, and 98% specificity). CONCLUSIONS: The observation of increased serum Cys-C in patients with suboptimal TSH would suggest the importance of a careful interpretation by clinicians of this biomarker in the case of hypothyroid patients.

How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy.

BACKGROUND: Estimated glomerular filtration (eGFR) results based on serum creatinine are frequently inaccurate with differences against measured GFR (mGFR) often attributed to unmeasured non-functional factors, such as muscle mass. METHODS: The influence of muscle mass (measured by dual-energy x-ray absorptiometry, DEXA) on eGFR error (eGFR-mGFR) was evaluated using isotopic mGFR (Tc99m DTPA plasma clearance) in 137 kidney transplant recipients. Serum creatinine was measured by isotopic-calibrated enzymatic analysis, converted to eGFR using Chronic Kidney Disease EPIdemiology (CKD-EPI) formula, then unindexed from body surface area. FINDINGS: Unindexed CKD-EPI eGFR error displayed absent fixed bias but modest proportional bias against reference mGFR. eGFR error correlated with total lean mass by DEXA (r=-0·350, P<0·001) and appendicular skeletal muscle index (ASMI), a proxy for muscularity (r=-0·420, P<0·001). eGFR was falsely reduced by -5·9 ± 1·4 mls/min per 10 kg lean mass. Adipose mass and percentage fat had no effect on error. Muscle-associated error varied with each eGFR formula and influenced all CKD stages. Systemic eGFR error was predicted by ASMI, mGFR, recipient age, and trimethoprim use using multivariable regression. Residual plots demonstrated heteroscedasticity and greater imprecision at higher mGFR levels (P<0·001), from increased variance corresponding to higher absolute values and unreliable prediction by serum creatinine of high mGFR. Serum creatinine correlated with ASMI independent of mGFR level (r = 0·416, P<0·001). The diagnostic test performance of CKD-EPI eGFR to predict CKD stage 3 (by mGFR) was weakest in cachexia (sensitivity 68·4%) and muscularity (specificity 47·4%, positive predictive value 54·5% for the highest ASMI quartile). INTERPRETATION: Serum creatinine and eGFR are imperfect estimates of true renal function, with systemic errors from muscle mass, tubular secretion, and intrinsic proportional bias; and additional inaccuracy at the extremes of renal function and patient muscularity. Cautious interpretation of eGFR results in the context of body habitus and clinical condition is recommended.