Tubular secretion of creatinine and kidney function: an observational study.

BACKGROUND: Prior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts. METHODS: To fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time. RESULTS: Observed CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories. CONCLUSIONS: These data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR.

Characterization of a novel model for investigation of radiocontrast nephrotoxicity.

OBJECTIVES: Radiocontrast agents are one of the most common causes of acute renal failure in the world. These agents are required for both diagnostic and therapeutic modalities of medical intervention, including computed tomography (CT), angiography and cardiac catheterization. Publications over the past 40 years support three potential mechanisms of toxicity: oxidative stress, haemodynamics and hyperosmolar effects. An in vitro model provides a rapid evaluation of cellular toxicity without the complications of haemodynamics. This study evaluated the renal toxicity of radiocontrast agents at clinically relevant concentrations. METHODS: This study investigated the toxicity of two radiocontrast agents, diatrizoic acid (DA) and iothalamic acid (IA), using an in vitro model. Renal cortical slices isolated from F344 rats were incubated with 0-111 mg I/ml DA or IA. RESULTS: Renal slices exposed to DA and IA showed toxicity as measured by increased lactate dehydrogenase (LDH) leakage at concentrations lower than previously published using isolated cell models. These data indicate that DA and IA are toxic to renal cortical slices, and this is a more sensitive model than previously used cell culture systems. DA and IA treatment failed to cause a significant decrease in total cellular glutathione or increase in percent glutathione disulphide (GSSG), implying that oxidative stress may not be an initial mechanism of toxicity. Finally, the addition of exogenous glutathione did provide complete protection from DA- and IA-induced LDH leakage. CONCLUSION: These data validate the renal cortical slice in vitro model for investigation of radiocontrast nephrotoxicity. These studies further showed that glutathione was cytoprotective. Future research using this model is aimed at further characterization of radiocontrast nephrotoxicity, which may allow for improved prevention and treatment of radiocontrast-induced acute renal failure.

Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis.

Idiopathic hypercalciuria (IH) is common among calcium stone formers (IHSF). The increased urinary calcium arises from increased intestinal absorption of calcium, but it is unclear whether increased filtered load or decreased renal tubular reabsorption of calcium is the main mechanism for the increased renal excretion. To explore this question, 10 IHSF and 7 normal subjects (N) were studied for 1 day. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, and calories. Fasting and fed, ultrafiltrable calcium levels, and filtered load of calcium did not differ between N and IHSF. Urine calcium rose with meals, and fractional reabsorption fell in all subjects, but the change was significantly higher in IHSF. The changes in calcium excretion were independent of sodium excretion. Serum parathyroid hormone levels did not differ between N and IHSF, and they could not account for the greater fall in calcium reabsorption in IHSF. Serum magnesium and phosphorus levels in IHSF were below N throughout the day, and tubule phosphate reabsorption was lower in IHSF than N after meals. The primary mechanism by which kidneys ferry absorbed calcium into the urine after meals is via reduced tubule calcium reabsorption, and IHSF differ from N in the magnitude of the response. Parathyroid hormone is not likely to be a sufficient explanation for this difference.

Renal extraction of cystatin C vs 125I-iothalamate in hypertensive patients.

BACKGROUND: Several markers are available to estimate the glomerular filtration rate (GFR) in patients. Cystatin C is a relatively new marker and has been suggested as an alternative for creatinine. Numerous studies have been performed to evaluate the usefulness of cystatin C to estimate GFR. The aim of this study is to compare the renal extraction of cystatin C with that of 125I-iothalamate in hypertensive patients. METHODS: Forty hypertensive patients with unilateral renal artery stenosis, and who used at least two antihypertensive agents, were studied. For the determination of the renal extraction ratio, blood samples were drawn simultaneously from the renal vein and the abdominal aorta. The renal extraction ratio was calculated as ([A]-[V])/[A], in which A is the plasma concentration of the compound from the abdominal aorta, and V is the plasma concentration of the compound from the renal vein. RESULTS: The mean difference between the renal extraction ratio of cystatin C and that of 125I-iothalamate was 0.002. The 95% confidence interval (CI) for the mean difference was -0.036 to 0.032, which was not statistically significant. However, the limits of agreement were large (-0.271 and 0.267). CONCLUSIONS: Despite a lower reported glomerular sieving coefficient of cystatin C, the mean renal extraction of cystatin C was equal to the mean renal extraction of 125I-iothalamate in hypertensive patients, suggesting tubular secretion of cystatin C. Combined with the large variation in the renal extraction of cystatin C, these findings cast doubts on its usefulness as a glomerular filtration marker.

Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia.

BACKGROUND: Medullary hypoxia is believed to play an important role in the pathogenesis of acute renal failure (ARF). Hypoxia-inducible transcription factors (HIF) are recognized as master regulators of hypoxic adaptation, but little is known about their role in renal disease. METHODS: A multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition was used to study chronology and distribution of the oxygen regulated HIF isoforms HIF-1alpha and HIF-2alpha in comparison with the hypoxia-marker pimonidazole between 10 minutes and 48 hours after injury induction. Treatment with furosemide was used to study HIF expression under conditions of ameliorated tissue injury. RESULTS: Contrast medium in combination with NOS and COX inhibition resulted in widespread induction of HIF in the outer and inner medulla that was initiated within 10 minutes, reached the highest levels at 2 hours and diminished 8 hours to 24 hours thereafter. HIF isoforms were expressed in a cell type-specific fashion: HIF-1alpha in tubular and HIF-2alpha in interstitial and endothelial cells. The degree of HIF-1alpha accumulation varied between nephron segments, being much stronger in collecting ducts than in medullary thick ascending limb of the loop of Henle (mTAL). Comparison with pimonidazole staining and the effect of furosemide indicated that HIF induction in mTAL is maximal with moderate hypoxia and declines with increasing severity of hypoxia. CONCLUSION: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury.

Influence of iothalamate on renal medullary perfusion and oxygenation in the rat.

PURPOSE: To evaluate controversial results regarding the effect of the contrast medium (CM) iothalamate on renal medullary blood flow by applying two different methods simultaneously. MATERIAL AND METHODS: The outer medullary blood flow (OMBF) response was estimated using laser-Doppler flowmetry and hydrogen gas wash-out (microelectrodes) simultaneously. Outer medullary oxygen tension (PO2) was measured using Clark type microelectrodes. Iothalamate was injected i.v. at 1600 mg I/kg body weight for 2 min. RESULTS: CM induced a transient 28% decrease in OMBF as measured with the laser Doppler. The hydrogen gas wash-out rate was reduced by 50%, indicating a reduced perfusion. CM induced a transient 60% reduction in PO2, while renal fluid and electrolyte excretion increased several fold. CONCLUSION: The CM iothalamate reduces outer medullary perfusion as estimated by two different techniques applied simultaneously. The PO2 in the same region was also reduced. Previous controversies regarding the effect of iothalamate on OMBF can be explained by extreme dosage and injection rates greatly exceeding clinical relevance.

Evaluation of the nitric oxide production in rat renal artery smooth muscle cells culture exposed to radiocontrast agents.

BACKGROUND: Radiocontrast agents (RC), substances largely used in diagnostic procedures, present the nephrotoxicity as one of its major side effects, which could be due to an altered synthesis of vasodilators. The aim of the present study was to evaluate the nitric oxide (NO) production in rat renal artery smooth muscle cells primary culture (rVSMC) exposed to RC. METHODS: The cells were treated for 72 hours with mannitol at 10% (MT10; 600 mOsm/kg H2O) or 35% (MT35; 2100 mOsm/kg H2O), with the nonionic iobitridol (IBT), the low-osmolality ioxaglate (IXG), the high-osmolality ioxitalamate (IXT), the nonionic, iso-osmolar iodixanol (IDX), and with lipopolysaccharide (LPS). We determined the NO and osmolality in the cell culture media and the cellular viability. RESULTS: By the Griess and chemiluminescence methods, the NO was not different in MT10 and IDX, but decreased in MT35, IBT, IXG, and IXT when compared with the control; it was increased in LPS and also decreased in all RC+LPS when compared with LPS. MT35, IXT, and IXT+LPS decreased the cellular viability, and the media osmolality was increased in MT35 and IXT compared with the control. CONCLUSION: The RC (except IDX) significantly reduced NO in rVSMC, which was more pronounced after IXT treatment (57.3%). This was not related to the reduced cell viability (15.8%) or to its high osmolality, because in MT35, with similar osmolality as IXT, NO decreased only 11.0% relatively to the control. Neither the media osmolality nor the cell viability was altered by IXG or IBT. The decreased NO could explain the vasoconstriction and, therefore, the acute renal failure by RC.

Salutary effects of radiopaque contrast media on the survival of random-pattern skin flaps in the rat: an experimental study.

The radiopaque contrast medium diatrizoate, has a vasodilator effect so that it is used in sudden-deafness secondary ischemic injury. However, ischemic problems are encountered, especially when longer flaps are elevated. A longer flap also has ischemic and relatively ischemic tissue, and may obtain some benefit from contrast media. Forty male Sprague-Dawley rats, weighing about 350-400 g, were used, and randomly divided into four groups (n = 10 rats each group): group 1 was the control, group 2 the diatrizoate, group 3 the iopamidol, and group 4 the iothalamate group. A rectangular 3 x 10 cm caudally based dorsal skin flap was elevated, and sutured back to its original place. In the control group, no pharmacologic agent was administered. Sodium-meglumine-diatrizoate 10 mg/kg/day was administered parenterally in the first experimental group (diatrizoate group); iopamidol 10 mg/kg/day in the second experimental group (iopamidol group); and iothalamate sodium 10 mg/kg/day in the third experimental group (iothalamate group) for 7 postoperative days. On postoperative day 7, all flaps were photographed, and the area of flap survival was measured by using a polar planimeter. The results were statistically evaluated with the Kruskal-Wallis test and Mann-Whitney U-test (P = 0.05). The mean flap survival ranged from 79% in the iopamidol group to 83% in the diatrizoate group, and was significantly greater in all experimental groups (P < 0.05) compared to the control group (59%). There was no significant difference between experimental groups (P < 0.05). We believe that radiopaque contrast media have a beneficial effect in improving skin flap viability when distal flap necrosis is a potential complication of longer flaps.

Diuretic Doppler ultrasonography in chronic unilateral partial ureteric obstruction in dogs.

OBJECTIVE: To compare the effects of diuresis induced by a loop diuretic (frusemide), an osmotic diuretic (mannitol) and a high-osmolar radio-contrast medium (sodium iothalamate) on the intrarenal resistive index (RI) in dogs with chronic unilateral partial ureteric obstruction (UPUO). MATERIALS AND METHODS: The split renal clearance and intrarenal RI were estimated in 11 dogs with chronic UPUO. Doppler ultrasonography measurements of the interlobar arteries were obtained before and 10 min after the intravenous infusion of 1 mg/kg frusemide, 1 g/kg mannitol or 20 mL 60% sodium iothalamate. The same experimental protocol was repeated with another drug at 1-week intervals. RESULTS: There was a significant difference between the intrarenal RI of obstructed and unobstructed kidneys in the chronic phase of UPUO. While mannitol and sodium iothalamate significantly increased the RI in both kidneys, differences in RI between the kidneys decreased after infusing the two drugs. However, while frusemide insignificantly increased the RI in the obstructed kidney, it decreased the RI in unobstructed one. Consequently, the difference in RI between the kidneys increased significantly after administering frusemide. There were no significant differences in urinary volume after administering each of the drugs. CONCLUSIONS: As there were no significant differences in the diuretic effects of the drugs, frusemide may have additional effects on the RI of unobstructed kidneys other than diuresis. Frusemide increased the difference between the intrarenal RI of the kidneys and therefore may improve the detection of unilateral urinary obstruction in humans.

Effect of radiocontrast agents on intrarenal nitric oxide (NO) and NO synthase activity.

BACKGROUND/AIMS: Contrast media (CM) induce a biphasic renal hemodynamic response, with late prominent cortical vasoconstriction and marked outer medullary vasodilation. The objective of the study was to explore a possible role for altered nitric oxide (NO) production or bioavailability in these hemodynamic responses. METHODS: We explored the impact of CM (sodium iothalamate) upon rat renal NO synthase (NOS) activity (citrulline recovery) and NO (using a NO electrode). RESULTS: The cortical NOS activity following CM was 11.5 +/- 1.0 versus 13.8 +/- 1.1 nmol/gww/min (gww = gram wet weight) in controls (p = 0.16, NS). In rats pretreated with the nonselective endothelin antagonist bosentan, CM reduced the cortical NOS activity to 8.5 +/- 1.2 nmol/gww/min (p < 0.005 vs. controls). Cortial NO readings declined over 30 min following CM by 13 +/- 8% (p < 0.05, Anova), in parallel with the decline in cortical blood flow. The outer medullary NOS activity was not affected by CM (5.2 +/- 1.5 vs. 5.5 +/- 1.3) nmol/gww/min in controls) or bosentan. Nevertheless, the outer medullary NO reading increased by 36 +/- 23% (p < 0.05), with a concomitant increase in regional blood flow. CONCLUSION: In the cortex, CM might reduce the NOS activity (an effect blunted by endothelin release). This may potentiate the effect of endothelin to induce regional vasoconstriction. In the outer medulla, the vasodilatory response to CM does not seem to be mediated by enhanced NOS activity and might reflect increased local NO bioavailability as the result of regional hypoxia.

Effect of ionic and nonionic contrast media on regional distribution of thallium-201 in rabbits.

Cardiac output is effectively redistributed to each part of the body by regional changes in vascular resistance. Thallium-201 distribution reflects the fractional distribution of cardiac output and parallels regional blood flow. The side effects of iodinated contrast media in different organs have been well documented in animal experiments and clinical studies. However, no simultaneous assessment of regional blood flow change in each part of the body after the administration of contrast media has been reported. Using a double-dose thallium-201 method, we investigated the effect of contrast media on the regional distribution of thallium-201 in each organ as an estimate of regional blood flow change in rabbits. The distribution of 201T1 and 99mTc-MAA was similar in the heart, spleen, kidneys, and leg muscles in the control animals (r = 0.99). The regional distribution of thallium-201 significantly increased in the heart and leg muscle, but decreased in the liver in the nonionic (Iohexol) and ionic (Iothalamate) contrast medium groups as compared with the control group. There were no significant changes in the kidneys or intestine in these three groups in our study. The intravenous infusion of contrast media in rabbits causes uneven redistribution of regional blood flow in the heart, leg muscle and liver. These changes are more prominent in the ionic contrast medium group.

Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction.

Infusion of radiocontrast agents in vivo results in renal artery constriction and subsequent renal hypoperfusion. To examine the role of endothelin and of prostaglandins in radiocontrast-mediated renal vasoconstriction, rats were treated with an endothelin receptor antagonist, CP170687, and with indomethacin. The dose of CP170687 utilized was sufficient to reverse endothelin1-mediated constriction of isolated aortic rings and of renal blood flow in intact rats. In normal rats there was a transient drop in renal blood flow to 80% of baseline following sodium iothalamate injection, an effect which was not prevented by CP170687. In rats first given indomethacin, the drop in renal blood flow was more pronounced (to 63% of baseline) and was sustained. In this instance, CP170687 fully reversed the sustained decrease of renal perfusion. CP170687 also diminished the rise in systemic blood pressure seen following iothalamate injection. In the absence of indomethacin, iothalamate increased urinary prostaglandin E2 to a maximum of sevenfold above baseline values. In summary, injection of radiocontrast results in an immediate decrease in renal blood flow that is counteracted by an increase in renal prostaglandin formation. When prostaglandin synthesis is inhibited, prolonged endothelin-mediated renal vasoconstriction is observed that is reversed by an endothelin receptor antagonist.

Effect of ionic contrast medium on plasma atrial natriuretic peptide.

To evaluate the effect of ionic contrast medium on plasma atrial natriuretic peptide (ANP) and its contributing factors, we measured plasma ANP, serum osmolality, pulmonary capillary wedge pressure (PCWP), femoral artery systolic pressure (FASP), and heart rate before and after left ventriculography with Rayvist in 13 patients suspected of coronary artery disease. The control values of plasma ANP, serum osmolality, and PCWP were 20.3 +/- 5.1 pg/ml, 293.5 +/- 1.5 mosm/kg, 6.6 +/- 0.8 mm Hg, respectively. Rayvist produced a significant increase in plasma ANP, serum osmolality, and PCWP at 1 minute (26.0 +/- 6.3 pg/ml, p < 0.05; 300.7 +/- 1.9 mosm/Kg, p < 0.001; 10.7 +/- 1.3 mm Hg, p < 0.001) and 5 minutes (27.3 +/- 6.3 pg/ml, p < 0.01; 296.8 +/- 1.9 mosm/Kg, p < 0.001; 10.4 +/- 1.7 mm Hg, p < 0.01) post left ventriculography. The FASP decreased significantly at 1 minute, followed by an insignificant increase at 5 minutes. The heart rate increased significantly at 1 minute but no significant change was noted at 5 minutes. We conclude that plasma ANP increases significantly after left ventriculography with Rayvist and its response may be related to left ventricular filling pressure and serum osmolality, but not to FASP or heart rate.

Effect of low-osmolality contrast media on red cell filterability.

The effects of low-osmolality contrast media (CM) on red blood cell (RBC) filterability were investigated using a recently developed nickel mesh filtration method. The conventional hypertonic CM iothalamate, low-osmolality iohexol, and the recently synthesized iomeprol were studied. Among them, the osmolality of iomeprol was the lowest. The impact of CM osmolality, viscosity, and iodine content on the RBC filterability was analyzed. Under equal iodine content or viscosity condition, the filterability order of RBCs suspended in CM was iomeprol > iohexol >> iothalamate, because of the osmolality of CM. Iomeprol caused small echinocytic changes but these had a negligible influence on RBC filterability. In conclusion, the osmotic effect of CM on RBC filterability is more predominant than the other CM effects, and iomeprol is the preferred CM for RBC filterability.

Changes in serum magnesium during excretory urography. A comparison of ionic and nonionic contrast media.

RATIONALE AND OBJECTIVES: It is known that ionic contrast media (CM) bind magnesium and that patients with asthma often benefit from magnesium injections. Similarly, asthmatics have a higher incidence of CM reactions. This work tests the hypothesis that ionic CM alter serum magnesium more than nonionic CM. METHODS: Ten patients were divided into two groups; one group received iothalamate and the other received iohexol. RESULTS AND CONCLUSIONS: The total magnesium level changed significantly from baseline in the iothalamate-treated group (P less than .01). Iothalamate produced a significant decrease in protein-bound magnesium (P less than .01) with a significant increase in filterable magnesium (P less than .01). Iohexol did not produce significant changes for any of the magnesium fractions. The patient with the most clinically significant adverse reaction (though minor) had the lowest baseline magnesium level. Further studies with larger groups including patients with asthma are needed.

Radiocontrast agents induce endothelin release in vivo and in vitro.

The intravascular administration of the ionic radiocontrast agent sodium iothalamate (2.9 g of iodine/kg body wt) to rats induced an increase in plasma concentration of immunoreactive endothelin from 21.3 +/- 1.2 to 36 +/- 3 fmol/mL, preceded by a transient rise in the plasma level of atrial natriuretic peptide and associated with a fall in RBF. Equi-iodine amounts of the nonionic agents ioxaglate and iohexol elicited similar or more marked changes in plasma endothelin, but hypertonic solutions of NaCl, mannitol, or glucose did not. Comparable levels of endothelin produced by infusions of endothelin-1 induced a reduction of up to 29% in RBF. Iothalamate and iohexol stimulated endothelin release from cultured bovine endothelial cells, suggesting a direct effect of ionic and nonionic agents on vascular endothelium. The data invite speculation that under some circumstances endothelin release might play a role in the circulatory changes caused by these compounds and in the pathogenesis of radiocontrast nephropathy.