Chromium 51-labeled Ethylenediaminetetraacetic Acid Research Articles

Effect of Dapagliflozin on Measured vs. Panel-Estimated Glomerular Filtration Rate.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors can cause a reversible decline in glomerular filtration rate (GFR), which may influence dosing recommendations for renally excreted medications. In practice, GFR is typically estimated by serum creatinine concentration, but creatinine may not be a reliable indicator of GFR decline in the setting of SGLT2 inhibitor use. Alternative filtration markers such as cystatin C, β-trace protein (BTP), and β2-microglobulin (B2M) may be more appropriate, but little is known about how these markers are affected by SGLT2 inhibitor use. Therefore, we determined creatinine, cystatin C, BTP, and B2M concentration in a crossover study of 35 people with type 2 diabetes receiving 12 weeks of dapagliflozin treatment or placebo. Estimated GFR (eGFR) based on creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of all four markers (eGFRpanel) was compared with measured GFR (mGFR) based on plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). Dapagliflozin treatment was associated with a significant decrease in mGFR (-9 mL/min/1.73 m2, P < 0.001) but not a corresponding increase in concentration of any filtration marker. No eGFR equation accurately predicted change in mGFR between treatment periods, but eGFRcomb and eGFRpanel yielded the highest overall accuracy relative to mGFR across both treatment periods. These findings highlight the stability in performance gained by combining multiple filtration markers but suggest that eGFR in general is not an ideal metric for assessing short-term GFR decline in people initiating SGLT2 inhibitor therapy.

Usefulness of urinary biomarkers to estimate the interstitial fibrosis surface in diabetic nephropathy with normal kidney function.

Kidney biopsies of patients with diabetic nephropathy (DN) and normal kidney function may exhibit interstitial fibrosis (IF) without reduction of glomerular filtration rate (GFR) because of hyperfiltration. The aim of our study was to analyse the performance of a set of biomarkers of tubular injury to estimate the extent of IF in patients with DN and normal kidney function. This cross-sectional study included 118 adults with DN diagnosed by kidney biopsy and GFR≥90mL/min/1.73 m2 and a control group of healthy subjects. We measured the urinary excretion of monocyte chemoattractant protein-1 (MCP-1) neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), β2-microglobulin and dickkopf-3 protein (DKK-3) at the time of kidney biopsy. GFR was measured by chromium-51 labeled ethylenediamine tetraacetic acid (Cr-EDTA) (measured GFR). IF was quantified using a quantitative morphometric procedure. Predictive multivariate models were developed to estimate the IF surface. Patients with DN showed significantly higher levels of DKK-3, MCP-1 and L-FABP and significantly lower levels of epidermal growth factor (EGF) than healthy controls. There were no significant between-group differences in the levels of β2-microglobulin, KIM-1 or NGAL. IF was negatively associated with EGF and positively with age, proteinuria, MCP-1, DKK-3 and L-FABP, but not with β2-microglobulin, KIM-1, NGAL or GFR. The best model to predict IF surface accounted for 59% of its variability and included age, proteinuria, EGF, DKK-3 and MCP-1. Our study provides a model to estimate the IF in DN that can be useful to assess the progression of IF in patients with normal kidney function.

The Utility of Combined Urine Urea and Creatinine Clearance for Pretransplant Renal Function Assessment

Evaluation of donor renal function as glomerular filtration rate (GFR) is a crucial part of pretransplant workup. Most guidelines recommend measured GFR (mGFR) using exogenous markers with creatinine clearance (CrCl) as an alternative. However, exogenous markers are difficult to obtain and perform, and CrCl may overestimate GFR. We explore the use of CrCl and combined urea and creatinine clearance as an alternative for GFR assessment. A retrospective study involving 81 kidney donors from 2007 to 2020, with mGFR collected by chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) and CrCl and combined urea and creatinine clearance. We analyzed the performance of CrCl and combined urea and creatinine clearance against 51Cr-EDTA. Adequacy of urine volume was taken into consideration. A total of 81 candidates with a mean age of 44.80 ± 10.77 years were enrolled. Mean mGFR from 51Cr-EDTA was 123.66 ± 26.91 mL/min/1.73 m2, and combined urea and creatinine clearance and CrCl were 122.13 ± 47.07 and 133.40 ± 36.32 mL/min/1.73 m2, respectively. CrCl overestimated 51Cr-EDTA. Though combined urea and creatinine clearance had minimal bias, it had a lower correlation coefficient (0.25 vs 0.43), lower precision (49.51 vs 38.10), and slightly lower accuracy within 30% of 51Cr-EDTA (74.07% vs 76.54%). Combined urea and creatinine clearance did not improve the performance of CrCl. Nevertheless, it can potentially be used as first-line GFR assessment, followed by mGFR in selected donors, to ascertain threshold of safe kidney donation. A stringent urine collection method is essential to ensure accurate measurement.

Measuring GFR: A Systematic Review

No comprehensive systematic review of the accuracy of glomerular filtration rate (GFR) measurement methods using renal inulin clearance as reference has been published. Systematic review with meta-analysis of cross-sectional diagnostic studies. Published original studies and systematic reviews in any population. Index and reference measurements conducted within 48 hours; at least 15 participants studied; GFR markers measured in plasma or urine; plasma clearance calculation algorithm verified in another study; tubular secretion of creatinine had not been blocked by medicines. Endogenous creatinine clearance; renal or plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA), diethylenetriaminepentaacetic acid (DTPA), iohexol, and iothalamate; and plasma clearance of inulin. Renal inulin clearance measured under continuous inulin infusion and urine collection. Mean bias <10%, median bias <5%, the proportion of errors in the index measurements that did not exceed 30% (P30) ≥80%, and P10 ≥50% were set as requirements for sufficient accuracy. Based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, the quality of evidence across studies was rated for each index method. Renal clearance of iothalamate measured GFR with sufficient accuracy (strong evidence). Renal and plasma clearance of 51Cr-EDTA and plasma clearance of iohexol were sufficiently accurate to measure GFR (moderately strong evidence). Renal clearance of DTPA, renal clearance of iohexol, and plasma clearance of inulin had sufficient accuracy (limited evidence). Endogenous creatinine clearance was an inaccurate method (strong evidence), as was plasma clearance of DTPA (limited evidence). The evidence to determine the accuracy of plasma iothalamate clearance was insufficient. With the exception of plasma clearance of inulin, only renal clearance methods had P30 >90%. The included studies were few and most were old and small, which may limit generalizability. Requirements for sufficient accuracy may depend on clinical setting. At least moderately strong evidence suggests that renal clearance of 51Cr-EDTA or iothalamate and plasma clearance of 51Cr-EDTA or iohexol are sufficiently accurate methods to measure GFR.

Glomerular Filtration Rate Measured by 51Cr-EDTA Clearance: Evaluation of Captopril-Induced Changes in Hypertensive Patients with and without Renal Artery Stenosis

INTRODUCTION:Renal artery stenosis can lead to renovascular hypertension; however, the detection of stenosis alone does not guarantee the presence of renovascular hypertension. Renovascular hypertension depends on activation of the renin-angiotensin system, which can be detected by functional tests such as captopril renal scintigraphy. A method that allows direct measurement of the baseline and post-captopril glomerular filtration rate using chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA) could add valuable information to the investigation of hypertensive patients with renal artery stenosis. The purposes of this study were to create a protocol to measure the baseline and post-captopril glomerular filtration rate using 51Cr-EDTA, and to verify whether changes in the glomerular filtration rate permit differentiation between hypertensive patients with and without renal artery stenosis.METHODS:This prospective study included 41 consecutive patients with poorly controlled severe hypertension. All patients had undergone a radiological investigation of renal artery stenosis within the month prior to their inclusion. The patients were divided into two groups: patients with (n=21) and without renal artery stenosis, (n=20). In vitro glomerular filtration rate analysis (51Cr-EDTA) and 99mTc-DMSA scintigraphy were performed before and after captopril administration in all patients.RESULTS:The mean baseline glomerular filtration rate was 48.6±21.8 ml/kg/1.73 m2 in the group wuth renal artery stenosis, which was significantly lower than the GFR of 65.1±28.7 ml/kg/1.73m2 in the group without renal artery stenosis (p=0.04). Captopril induced a significant reduction of the glomerular filtration rate in the group with renal artery stenosis (to 32.6±14.8 ml/ kg/1.73m2, p=0.001) and an insignificant change in the group without RAS (to 62.2±23.6 ml/kg/1.73m2, p=0.68). Scintigraphy with technetium-99m dimercapto-succinic acid (DMSA) did not show significant differences in differential renal function from baseline to post-captopril images in either group.CONCLUSIONS:Captopril induced a decrease in the GFR that could be quantitatively measured with 51Cr-EDTA. The reduction is more pronounced in hypertensive patients with RAS.

Pregnancy aggravates proteinuria in subclinical glomerulonephritis in the rat

Because subclinical renal disease may be aggravated during pregnancy—as reflected in the occurrence of proteinuria, for example—we investigated whether a subclinical glomerulonephritis (SG) in the non-pregnant rat (passive Heymann nephritis), a condition without proteinuria, is aggravated when the animals become pregnant and, if so, whether this is associated with a glomerular inflammatory reaction. SG was induced in non-pregnant rats 8 days before pregnancy. On day -1, part of the group of rats became pregnant. Three experiments were performed. In experiment 1, 4-hour urine albumin excretions and blood pressure (tail cuff) were measured. In experiment 2, the glomerular filtration rate (GFR) was measured with the chromium 51-labeled ethylenediaminetetraacetic acid method, while in experiment 3, parameters characteristic of a glomerular inflammation were studied. Experiment 1 revealed that non-pregnant rats with SG did not exhibit proteinuria. However, after the rats became pregnant, a significant proteinuria occurred, without an increase in systolic blood pressure. Experiment 2 revealed that the GFR did not increase in pregnant rats with SG, while experiment 3 showed that only pregnant animals exhibited a significant glomerular inflammation; this glomerular inflammation was characterized by intraglomerular influx of polymorphonuclear cells and monocytes. The results suggest that an SG in the rat may flare up during pregnancy. This exacerbation is characterized by proteinuria and coincides with a glomerular inflammatory reaction. It is suggested that proteinuria and the glomerular inflammatory reaction are causally related and promoted by the pregnant condition.

Cooling strangulated intestine before and following release of an obstruction protects from ischemia/reperfusion injury.

To evaluate whether cooling of ischemic intestine before and immediately after the release of the obstruction is more advantageous than is warming in an isolated ileal loop rat model. Prospective randomized experimental trials. Laboratory. Male Sabra rats. An isolated loop of ileum was created in rats and constantly perfused with warmed normal saline (37 degrees C). Intestinal ischemia was caused by clamping of the superior mesenteric artery for 15 minutes. Cooling of the isolated ileal loop to 32 degrees C by the application of cold saline was done for the last half of the ischemic period and continued during the first 10 minutes of reperfusion. The intestine was warmed to 37 degrees C for the next 20 minutes of reperfusion. The chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) plasma-to-lumen clearance rate was used for the evaluation of intestinal mucosal injury. Multiple intestinal samples were harvested at the end of the reperfusion period, and the histological features were evaluated. The 51Cr-EDTA plasma-to-lumen clearance rates were significantly lower (P < .001) in the rats in which cooling of the ischemic intestine was performed in comparison with the control group, indicating reduced intestinal mucosal injury in all three 10-minute reperfusion periods. Cooling also significantly changed the resultant histological damage to the intestinal mucosa exerted by ischemia (P < .001). Cooling of the ischemic intestine before the release of the obstruction and for a short period during reperfusion provides significant protection from ischemia/ reperfusion injury compared with the traditional method of warming the ischemic intestine.

Renal function and histopathologic changes in children after liver transplantation

Up to 60% reduction of renal function has been reported after orthotopic liver transplantation (OLT) in patients receiving cyclosporine. We prospectively investigated renal function and histopathology in 16 children on triple immunosuppression therapy during 3 years after OLT. Cyclosporine was administered in 3 doses/day to preschool children. The median age at OLT was 5.4 years. Determinations of chromium 51-labeled ethylenediaminetetraacetic acid, p = aminohippuric acid, lithium, and sodium clearances, measurements of serum and urinary electrolytes, and urinary concentration tests were performed. Renal biopsy specimens were taken 18 and 36 months after transplantation. The mean glomerular filtration rate was 121.5 ml/min per 1.73 m 2 before transplantation, 86.3 at discharge, and 119.4 36 months after OLT. Hyperuricemia, hyperkalemia, and reduced urinary concentrating capacity were common. Hyperkalemia occurred in 13% to 19% of the patients, only during the first 6 months. Hyperuricemia and reduced concentrating capacity occurred with incidences of 17% to 44% and 40% to 63%, respectively. Histopathologic changes were mild, and severe nephrotoxic effects of cyclosporine was not seen. However, tubular atrophy, mesangial matrix increase, and mesangial cell proliferation were common. We conclude that triple immunosuppression with cyclosporine administration, in three doses per day, to small children and careful renal follow-up ensure good renal function after OLT. (J P EDIATR 1994;125:863-9)

Partial reversibility of cisplatin nephrotoxicity in children

To evaluate the long-term renal toxicity of cisplatin, 40 children who had been without treatment at least 18 months (range 18 months to 7 years) were observed. In all the children, glomerular filtration rate (GFR) was estimated from the plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid, both at the end of treatment and at a median follow-up of 2 years 6 months after treatment was stopped (range 18 months to 7 years). In 21 children, serum magnesium level was also measured at follow-up. Median age at diagnosis was 15 months (range 13 days to 13 years 8 months), and median cumulative doses of cisplatin was 500 mg/m2 (range 120 to 1860 mg/m2). In 22 of 24 children with an end-of-treatment GFR of less than 80 ml/min per 1.73 m2, the median improvement in GFR at follow-up was 22 ml/min per 1.73 m2 (range 2 to 56 ml/min per 1.73 m2). Hypomagnesemia was found in 6 of 21 children and was independent of GFR. No significant correlation was found between improvement in renal function and total cisplatin dose, age, gender, tumor type, or associated nephrotoxic medication. We conclude that most children have some recovery from cisplatin glomerular toxicity, especially if damage is not severe, but that hypomagnesemia may persist.

Mucosal injury induced by ischemia and reperfusion in the piglet intestine: Influences of age and feeding

The pathogenesis of neonatal necrotizing enterocolitis is unknown, but enteral alimentation, infectious agents, and mesenteric ischemia have been frequently invoked as primary initiators of the disease. To define the vulnerability of the intestinal mucosa to ischemia and reperfusion in the developing piglet, we evaluated changes in mucosal permeability using plasma-to-lumen clearance of chromium 51-labeled ethylenediaminetetraacetic acid in the ileum of anesthetized 1-day-, 3-day-, 2-wk-, and 1-mo-old piglets as a function of (a) duration of intestinal ischemia (20, 40, or 60 min of total superior mesenteric artery occlusion), (b) feeding status (fasted or nursed), and (c) composition of luminal perfusate (balanced salt solution vs. predigested cow milk-based formula). Baseline chromium 51-labeled ethylenediaminetetraacetic acid clearance was not significantly altered by ischemia, irrespective of duration, or feeding in all age groups. However, clearances were significantly elevated during reperfusion after l h of total intestinal ischemia in all age groups, whether fasted or fed. Reperfusion-induced increases in clearance did not differ among age groups when the bowel lumen was perfused with a balanced salt solution. However, luminal perfusion with formula resulted in higher clearances in 1-day-old piglets compared with all older animals. Thus, the neonatal intestine appears to be more vulnerable to mucosal injury induced by ischemia and reperfusion in the presence of formula than the intestine of older animals.

Effect of immunologic reactions on rat intestinal epithelium: Correlation of increased permeability to chromium 51-labeled ethylenediaminetetraacetic acid and ovalbumin during acute inflammation and anaphylaxis

In these studies we compared jejunal permeability to two probes—chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)—under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities (<0.04% and 0.002% of the administered dose for 51Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p < 0.005), (b) increased ~20-fold at day 10 (p < 0.005 and <0.01, respectively), and (c) normal at day 35. Urinary recovery of 51Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values ~10-fold those in controls (p < 0.001 and <0.01, for 51Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51Cr-EDTA reflect gut permeability changes to macromolecular antigens. If similar conditions exist in humans, urinary recovery of 51Cr-EDTA may be useful in monitoring intestinal abnormalities associated with inflammation.

Effect of immunologic reactions on rat intestinal epithelium

Abstract In these studies we compared jejunal permeability to two probes—chromium 51-labeled ethylenediaminetetraacetic acid ( 51 Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)—under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities ( 51 Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51 Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p 51 Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values ~10-fold those in controls (p 51 Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51 Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51 Cr-EDTA reflect gut permeability changes to macromolecular antigens. If similar conditions exist in humans, urinary recovery of 51 Cr-EDTA may be useful in monitoring intestinal abnormalities associated with inflammation.

Effects of Prostacyclin Infusion on Renal Function during Cardiopulmonary Bypass

Infusion of prostacyclin inhibits platelet activation during cardiopulmonary bypass (CPB) but also results in systemic arterial hypotension. Therefore, the effects of CPB and prostacyclin on renal function were studied in 36 male patients undergoing aortocoronary bypass. Nineteen patients (Group 1) received prostacyclin, 50 ng per kilogram of body weight per minute, during CPB, and 17 patients (Group 2) served as controls. There was pronounced hypotension in Group 1 only. Urine production during CPB averaged 88 ± 140 ml and 2,306 ± 1,112 ml in Groups 1 and 2, respectively. No patient had renal failure. Glomerular filtration rate (GFR), as measured by clearance of chromium 51-labeled ethylenediaminetetraacetic acid, was increased in Group 1 from 86 ± 14 to 99 ± 22 ml/1.73 m 2/min ( p < 0.05) the day after operation, but remained unchanged in Group 2 (81 ± 15 to 82 ± 21 ml/1.73 m 2/min). The increased GFR in Group 1 can be regarded as an expected adaptation to the change in body fluids after CPB. Therefore, the unchanged GFR in Group 2 must be regarded as caused by insufficient adaptation or impaired renal function. Proximal tubular function was evaluated by determination of β 2-microglobulin in urine. In both groups, urinary β 2-microglobulin and the ratio of urinary β 2-microglobulin to urinary creatinine were increased the day after operation. The hypotension in Group 1 did not exacerbate the damage to tubular function.