Determination Of Glomerular Filtration Rate Research Articles

Estudio de la asociación de marcadores de rigidez arterial central y periférica con la función renal en pacientes con hipertensión arterial, diabetes mellitus y enfermedad renal crónica

Rationale and objectivesIncreased aortic or central arterial stiffness (CAS) is a major factor in cardiovascular morbidity and mortality in patients with vascular risk factors. Decreased glomerular filtration rate (GFR) and increased urinary albumin excretion (uALB) are associated with lethal and non-lethal cardiovascular events. The pathophysiological mechanisms of this association are not fully defined.The aim of this study was: 1.- To analyze the CAS, comparing several markers, in subjects with arterial hypertension (HTN), diabetes mellitus (DM), chronic kidney disease (CKD) and their combination. 2.- To study the possible association of CAS with renal dysfunction (decrease in GFR and increase in uALB). Material and methodsA total of 286 subjects were included, divided into several groups: Control (n: 38); HTN (n:51); DM without CKD (n:26); CKD without DM (n:77); CKD with DM (n:94). Several indices obtained by applanation tonometry were used to determine the CAS: carotid-femoral pulse velocity (VPc-f); central pulse pressure (cPP); augmentation index standardized to a cardiac frequency of 75 l/min (IA75); peripheral / aortic arterial stiffness gradient (ASGp-a). As a marker of peripheral arterial stiffness, the carotid-radial pulse velocity (PVc-r) was determined. The ASGp-a was calculated from the PVc-r /PVc-f ratio. The subendocardial viability index (iBuckberg) was obtained from the aortic pulse wave.Multiple regression, binary logistic regression, and multinomial regression were used to study the association between arterial stiffness markers and renal function. ResultsThe adjusted values of the PVc-f [(median (interquartile range) (m/sec)] were significantly higher in subjects with DM [(9 (1.2)], CKD [(9.4 (0.7)] and DM with CKD [(10.9 (0.7)] than in the control group [(8.2 (1.3)] and group with HTN [(8.3 (0.9)], (p:0.001). Patients with DM with CKD had higher PVc-f values than all other groups (p: 0.001). The ASGp-a of the patients was significantly lower than that of the controls, and the group with DM with CKD had significantly lower values than the other groups. The cPP in the DM with CKD group was significantly higher than in the other groups. All patients had an AI75 higher than the control group.When all aortic stiffness markers were introduced together in the regression, PV c-f was the only one that, after multivariate adjustment, was independently and inversely associated with GFR (β; –4, p:0.001) and predicted the presence of GFR decrease (< 60mL/min/1.73 m2), [(OR (95%CI): 1.50 (1.17-1.92; p:0.001]. The PVc-f was the only index directly associated with albuminuria (β: 0.15, p: 0.02) and predicted the existence of abnormal albuminuria (> 30mg/g), [(OR; 1.66 (1.25-2.20), p:0.001)]. The PVc-f was also associated with the iBuckberg (β: -2.73, p: 0.01).Multinomial regression confirmed that PVc-f is a significant determinant of GFR and uALB. On the other hand, the increase in PVc-f and the presence of DM contribute significantly to the magnitude of albuminuria. ConclusionsAortic stiffness increases in the presence of vascular risk factors such as hypertension, DM and CKD. This increase is greater when DM and CKD coexist. Increased aortic stiffness is inversely associated with GFR and directly with uALB, and is predictive of decreased GFR and abnormal uALB. The VPc-f is the parameter of aortic stiffness that is most consistently associated with renal dysfunction. Increased aortic stiffness could be one of the pathomechanisms linking renal dysfunction to cardiovascular events.

Objectification of the method for glomerular filtration rate assessing in patients with diffuse large B-cell lymphoma during induction immunochemotherapy

Aim. To study the glomerular filtration rate (GFR) dynamics calculated by creatinine and cystatin C during induction immunochemotherapy in patients with newly diagnosed diffuse large B-cell lymphoma in order to objectify the method for estimation.Materials and methods. The open longitudinal study included 39 patients with newly diagnosed diffuse large B-cell lymphoma who received specialized treatment at the Oncohematology Department of National Medical Research Centre for Oncology (Rostov-on-Don) in 2021. Patients received induction immunochemotherapy according to the R-CHOP regimen (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone) in combination with accompanying therapy (allopurinol 300 mg/day). Blood sampling was carried out at 0, 24, 48, 72, 120 hours and on 21st day of the 1st therapy cycle. Patients were divided into 2 groups depending on the GFR level, calculated by creatinine, before treatment: group A – 27 (69 %) patients with GFR &gt;90 ml/min/1.73 m2, group B – 12 (31 %) patients with GFR &lt;90 ml/min/1.73 m2.Results. During the immunochemotherapy in patients with initially reduced GFR, a further decrease was observed with the restoration of the initial level by day 21 of therapy. When calculating GFR by cystatin C, in contrast to the calculation by creatinine, it revealed the dependence of GFR level on pathological process stage: GFR in group A patients with stages I–II is 20.4 % lower than in patients with stages III–IV, in group B – by 30.5 %. The use of the fisher test at GFR thresholds of 90 and 60 ml/min/1.73 m2 revealed a greater advantage in establishing absolute GFR levels, especially in the range of 60 to 90 ml/min/1.73 m2.Conclusion. The data obtained confirm that the determination of GFR by cystatin C in patients with diffuse large B-cell lymphoma is a more sensitive method that objectively reflects the functional state of the kidneys, especially when values are within the “gray area” – from 90 to 60 ml/min/1.73 m2.

Comparison of different estimated glomerular filtration rates for monitoring of kidney function in oncology patients.

Tyrosine kinase inhibitors (TKIs) are associated with kidney function deterioration. A shift is ongoing towards glomerular filtration rate (GFR) equations based on other protein markers, such as cystatin C (CSTC) and β-trace protein (BTP). We evaluated various GFR equations for monitoring of kidney function in actively treated oncology patients. We monitored 110 patients receiving a TKI. Blood and urine were collected during therapy. Serum analysis included creatinine (Cr), CSTC and BTP; for consequent GFR determination. Urine was analysed for protein, albumin, immunoglobulin G, and α-1-microglobulin. A similar analysis was done in a patient subgroup receiving immune checkpoint inhibitors (ICI) as prior or subsequent line of therapy. Cr remained constant during TKI treatment (P=0.7753), whereas a significant decrease in CSTC (from week 2 onward, P<0.0001) and BTP (at weeks 2 and 4, P=0.0100) were noticed. Consequently, GFR estimations, using CSTC and/or BTP as a biochemical parameter, showed an apparent increase in GFR, whereas this was not observed for Cr-related GFR estimations. As a result, the GFR gap (ΔGFR) was significantly different from week 2 onward between Cr-based and CSTC-based GFR and between BTP-based and CSTC-based GFR. Glomerular damage was noticed with significant increase in urine protein-to-creatinine ratio, albumin-to-creatinine ratio and immunoglobulin G (all P<0.0001). No change in α-1-microglobulin was seen. ICI treatment had no effect on Cr (P=0.2262), CSTC (P=0.7341), and BTP concentrations (P=0.3592). GFR equations, in which CSTC is incorporated, fail to correctly estimate the GFR in oncology patients treated with TKIs. As TKI-treated patients show clear signs of glomerular injury, further assessment is needed on how to correctly monitor the kidney function in actively treated oncology patients.

Volumetric microsampling for simultaneous remote immunosuppressant and kidney function monitoring in outpatient kidney transplant recipients.

Immunosuppressant and kidney function monitoring are crucial for kidney transplant recipient follow-up. Microsamples enable remote sampling and minimise patient burden as compared to conventional venous sampling at the clinic. We developed a liquid chromatography-tandem mass spectrometry assay to quantify tacrolimus, mycophenolic acid (MPA), creatinine and iohexol in dried blood spot (DBS), and volumetric absorptive microsample (VAMS) samples. The assay was successfully validated analytically for all analytes. Clinical validation was conducted by direct comparison of paired DBS, VAMS and venous reference samples from 25 kidney transplant recipients. Patients received iohexol 5-15 minutes before immunosuppressant intake and were sampled 0, 1, 2 and 3hours thereafter, enabling tacrolimus and MPA area under the concentration-time curve (AUC) and creatinine-based and iohexol-based glomerular filtration rate (GFR) estimation. Method agreement was evaluated using Passing-Bablok regression, Bland-Altman analysis and the percentages of values within 15-30% of the reference (P15 -P30 ) with a P20 acceptance threshold of 80%. For DBS samples, method agreement was excellent for tacrolimus trough concentrations (n =25, P15 = 92.0%) and AUCs (n =25; P20 = 95.8%) and adequate for creatinine-based GFR trend monitoring (n =25; P20 = 80%). DBS-based MPA AUC assessment showed suboptimal agreement (n =16; P20 = 68.8%), but was considered acceptable given its P30 of 100%. The assay performed inadequately for DBS-based iohexol GFR determination (n =24; P20 = 75%). The VAMS technique generally showed inferior performance, but can be considered for certain situations. The assay was successfully validated for tacrolimus, MPA and creatinine quantification in DBS samples, enabling simultaneous remote kidney function trend monitoring and immunosuppressant therapeutic drug monitoring in kidney transplant recipients.

Short course of immune-suppressive doses of prednisolone, evaluated through a prospective double-masked placebo-controlled clinical trial in healthy Beagles, is associated with sustained modifications in renal, hydration, and electrolytic status.

To investigate the effects and duration of orally administered prednisolone on renal function evaluated by glomerular filtration rate (GFR) determination and creatinine (Cr) and symmetric dimethylarginine (SDMA) concentrations as well as on urinalysis, electrolytes, and hydric status in healthy dogs. 14 healthy Beagles. In this prospective double-masked placebo-controlled study, dogs were randomized after baseline evaluation to receive a 7-day course of either prednisolone (1.5 to 2.0 mg/kg, PO, q 12 h) or a placebo. A repeated-measure design was performed, each dog participating in 4 successive sampling sessions. Clinical data, systolic blood pressure, CBC, and biochemical analyses including serum SDMA concentration, GFR determination, urine output quantification, and complete urinalysis were performed for all dogs the day before (D0) and at the end of steroid administration (D7) as well as 2 weeks (D21) and 4 weeks (D35) after the end of treatment. At D7, when compared with baseline, GFR increased significantly in treated dogs, whereas creatinine and SDMA concentrations decreased significantly. GFR and Cr but not SDMA modifications persisted significantly at D21. None of the variables differed significantly from baseline at D35. The OR of presenting an albumin band on urine electrophoresis was 2.4 times as high in treated versus control dogs (OR, 36; 95% CI, 1.8 to 719.4; P = 0.02). A short-term course of immune-suppressive prednisolone treatment in healthy dogs leads to a sustained but reversible renal hyperfiltration state. Modification in electrolytic variables can affect the clinical interpretation of blood work in such patients.

Comparison of double plasma sampling method and gates method for estimation of glomerular filtration rateComparison of double plasma sampling method and gates method for estimation of glomerular filtration rateComparison of double plasma sampling method a

Glomerular filtration rate (GFR) is an important indicator of renal function. Several methods have been applied to calculate GFR in clinical exams. In this study, we evaluated and compared between radionuclide plasma sampling methods (double blood samples, in vitro methods) and in vivo Gate’s method using 99mTc-diethylene triamine penta-acetic acid (99mTc-DTPA) renography. Subejct and method: 42 patients were participated in this study, including 12 patients with obstructive uropathy (group 1) and 30 renal donors (group 2). The administered doses were in a range of 5 – 7mCi. Then, scintigraphy was performed simultaneously after injection, and GFR was calculated by Gate’s method. Blood samples were collected at 60 mins and 120 mins post-injection, which were counted by a thyroid uptake system, and GFR results were determined using a double plasma sample (DPSM) method. Result: The mean GFRs calculated by renography in groups 1 and 2 were 85.8 ± 16.2 (ml/min) and 118.9 ± 13.9 (ml/min), respectively. Meanwhile, using the in vitro DPSM, the mean GFRs in group 1 and 2 were 73.8 ± 15.4 (ml/min) and 117.0 ± 13.0 (ml/min) respectively. They showed a high correlation between the two methods in the two groups (r = 0.86 and 0.71, respectively). Conclusion: Renography is a simple technique but considered inaccurate for determination of GFR. However, in vitro DPSM is rarely used in Vietnam. In this study, Gate’s method corresponded well with plasma sampling method and tended to overestimate the glomerular filtration rate.

Association of decreased glomerular filtration rate with renal hemodynamic disorders and inflammatory biomarkers in patients with medically-controlled hypertension of high cardiovascular risk

Aim. To assess markers of chronic kidney disease (CKD) in patients with medically-controlled hypertension (HTN) (&lt;140/90 mm Hg), as well as to analyze potential association of decreased glomerular filtration rate (GFR) &lt;60 ml/min/1,73 m2 with clinical data and therapy; to establish significant determinants of GFR decrease in this category of patients.Material and methods. The study included 70 patients with HTN and office blood pressure (BP) &lt;140/90 mm Hg aged 64 (57; 68) years (men, 48,6%), of whom 40 patients were examined within the Russian multicenter CHRONOGRAPH program. Office BP was 130 (120; 140)/80 (72; 82) mm Hg. GFR and albuminuria were assessed. Twenty-four-hour BP monitoring and Doppler ultrasound of renal blood flow with estimation of resistance indices (RI) were performed. The content of highsensitivity C-reactive protein (hsCRP), interleukins (IL) 1β, 6, 10 and lipid transport function parameters was determined.Results. CKD markers were detected in 31,4% of patients (in 27,1% — a decrease in GFR &lt;60 ml/min/1,73 m2; in 12,9% — pathological albuminuria). Patients with CKD markers were older, had higher office systolic BP and nocturnal pulse pressure, higher blood hsCRP and RI levels throughout the renal flow, and lower high-density lipoprotein cholesterol levels. In the presence of CKD markers, calcium channel blockers, aldosterone receptor antagonists and statins were used more often. The results of correlation analysis were used to determine the determinants of GFR decline. In the general group, GFR values had inverse correlations with age (Rs=-0,58, p&lt;0,0001), segmental intrarenal artery RI (Rs= -0,4232, p=0,0005), blood hsCRP (Rs=-0,3998, p=0,0007), IL-1β (Rs=-0,3139, p=0,0086), office BP and some 24-hour BP parameters. In the presence of CKD markers, a direct association of GFR and IL-10 was determined (Rs=0,4293, p=0,046). In the absence of such markers, GFR had an inverse correlation with IL-1β content (Rs=-0,3110, p=0,0333). A multiple linear regression model included following independent determinants of GFR: age, blood hsCRP and RI in the segmental intrarenal arteries.Conclusion. Among patients with medically-controlled HTN of high cardiovascular risk, a high prevalence of CKD markers was revealed (31,4%). Compared with patients with preserved renal function, in the presence of CKD markers, there were higher levels of office systolic BP, nocturnal pulse pressure, blood hsCRP, and intrarenal artery RI. Associations were established between GFR and the levels of hsCRP, IL-1β and IL-10, which confirms the pathological role of inflammatory biomarkers in developing renal dysfunction in high-risk HTN. Age, elevated blood hsCRP levels, and intrarenal artery RI are independent determinants of decreased GFR in patients with medically-controlled HTN of high and very high cardiovascular risk. The data obtained shows the need for early prescription of combination antihypertensive therapy with nephro- and vasoprotective effects in this category of patients, as well as with an ability to depress the chronic subclinical inflammation.

Comparison between Three Techniques for Determining Glomerular Filtration Rates: 99mTc-Diethylene Triamine Penta-Acetic Acid Renography, Double Plasma Sampling Method, and Single Plasma Sampling Method in Vietnamese Patients.

Glomerular filtration rate (GFR) is an important indicator of renal function. Many methods have been developed to determine GFR in clinical examinations. This study aims to correlate between radionuclide plasma sampling methods (single and double blood samples, in vitro methods) and in vivo Gate's method using 99mTc-diethylene triamine penta-acetic acid (99mTc-DTPA) renography.Materials and Methods:43 patients underwent this study, including 31 renal donors (Group 1) and 12 patients with obstructive uropathy (Group 2). All patients were administered with a range of 5–7 mCi of 99mTc-DTPA. Then, renography performed simultaneously after injection and GFR calculation followed by Gate's method. Blood samples were collected at 60- and 120-min postinjection, samples were counted by a thyroid uptake system, and GFR was calculated using a single plasma sample method (SPSM) and a double plasma sample method (DPSM).Results:The mean GFRs calculated by Gate's method in Groups 1 and 2 were 85.8 ± 18.2 ml/min and 118.4 ± 13.9 ml/min, respectively. Meanwhile, using the in vitro blood sampling methods (DPSM and SPSM), the mean GFRs in Group 1 were 73.8 ± 15.4 ml/min and 56.4 ± 20.9 ml/min, respectively, and in Group 2 were 116.8 ± 12.9 ml/min and 106.3 ± 18.5 ml/min, respectively. There is a high correlation between Gate's method and DPSM in two groups (r = 0.86 and 0.72, respectively), and a moderate correlation was found between Gate's method and SPSM in both groups (r = 0.49 and r = 0.37, respectively). The two in vitro methods (DPSM and SPSM) revealed that moderate correlation in both groups (r = 0.74 and r = 0.67, respectively) was observed.Conclusion:Renography is a simple method but considered inaccurate for GFR determination. However, in vitro plasma sampling is rarely used in Vietnam. In this study, Gate's method correlated well with DPSM and tended to overestimate GFR. Further, the in vitro methods can be applied to correct the in vivo method as a confirmatory test in some cases.

Novel in vivo and ex vivo hybrid in vivo imaging system (IVIS) imaging offers a convenient and precise way to measure the glomerular filtration rate in conscious mice

IntroductionIn pharmacology and toxicology studies, the glomerular filtration rate (GFR) is the gold standard for the assessment of renal function, and the renal clearance of inulin in blood measured by photometers is known as a filtration marker for the determination of GFR. Preclinically, a non-invasive GFR measurement method was recently developed in which near-infrared fluorescently labelled inulin (GFR-Vivo 680) was scanned with fluorescence molecular tomography (FMT). However, measurement of GFR using FMT has major disadvantages and technical challenges, such as requiring experienced skills in animal handling and rapid and precise time management. Additionally, fur and skin pigmentation may severely compromise imaging due to tissue fluorescence absorption. To overcome these drawbacks of FMT imaging, we have developed an in- and ex vivo hybrid method for measuring GFR using the in vivo imaging system (IVIS). MethodsAn IVIS-based imaging method was tested to determine the clearance kinetics of plasma GFR-Vivo 680 after a single bolus injection in conscious C57BL/6 mice administered vehicle or cyclosporine A (CsA, 80 mg/kg) for 14 days. ResultsBased on a two-compartment model fitting, the estimated GFR was 235 ± 53 and 189 ± 19 μL/min in vehicle-treated and CsA-treated male mice, respectively (p < 0.01). Our assay revealed the decreased GFR, similar to the sensitivity of FMT imaging, which yielded comparable GFR values (229 ± 61 and 151 ± 35 μL/min in vehicle-treated and CsA-treated mice, respectively, p < 0.01), and to those previously reported in the literature. DiscussionThese studies demonstrate the feasibility of IVIS imaging measurement of inulin clearance in untreated, vehicle-treated and cyclosporine A-treated mice. We propose this new method as an alternative, simple, and versatile way to measure GFR in vivo and ex vivo in pharmacological and toxicological studies.

Iohexol plasma clearance for measuring glomerular filtration rate: effect of different ways to calculate the area under the curve

BackgroundMeasuring glomerular filtration rate (GFR) using iohexol plasma clearance has been proposed as the preferred way for GFR determination. The extended multiple-sample protocol is based on fitting the full concentration-time decay-curve, and from the obtained fit-parameters, the area under the curve (AUC) and GFR (the injected dose divided by the AUC) were calculated. The goal of the current study is to evaluate the impact of different fitting procedures on the precision of GFR-results obtained from the full concentration-time curve, and compare these results with those obtained with simplified multiple-samples and single-sample protocols.MethodsThe concentration-time curves of 8 samples at times 30, 60, 90, 120, 150, 180, 240 and 300 min after bolus injection of iohexol of 570 adults, aged 70+, from the Berlin Initiative Study (BIS), were analysed. The fit-parameters for the two-compartment model (double-exponential decay curve), and from these, the AUC and GFR were obtained with 8 different fitting procedures.ResultsThe two-compartmental non-linear least squares fitting procedure showed the best accuracy (541 out of 570 reported GFR-results were within 5% of the majority of the 8 fitting methods). The two-compartmental slope-intercept fitting procedure was not always applicable and the non-compartmental fitting procedures did not always allow to calculate the GFR. All correction formulas for the simplified late multiple-samples methods showed acceptable accuracy and precision with a preference for Ng’s correction formula (Lin’s CCC = 0.992, bias = 0.5 ± 2.5). Jacobsson’s iterative method was the best one-sample method, with Lin’s CCC = 0.983 and bias = − 0.6 ± 3.4.ConclusionThe fitting procedure has an important impact on the precision of the calculated AUC and GFR. The simplified late-sample protocols and one-sample methods did not suffer from fitting problems and showed acceptable equivalence when compared to the full compartment GFR-results.Trial registrationThe “Berlin Initiative Study” is officially registered with the German Register for Clinical Studies (“Deutschen Register Klinischer Studien”(DRKS)) under registration number DRKS00017058, since April 12, 2019, and it is also visible on the WHO clinical trials registry platform (within the next 4 weeks after the registration date).

Comparison of Early-Compartment Correction Equations for GFR Measurements

Measuring the glomerular filtration rate (GFR) remains indicated in specific patients and/or specific clinical contexts.1,2 For practical reasons, plasma clearances are preferred instead of urinary clearance. In most centers, the plasma clearance is calculated from exogenous marker concentrations obtained during the excretion phase (the second or slow GFR compartment), which is the most important for GFR determination. However, GFR is systematically overestimated because the part of the area under the curve (AUC) from the first (or early) compartment, which corresponds to the distribution of the marker in the body, is neglected.

Determination of the glomerular filtration rate in patients with type 2 diabetes: An assessment of the agreement between 51Cr-EDTA plasma clearance and 99mTc-DTPA plasma clearance, 99mTc-DTPA renography and plasma creatinine prediction equation

AimsTo investigate the agreement of glomerular filtration rate (GFR) determination between 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA) plasma clearance (GFREDTA) and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) plasma clearance (GFRDTPA), the Gates 99mTc-DTPA renographic method (GFRGates) and the serum creatinine Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI, GFRSCr) in patients with type 2 diabetes mellitus (T2DM). MethodsNinety-nine T2DM patients underwent GFR determinations simultaneously with 51Cr-EDTA and 99mTc-DTPA (using the slope-intercept technique and the Brochner-Mortensen correction) and also with GFRGates and GFRSCr. ResultsIn the comparison between GFREDTA versus GFRDTPA, GFRGates and GFRSCr, the Bland-Altman statistic provided 0.0 ± 13.2, 17.4* ± 28.8 and −5.9* ± 30.1 (*p < 0.001 for the difference from 0). Lin’s concordance correlation coefficient showed substantial (0.976), poor (0.737) and poor (0.872) agreement, respectively. The proportion of the index results within the 30% and 10% of GFREDTA measurements were 95% and 74% for GFRDTPA, 53% and 19% for GFRGates, and 83% and 26% for GFRSCr, respectively. ConclusionIn T2DM patients, a clinically acceptable agreement is demonstrated between 51Cr-EDTA and 99mTc-DTPA plasma clearance for GFR measurements, suggesting conditional interchangeability between those compounds. Both the CKD-EPI prediction equation and the Gates’ renographic method cannot assess GFR reliably, the latter appearing less unfailing than the former.

Proenkephalin Compared to Conventional Methods to Assess Kidney Function in Critically Ill Sepsis Patients.

ABSTRACTBackground:The assessment of renal function in clinical practice remains challenging. Using creatinine to assess the glomerular filtration rate (GFR) is notoriously inaccurate, and determination of the true GFR, e.g., using inulin or iohexol, is laborious and not feasible in daily practice. Proenkephalin (PENK) is a novel candidate biomarker for kidney function that is filtrated in the glomerulus, has shown to represent steady-state GFR in patients with different severities of renal insufficiency. In this pilot study in non-steady-state critically ill patients, we compared plasma PENK concentrations with creatinine-based GFR assessments and validated both against the “true GFR” measured using a gold standard method: iohexol plasma clearance.Methods:Twenty-three critically ill patients with septic shock were included. Kidney function was determined using the Modification of Diet in Renal Disease formula (eGFRMDRD), Endogenous Creatinine Clearance (GFRECC), and iohexol plasma clearance (GFRiohexol) during a 6-h window. Plasma PENK concentrations were measured using the penKid immunoassay.Results: The eGFRMDRD and GFRECC correlated with the GFRiohexol (R2 = 0.82, P < 0.0001 and R2 = 0.82, P < 0.0001 respectively); however, bias and variability were considerable: the eGFRMDRD overestimated the true GFR with 31 ± 35% (95% limits of agreement: −37% to 100%) and the GFRECC with 37 ± 49% (95% limits of agreement: −59% to 133%). Plasma PENK concentrations showed a very strong inverse correlation with the GFRiohexol (R2 = 0.90, P < 0.0001) which tended to be better compared with the correlation of eGFRMDRD (P = 0.06) and GFRECC (P = 0.08) with the GFRiohexol.Conclusions:In this pilot study in non-steady-state critically ill sepsis patients, GFR appears to be more accurately reflected by plasma PENK concentrations compared to conventional creatinine-based methods. Therefore, PENK holds promise as an accurate and feasible biomarker to determine kidney function during non-steady-state conditions in the critically ill.

Renal Functional Reserve Is Related to the Nondipping Phenotype and to the Exercise Heart Rate Response in Patients with Essential Hypertension and Preserved Renal Function

Background: Renal functional reserve (RFR), defined as the difference between stress and resting glomerular filtration rate (GFR), may constitute a diagnostic tool to identify patients at higher risk of developing acute kidney injury or chronic kidney disease. Blunted RFR has been demonstrated in early stages of hypertension and has been attributed to impaired vascular reactivity due to an overactive sympathetic nervous system (SNS). Objective: The purpose of this study was to investigate whether RFR correlates with other phenotypes expressing overactivity of the SNS in patients with essential hypertension and preserved renal function. Methods: Thirty-six patients with untreated essential hypertension and a GFR >60 mL/min/1.73 m² were enrolled. The following parameters were measured: RFR, 24-h ambulatory blood pressure (BP) profile, a treadmill stress test, and an echocardiographic examination. Urine and venous samples were obtained at specific time points for the determination of clinical parameters, and both resting and stress GFR were calculated by using endogenous creatinine clearance for the measurement of RFR after an acute oral protein load (1 g/kg). Results: Twenty-one patients had a RFR <30 mL/min/1.73 m² and 15 had a RFR above this cutoff. A nondipping pattern of 24-h BP was significantly more frequent in patients with low RFR (57.1 vs. 25.0%, p < 0.05 for systolic BP and 52.3 vs. 10.0%, p < 0.02 for diastolic BP). Moreover, patients with lower RFR values showed a blunted heart rate (HR) response to exercise during treadmill test (r = 0.439, p < 0.05). None of the echocardiographic parameters differed between the two groups of patients. Conclusions: In hypertensive patients with preserved GFR, reduced RFR is related to nondipping BP phenotype as well as to attenuated exercise HR response. Overactivity of the SNS may be a common pathway. Since loss of RFR may represent a risk factor for acute or chronic kidney injury, hypertensive patients with blunted RFR might need a more careful renal follow-up.

Measured GFR by Utilizing Population Pharmacokinetic Methods to Determine Iohexol Clearance

IntroductionThere is an increasing demand for accurately measured glomerular filtration rate (GFR). Iohexol serum clearance has become a new gold standard, but it is challenging when GFR is low and 24-hour sampling is required for accurate results. The primary aim of this study was to develop an iohexol pharmacokinetic population model for accurate determination of individual GFR using limited sampling for up to 5 hours also when renal function is <40 ml/min.MethodsA nonparametric iohexol population pharmacokinetic model was developed with rich data from 176 patients. In a validation cohort of 43 patients, a model-determined GFR (iohexol clearance) using different limited sampling strategies for up to 5 hours was compared with the strategy currently used in routine care, a log-linear 2-point method. In all, 1526 iohexol concentrations were used, from patients ranging in age from 1 to 82 years and GFR from 14 to 149 ml/min.ResultsThe clinical 2-point method showed insufficient agreement compared with reference values; 15% of GFR values had an error of greater than ±10% even when sampling for 24 hours when estimating GFR <40 ml/min per 1.73 m2 (standard procedure). Restricted sampling the first 5 hours with the population model required 4 samples to determine GFR accurately. This strategy showed excellent agreement with the reference; <3% of GFR values had an error greater than ±10 %.ConclusionUsing an iohexol population pharmacokinetic model allows for accurate determination of GFR within 5 hours when applying 4 optimally timed samples, even in patients with GFR <40 ml/min.

Validation of Glomerular Filtration Rate Measurement with Blood Sampling from the Injection Site.

Measurement of glomerular filtration rate (GFR) from the plasma clearance of a radionuclide-labeled tracer is reliable and accurate. However, to avoid contamination of the blood samples with radioactivity remaining at the injection site, venepuncture at 2 or more sites is required: one for tracer administration and the others for blood sampling. This requirement is uncomfortable for patients, particularly when venous access is difficult. The objective of this study was to validate the use of a single site of venous access in combination with injection site imaging, for GFR measurement. Methods: Twenty-two adults (≥18 y) who were referred for GFR determination were included prospectively. GFR was measured from the plasma clearance of 99mTc-diethylenetriaminepentaacetic acid according to international guidelines. After administration of the tracer through an intravenous cannula, a 60-s static image of the injection site was acquired. A second intravenous cannula was inserted into the contralateral arm. Venous blood samples were collected at 2, 3, and 4 h after administration of the radiotracer from both the injection site (experimental) and the contralateral arm (conventional). GFR was calculated using slope-intercept and single-sample methods. The median conventional and experimental plasma counts (decay- and background-corrected) were compared for the 2-, 3-, and 4-h venous samples. Conventional and experimental GFRs were then compared, with a more than 10% difference between conventional and experimental GFRs being regarded as significant. Results: Four individuals had visible residual activity at the injection site. The median 2-h counts differed significantly between the conventional and experimental sampling sites (P = 0.007), whereas no significant difference was found at 3 or 4 h. When there was a clear injection site image, the difference between the experimental and conventional GFRs was more than 10% in 1 case for single-sample GFR but less than 8% in all cases for slope-intercept GFR. Conclusion: In cases with clear injection site images, slope-intercept GFR calculated after injection site blood sampling showed no clinically significant difference from conventional contralateral-arm sampling.

Fundamental problems with pediatric adaptive dosing of carboplatin using nuclear-medicine-based estimates of renal function.

Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1737) mg/m2 . Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.

Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children

Most validations of paediatric glomerular filtration rate (GFR) estimating equations using standardized creatinine (CR) and cystatin C (CYS) assays have comprised relatively small cohorts, which makes accuracy across subgroups of GFR, age, body mass index (BMI) and gender uncertain. To overcome this, a large cohort of children referred for GFR determination has been established from several European medical centres. Three thousand four hundred eight measurements of GFR (mGFR) using plasma clearance of exogenous substances were performed in 2218 children aged 2-17years. Validated equations included Schwartz-2009CR/2012CR/CYS/CR+CYS, FASCR/CYS/CR+CYS, LMRCR, Schwartz-LyonCR, BergCYS, CAPACYS, CKD-EPICYS, AndersenCR+CYS and arithmetic means of the best single-marker equations in explorative analysis. Five metrics were used to compare the performance of the GFR equations: bias, precision and three accuracy measures including the percentage of GFR estimates (eGFR) within ± 10% (P10) and ± 30% (P30) of mGFR. Three of the cystatin C equations, BergCYS, CAPACYS and CKD-EPICYS, exhibited low bias and generally satisfactory accuracy across all levels of mGFR; CKD-EPICYS had more stable performance across gender than the two other equations. Among creatinine equations, Schwartz-LyonCR had the best performance but was inaccurate at mGFR < 30mL/min/1.73m2 and in underweight patients. Arithmetic means of the best creatinine and cystatin C equations above improved bias compared to the existing composite creatinine+cystatin C equations. The present study strongly suggests that cystatin C should be the primary biomarker of choice when estimating GFR in children with decreased GFR. Arithmetic means of well-performing single-marker equations improve accuracy further at most mGFR levels and have practical advantages compared to composite equations.

СКРИНИНГ ХРОНИЧЕСКОЙ БОЛЕЗНИ ПОЧЕК У ЖИТЕЛЕЙ ТАДЖИКИСТАНА

Objective: Assessment of the prevalence causes and risk factors for the development of chronic kidney disease (CKD) in the Republic of Tajikistan Methods: Screening of CKD and risk factors for its development among 374 persons in the course of scheduled prophylactic examinations in the urban health centers of Dushanbe city in 2017. The age of residents ranged from 18 to 82 years, averaging 55.2±12.3 years. Of these, 201 (53.7%) were females, 173 (46.3%) were males. The average weight of the examined was 85.9±11.2 kg, height – 168.3±6.92 cm, and body mass index (BMI) – 30.4±3.75. CKD was established on the basis of albuminuria, a reduction in glomerular filtration rate (GFR) and the identification of risk factors. Results: Albuminuria was detected in 63 (16.8%) residents (29 men; 34 women), more often among the age group 45-74 years (46 cases), as well as among patients with the first (n=34) and the second (n=11) degrees of obesity. Increased creatinine level in venous blood was detected in 37 patients with albuminuria (average concentration 165.5±52.5 μmol/l), mainly among people aged 45-74 years (n=23). A decrease in GFR was detected in 18 (9.9% of the total number of the examined) men and 19 (9.9% of the total number of the examined) women. A population-based screening of CKD based on the results of albuminuria, endogenous creatinine, and GFR, and other risk factors allowed us to identify various stages of CKD out of 63 cases of the positive result of albuminuria in 37 cases, which was 9.9%. The first stage of CKD was in 8 (21.6%) patients, the second stage in 15 (40.5%) patients, the third stage in 12 (32.4%) cases, and the fourth stage in 2 (5.4%) cases. Depending on age, CKD prevailed among people aged 45-74 years (62.1%). In young people (18-44 years), it occurred in 9 (24.3%) cases, and in elderly patients (75-90 years) – in 5 (13.5%) cases. Depending on the gender of the surveyed, various stages of CKD occurred in 18 (48.6%) men and 19 (51.4%) women, the diagnosis of CKD among the general population in men was 10.9%, in women – 8.9%. Conclusion: The incidence of CKD among the general population was 9.9%. Diagnosis of CKD is based on the determination of GFR and the detection of albuminuria. For the early diagnosis of CKD and adequate treatment, an algorithm has been proposed that is acceptable both economically and in terms of use in daily clinical practice. Keywords: Chronic kidney disease, screening, albuminuria, glomerular filtration rate, risk factors, prevention.

CLINICAL IMPORTANCE OF MARKERS OF RENAL DYSFUNCTION IN CARDIO-VASCULAR RISK STRATIFICATION

Purpose of the study. To study the significance of cystatin C of blood plasma and its relationship with central arterial pressure and carotid intima-media thickness (CIMT) in the stratification of cardiovascular risk.Materials and methods. A general clinical and laboratory examination of 206 patients aged 16 to 88 years was performed, of which men were 101 (49%), women - 105 (51%). The mean age of the examined subjects was 51.8±14.3 years. Lipid spectrum parameters [total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C)], cystatin C, plasma uric acid and fibrinogen were studied. Glomerular filtration rate (GFR) was calculated using the F.J. Hoek et al. (2003) formula. To assess the central blood pressure, all patients underwent a contour analysis of the pulse wave on the AngioScan-01 (AngioScan-Electronics, Russia) and ultrasound examination of carotid artery (CA) on Vivid Q (USA). The type of research was single-step cross-sectional. Depending on the content of cystatin C of the blood plasma, all the examined subjects were divided into three groups. Group 1 (n=62) consisted of patients with cystatin C concentration of up to 0.99 mg/l; group 2 (n=91) - from 1.0 mg/l to 1.5 mg/l; group 3 (n=53) - over 1.51 mg/l.Results. Patients with excessive body weight, stable angina, type 2 diabetes, cerebrovascular diseases (CVD) and chronic glomerulonephritis (CGN) significantly prevailed in group 3, in comparison with groups 1 and 2 (p&lt;0.5). Mean levels of systolic and central blood pressure (BP) were significantly higher in patients from group 3 (p&lt;0.05). In the same group, there was a significant decrease in HDL cholesterol level (p&lt;0.05), an increase in TG concentration (p&lt;0.05), and blood plasma uric acid (p&lt;0.05), as well as CIMT. Statistically and clinically significant decrease in GFR and an increase in the level of cystatin C in blood plasma was noted both in groups 2 and 3 (p&lt;0.05). Positive correlation between CIMT and the level of cystatin C of blood plasma (r=0.578, p&lt;0.05) and negative correlation with the value of GFR (r=-0.556, p&lt;0.05) were recorded among the patients of group 1. In group 2, strong correlation was observed between CIMT and the content of HDL cholesterol plasma (r=-0.343; p&lt;0.05). A significant direct relationship between CIMT and systolic level (r=0.482, p&lt;0.05) and central arterial pressure (r=0.479, p&lt;0.05) was found in individuals from group 3.Conclusion. Studying the content of cystatin C of blood plasma in conjunction with determination of GFR is a priority for early diagnosis of renal dysfunction and assessment of cardiovascular disorders, providing stratification of groups of cardiovascular risk and subsequent implementation of preventive measures to reduce the level of total cardiovascular risk.