Measured Glomerular Filtration Rate: The Query for a Workable Golden Standard Technique

Inulin clearance has, for a long time, been considered as the reference method to determine measured glomerular filtration rates (mGFRs). However, given the known limitations of the standard marker, serum creatinine, and of inulin itself, and the frequent need for accurate GFR estimations, several other non-radioactive (iohexol and iothalamate) and radioactive (51Cr-EDTA, 99mTc-DTPA, 125I iothalamate) exogenous mGFR filtration markers are nowadays considered the most accurate options to evaluate GFR. The availability of 51Cr-EDTA is limited, and all methods using radioactive tracers necessitate specific safety precautions. Serum- or plasma-based certified reference materials for iohexol and iothalamate and evidence-based protocols to accurately and robustly measure GFR (plasma vs. urinary clearance, single-sample vs. multiple-sample strategy, effect of sampling time delay) are lacking. This leads to substantial variation in reported mGFR results across studies and questions the scientific reliability of the alternative mGFR methods as the gold standard to evaluate kidney function. On top of the scientific discussion, regulatory issues are further narrowing the clinical use of mGFR methods. Therefore, this review is a call for standardization of mGFR in terms of three aspects: the marker, the analytical method to assess concentrations of that marker, and the procedure to determine GFR in practice. Moreover, there is also a need for an endogenous filtration marker or a panel of filtration markers from a single blood draw that would allow estimation of GFR as accurately as mGFR, and without the need for application of anthropometric, clinical, and demographic characteristics.

Laju Filtrasi Glomerulus pada Anak: Metode Apa yang Digunakan?

Abstrak Laju filtrasi glomerulus (LFG) adalah kecepatan filtrasi volume plasma melalui ginjal per unit waktu per luas permukaan tubuh (LPB) dan merupakan salah satu indikator utama untuk pemantauan fungsi ginjal. Standar baku emas untuk menentukan LFG saat ini adalah dengan menghitung klirens inulin ginjal. Akan tetapi, karena prosedur tersebut dinilai kompleks, maka klirens inulin tidak digunakan dalam praktik klinik. Estimasi LFG menggunakan penanda eksogen lainnya seperti kreatinin serum dan sistatin C merupakan pilihan praktis yang dapat menggantikan perhitungan klirens inulin ginjal. Penentuan LFG pada anak berbeda dengan pada dewasa karena tidak mudah mengumpulkan urin per hari pada anak, sehingga diperlukan formula untuk mempermudah menentukan LFG. Berbagai peneliti telah melakukan penelitian untuk menemukan rumus untuk menentukan LFG dengan mudah dan praktis. Pemeriksaan LFG biasanya dilakukan berbasis klirens kreatinin dan belakangan ini dilakukan degan pemeriksaan sistatin C. Beberapa penanda yang digunakan untuk pengukuran LFG antara lain zat radiofarmaka seperti chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), technetium 99-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA), iodine 125-labeled iothalamate (125I-iothalamate), dan zat kontras radiografik. Dari berbagai rumus estimasi LFG, salah satu yang kini direkomendasikan untuk digunakan pada praktik klinis sehari-hari adalah rumus Schwartz yang dimodifikasi, karena dinilai sederhana, relatif akurat, tidak invasif, dan tidak membutuhkan biaya yang mahal. Kata kunci: laju filtrasi glomerulus, penyakit ginjal pada anak, kreatinin, sistatin C Abstract Glomerular filtration rate (GFR), which represents the plasma volume filtered through the kidney for each time unit and body surface area (BSA) unit, is one of the main indicators for renal function. The current gold standard for determining GFR is by calculating the renal inulin clearance. However, because this involves a complex procedure, inulin clrearance was not used in clinical practice. GFR estimation using other exogenous markers such as serum creatinine and cystatin C can be considered as practical alternatives. Determining GFR in children is difference with in adult because difficulty of 24 hours urine collection in children, so iti is needed a simple formula for determining GFR. Some researchers performed studies for determining easy and practical formula. GFR examinations usually based on creatinine clearance and nowadays by cyatatin C examination. Some markers are used in measuring of GFR such as chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), technetium 99-labeled diethylenetriaminepentaacetic acid (99mTc-DTPA), iodine 125-labeled iothalamate (125I-iothalamate), and radiographic contrast. Among the various existing formulas to estimate GFR, one of the most commonly recommended in daily clinical practice is the modified Schwartz formula, as it is thought to be simple, relatively accurate, non-invasive, and inexpensive. Keywords: glomerular filtration rate, pediatric kidney diseases, creatinine, cystatin C

Urinary Excretion of Iohexol as a Permeability Marker in a Mouse Model of Intestinal Inflammation: Time Course, Performance and Welfare Considerations

Intestinal permeability (IP) tests are used to assess intestinal damage in patients and research models. The probe iohexol has shown advantages compared to 51Cr-EDTA or absorbable/nonabsorbable sugars. During IP tests, animals are housed in metabolic cages (MCs) to collect urine. We examined the performance of an iohexol IP test in mice. Rag1-/- (C57BL/6) mice of both sexes were divided into controls or treatment groups, the latter receiving injections of effector/memory T cells to induce intestinal inflammation. After two, four and five weeks (W), a single dose of iohexol was orally administered. Urine was collected seven times over 24 h in MCs. Iohexol concentration was measured by ELISA. Intestinal histological damage was scored in duodenal sections. In control and treated mice of both sexes, urinary excretion of iohexol peaked at 4 h. From W2 to W4/W5, urinary iohexol excretion increased in treated mice of both sexes, consistent with development of duodenitis in this model. Positive correlations were observed between the urinary excretion of iohexol in W4/W5 and the histological severity of duodenitis in treated male mice. We conclude that a 6 h cumulative urine sample appears sufficient to evaluate small IP to iohexol in this mouse model, improving animal welfare by reducing cage periods.

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

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 < 0.01). Mean absolute bias between Ccr and 51Cr-EDTA was 10.59 ± 37.99 ml/min/1.73m2 (p < 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.

P0199ASSESMENT OF FILTRATION RATE IN ONCOLOGICAL PATIENTS

Background and Aims Accuracy in the estimation of the glomerular filtration rate (GFR) in oncological patients is essential in order to adjust chemotherapy doses accordingly. Finding an appropriate formula for this subgroup of patients is a subject of ongoing debate. The present study introduces a cohort of the aforementioned patients followed in the Onconephrology outpatients clinic, in which different formulas were applied for the calculation of the GFR. Method A retrospective study with a cohort of 17 onconephrological patients was conducted. The following variables were evaluated: age, sex, height, weight, body mass index, body surface area and type of tumor. Renal function was estimated with the Cockcroft Gault, the Janowitz-Williams, the CKD-EPI, the adjusted by body surface-CKD-EPI, the MDRD, the adjusted by body surface-MDRD, the CKD-EPI Cystatin C, the adjusted by body surface-CKD-EPI Cystatin C formulas and 24-hour urine creatinine clearance. Every equation was compared with the Cr EDTA clearance which is considered the gold standard. The statistical analysis was carried out by means of the IBM SPSS Statistics software. Concordance between chromatography and the remaining formulas was assessed with the Wilcoxon (null hypothesis of no difference between medians) and Bland-Altman tests. Results 6 women and 11 men were included in the study, with a mean age of 64.24 years (SD 9.9), a mean BMI of 28.25kg/m2 (SD 7.98), and a mean Cr EDTA clearance was 37.07ml/min (SD 15.45). 15 patients suffered from solid malignancies, whereas the remaining 2 patients suffered from hematological tumors. The most common solid tumor was lung cancer (n=5), followed by rectal carcinoma (n=2). The null hypothesis was accepted for the adjusted for body surface-CKD-EPI Cystatin C equation (p-0,089) and 24-hour urine creatinine clearance (p 0.955), when compared to 51Cr EDTA clearance. The Bland-Altman test revealed the smallest differences between the 24-hour urine creatinine clearance and 51Cr EDTA clearance (-0.09867), with 95% concordance limits of -36.14 and 34.17, and a non-significant linear regression coefficient (p 0.915). Conclusion This study revealed that the 24-hour urine creatinine clearance is the closest formula to the gold standard for the assessment of the GFR in patients with malignancies. However, the small sample size hinders the generalization of these results. Larger sample size studies are mandatory to confirm these findings.