Inulin as carriers for renal targeting delivery of ferulic acid.

Inulin (IN), as a classic diagnostic for determination of glomerular filtration rate, reached high concentration in kidney. Introducing drug into IN derivatives may be a new method to target kidney for drug delivery. To test the hypothesis, ferulic acid (FeA) was conjugated into IN by ester bond and amide bond (ethylenediamine as spacer), respectively, and the two FeA-IN conjugations, inulin ferulate (IN-FeA) and inulin ethylenediamine ferulate (IN-EDA-FeA) were obtained. NMR spectrum was involved to characterize the conjugations. The FeA in vitro release profiles were tested in mice plasma and renal homogenate. Finally, the biodistribution test was performed to evaluate their renal-targeting ability. Both IN-FeA and IN-EDA-FeA showed a higher release rate of FeA in renal homogenate than in mouse plasma suggesting the conjugates are relatively stable in plasma and more likely FeA release in kidney. The renal area under the curve (AUC) for IN-FeA and IN-EDA-FeA were 539.6 ± 107.9 and 558.5 ± 131.6 µg h/mL, respectively, which were 4.47 and 4.62 times of 120.8 ± 18.1 µg h/mL for free FeA. Meanwhile, significant smaller FeA accumulation in other organs was observed. These data indicated that IN-FeA and IN-EDA-FeA effectively targeted kidney for FeA delivery.

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

BACKGROUND: 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 (R = 0.82, P < 0.0001 and R = 0.82, P < 0.0001 respectively); however, bias and variability were considerable: the eGFRMDRD overestimated the true GFR with 31 ±â€Š35% (95% limits of agreement: -37% to 100%) and the GFRECC with 37 ±â€Š49% (95% limits of agreement: -59% to 133%). Plasma PENK concentrations showed a very strong inverse correlation with the GFRiohexol (R = 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.

A Randomized, Placebo-Controlled, Pilot Clinical Trial to Evaluate the Effect of Supplementation with Prebiotic Synergy 1 on Iron Homeostasis in Children and Adolescents with Celiac Disease Treated with a Gluten-Free Diet.

Iron deficiency anemia (IDA) occurs in 15⁻46% of patients with celiac disease (CD), and in some cases, it may be its only manifestation. Studies in animal models have shown that prebiotics, including inulin, may help to increase intestinal absorption of iron. The aim of this study was to evaluate the effect of a prebiotic, oligofructose-enriched inulin (Synergy 1), on iron homeostasis in non-anemic children and adolescents with celiac disease (CD) in association with a gluten-free diet (GFD). Thirty-four CD patients (4⁻18 years old) were randomized into two groups receiving Synergy 1 (10 g/day) or a placebo (maltodextrin) for three months. Before and after intervention, blood samples were collected from all patients for assessment of blood morphology, biochemical parameters and serum hepcidin concentration. We found that serum hepcidin concentration after the intervention was significantly decreased by 60.9% (p = 0.046) in the Synergy 1 group, whereas no significant difference was observed in the placebo group. No differences in morphological and biochemical blood parameters (including ferritin, hemoglobin and C-reactive protein (CRP)) were observed after intervention in either group. Given that hepcidin decrease may improve intestinal iron absorption, these results warrant further investigation in a larger cohort and especially in patients with IDA.

Combining GFR estimates from cystatin C and creatinine-what is the optimal mix?

BACKGROUND: Combining estimated glomerular filtration rate (eGFR) equations based on creatinine and cystatin C has been shown to improve the accuracy of GFR estimation. This study aims to optimize this strategy for height-independent GFR estimation in children. METHODS: Retrospective study of 408 inulin clearance tests with simultaneous International Federation of Clinical Chemistry-calibrated measurements of creatinine, cystatin C, and urea in children (mean age 12.5 years, GFR 91.2 ml/min/1.73m2) comparing the arithmetic (meanarith) and geometric means (meangeom) of a height-independent creatinine-based (full age spectrum, based on age (FASage)) and a cystatin C-based equation (FAScys), with the complex height-dependent CKiD3 equation incorporating gender, height, cystatin C, creatinine, and urea. RESULTS: Meangeom had a P30 accuracy of 89.2% compared to meanarith 87.7% (p = 0.030) as well as lower bias and %precision error and performed almost as well as CKiD3 (P30 accuracy 90.9%). Modifying the weight of FASage and FAScys when calculating the means showed that an equal contribution was most accurate in most patients. In spina bifida patients, FAScys alone outperformed any combination. Malignancy or nephritis patients had slightly higher accuracy with weighted means favoring cystatin C or creatinine, respectively. Disagreement between FAScys and FASage was inversely correlated with the accuracy of meangeom. When disagreement exceeded 40%, application of weighted means based on diagnosis improved the performance of eGFR. CONCLUSIONS: In the absence of height data, the optimal strategy for estimating GFR in children is by using the geometric mean of FASage and FAScys. When there is large disagreement between the two, weighted means based on diagnosis improve accuracy.

Existing creatinine-based equations overestimate glomerular filtration rate in Indians.

BACKGROUND: Accurate estimation of glomerular filtration rate (GFR) is important for diagnosis and risk stratification in chronic kidney disease and for selection of living donors. Ethnic differences have required correction factors in the originally developed creatinine-based GFR estimation equations for populations around the world. Existing equations have not been validated in the vegetarian Indian population. We examined the performance of creatinine and cystatin-based GFR estimating equations in Indians. METHODS: GFR was measured by urinary clearance of inulin. Serum creatinine was measured using IDMS-traceable Jaffe's and enzymatic assays, and cystatin C by colloidal gold immunoassay. Dietary protein intake was calculated by measuring urinary nitrogen appearance. Bias, precision and accuracy were calculated for the eGFR equations. RESULTS: A total of 130 participants (63 healthy kidney donors and 67 with CKD) were studied. About 50% were vegetarians, and the remainder ate meat 3.8 times every month. The average creatinine excretion were 14.7 mg/kg/day (95% CI: 13.5 to 15.9 mg/kg/day) and 12.4 mg/kg/day (95% CI: 11.2 to 13.6 mg/kg/day) in males and females, respectively. The average daily protein intake was 46.1 g/day (95% CI: 43.2 to 48.8 g/day). The mean mGFR in the study population was 51.66 ± 31.68 ml/min/1.73m2. All creatinine-based eGFR equations overestimated GFR (p < 0.01 for each creatinine based eGFR equation). However, eGFR by CKD-EPICys was not significantly different from mGFR (p = 0.38). The CKD-EPICys exhibited lowest bias [mean bias: -3.53 ± 14.70 ml/min/1.73m2 (95% CI: -0.608 to -0.98)] and highest accuracy (P30: 74.6%). The GFR in the healthy population was 79.44 ± 20.19 (range: 41.90-134.50) ml/min/1.73m2. CONCLUSION: Existing creatinine-based GFR estimating equations overestimate GFR in Indians. An appropriately powered study is needed to develop either a correction factor or a new equation for accurate assessment of kidney function in the Indian population.

Clinical benefits of using inulin clearance and cystatin C for determining glomerular filtration rate in HIV-1-infected individuals treated with dolutegravir.

INTRODUCTION: Dolutegravir may inhibit creatinine transporters in renal tubules and elevate serum creatinine levels. We investigated the usefulness of glomerular filtration rate (GFR) measured using inulin clearance (Cin), creatinine clearance (Ccr), and estimated GFR based on both serum creatinine (eGFRcre) and serum cystatin C (eGFRcys). PATIENTS & METHODS: HIV-1-infected Japanese patients with suppressed viremia and whose antiretroviral drug was switched to dolutegravir from other drugs were included (n = 108, Study 1). We compared eGFRcre and eGFRcys at the start and after 48 weeks of dolutegravir administration. For the patients providing consent, we measured Cin and Ccr (n = 15, Study 2). We assessed biases and accuracy and compared Cin with eGFRcre, eGFRcys, and Ccr. RESULTS: There were no differences in serum cystatin C and eGFRcys between baseline and at 48 weeks. Moreover, eGFRcre was significantly less accurate (within 30% of measured GFR) than both eGFRcys and Ccr (40% accuracy compared to 93% and 93%, respectively). eGFRcys was significantly less biased than eGFRcre and Ccr (p < 0.0001, p = 0.00036, respectively). No significant difference between Cin and eGFRcys was observed. eGFRcys was significantly correlated with Cin (γ = 0.85, p < 0.0001). CONCLUSIONS: eGFRcys provided the most precise estimate and most closely approximate Cin in HIV-1-infected Japanese patients with suppressed viremia treated with dolutegravir. We demonstrated clinical benefits of inulin clearance and eGFRcys. This is the first study performing inulin clearance for HIV-1-infected individuals and to show data for eGFRcys from a large cohort following a switch to dolutegravir from other antiretroviral agents.

Effects of Aerobic Exercise Combined with Panaxatriol Derived from Ginseng on Insulin Resistance and Skeletal Muscle Mass in Type 2 Diabetic Mice.

Insulin resistance reduces insulin-induced muscle protein synthesis and accelerates muscle protein degradation. Ginseng ingestion has been reported to improve insulin resistance through the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. We hypothesized that panaxatriol (PT) derived from ginseng in combination with aerobic exercise (EX) may further promote protein synthesis and suppress protein degradation, and subsequently maintain muscle mass through the amelioration of insulin resistance. KKAy insulin-resistant mice were divided into control, panaxatriol only (PT), exercise only (EX), and EX+PT groups. EX and EX+PT ran on the treadmill for 45 min at 15 m/min 5 d/wk for 6 wk. PT and EX+PT groups were fed a standard diet containing 0.2% PT for 6 wk. Homeostasis model assessment for insulin resistance (HOMA-R) values was significantly improved after exercise for 6 wk. Moreover, EX+PT mice showed improved HOMA-R as compared to EX mice. p70S6K phosphorylation after a 4 h fast was significantly higher in EX than in the non-exercise control, and it was higher in EX+PT mice than in EX mice. Atrogin1 mRNA expression was significantly lower in EX than in the non-exercise control, and was significantly lowered further by PT treatment. EX and EX+PT mice showed higher soleus muscle mass and cross-sectional area (CSA) of the soleus myofibers than control animals, with higher values noted for both parameters in EX+PT than in EX. These results suggest that aerobic exercise and PT ingestion may contribute to maintain skeletal muscle mass through the amelioration of insulin resistance.

Estimating glomerular filtration rate (GFR) in children. The average between a cystatin C- and a creatinine-based equation improves estimation of GFR in both children and adults and enables diagnosing Shrunken Pore Syndrome.

Estimating glomerular filtration rate (GFR) in adults by using the average of values obtained by a cystatin C- (eGFRcystatin C) and a creatinine-based (eGFRcreatinine) equation shows at least the same diagnostic performance as GFR estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparison of eGFRcystatin C and eGFRcreatinine plays a pivotal role in the diagnosis of Shrunken Pore Syndrome, where low eGFRcystatin C compared to eGFRcreatinine has been associated with higher mortality in adults. The present study was undertaken to elucidate if this concept can also be applied in children. Using iohexol and inulin clearance as gold standard in 702 children, we studied the diagnostic performance of 10 creatinine-based, 5 cystatin C-based and 3 combined cystatin C-creatinine eGFR equations and compared them to the result of the average of 9 pairs of a eGFRcystatin C and a eGFRcreatinine estimate. While creatinine-based GFR estimations are unsuitable in children unless calibrated in a pediatric or mixed pediatric-adult population, cystatin C-based estimations in general performed well in children. The average of a suitable creatinine-based and a cystatin C-based equation generally displayed a better diagnostic performance than estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparing eGFRcystatin and eGFRcreatinine may help identify pediatric patients with Shrunken Pore Syndrome.

Drinking and water permeability in the Pacific hagfish, Eptatretus stoutii.

Hagfish are osmoconformers, maintaining an internal osmolality that matches their seawater habitats. Hagfish would, therefore, appear to have no physiological need to drink, but previous studies are equivocal regarding whether drinking in hagfish occurs. The current study addressed this knowledge gap, by examining drinking and water permeability in the Pacific hagfish, Eptatretus stoutii. One-third of analysed hagfish were shown to accumulate radiolabelled drinking rate markers (tritiated inulin and polyethylene glycol-4000) in their gut tissues; however, this was attributed to the presence of markers in the blood perfusing the digestive tract, following absorption through paracellular pathways at the gill. No accumulation of marker was observed in hagfish subjected to more dilute (75% seawater) or more concentrated (125% seawater) media. Diffusive water efflux, measured by tritiated water washout, was shown to be very high, with 50% of body water exchanged within 14 to 16 min, depending on exposure salinity. In full-strength seawater, the total exchangeable pool of water was 78% of hagfish mass. We conclude that hagfish do not drink, and their high water permeability is likely to result in rapid osmotic equilibration under circumstances where perturbations may occur.

Measuring and estimating glomerular filtration rate in children.

Glomerular filtration rate (GFR) is the best index for kidney function in health and disease. Knowledge of the GFR is essential for the detection (diagnosis) and monitoring of renal function during disease progression and for ensuring correct medication doses. Inulin clearance (plasma or urine) is currently considered to be the gold standard for measuring GFR, but in clinical practice the measurement of other exogenous filtration markers from the plasma often replaces that of inulin clearance. Different protocols can be used to determine the area under the plasma disappearance curve, and an understanding of these methods is important. GFR can also be estimated by GFR equations (eGFR), which are most often used in clinical practice because they only require a knowledge of the serum creatinine or cystatin C level and demographic information. eGFR equations are easy to use but they do have their limitations, and it is important to know how these equations were derived and in which circumstances they can be used most accurately. The aim of this review is to explain how GFR can be measured using the renal clearance and the plasma clearance method and which eGFR equations can be applied to children, as well as how and when these equations can be used in clinical practice.

Impact of Iodinated Contrast on Renal Function and Hemodynamics in Rats with Chronic Hyperglycemia and Chronic Kidney Disease.

Iodinated contrast (IC) is clinically used in diagnostic and interventional procedures, but its use can result in contrast-induced acute kidney injury (CI-AKI). Chronic kidney disease (CKD) and chronic hyperglycemia (CH) are important predisposing factors to CI-AKI. The aim of this study was to investigate the impact of iodinated contrast on the renal function and hemodynamics in rats with chronic hyperglycemia and chronic kidney disease. A total of 30 rats were divided into six groups; Sham: control of chronic renal disease; Citrate: control of chronic hyperglycemia (CH); Nx5/6: rats with 5/6 nephrectomy; Chronic Hyperglycemia: rats receiving Streptozotocin 65 mg/kg; Nx5/6 + IC: rats Nx5/6 received 6 mL/kg of IC; CH + IC: Chronic hyperglycemia rats receiving 6 mL/kg of IC. Renal function (inulin clearance; urinary neutrophil gelatinase-associated lipocalin, NGAL) and hemodynamics (arterial blood pressure; renal blood flow; renal vascular resistance) were evaluated. Iodinated contrast significantly increased urinary NGAL and reduced inulin clearance, while the hemodynamics parameters showed changes in arterial blood pressure, renal blood flow, and renal vascular resistance in both CKD and CH groups. The results suggest that the iodinated contrast in risk factors models has important impact on renal function and hemodynamics. NGAL was confirmed to play a role of highlight in diagnosis of CI-AKI.

Validity of new methods to evaluate renal function in cancer patients treated with cisplatin.

PURPOSE: Creatinine clearance (Ccr) is used as a marker of renal function in cancer chemotherapy, but it is not correlated with glomerular filtration rate (GFR) after high-dose cisplatin treatment. In addition to Ccr, measured using 24-h urine collection (24-h Ccr) or Cockcroft-Gault formula (CGF), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Japanese GFR estimation equation (the Japanese equation) have been recently developed to estimate GFR for predicting renal function. However, these equations remain to be evaluated, particularly in cancer patients treated with cisplatin. Therefore, we investigated the validity of these equations for predicting the GFR in cancer patients treated with cisplatin. METHODS: GFR was measured by inulin clearance (Cin) in 50 cancer patients and compared with GFR estimated by the CKD-EPI equation, the Japanese equation, and Ccr estimated by CGF or measured by 24-h Ccr before the first and third cisplatin-containing chemotherapy cycles (considered pretreatment and posttreatment, respectively). RESULTS: Before treatment, the CKD-EPI and the Japanese equations estimated GFR with higher accuracy than Ccr. Posttreatment bias values for GFR estimation using the CKD-EPI and the Japanese equations were lower than those for Ccr. The CKD-EPI and the Japanese equations were also more precise than Ccr. However, for patients with low renal function, these equations still overestimated Cin. CONCLUSION: The CKD-EPI and the Japanese equations estimated GFR with lower bias and higher precision than Ccr pre- and postcisplatin treatment. This study is registered at UMIN: 000002167.

Validation of the Korean coefficient for the modification of diet in renal disease study equation.

BACKGROUND/AIMS: Race and ethnicity are important determinants when estimatingglomerular filtration rate (GFR). The Korean coefficients for the isotope dilution mass spectrometry (IDMS) Modification of Diet in Renal Disease (MDRD) Study equations were developed in 2010. However, the coefficients have not been validated. The aim of this study was to validate the performance of the Korean coefficients for the IDMS MDRD Study equations. METHODS: Equation development and validation were performed in separate groups (development group, n = 147 from 2008 to 2009; validation group, n = 125 from 2010 to 2012). We compared the performance of the original IDMS MDRD equations and modified equations with Korean coefficients. Performance was assessed by comparing correlation coefficients, bias, and accuracy between estimated GFR and measured GFR, with systemic inulin clearance using a single injection method. RESULTS: The Korean coefficients for the IDMS MDRD equations developed previously showed good performance in the validation group. The new Korean coefficients for the four- and six-variable IDMS MDRD equations using both the development and validation cohorts were 1.02046 and 0.97300, respectively. No significant difference was detected for the new Korean coefficients, in terms of estimating GFR, between the original and modified IDMS MDRD Study equations. CONCLUSIONS: The modified equations with Korean coefficients for the IDMS MDRD Study equations were not superior to the original equations for estimating GFR. Therefore, we recommend using the original IDMS MDRD Study equation without ethnic adjustment in the Korean population.

A method for estimating the glomerular filtration rate in conscious monkeys.

To establish a method for estimating the glomerular filtration rate (GFR) in conscious monkeys, the radiographic contrast medium iodixanol and the standard agent inulin were coadministered as tracers to male cynomolgus monkeys (Macaca fascicularis) as a bolus injection; blood was collected after 60, 90 and 120 min. An equation based on a single-blood-sample method derived from Jacobsson's formula was prepared using the data from healthy and saline- and gentamicin-treated monkeys by a multisample strategy with iodixanol. The GFR using the equation with iodixanol was in agreement with that from the multisample method with inulin or iodixanol. When the GFR decreased to more than 60% of the basal reference level, serum creatinine concentrations tended to increase, whereas serum blood urea nitrogen concentrations fluctuated. The results suggest that the single-sample-blood method with iodixanol is a practical tool for estimating the monkey GFR in a toxicological research setting therefore minimizing animal sufferings.

Is the new GFR equation using inulin clearance a more accurate method for Asian patients?

Recently, a new glomerular filtration rate (GFR) equation for the Japanese population was proposed using measured inulin clearance. To expand its applicability to other Asian populations, we performed a comparative study in the Korean population. Inulin clearance was measured in 166 patients from seven participating medical centers in Korea. Patient's sera and urine were collected, and baseline clinical characteristics were measured to provide an estimated GFR (eGFR) by the Japanese GFR equation using inulin clearance (Japanese-GFR equation), the Modification of Diet in Renal Disease (MDRD) study equation, and the Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) equation. We compared the results to determine which equation best estimated the measured GFR (mGFR). Accuracy (95% CI) within 30% of mGFR by the Japanese-GFR equation, the CKD-EPI equation and the MDRD study equation were 66 (58 - 72), 51 (43 - 58), and 55 (47 - 62)%, respectively. Bias (mGFR minus eGFR) were 3.4 ± 22.4, -12.0 ± 22.1, and -9.7 ± 23.8 mL/min/1.73 m2, respectively. The accuracy of the Japanese-GFR equation was significantly better than MDRD study equation in subjects with mGFR < 60 mL/min/1.73 m2 and in total subjects. The bias of the Japanese-GFR equation was significantly smaller compared with other two equations in total subjects. The Japanese-GFR equation has a higher accuracy with less bias than the other equations in estimating GFR in Korean populations. Further studies are required to determine if the current Japanese-GFR equation could represent the standard eGFR for other Asian populations.

Bioavailability of insulin detemir and human insulin at the level of peripheral interstitial fluid in humans, assessed by open-flow microperfusion.

AIMS: To find an explanation for the lower potency of insulin detemir observed in humans compared with unmodified human insulin by investigating insulin detemir and human insulin concentrations directly at the level of peripheral insulin-sensitive tissues in humans in vivo. METHODS: Euglycaemic-hyperinsulinaemic clamp experiments were performed in healthy volunteers. Human insulin was administered i.v. at 6 pmol/kg/min and insulin detemir at 60 pmol/kg/min, achieving a comparable steady-state pharmacodynamic action. In addition, insulin detemir was doubled to 120 pmol/kg/min. Minimally invasive open-flow microperfusion (OFM) sampling methodology was combined with inulin calibration to quantify human insulin and insulin detemir in the interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissue. RESULTS: The human insulin concentration in the ISF was ∼115 pmol/l or ∼30% of the serum concentration, whereas the insulin detemir concentration in the ISF was ∼680 pmol/l or ∼2% of the serum concentration. The molar insulin detemir interstitial concentration was five to six times higher than the human insulin interstitial concentration and metabolic clearance of insulin detemir from serum was substantially reduced compared with human insulin. CONCLUSIONS: OFM proved useful for target tissue measurements of human insulin and the analogue insulin detemir. Our tissue data confirm a highly effective retention of insulin detemir in the vascular compartment. The higher insulin detemir relative to human insulin tissue concentrations at comparable pharmacodynamics, however, indicate that the lower potency of insulin detemir in humans is attributable to a reduced effect in peripheral insulin-sensitive tissues and is consistent with the reduced in vitro receptor affinity.

Comparison of different equations to assess glomerular filtration in critically ill patients.

PURPOSE: To evaluate equations for estimation of glomerular filtration rate (GFR) and measured urinary creatinine clearance, compared to measured GFR in critically ill patients. METHODS: GFR was measured using inulin clearance. Multiple blood samples were collected per patient for determination of serum creatinine, cystatin C and inulin. GFR was estimated by the use of the following estimation equations (eGFR): four commonly used creatinine-based equations [Cockcroft-Gault, Modification of Diet in Renal Disease (both the short and long formula) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)], five cystatin C based estimation equations (Hoek, Larsson, Filler, Le Bricon, CKD-EPIcys) and one equation combining cystatin C and serum creatinine (CKD-EPIcr-cys). In addition we measured urinary creatinine clearance. Bias, precision and accuracy of all estimates were compared to those of the inulin clearance. RESULTS: Data were collected from 83 patients, of whom 68 were considered evaluable. The median age was 58 years [interquartile range (IQR) 39-68]. The median inulin clearance was 80 mL/min/1.73 m(2) (IQR 31-114). Equations based on creatinine had much bias and poor precision and accuracy. Measured urinary creatinine clearances overestimated GFR. Equations based on cystatin C were free of bias, but also had limited precision and accuracy. CONCLUSIONS: In this cohort of patients, estimates of GFR had low accuracy and precision. Cystatin C based formulas, especially CKD-EPIcr-cys, showed limited bias; however, the accuracy and precision of these estimates were still insufficient. Measured urinary creatinine clearance overestimates GFR, but may provide a cheap alternative, when this is taken into account.

Is there an age cutoff to apply adult formulas for GFR estimation in children?

BACKGROUND: Estimation of glomerular filtration rate (eGFR) using a common formula for both adult and pediatric populations is challenging. Using inulin clearances (iGFRs), this study aims to investigate the existence of a precise age cutoff beyond which the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or the Cockroft-Gault (CG) formulas, can be applied with acceptable precision. Performance of the new Schwartz formula according to age is also evaluated. METHOD: We compared 503 iGFRs for 503 children aged between 33 months and 18 years to eGFRs. To define the most precise age cutoff value for each formula, a circular binary segmentation method analyzing the formulas' bias values according to the children's ages was performed. Bias was defined by the difference between iGFRs and eGFRs. To validate the identified cutoff, 30% accuracy was calculated. RESULTS: For MDRD, CKD-EPI and CG, the best age cutoff was ≥14.3, ≥14.2 and ≤10.8 years, respectively. The lowest mean bias and highest accuracy were -17.11 and 64.7% for MDRD, 27.4 and 51% for CKD-EPI, and 8.31 and 77.2% for CG. The Schwartz formula showed the best performance below the age of 10.9 years. CONCLUSION: For the MDRD and CKD-EPI formulas, the mean bias values decreased with increasing child age and these formulas were more accurate beyond an age cutoff of 14.3 and 14.2 years, respectively. For the CG and Schwartz formulas, the lowest mean bias values and the best accuracies were below an age cutoff of 10.8 and 10.9 years, respectively. Nevertheless, the accuracies of the formulas were still below the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target to be validated in these age groups and, therefore, none of these formulas can be used to estimate GFR in children and adolescent populations.

The relationship between estimated GFR based on the CKD-EPI formula and renal inulin clearance in potential kidney donors.

It is not yet clear whether or not renal function in the living donor can be sufficiently assessed by estimated glomerular filtration rate (GFR) using creatinine-based equations. The present paper investigates the relationship between GFR values determined using renal inulin clearance (Cin) and those estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Our study was performed in 287 potential kidney donors with a mean age of 48 ± 10 years. Mean Cin was 1.47 ± 0.28 (1.10 - 2.50) mL/s/1.73 m2. Total bias when using the CKDEPI formula was -0.0183 mL/s/1.73 m2, precision 0.263 mL/s/1.73 m2, and accuracy 90.6% within ± 30% of Cin. The sensitivity of CKD-EPI to estimate a decrease in Cin below 1.33 mL/s/1.73 m2 was 50.5%, with an 85% specificity of detecting a value above the cutoff. Receiver-operating curve analysis for the above produced an area under the curve of 0.766 ± 0.0285 (CI 0.712 - 0.813). For donor screening purposes, CKD-EPI should be interpreted with great caution.

Measurement of cerebrospinal fluid formation and absorption by ventriculo-cisternal perfusion: what is really measured?

The generally accepted hypothesis on cerebrospinal fluid (CSF) hydrodynamics suggests that CSF is actively formed mainly by the choroid plexuses, circulates unidirectionally along the brain ventricles and subarachnoid space, and is passively absorbed mainly into the dural venous sinuses. CSF formation rate (Vf) has been extensively studied using the ventriculo-cisternal perfusion technique and the results have been used as the key evidence confirming the mentioned hypothesis. This technique and the equation for Vf calculation are based on the assumption that the dilution of the indicator substance is a consequence of the newly formed CSF, ie, that a higher CSF formation rate will result in a higher degree of dilution. However, it has been experimentally shown that the indicator substance dilution inside the CSF system does not occur because of a "newly formed" CSF, but as consequence of a number of other factors (departure of substances into the surrounding tissue, flowing around the collecting cannula into the cortical and spinal subarachnoid space, departure into the contralateral ventricle, etc). This technique allows "calculation" of the CSF formation even in dead animals, in an in vitro model, and in any other part of the CSF system outside the ventricles that is being perfused. Therefore, this method is indirect and any dilution of the indicator substance in the perfusate caused by other reasons would result in questionable and often contradictory conclusions regarding CSF formation rates.