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Background Studies have shown that losartan reduces serum uric acid in adults, unlike angiotensin-converting enzyme inhibitors. A previous study demonstrated that losartan and enalapril had comparable effects on proteinuria in children. Methods We conducted a post hoc analysis of results from a prospective trial in which the proteinuria-reducing effects of losartan and enalapril were compared. We have now evaluated (a) the effects of these medications on SUA in 248 children with proteinuria and (b) the correlation between changes in SUA and eGFR. Results SUA levels after 36 months were found to be increased when compared to baseline in both losartan and enalapril groups. The mean change in SUA from baseline was significantly different at 12 months between 23 hypertensive patients randomised to losartan (3.69% decrease [95% CI 11.31%, 3.93%]) and 24 randomised to enalapril (12.57% increase [95% CI 3.72%, 21.41%]), p = 0.007. This significant difference remained after 24, 30 and 36 months but was observed in the entire group of 248 patients only at 12 months. There was a statistically significant negative correlation between changes in SUA and changes in eGFR at each time point over 36 months. Conclusions Losartan may have long-term beneficial effects on SUA and eGFR in children with proteinuria., Author(s): Charlotte E. Bryant [sup.1] , Azita Rajai [sup.1] [sup.2] , Nicholas J. A. Webb [sup.1] , Ronald J. Hogg [sup.3] Author Affiliations: (1) grid.498924.a, Research and Innovation, Manchester University [...]

Background Creatinine-based glomerular filtration rate (GFR)-estimating equations frequently do not perform well in populations that differ from the development populations in terms of mean GFR, age, pathology, ethnicity, and diet. After first evaluating the performance of existing equations, the aim of this study was to demonstrate the utility of an in-house modification of the equations to better fit a specific population. Methods Estimated GFR using 8 creatinine-based equations was first compared to 2-sample .sup.51Cr-ethylenediaminetetra-acetic acid plasma clearance in non-cancer and cancer groups independently. The groups were then divided into development and validation sets. Using the development set data, the Microsoft® Excel SOLVER add-in was used to modify the parameters of 7 equations to better fit the data. Using the validation set data, the performance of the original and modified equations was compared. Results Two hundred fifty-six GFR measurements were performed in 160 children. GFR was overestimated in both groups (non-cancer 4.3-22.6 ml/min/1.73 m.sup.2, cancer 17.2-46.6 ml/min/1.73 m.sup.2). The root mean square error (RMSE) was 19.1-21.8 ml/min/1.73 m.sup.2 (non-cancer) and 18.6-20.8 ml/min/1.73 m.sup.2 (cancer). The P.sub.30 values were 49.1-73.0% (non-cancer) and 19.6-66.0% (cancer). Modifying the parameters of seven equations resulted in significant improvements in the P.sub.30 values in the non-cancer (65.0-85.0%) and cancer (79.6-87.8%) groups. Conclusions Modifying the parameters of pediatric GFR estimating-equations using a simple Excel-based tool significantly improved their accuracy in both non-cancer and cancer populations., Author(s): Jennifer L. Holness [sup.1] [sup.2] , Anita Brink [sup.2] , M. Razeen Davids [sup.3] , James M. Warwick [sup.1] Author Affiliations: (1) grid.11956.3a, 0000 0001 2214 904X, Nuclear Medicine [...]

Importance Changes in kidney function are typically followed by the sequential estimation of glomerular filtration rate (eGFR). Formulae for eGFR work well on a population basis, but there are well-known conditions where they do not work. Objective The purpose of this review is to summarize the existing literature on special populations in the pediatric age range and provide recommendations on how to estimate GFR in these populations. Findings The reliability of creatinine depends on muscle mass, while cystatin C (not widely available) is limited by inflammation and changes in protein catabolism. Various dietary factors can alter eGFR. Renal function in neonates changes drastically every day, and there are currently no satisfactory reference intervals for routine pediatric use. Gender effects and conditions such as wasting disease and obesity require alternative ways to obtain eGFR. In oncology patients, chemotherapy may negatively affect renal function, and nuclear GFR measurements may be necessary. For body builders, high muscle mass may lead to underestimation of eGFR using creatinine. Conclusions and relevance Clinicians should be aware of special populations that may yield misleading eGFRs with conventional creatinine-based formulae, and that the alternative methods may be more appropriate for some populations., Author(s): Guido Filler [sup.1] [sup.2] [sup.3] [sup.4] , Misan Lee [sup.1] Author Affiliations: (Aff1) 0000 0004 1936 8884, grid.39381.30, Department of Pediatrics, Schulich School of Medicine & Dentistry, University of [...]

Background The non-ionic agent iohexol is increasingly used as the marker of choice for glomerular filtration rate (GFR) measurement. Estimates of GFR in children have low accuracy and limiting the number of blood-draws in this patient population is especially relevant. We have performed a study to evaluate different formulas for calculating measured GFR based on plasma iohexol clearance with blood sampling at only one time point (GFR1p) and to determine the optimal sampling time point. Methods Ninety-six children with chronic kidney disease (CKD) stage 1-5 (median age 9.2 years; range 3 months to 17.5 years) were examined in a cross-sectional study using iohexol clearance and blood sampling at seven time points within 5 h (GFR7p) as the reference method. Median GFR7p was 66 (range 6-153) mL/min/1.73 m.sup.2. The performances of six different single time-point formulas (Fleming, Ham and Piepsz, Groth and Aasted, Stake, Jacobsson- and Jacobsson-modified) were validated against the reference. The two-point GFR (GFR2p) was calculated according to the Jødal and Brøchner-Mortensen formula. Results The GFR1p calculated according to Fleming with sampling at 3 h (GFR1p.sub.3h-Fleming) had the best overall performance, with 82% of measures within 10% of the reference value (P10). In children with a GFR [greater than or equal to] 30 mL/min/1.73 m.sup.2 (n = 78), the GFR1p.sub.3h-Fleming had a P10 of 92.3%, which is not significantly different (p = 0.29) from that of GFR2p (P10 = 96.2%). Considerable differences within and between the different formulas were found for different CKD stages and different time points for blood sampling. Conclusions For determination of mGFR in children with CKD and an assumed GFR of [greater than or equal to] 30 mL/min/1.73 m.sup.2 we recommend GFR1p.sub.3h-Fleming as the preferred single-point method as an alternative to GFR2p. For children with a GFR < 30 mL/min/1.73 m.sup.2, we recommend the slope-GFR with at least two blood samples. Clinical Trial Registration: http://clinicaltrials.gov http://clinicaltrials.gov , Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2, Author(s): Camilla Tøndel [sup.1] [sup.2] , Cathrin Lytomt Salvador [sup.3] [sup.4] , Karl Ove Hufthammer [sup.5] , Bjørn Bolann [sup.6] [sup.7] , Damien Brackman [sup.1] , Anna Bjerre [sup.8] , [...]

Accurate assessment of renal function is critical for appropriate drug dosing of renally excreted compounds. Glomerular filtration rate (GFR) is considered the best marker of kidney function. Inulin clearance forms the gold standard for measuring GFR, both in adults and in children. The method is invasive, cumbersome, and smaller children require urinary catheterization for accurate timed urine collections. Nuclear medicine methods replaced inulin clearance in the 1970s after [sup.51]Cr EDTA clearance was introduced. Inulin has no plasma protein binding, whereas all commonly used radioisotopes have a small amount of plasma protein binding that leads to lower values. Only iohexol does not have significant plasma protein binding. The underestimation due to plasma protein binding is partially offset by overestimation due to the use of non-compartmental pharmacokinetic modeling of the plasma disappearance of the radioisotope. The problem could be overcome with a urinary nuclear medicine clearance method, but these have not been validated in children. Endogenous markers of GFR include serum creatinine and low molecular weight proteins such as cystatin C and beta-trace protein. Of these, estimation of GFR using cystatin C appears to be the most promising, although its accuracy in pregnancy and in the neonatal period may be limited. Keywords Inulin * Nuclear medicine * Cystatin C * eGFR * Creatinine * Chronic kidney disease, Introduction Adequate measurement of kidney function is important for the management of all children and adolescents. In the neonatal period, there is considerable ontogeny of drug disposition, largely due to [...]

The screening for chronic kidney diseases (CKD) patients with impaired GFR needs the measurement of serum creatinine (SCr) or cystatin C (SCys). GFR can also be predicted from SCr or SCys with different formulas. The aim of this study, performed in a group of CKD patients with different levels of GFR, was to evaluate the possibility to select the patients with a GFR glomerular filtration rate; screening for GFR impairment; low-molecular-weight proteins; sensitivity and specificity doi: 10.1152/ajprenal.00507.2009

The molecular weight cutoff for glomerular filtration is thought to be 30-50 kDa. Here we report rapid and efficient filtration of molecules 10-20 times that mass and a model for the mechanism of this filtration. We conducted multimodal imaging studies in mice to investigate renal clearance of a single-walled carbon nanotube (SWCNT) construct covalently appended with ligands allowing simultaneous dynamic positron emission tomography, near-infrared fluorescence imaging, and microscopy. These SWCNTs have a length distribution ranging from 100 to 500 nm. The average length was determined to be 200-300 nm, which would yield a functionalized construct with a molecular weight of ~350-500 kDa. The construct was rapidly ([t.sub.1/2] ~ 6 min) renally cleared intact by glomerular filtration, with partial tubular reabsorption and transient translocation into the proximal tubular cell nuclei. Directional absorption was confirmed in vitro using polarized renal cells. Active secretion via transporters was not involved. Mathematical modeling of the rotational diffusivity showed the tendency of flow to orient SWCNTs of this size to allow clearance via the glomerular pores. Surprisingly, these results raise questions about the rules for renal filtration, given that these large molecules (with aspect ratios ranging from 100:1 to 500:1) were cleared similarly to small molecules. SWCNTs and other novel nanomaterials are being actively investigated for potential biomedical applications, and these observations--that high aspect ratio as well as large molecular size have an impact on glomerular filtration--will allow the design of novel nanoscale-based therapeutics with unusual pharmacologic characteristics. multimodal imaging | nanotechnology | renal doi/10.1073/pnas.0913667107

This study aims to assess the feasibility of a protocol to diagnose renovascular disease using dual MR renography acquisitions: before and after administration of angiotensin-converting enzyme inhibitor (ACEi). Results of our simulation study aimed at testing the reproducibility of glomerular filtration rate (GFR) and renal plasma flow demonstrate that for a fixed overall dose of 12 ml gadolinium-based contrast material (500 mmol/ 1), the second dose should be approximately twice as large as the first dose. A three-compartment model for analyzing the second-injection data was shown to appropriately handle the tracer residue from the first injection. The optimized protocol was applied to 18 hypertensive patients without renovascular disease, showing minimal systematic difference in GFR measurements before and after ACEi of 0.8 [+ or -] 4.4 ml/min or 2.7 [+ or -] 14.9%. For 10 kidneys with significant renal artery stenosis, GFR decreased significantly after ACEi (P < 0.001, T value = 3.79), and the difference in GFR measurements before and after ACEi averaged 8.3 [+ or -] 6.9 ml/min or 26.2 [+ or -] 43.9%. Dual-injection MRI with optimized dose distribution appears promising for ACEi renography by offering measures of GFR changes with clinically acceptable precision and accuracy. glomerular filtration rate; renovascular disease; compartmental modeling

Nuclear factor-[kappa]B (NF-[kappa]B) plays an important role in hypertensive renal injury; however, its roles in perpetuating mitochondrial oxidative stress and renal dysfunction remain unclear. In this study, we assessed the effects of chronic NF-[kappa]B blockade with pyrrolidine dithiocarbamate (PDTC) on renal dysfunction and mitochondrial redox status in spontaneously hypertensive rats (SHR). PDTC (150 mg*kg body [wt.sup.-1] [day.sup.-1]) or vehicle was administered orally to 8-wk-old SHR and their respective controls for 15 wk. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography at the start of and at every third week throughout the study. After 15 wk of treatment, anesthetized rats underwent acute renal experiments to determine renal blood flow and glomerular filtration rate using PAH and inulin clearance techniques, respectively. Following renal experiments, kidneys were excised from killed rats, and cortical mitochondria were isolated for reactive oxygen species (ROS) measurements using electron paramagnetic resonance. Tissue mRNA and protein levels of NF-[kappa]B and oxidative stress genes were determined using real-time PCR and immunofluorescence or Western blotting, respectively. PDTC treatment partially attenuated the increase in SBP (196.4 [+ or -] 9.76 vs. 151.4 [+ or -] 2.12; P < 0.05) and normalized renal hemodynamic and excretory parameters and ATP production rates in SHR. PDTC treatment also attenuated the higher levels of cytosolic and mitochondrial ROS generation and tissue mRNA and protein expression levels of NF-[kappa]B and oxidative stress genes in SHR without any comparable responses in control rats. These findings suggest that NF-[kappa]B activation by ROS induces the cytosolic and mitochondrial oxidative stress and tissue injury that contribute to renal dysfunction observed in SHR. glomerular filtration rate; mitochondria; reactive oxygen species

This study was performed to investigate the glomerular permeability alterations responsible for the microalbuminuria occurring in endotoxemia and during anaphylactic shock. In anesthetized Wistar rats, the left ureter was catheterized for urine collection while, simultaneously, blood access was achieved. Endotoxemia was induced by lipopolysaccharide (LPS) from Escherichia coli, and glomerular permeability was assessed at 60 and 90 (n = 7) and 120 (n = 7) min. Anaphylaxis was induced by a bolus dose of Dextran-70, and glomerular permeability assessed at 5 min (n = 8) and 40 min (n = 9). Sham animals were followed for either 5 or 120 min. The glomerular sieving coefficients ([theta]) to fluorescein isothiocyanate-Ficoll (70/400) were determined from plasma and urine samples and assessed using size-exclusion chromatography (HPLC). After start of the LPS infusion (2 h), but not at 60 or 90 min, [theta] for [Ficoll.sub.70A] had increased markedly [from 2.91 x [10.sup.-5] [+ or -] 6.33 x [10.sup.-6] to 7.78 x [10.sup.-5] [+ or -] 6.21 x [10.sup.-6] (P < 0.001)]. In anaphylaxis, there was a large increase in [theta] for Ficolls >60 [Angstrom] in molecular radius already at 5 min, but the glomerular permeability was completely restored at 40 min. In conclusion, there was a transient, immediate increment of glomerular permeability in dextran-induced anaphylaxis, which was completely reversible within 40 min. By contrast, endotoxemia caused an increase in glomerular permeability that was manifest first after 2 h. In both cases, [theta] to large Ficoll molecules were markedly increased, reflecting an increase in the number of large pores in the glomerular filter. endotoxin; systemic inflammatory response syndrome

The study explored the long-term renal outcomes of kidney donation by establishing vital status and the risk of end-stage renal disease (ESRD) in a group of kidney donors. Results show carefully-screened donors had a preserved glomerular filtration rate, normal albumin excretion and excellent quality of life, indicating survival and risk of ESRD similar to those in the general population.

This is the first description of functional immunoassay technology (FIT), which as a diagnostic tool has broad application across the whole spectrum of physiological measurements. In this paper, FIT is used to measure the renal clearance of an ultra low-dose administration of a clinically available contrast reagent for the purpose of obtaining an accurate glomerular filtration rate (GFR) measurement. Biomarker-based GFR estimates offer convenience, but are not accurate and are often misleading. FIT overcomes previous analytic barriers associated with obtaining an accurate GFR measurement. We present the performance characteristics of this diagnostic test and demonstrate the method by directly comparing GFR values obtained by FIT to those obtained by an FDA approved nuclear test in 20 adults. Two subjects were healthy volunteers and the remaining 18 subjects had diagnosed chronic kidney disease, with 12 being kidney transplant recipients. Measured GFR values were calculated by the classic UV/P method and by the blood clearance method. GFR obtained by FIT and the nuclear test correlated closely over a wide range of GFR values (10.9-102.1 ml x [min.sup.-1] x 1.73 [m.sup.-2]). The study demonstrates that FIT-GFR provides an accurate and reproducible measurement. This nonradioactive, immunoassay-based approach offers many advantages, chiefly that most laboratories already have the equipment and trained personnel necessary to run an ELISA, and therefore this important diagnostic measurement can more readily be obtained. The FIT-GFR test can be used throughout the pharmaceutical development pipeline: preclinical and clinical trials. renal function; chronic kidney disease; transplant

Urotensin II (UII) has been implicated widely in cardiovascular disease. The mechanism(s) through which it contributes to elevated blood pressure is unknown, but its emerging role as a regulator of mammalian renal function suggests that the kidney might be involved. The aim of this study was to determine the effect of UII on renal function in the spontaneously hypertensive rat (SHR). UII infusion (6 pmol x [min.sup.-1] x 100 g body [wt.sup.-1]) in anesthetized SHR and control Wistar-Kyoto (WKY) rats produced marked reductions in glomerular filtration rate (AGFR WKY, n = 7, -0.3 [+ or -] 0.1 vs. SHR, n = 7, -0.6 [+ or -] 0.1 ml x [min.sup.-1] x 100 g body [wt.sup.-1], P = 0.03), urine flow, and sodium excretion rates, which were greater in SHR by comparison with WKY rats. WKY rats also showed an increase in fractional excretion of sodium ([DELTA]F[E.sub.Na]; +0.6 [+ or -] 0.1%, P = 0.02) in contrast to SHR in which no such change was observed ([DELTA][FE.sub.Na] -0.6 [+ or -] 0.2%). Blockade of the UII receptor (UT), and thus endogenous UII activity, with urantide evoked an increase in GFR which was greater in SHR (+0.3 [+ or -] 0.1) compared with WKY rats (+0.1 [+ or -] 0.1 ml x [min.sup.-1] x 100 g body [wt.sup.-i], p = 0.04) and was accompanied by a diuresis and natriuresis. UII and UT mRNA expression were greater in the renal medulla than the cortex of both strains; however, expression levels were up to threefold higher in SHR tissue. SHR are more sensitive than WKY to UII, which acts primarily to lower GFR thus favoring salt retention in this model of hypertension. UT receptor; kidney; glomerular filtration rate; sodium

The heat shock protein subfamily of 90 kDa (HSP90) is composed of five isoforms. The more abundant proteins of this subfamily are cytosolic isoforms known as HSP90[alpha] and HSP90[beta]. More than 100 client proteins have been found to be regulated by HSP90. Several studies have shown that HSP90 regulates nitric oxide synthesis that is dependent on endothelial nitric oxide synthase (eNOS). Because eNOS regulates renal vascular tone and glomerular filtration rate (GFR), the present study was designed to evaluate the effect of acute HSP90 inhibition with radicicol on GFR and the eNOS pathway. Twenty male Wistar rats were divided into two groups: control vehicle animals and radicicol-infused animals (25 [micro]g x [ml.sup.-1] x [min.sup.-1]). Basal levels were taken before experimental measurements. Mean arterial pressure and renal blood flow (RBF) were recorded, as well as GFR, urinary nitrite and nitrate excretion (UN[O.sub.2]/N[O.sub.3]V). Additionally, we evaluated eNOS expression, Ser1177 and Thr495 eNOS phosphorylation levels, the eNOS dimer-to-monomer ratio, as well as oxidative stress by assessing renal lipoperoxidation and urinary isoprostane [F.sub.2[alpha]] and hydrogen peroxide. HSP90 inhibition with radicicol produced a fall in RBF and GFR that was associated with a significant reduction of UN[O.sub.2]]N[O.sub.3]V. The effects of radicicol were in part mediated by a significant decrease in eNOS phosphorylation and in the eNOS dimer-to-monomer ratio. Our findings suggest that GFR is in part maintained by HSP90-eNOS interaction. renal blood flow; heat shock protein 90 isoforms

To investigate the mechanisms responsible for the neonatal increase in glomerular filtration rate (GFR), renal function studies (whole kidney and micropuncture) were carried out in anesthesized fetal sheep (133-140 days gestation; term = 150 days) and lambs (12-18 days). Fetuses were delivered and placed in a water bath (39.5[degrees]C), keeping the umbilical cord moist and intact. Lambs were studied on a thermostatically controlled heating pad. Animals were prepared for either blood flow studies or micropuncture measurements. Expected differences in blood composition and cardiovascular and renal function were observed between fetuses and lambs, and values obtained for most variables were similar to those measured in chronically catheterized unanesthetized animals. Fetal GFR was much lower than that of lambs (0.20 vs. 0.62 ml x [min.sup.-1] x g [kidney.sup.-1], P < 0.001). Free-flow, stop-flow, and net filtration pressures (NFP) were lower in the fetuses than the lambs (NFP 20.8 vs. 23.8 mmHg, P < 0.001), as was the calculated ultrafiltration coefficient (0.014 vs. 0.022 ml x [min.sup.-1] x [g.sup.-1] x mm[Hg.sup.-1], P < 0.001). Thus, we conclude that rises in both net filtration pressure and the ultrafiltration coefficient contribute to the large increase in GFR between fetal life and ~2 wk after birth. fetus; lamb; micropuncture; flee-flow pressure; stop-flow pressure

Infusion of L-arginine produces an increase in glomerular filtration via kidney vasodilation, correlating with increased kidney excretion of nitric oxide (NO) metabolites, but the specific underlying mechanisms are unknown. We utilized clearance and micropuncture techniques to examine the whole kidney glomerular filtration rate (GFR) and single nephron GFR (SNGFR) responses to 1) L-arginine (ARG), 2) ARG+octreotide (OCT) to block insulin release, 3) ARG+OCT+insulin (INS) infusion to duplicate ARG-induced insulin levels, and 4) losartan (LOS), an angiotensin AT-1 receptor blocker, +ARG+OCT. ARG infusion increased GFR, while increasing insulin levels. OCT coinfusion prevented this increase in GFR, but with insulin infusion to duplicate ARG induced rise in insulin, the GFR response was restored. Identical insulin levels in the absence of ARG had no effect on GFR. In contrast to ARG infusion alone, coinfusion of OCT with ARG reduced proximal tubular fractional and absolute reabsorption potentially activating tubuloglomerular feedback. Losartan infusion, in addition to ARG and OCT (LOS+ARG+OCT), restored the increase in both SNGFR and proximal tubular reabsorption, without increasing insulin levels. In conclusion, 1) hyperfiltration responses to ARG require the concurrent, modest, permissive increase in insulin; 2) inhibition of insulin release after ARG reduces proximal reabsorption and prevents the hyperfiltration response; and 3) inhibition of ANG II activity restores the hyperfiltration response, maintains parallel increases in proximal reabsorption, and overrides the arginine/octreotide actions. nitric oxide; glomerular filtration rate; octreotide

We evaluated the early postpartum recovery of glomerular function over 4 wk in 57 women with preeclampsia. We used physiological techniques to measure glomerular filtration rate (GFR), renal plasma flow, and oncotic pressure ([pi].sub.A]) and computed a value for the two-kidney ultrafiltration coefficient ([K.sub.f]). Compared with healthy, postpartum controls, GFR was depressed by 40% on postpartum day 1, but by only 19% and 8% in the second and fourth postpartum weeks, respectively. Hypofiltration was attributable solely to depression, at corresponding postpartum times, of [K.sub.f] by 55%, 30%, and 18%, respectively. Improvement in glomerular filtration capacity was accompanied by recovery of hypertension to near-normal levels and significant improvement in albuminuria. We conclude that the functional manifestations of the glomerular endothelial injury of preeclampsia largely resolve within the first postpartum month. glomerular filtration rate; ultrafiltration coefficient; postpartum recovery

Production of urine is initiated by fluid and solute flux across the glomerular filtration barrier. Recent ultrastructural studies have shown that under extreme conditions of no filtration, or very high filtration, a restriction to flow is predicted in a space underneath the podocyte cell body or its processes, the subpodocyte space (SPS). The SPS covered up to two-thirds of the glomerular filtration barrier (GFB) surface. The magnitude of this restriction to flow suggested that it might be unlikely that filtration into and flow through the SPS would contribute significantly to total flow across the entire GFB under these conditions. To determine whether the SPS has similar properties under normal physiological conditions, we have carried out further three-dimensional reconstruction of rat glomeruli perfused at physiologically normal hydrostatic and colloid osmotic pressures. These reconstructions show that the sub-podocyte space is even more restricted under these conditions, with a mean height of the SPS of 0.34 [micro]m, mean pathlength of 6.7 [+ or -] 1.4 [micro]m, a mean width of the SPS exit pore of 0.15 [+ or -] 0.05 [micro]m, and length of 0.25 [+ or -] 0.05 [micro]m. Mathematical modeling of this SPS based on a circular flow model predicts that the resistance of these dimensions is 2.47 times that of the glomerular filtration barrier and exquisitely sensitive to changes in the dimensions of the SPS exit pore (SEP), indicating that the SEP could be the principal regulator of the extravascular pressure in the SPS. This suggests a physiological role of the podocyte in the regulation of glomerular fluid flux across most of the GFB. glomerular filtration barrier; podocyte; mathematical modeling

The purpose of this study was to determine the accuracy and sources of error in estimating single-kidney glomerular filtration rate (GFR) derived from low-dose gadolinium-enhanced T1-weighted MR renography. To analyze imaging data, MR signal intensity curves were converted to concentration vs. time curves, and a three-compartment, six-parameter model of the vascular-nephron system was used to analyze measured aortic, cortical, and medullary enhancement curves. Reliability of the parameter estimates was evaluated by sensitivity analysis and by Monte Carlo analyses of model solutions to which random noise had been added. The dominant sensitivity of the medullary enhancement curve to GFR 1-4 min after tracer injection was supported by a low coefficient of variation in model-fit GFR values (4%) when measured data were subjected to 5% noise. These analyses also showed the minimal effects of bolus dispersion in the aorta on parameter reliability. Single-kidney GFR from MR renography analyzed by the three-compartment model (4.0-71.4 ml/min) agreed well with reference measurements from [sup.99m]Tc-DTPA clearance and scintigraphy (r = 0.84, P < 0.001). Bland-Airman analysis showed an average difference of 11.9 ml/min (95% confidence interval = 5.8-17.9 ml/min) between model and reference values. We conclude that a nephron-based multicompartmental model can be used to derive clinically useful estimates of single-kidney GFR from low-dose MR renography. multicompartmental modeling; magnetic resonance imaging; tracer kinetics; glomerular filtration rate; radionuclide scintigraphy; gadolinium chelates doi:10.1152/ajprenal.00347.2006

Abstract Glomerular filtration rate (GFR) in children can be estimated by the formula GFR=kxBH/Pcr (where BH is body height in centimetres and Pcr is the plasma creatinine concentration in micromoles [...]

Byline: Stanley Hellerstein (1,2), Max Berenbom (1), Pat Erwin (1), Nancy Wilson (1), Sylvia DiMaggio (1) Keywords: Glomerular filtration rate; Creatinine; Cimetidine; Glomerular hyperfiltration Abstract: Renal functional reserve was measured during 89 studies in 78 children as the difference between the baseline glomerular filtration rate (GFR) and that following a protein meal. GFR was measured using creatinine as the filtration marker in children pre-treated with cimetidine. The children had been on a diet free of meat, fish, and fowl for 24 h. The protein meal to stimulate GFR was derived from milk, cheese, eggs, and baked goods. The increase in GFR following the protein meal was due mainly to an increase in the glomerular filtration of creatinine, with a small contribution by decreased serum creatinine concentration. This study confirmed that renal functional reserve can be measured using a meat-free protein meal to stimulate GFR. The protocol employed is a relatively noninvasive and inexpensive procedure for identifying glomerular hyperfiltration in children. Author Affiliation: (1) Section of Nephrology, The Children&apos;s Mercy Hospital, The University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, USA (2) Section of Nephrology, The Children&apos;s Mercy Hospital, 2401 Gillham Road, Kansas City, Missouri, 64108, USA Article History: Registration Date: 19/05/2004 Received Date: 02/02/2004 Accepted Date: 06/05/2004 Online Date: 16/07/2004

Byline: Kristina Sward (1), Felix Valsson (1), Johan Sellgren (1), Sven-Erik Ricksten (1) Keywords: Renal blood flow; Glomerular filtration rate; Thermodilution; Renal veins; Paraaminohippurate (PAH); Ethylenediaminetetraacetic acid (EDTA); Intensive care Abstract: Objective To evaluate various treatment strategies in critically ill patients with ischaemic acute renal failure, there is a need for reliable bedside measurements of total renal blood flow (RBF), glomerular filtration rate (GFR) and renal oxygen consumption without the need for urine collection. Design The continuous renal vein thermodilution method and the infusion clearance techniques were validated against the gold standard technique, the urinary clearance of paraaminohippurate (PAH) and chromium ethylenediaminetetraacetic acid, respectively. Setting University hospital cardiothoracic ICU. Patients Seventeen uncomplicated mechanically ventilated post-cardiac surgical patients. Interventions None. Measurements and results Renal blood flow, GFR and the renal filtration fraction (FF) were measured for two consecutive 30-min periods by urinary clearance and compared with simultaneous measurements made by the thermodilution and infusion clearance techniques. Urinary clearance for PAH was corrected for by renal extraction of PAH. The within-group error, repeatability coefficient and the coefficient of variation were highest for the thermodilution technique and lowest for the infusion clearance technique with regard to RBF, GFR and FF. The infusion clearance technique had a higher agreement with the urinary clearance method than the thermodilution method. For estimations of RBF and GFR, the between-group errors were 33% and 43% comparing infusion clearance with urinary clearance and 65% and 67% comparing thermodilution with urinary clearance. Conclusions The infusion clearance method had the highest reproducibility and the highest agreement with the urinary clearance reference method. The renal vein thermodilution technique is less reliable in the ICU setting due to poor repeatability and poor agreement with the reference method. Author Affiliation: (1) Department of Cardiothoracic Anaesthesia and Intensive Care, Sahlgrenska University Hospital Goteborg, 41345, Goteborg, Sweden Article History: Registration Date: 23/06/2004 Received Date: 07/01/2004 Accepted Date: 18/06/2004 Online Date: 28/07/2004

Byline: Pierre Delanaye (1), Bernard Lambermont (2), Jean-Paul Chapelle (3), Jacques Gielen (3), Paul Gerard (4), Georges Rorive (1) Keywords: Creatinine; Critical care; Cystatin C; Glomerular filtration rate; Kidney function tests Abstract: Objective To compare the sensitivity of cystatin C and creatinine in detecting decreased glomerular filtration rate. Design Prospective observational study. Setting Medical intensive care unit at a university hospital. Patients and participants Fourteen patients hospitalised in a medical intensive care unit. Interventions Cystatin C and creatinine plasmatic levels were measured in 40 blood samples taken with an interval of at least 24 h. Measurements and results Glomerular filtration rate was estimated by creatinine clearance using 24-h urine collection and the classical Cockcroft-Gault equation. The ability of cystatin C to detect a glomerular filtration rate under 80 ml/min per 1.73 m.sup.2 was significantly better than that of creatinine (p Conclusions Cystatin C, a new plasmatic marker of renal function, could be used to detect renal failure in intensive care in the future. Author Affiliation: (1) Nephrology, Department of Medicine, Liege University Hospital, CHU Sart Tilman (B35), 4000, Liege, Belgium (2) Medical Intensive Care Unit, Department of Medicine, Liege University Hospital, CHU Sart Tilman (B35), 4000, Liege, Belgium (3) Department of Clinical Chemistry, Liege University Hospital, CHU Sart Tilman (B35), 4000, Liege, Belgium (4) Department of Statistics, University of Liege, 4000, Liege, Belgium Article History: Registration Date: 15/01/2004 Received Date: 21/05/2003 Accepted Date: 15/01/2004 Online Date: 24/02/2004

Byline: Stanley Hellerstein (1,2), Max Berenbom (1), Pat Erwin (1), Nancy Wilson (1), Sylvia DiMaggio (1) Keywords: Serum cystatin C; Urine cystatin C; Serum creatinine; Urine creatinine; Glomerular filtration rate; Cimetidine protocol Abstract: Glomerular filtration rate (GFR) and urine and serum concentrations of cystatin C and creatinine were measured in 40 boys and 42 girls. The fractional excretion of cystatin C (FE Cyst C) increased in proportion to the decrease in GFR. Since serum creatinine concentration (S-Creatinine) in the numerator of the fractional excretion equation and serum cystatin C concentration (S-Cystatin C) in the denominator have similar numerical values, they cancel out. The result is an equation in which the FE Cyst C is equal to the ratio of urinary cystatin C to urinary creatinine (u[cystatin-C/Cr]). The ratio of u[cystatin C/Cr] was compared with GFR. Using a receiving operating characteristic (ROC) plot, the data showed that a ratio of u[cystatin C/Cr]*100 that is aY=0.100 has a sensitivity of 90.0% for identification of children with GFR a$?60 ml/min per 1.73 m.sup.2. The false-positive rate is 16.1%. The u[cystatin C/Cr] ratio is a reliable screening tool for detecting decreased GFR that does not require a serum sample. Author Affiliation: (1) Section of Nephrology at The Children&apos;s Mercy Hospital, The University of Missouri School of Medicine at Kansas City, Kansas City, Missouri, USA (2) Section of Nephrology, The Children&apos;s Mercy Hospital, 2401 Gillham Road, Kansas City, Missouri 64108, USA Article History: Registration Date: 11/11/2003 Received Date: 03/09/2003 Accepted Date: 03/11/2003 Online Date: 10/03/2004

Renal function was studied in mice of different ages. In metabolic cage experiments, the renal electrolyte excretion was similar in young (n = 8; 5-to 7-wk-old) and adult (n = 6; 20- to 22-wk-old) CD-1 (ICR) BR mice, whereas spontaneous drinking volume and urinary flow rate were significantly higher in the adult compared with the young mice. Subsequently, the renal functional reserve was investigated by amino acid (AA) infusion (10%) in anesthetized young (n = 8) and adult (n = 6) mice. Because the body weight of adult mice was significantly higher than that of young animals, one group of adult mice (n = 8) received 12.5% AA to ensure that the dose of AA related to body weight was similar in both groups. Young animals constantly infused with Ringer solution served as time controls (n = 8). Glomerular filtration rate (GFR) at baseline was similar in each group. Because of AA, GFR significantly increased in young mice but not in both groups of adult animals, whereas in time controls GFR remained constant. Urinary flow rate and sodium excretion were elevated by AA in young and adult mice. We conclude that in CD-1 mice the first signs of age-related changes in kidney function concern alterations in renal hemodynamics, whereas renal tubular function appears to be preserved. kidney; amino acids; glomerular filtration rate; physiological aging

The responses to A[T.sub.1]-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition ([N.sup.G]-nitro-Larginine methyl ester 30 [micro]g*[kg.sup.-1]*[min.sup.-1]) were investigated in separate experiments in normal dogs. A[T.sub.1] blockade decreased arterial pressure (106 [+ or -] 4 to 96 + 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 [+ or -] 3 to 116 [+ or -] 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1 blockade and NOS inhibition (21 [+ or -] 4 mmHg). Volume expansion during A[T.sub.1] blockade elicited marked natriuresis (26 [+ or -] 11 to 274 [+ or -] 55 [micro]mol/min) that was severely reduced by concomitant NOS inhibition (10 [+ or -] 3 to 45 [+ or -] 11 [micro]mol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 [+ or -] 1 to 23 [+ or -] 7 [micro]mol/min). Volume expansion during A[T.sub.1] blockade increased GFR (+30%), less so during combined A[T.sub.1] blockade and NOS inhibition (+ 13%), but it did not increase GFR significantly (P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with A[T.sub.1] blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute A[T.sub.1] blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system. sodium excretion; blood pressure; glomerular filtration rate; [N.sup.G]-nitro-L-arginine methyl ester; candesartan

Although glycine prevents renal tubular cell injury in vitro, its effect in vivo is not clear. The purpose of this study was to investigate whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward would reduce renal injury caused by ischemia-reperfusion. Female Sprague-Dawley rats received a semisynthetic powdered diet containing 5% glycine and 15% casein (glycine group) or 20% casein (control group). Two days later, renal ischemia was produced by cross-clamping the left renal vessels for 15 min, followed by reperfusion. The right kidney was removed before reperfusion. The postischemic glomerular filtration rate (GFR) showed that renal function was less impaired and recovered more quickly in rats receiving glycine. For example, at day 7, GFR in controls (0.31 [+ or -] 0.03 ml * [min.sup.-1] * 100 [g.sup.-1]) was about one-half that of glycine-treated rats (0.61 [+ or -] 0.06 ml * [min.sup.-1] * 100 [g.sup.-1], P < 0.05). Furthermore, tubular injury and cast formation observed in controls was minimized by glycine (pathology score, 3.2 [+ or -] 0.4 vs. 1.0 [+ or -] 0.4, P < 0.05). Urinary lactate dehydrogenase (LDH) concentration was elevated by ischemia-reperfusion in the control group (260 [+ or -] 22 U/l), but values were significantly lower by about fourfold (60 [+ or -] 30 U/l) in glycine-fed rats. Similarly, free radical production in urine was significantly lower in glycine-treated animals. Importantly, on postischemic day 1, binding of pimonidazole, an in vivo hypoxia marker, was increased in the outer medulla in controls; however, this phenomenon was prevented by glycine. Two weeks later, mild leukocyte infiltration and interstitial fibrosis were still observed in controls, but not in kidneys from glycine-treated rats. In conclusion, these results indicate that administration of glycine indeed reduces mild ischemia-reperfusion injury in the kidney in vivo, in part by decreasing initial damage and preventing chronic hypoxia. kidney; hypoxia; rat

Bodybuilders and athletes completed a nutritional analysis and medical tests to determine effects of a high-protein diet on kidney function. Results indicate that although excessive protein can impair kidney function, quantities ingested by athletes do not pose increased risk for renal disease.

The level of serum cystatin C may be superior to serum creatinine as an indicator of kidney function in children. While both metabolites are excreted by glomerular filtration in the kidneys, creatinine measurements must be adjusted to the child's height, body composition, age, and gender. Researchers compared both measurements in 184 children undergoing kidney function tests. Cystatin C was a more accurate indicator of glomerular filtration rate, and was not affected by the gender or size of the child., Objectives. Serum creatinine is the most common endogenous marker of renal function. The proportionality between creatinine production and muscle mass requires adjustment for height and body composition. The low molecular weight protein cystatin C is produced by all nucleated cells and eliminated by glomerular filtration. Therefore, cystatin C was studied as an alternative marker of glomerular filtration rate (GFR) in children. Methods. Cystatin C and creatinine were measured in sera from inulin clearance ([C.sub.In]) examinations performed in 184 children aged 0.24 to 17.96 years. [C.sub.In] ranged from 7 to 209 mL/min/1.73 [m.sup.2] (median, 77). Results. The reciprocal of cystatin C correlated better with [C.sub.In] (r = 0.88) than the reciprocal of creatinine (r = 0.72). Stepwise regression analysis identified no covariates for the correlation between cystatin C and [C.sub.In], whereas height was a covariate for creatinine. Using an estimate of GFR from serum creatinine and height, correlation with [C.sub.In] was similar to cystatin C, but female gender and dystrophy were associated with an overestimation of GFR. Diagnostic accuracy in the identification of reduced GFR measured as area under the receiver-operating characteristic plot was 0.970 [+ or -] 0.135 (mean [+ or -] SE) for cystatin C and 0.894 [+ or -] 0.131 for creatinine (NS). A cutoff cystatin C concentration of 1.39 mg/L had 90% sensitivity and 86% specificity for detecting abnormal GFR. Conclusion. Unlike creatinine, serum cystatin C reflects renal function in children independent of age, gender, height, and body composition. Pediatrics 1998;101: 875-881; children, renal function tests, inulin clearance, cystatin C, creatinine., ABBREVIATIONS. GFR, glomerular filtration rate; [C.sub.In], inulin clearance; [GFR.sub.Crea], GFR from creatinine; [GFR.sub.Cys], GFR from cystatin C; PAP, para-aminophenazone; ROC, receiver-operating characteristic. An ideal endogenous marker of glomerular filtration rate [...]

Sixteen women were studied to investigate the renal and systemic hemodynamic changes in the midluteal and midfollicular phases of the menstrual cycle. The decrease in mean arterial pressure, which was caused by the primary vasolidation during the midluteal phase of the menstrual cycle, was found to be similar to the increase in cardiac output experienced during early pregnancy. Both the peripheral vasodilation during the luteal phase of the menstrual cycle and the early part of pregnancy were related to the rise in renal plasma flow and renal vascular resistance.

Autoregulation of glomerular filtration rate (GFR) is most efficient in the inner cortex of spontaneously hypertensive rats. This autoregulation of GFR is calculated from the tubular uptake of 125I-labeled aprotinin (125I-Ap) and 131I-Ap. Autoregulation of GFR is less efficient than the autoregulation of renal blood flow (RBF) in both normotensive and hypertensive rats. The regulation of RBF during decreased arterial pressure shows a preglomerular vasodilation.

A study of the effects on renal excretion and hemodynamics confirms that nitric oxide regulates the renal vasoconstrictor effects of angiotensin II (ANG II). NO synthesis inhibition within the kidney through intrarenal L-NAME administration improves the renal hemodynamic effects of ANG II and reduces the glomerular filtration rate. NO synthesis blockade improves the effect of ANG II on sodium excretion in a dose-dependent-manner, due to the significant decrease in glomerular filtration rate and filtered sodium load.

An experimental analysis of the dose-response relationship of plasma amino acid (AA) levels with renal hemodynamics in 8 human subjects shows that enhancement of plasma AA levels by AA infusion to physiological hyperaminoacidemia levels improves renal hemodynamics by increasing renal plasma flow (RPF) and basal glomerular filtration rate (GFR). However, pharmacological enhancement of plasma AA levels beyond hyperaminoacidemia levels does not increase GFR or RPF levels. The increase in RPF and GFR is related to an increase in plasma glucagon levels, but not to insulin, growth hormone or IGF-1 levels.