Standard Glomerular Filtration Rate Research Articles

Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate

Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable physicochemical and renal clearance properties. In vitro studies show that these two compounds have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that 4d and 5c have a higher urine recovery of the injected dose than iothalamate (a commonly considered gold standard GFR agent). Pharmacokinetic studies show that these two compounds exhibit a plasma clearance equivalent to iothalamate, but with a faster (i.e. lower) terminal half-life than iothalamate (possibly from restricted distribution into the extracellular space due to large molecular size and hydrodynamic volume). Furthermore, the plasma clearance of 4d and 5c remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration exclusively. Finally, noninvasive real-time monitoring of this class of compounds was demonstrated by pharmacokinetic clearance of 5c by optical measurements in rat model, which correlates strongly with plasma concentration of the tracer. Hence, 4d and 5c are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.

GFR estimation in the morbidly obese pre- and postbariatric surgery: one size does not fit all

Glomerular hyperfiltration commonly associated with obesity is expected to improve postbariatric surgery. However, formula-based glomerular filtration rate (GFR) estimation in these patients is limited by body size confounders necessitating use of modified equations, the reliability of which remains uncertain. In this study, various GFR-estimating formulae were compared in morbidly obese patients at baseline and postbariatric surgery. Through a retrospective chart review, we identified 220 patients who had undergone this procedure, with over 6-month follow-up, during which major weight reduction was achieved. A significant decrease in BP and glomerular hyperfiltration was observed, though there was large variability in GFR estimation using the different formulae. Gross over and underestimation was observed which improved with correction for body size confounders especially lean body weight (LBW). Postoperatively, significant attenuation in estimated GFR was demonstrated when LBW or body surface area-adjusted versions were used. In a subgroup of patients with chronic kidney disease, a significant improvement in GFR was seen postoperatively with the LBW-modified formula but there were again inconsistencies when using other equations. Though clinicians must be critical in the application of GFR estimates to patient care, LBW adjustment appears to be the most practical solution to its estimation in the obese patients. This is particularly true for patients with normal renal function but appears to be also applicable to those with compromised kidney function. Future studies are needed to compare these equations with a gold standard GFR measure as well as to explore whether the renal benefits from bariatric surgery are sustained or seen in more advanced CKD stages.

Variability of glomerular filtration rate estimation equations in elderly Chinese patients with chronic kidney disease

BackgroundChronic kidney disease (CKD) is recognized worldwide as a public health problem, and its prevalence increases as the population ages. However, the applicability of formulas for estimating the glomerular filtration rate (GFR) based on serum creatinine (SC) levels in elderly Chinese patients with CKD is limited.Materials and methodsBased on values obtained with the technetium-99m diethylenetriaminepentaacetic acid (99mTc-DTPA) renal dynamic imaging method, 319 elderly Chinese patients with CKD were enrolled in this study. Serum creatinine was determined by the enzymatic method. The GFR was estimated using the Cockroft–Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Jelliffe-1973 equation, and the Hull equation.ResultsThe median of difference ranged from −0.3–4.3 mL/min/1.73 m2. The interquartile range (IQR) of differences ranged from 13.9–17.6 mL/min/1.73 m2. Accuracy with a deviation less than 15% ranged from 27.6%–32.9%. Accuracy with a deviation less than 30% ranged from 53.6%–57.7%. Accuracy with a deviation less than 50% ranged from 74.9%–81.5%. None of the equations had accuracy up to the 70% level with a deviation less than 30% from the standard glomerular filtration rate (sGFR). Bland–Altman analysis demonstrated that the mean difference ranged from −3.0–2.4 mL/min/1.73 m2. However, the agreement limits of all the equations, except the CG equation, exceeded the prior acceptable tolerances defined as 60 mL/min/1.73 m2. When the overall performance and accuracy were compared in different stages of CKD, GFR estimated using the CG equation showed promising results.ConclusionsOur study indicated that none of these equations were suitable for estimating GFR in the elderly Chinese population investigated. At present, based on overall performance, as well as performance in different CKD stages, the CG equation may be the most accurate for estimating GFR in elderly Chinese patients with CKD.

Hydrophilic Pyrazine Dyes as Exogenous Fluorescent Tracer Agents for Real-Time Point-of-Care Measurement of Glomerular Filtration Rate

Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutral dihydroxypropyl 2h, exhibited favorable physicochemical and clearance properties. In vitro studies show that 2d, 2h, and 2j have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that these three compounds exhibit a plasma clearance equivalent to iothalamate (a commonly considered gold standard GFR agent). In addition, these compounds have a higher urine recovery compared to iothalamate. Finally, the plasma clearance of 2d, 2h, and 2j remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration only. Hence, 2d, 2h, and 2j are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.

Serum creatinine, cystatin C, and beta-trace protein in diagnostic staging and prediction of progression of primary non-diabetic chronic kidney disease

Background: Chronic kidney disease (CKD) is a growing public health problem with increasing incidence and prevalence rates, poor outcomes and high health care costs. Impaired baseline kidney function is a well defined risk factor for progression of CKD. Measured glomerular filtration rate (GFR) is widely accepted as the best measure of overall renal function. Alternatively, serum markers, such as serum creatinine, or the newer low-molecular weight markers, cystatin C and beta-trace protein (BTP), are used to assess kidney function. We compared the diagnostic performance of creatinine, cystatin C, and BTP for staging kidney impairment measured by GFR and for predicting progression of CKD. Methods: Serum marker concentrations were measured in 227 patients with primary non-diabetic CKD and various degrees of renal impairment. 177 patients were followed prospectively for up to 7 years to assess progression of CKD. Results: At baseline, creatinine, cystatin C, and BTP were strongly correlated with GFR. Concentrations of all three markers increased progressively with decreasing GFR. Their diagnostic performance for the detection of even minor deteriorations of renal function (indicated by a GFR<90 mL/min/1.73m2) was similar. 65 patients experienced progression of CKD defined as doubling of baseline creatinine and/or terminal renal failure during follow-up. These patients had a lower GFR, higher serum creatinine, cystatin C, and BTP values at baseline (all P<0.001) compared to the patients who did not reach the predefined renal endpoint. Cox proportional hazard regression analysis revealed that all three clearance markers were equally strong predictors of CKD progression, even after adjustment for age, sex, GFR, and proteinuria. Conclusions: The diagnostic performance of serum creatinine, cystatin C or BTP for detecting even minor degrees of deterioration of renal function is good and these markers provide reliable risk prediction for progression of kidney disease in patients with CKD beyond the gold standard marker GFR.

M1717 Serum Cystatin-C and Creatinine Compared with Standard GFR in Cirrhotic Patients

Background: Assessment of glomerular filtration rate (GFR) by common creatinine-based methods is potentially inaccurate in patients with cirrhosis. Cirrhotic patients have several underlying conditions that contribute to falsely low serum creatinine concentrations, even in the presence of moderate to severe renal impairment, therefore creatinine-based methods usually overestimate true GFR in these patients. Cystatin-C is a low molecular weight protein and an endogenous marker of GFR. We compared the accuracy of plasma cystatin-C and creatinine in assessing renal function in cirrhotic patients. Methods: We serially enrolled cirrhotic patients admitted in our ward if they met the inclusion criteria and consented to participate. Child-Pugh (CP) score was calculated for all patients. GFR was calculated using serum creatinine, serum Cystatin-C, and 99mTc-DTPA clearance with the last one serving as the gold standard. The area under curve (AUC) on Receiver-operating characteristic curves were used to compare the diagnostic accuracy of each calculated GFR with that measured by DTPA. Results: Fourty-eight patients were enrolled (32 males, 66.7%). Nine were in class-A, 20 in class-B and 19 in class-C of CP score. Cystatin-C did not perform well in predicting the true GFR, while serum creatinine performed relatively accurate at GFR 20 a GFR<80 could also be predicted by serum creatinine (ROC curve AUC=0.739, p=0.034). Serum creatinie could also predict GFR<80ml/min in patients with CP class A & B (ROC curve AUC=0.795, p=0.01), but not in patients with CP class C. Conclusion: Neither serum creatinine nor Cystatin-C are good predictors of GFR in cirrhostic patients, although serum creatinine seems to perform better in selected subgroups.

Performance of Creatinine-Based Estimates of GFR in Kidney Transplant Recipients: A Systematic Review

Glomerular filtration rate (GFR) commonly is estimated in kidney transplantation by using creatinine-based estimation equations. The performance of these equations in kidney transplant recipients is unclear, with conflicting results between studies. Systematic review. Stable adult kidney transplant recipients more than 6 months posttransplantation. Reporting of or ability to calculate from available data the GFR estimation equation bias (mean difference between measured GFR and estimated GFR) and percent accuracy (percentage of GFR estimates within 10%, 20%, or 30% of measured GFR). Creatinine-based GFR estimation equations (Cockcroft-Gault, 6-variable Modification of Diet in Renal Disease [MDRD] Study, 4-variable MDRD Study, and Nankivell). GFR determination using plasma or renal clearance of inulin, radioisotopes, or nonradiographic contrast. The search yielded 23 studies. For the 4-variable MDRD Study equation, bias ranged from -11.4 to +9.2 mL/min/1.73 m(2) (0.15 mL/s/1.73 m(2)). Only 76% of estimates were within 30% of measured GFR. For the Cockcroft-Gault equation, bias ranged from -4.0 to +16 mL/min/1.73 m(2) and 73% of estimates were within 30% of measured GFR. For the Nankivell equation, bias ranged from -1.4 mL/min to 36.3 mL/min with a 30% accuracy of only 68%. This review is limited by the inability to pool bias data, lack of calibration of serum creatinine in the majority of studies, and inclusion of nonindependent observations in many studies. Differences in patient populations, baseline GFRs of the study group, reference standard GFR used, and creatinine assay calibration likely account for the heterogeneity in results. These factors need to be considered by investigators and clinicians when interpreting estimates of GFR in kidney transplant recipients.

Measured creatinine clearance from timed urine collections substantially overestimates glomerular filtration rate in patients with liver cirrhosis: a systematic review and individual patient meta-analysis

Accurate glomerular filtration rate (GFR) assessment in patients with liver cirrhosis is important for prognostication, chronic kidney disease staging, drug dosing and identifying combined liver-kidney transplantation candidates. The objective of this study was to review the accuracy of measured creatinine clearance (MCrCl) from timed urine collections for estimating true GFR. A systematic review and individual patient meta-analysis was performed. MEDLINE, old MEDLINE, Index Medicus and Cochrane library bibliographic databases and conference proceedings were searched up to June 2004. Reference lists of relevant studies were searched and experts were contacted. Comparative diagnostic studies describing stable adult patients with cirrhosis categorized according to the Child-Pugh classification were included if a gold standard GFR measurement was performed within 3 days of MCrCl. Individual patient data were abstracted from graphs of primary articles to allow a pooled analysis of agreement between renal measures. Seven studies of 193 patients from 1974 to 2002 were summarized. MCrCl overestimated inulin clearance (CIn) by a mean of +13 ml/min/1.73 m2 and the limits of agreement (mean of the differences+/-2 SD) were +60 ml/min/1.73 m2 and -34 ml/min/1.73 m2. This overestimation was highest in patients with lower GFR. The mean clearance ratios [95% confidence interval (CI)] between MCrCl and CIn in the high (> or =60 ml/min/1.73 m2) and low (<60 ml/min/1.73 m2) GFR subgroups were 1.18 (1.12-1.23) and 1.49 (1.33-1.66), respectively (P<0.0001). Fourteen percent of patients with a MCrCl > or =60 ml/min/1.73 m2 had a CIn of <30 ml/min/1.73 m2. For patients with liver cirrhosis, MCrCl from timed urine collections consistently overestimates the true GFR. For patients requiring complete clinical evaluation, GFR assessment by CIn is justified.

Contrast Enhanced Spiral Computerized Tomography in Live Kidney Donors:: A Single Session for Anatomical and Functional Assessment

We evaluated contrast enhanced spiral computerized tomography (CT) as a single session for anatomical and functional assessment of potential live kidney donors. The study included 80 consecutive kidney donors. In addition to routine donor evaluation, radiological imaging of the kidneys was performed with spiral CT, which was also used for selective determination of the glomerular filtration rate (GFR) of each kidney. All donors underwent 99mTc-mercaptoacetyltriglycine renal scan as a gold standard for GFR determination. Anatomical results of spiral CT were compared to operative findings at donor nephrectomy. Moreover, the results of CT GFR were compared with those of standard 99mTc-mercaptoacetyltriglycine GFR. Spiral CT detected major renal abnormalities that might be potentially significant for safe renal donation in 4 of the 80 donors (5%). Spiral CT had 100% sensitivity, 85.7% specificity and 97.2% overall accuracy for detecting the number of renal arteries. To identify the number of renal veins spiral CT had 100% sensitivity, 92.3% specificity and 98.6% overall accuracy. A comparison between the isotope GFR of each kidney with the corresponding CT GFR showed a perfect correlation (r = 0.54, p <0.001). For the right and left kidneys mean isotope clearance was not significantly different from that of mean CT clearance. Multidetector row spiral CT with contrast medium can provide accurate information regarding the anatomy of the urinary tract and vasculature of the kidney. Moreover, it can detect renal and vascular abnormalities that might be potentially significant for safe renal donation. In addition, it can accurately demonstrate selective GFR of each kidney. Therefore, we recommend spiral CT with contrast material as a single radiological diagnostic modality for the assessment of potential live kidney donors.

Assessment of renal function from plasma urea and plasma creatinine in children.

The diagnostic value of plasma urea and plasma creatinine, used separately and in combination, for assessment of renal function in children was determined from simultaneously measured values of plasma urea, plasma creatinine and glomerular filtration rate (GFR) in 357 children with different nephro-urological disorders. GFR was determined from the total [51Cr]EDTA plasma clearance measured by a reliable single injection method. Four levels of renal function (with the limits expressed as % of the age-dependent normal mean standard GFR) were defined: normal (greater than 75%); moderately decreased (75-52%); considerably decreased (51-28%); and severely decreased (less than 28%). Plasma concentrations of urea (mmol/l) and creatinine (expressed as a percentage of age-dependent normal mean value) were graded into low and high normal, moderately increased, considerably increased and severely increased values. Only by using plasma urea and plasma creatinine in combination all four levels of renal function could be predicted in the individual child with a high degree of certainty (probability 0.94-1.00). The results of the study indicate that the plasma concentration of urea and creatinine should be measured simultaneously, the results being used in combination with due consideration to the variability of plasma creatinine with age. By this procedure the majority of children, i.e. approximately 80%, with nephro-urological disorders who are referred to a paediatric clinic can have their level of renal function predicted with a high degree of certainty. Using plasma urea and plasma creatinine separately the corresponding figure is 50 and 60%, respectively.

Renal function and body composition before and after intestinal bypass operation in obese patients.

The distribution volume of [51Cr]EDTA, as an estimate of the extracellular fluid volume (ECV), glomerular filtration rate (GFR) and urinary excretion rate of endogenous creatinine (uc), as an index of muscle mass, were determined in obese patients before and after intestinal bypass operations. The results were compared to those in non-obese controls with the same age and height. GFR, ECV and uc were all significantly increased to the same extent (about 40%) in thirteen patients examined before operation (overweight 86-159%). Means of the ratio GFR/ECV and standard GFR (i.e. GFR corrected to a body surface area of 1.73 m2) did not differ from those in the controls. In eight patients examined before and 1 year after operation (body weight reduction 23-79 kg), GFR were unchanged and remained normal. ECV was significantly increased by 20% in nineteen patients investigated 1-7 years after operation (mean overweight 42%) whereas the mean of uc did not differ from that in the controls. Using the ratio GFR/ECV as reference for the function of the kidneys, the present study shows that the renal function in otherwise healthy obese subjects is normal throughout the whole range of overweight, and that standard GFR is a reliable parameter to assess the renal function even in patients with extreme obesity. The body weight reduction following intestinal bypass operation is in part due to fall in muscle mass, but the results suggest that a normal relation between body cell mass and body water is not achieved.