Radiocontrast-induced Acute Renal Failure Research Articles

Characterization of a novel model for investigation of radiocontrast nephrotoxicity

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. 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. 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. 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.

Hypoxia-inducible factors and tubular cell survival in isolated perfused kidneys

Adaptation to hypoxic environment is conferred through hypoxia-inducible transcription factors (HIFs). We have previously shown that the HIF system is transiently activated in vivo in radiocontrast-induced acute renal failure, associated with profound hypoxia in the renal medulla. Medullary thick ascending limbs (mTALs), the most affected nephron segments in this model, were virtually unable to mount an adaptive HIF response. Here, we study correlations between oxygenation, HIF activation, and cell viability in a related ex vivo model, the isolated perfused rat kidney (IPK). In IPKs perfused with cell-free oxygenated medium, severe medullary hypoxic damage developed, affecting 42+/-9% of mTALs in the mid-inner stripe. HIF-1alpha tubular immunostaining was noted with a zonal and tubular pattern largely similar to our findings in vivo: in 34+/-3% of collecting ducts (CDs) within the mid-inner stripe and extensively in the papillary tip, whereas mTALs were all HIF-negative. In IPKs supplemented with RBCs (improved oxygen supply), mTAL damage was totally prevented and CDs' HIF expression was attenuated (22+/-4%). By contrast, although measures designed to reduce medullary hypoxia by decreasing tubular reabsorptive activity (furosemide, ouabain, or high-albumin-non-filtering system) reduced mTAL damage, all paradoxically resulted in increased HIF expression in CDs (51+/-4%), and 17+/-3% of mTALs became immunostained as well. Our data confirm that CDs and mTALs have markedly different HIF responses, which correlate with their viability under hypoxic stress. mTALs transcriptional adaptation occurs within a narrow hypoxic range, and it appears that workload reduction can shift mTALs into this window of opportunity for HIF activation and survival.

Radiocontrast-Induced Acute Renal Failure—Impact beyond the Acute Phase

Radiocontrast-induced nephropathy is a well known consequence of cardiologic interventions. Acute radiocontrast nephropathy is the third most common cause of acute renal failure in patients admitted to a hospital ([1][1]). Up to 7% of patients with this condition need temporary dialysis or progress

A1adenosine receptor knockout mice are protected against acute radiocontrast nephropathy in vivo

The role of renal A1 adenosine receptors (A1AR) in the pathogenesis of radiocontrast nephropathy is controversial. We aimed to further elucidate the role of A1AR in the pathogenesis of radiocontrast nephropathy and determine whether renal proximal tubule A1AR contribute to the radiocontrast nephropathy. To induce radiocontrast nephropathy, A1AR wild-type (WT) or knockout (KO) mice were injected with a nonionic radiocontrast (iohexol, 1.5-3 g iodine/kg). Some A1WT mice were pretreated with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; a selective A1AR antagonist) before iohexol injection. A1AR contribute to the pathogenesis of radiocontrast nephropathy in vivo as the A1WT mice developed significantly worse acute renal failure, more renal cortex vacuolization, and had lower survival 24 h after iohexol treatment compared with the A1KO mice. DPCPX pretreatment also protected the A1WT mice against radiocontrast-induced acute renal failure. No differences in renal cortical apoptosis or inflammation were observed between A1WT and A1KO mice. To determine whether the proximal tubular A1AR mediate the direct renal cytotoxicity of radiocontrast, we treated proximal tubules in culture with iohexol with or without 2-chloro-N6-cyclopentyladenosine (a selective A1AR agonist) or DPCPX pretreatment. We also subjected cultured proximal tubule cells overexpressing A1AR or lacking A1AR to radiocontrast injury. Iohexol caused a direct dose-dependent reduction in proximal tubule cell viability as well as proliferation. Neither the A1AR agonist nor the antagonist treatment affected proximal tubule viability or proliferation. Moreover, overexpression or lack of A1AR failed to impact the iohexol toxicity on proximal tubule cells. Therefore, we conclude that radiocontrast causes acute renal failure via mechanisms dependent on A1AR; however, renal proximal tubule A1AR do not contribute to the direct tubular toxicity of radiocontrast.

A Role for Erythropoietin in the Attenuation of Radiocontrast-Induced Acute Renal Failure in Rats

Background. Radiocontrast-induced nephropathy (CIN) remains an important iatrogenic cause of acute renal failure in high-risk patients, despite the development of safer contrast media, the improvement of hydration protocols, and the introduction of additional preventive strategies. Erythropoietin (EPO) pretreatment may confer protection against acute renal failure through the induction of stress response genes. Methods. The effect of EPO has been evaluated in a rat model of CIN, induced by iothalamate, following the inhibition of nitric oxide- and prostaglandin-synthesis with indomethacin and Nω nitro-L-arginine methyl ester (L-NAME). Twenty-two male Sprague-Dawley rats were subjected to saline (CTR) or EPO injections (3000 U/kg and 600 U/kg, 24 and 2 h before the induction of CIN, respectively). Results. The decline in creatinine clearance in CTR animals from 0.38 ± 0.03 to 0.28 ± 0.03 mL/min/100 g (p < 0.005), was prevented by EPO pretreatment (from 0.34 ± 0.02 to 0.32 ± 0.03 mL/min/100 g, NS). The extent of medullary thick ascending limb- and S3-tubular damage in the outer medulla, however, was comparable in the two experimental groups. Conclusions. EPO pretreatment prevents renal dysfunction in a rat model of CIN. Further experimental and clinical studies are required to confirm these preliminary conclusions regarding a potential protective potency of EPO against CIN.

Radiocontrast-Induced Acute Renal Failure

The intravascular administration of iodinated radiocontrast media can lead to acute renal dysfunction. Even small changes in renal function have been associated with increased morbidity and mortality, making the prevention of radiocontrast nephropathy of paramount importance. This review summarizes the principal risk factors for radiocontrast nephropathy and evidence-based preventive strategies that should be used to limit its occurrence. Risk factors for radiocontrast nephropathy include preexistent kidney disease, diabetes mellitus, dose of radiocontrast used, advanced congestive heart failure, and intravascular volume depletion. Proven preventive measures include volume expansion with intravenous saline or sodium bicarbonate and the use of low-osmolar or iso-osmolar radiocontrast media. Studies evaluating N-acetylcysteine have been conflicting, with meta-analyses suggesting a small beneficial effect. Studies of other pharmacologic agents have not demonstrated clinical benefit.

Current Trials of Interventions to Prevent Radiocontrast-Induced Nephropathy

Radiocontrast administration is a common cause of hospital-acquired acute renal failure. It is associated with significant in-hospital and long-term morbidity and mortality and increases the costs of medical care by at least extending the hospital stay. A variety of therapeutic interventions, including saline hydration, diuretics, mannitol, calcium channel antagonists, theophylline, endothelin receptor antagonists, and dopamine, have been employed to prevent radiocontrast-induced acute renal failure. Recent advances have examined the impact of fenoldopam (dopamine-1 receptor agonist), N-acetylcysteine (antioxidant), iso-osmolar contrast agents, hemodialysis, and hemofiltration on ameliorating radiocontrast-induced acute renal failure. Although hydration with half-normal saline had remained the gold standard for the prevention of radiocontrast-induced nephropathy, recent data have revealed the superiority of hydration with normal saline over half-normal saline. This review focuses on the most recent studies of interventions to ameliorate radiocontrast-induced acute renal failure and provides a critical analysis of some of the recent studies conducted to prevent radiocontrast-induced nephropathy.

Cell polarity in the cardiovascular system

The importance of cell polarity as a fundamental biological principle is increasingly recognized in the cardiovascular system. Polar cell mechanisms underlie not only the development of the heart and blood vessels, but also play a major role in the adult organism for polarized endothelial functions such as the separation of the intra- and extravascular compartment and the vectorial exchange of substances between these compartments. Endothelial cells are connected through intercellular junctions which separate the functionally and structurally distinct luminal and abluminal cell surfaces. The luminal plasma membrane is in contact with the blood and takes part in the regulation of hemostasis. The abluminal cell membrane connects the endothelial cell with the basement membrane and modulates blood flow through the release of vasoactive substances. Results from epithelial model systems have shown that the polarized cell phenotype is generated by specific protein sorting and regulated protein trafficking between the trans-Golgi network and the cell surface. The polarized distribution of cell membrane proteins is maintained by anchorage with the cytoskeleton and limitation of lateral diffusion by tight junctions. Disturbances of cell polarity may contribute to the pathogenesis of disease states, including ischemic and radiocontrast-induced acute renal failure and carcinomas. Recent results have demonstrated the importance of cholesterol for protein traffic from the trans-Golgi network to the apical cell membrane. This novel intracellular function of cholesterol could point to a connection between cell polarity and the pathogenesis of arteriosclerosis. The polarity of the endothelium also has to be taken into account when developing gene-therapeutic strategies, since therapeutic success will not only depend on the efficient expression of the desired gene product, but also on its correct cellular location or secretion into the correct extracellular compartment. These examples demonstrate the biological and potentially clinical relevance of cell polarity in the cardiovascular system.

Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys

Extensive DNA fragmentation, a marker for programmed cell death, was selectively and rapidly induced by hypoxia in the thick ascending limbs of rat kidneys. In isolated perfused kidneys, DNA breaks were present in medullary tubules as early as after 10 minutes of local hypoxia and were prevented by reduction of metabolic work. In a model of radiocontrast-induced acute renal failure, DNA breaks were detected selectively along thick ascending limbs as early as 15 minutes following insult, preceding overt morphological damage. Hypoxia induces rapid DNA fragmentation along thick ascending limbs, where programmed cell death could play an important role in nephron injury and kidney failure.

Role of nitric oxide (EDRF) in radiocontrast acute renal failure in rats.

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.

Prevention and attenuation of acute renal failure.

Recent progress in our understanding of the pathogenetic processes involved in ischemic acute renal failure is considerable. Blockade of the production of endothelium-derived relaxing factor may markedly improve survival in patients with septic shock. Atrial natriuretic peptide and growth factors enhance renal recovery in animal models of acute renal failure, even when administered well after the ischemic insult. Aminoglycosides and radiocontrast agents are the most common causes of drug-induced acute renal failure. Once-daily administration of aminoglycosides is an effective treatment modality that may limit the occurrence of nephrotoxicity. Awareness of the patient's volume status has decreased the incidence of radiocontrast-induced acute renal failure. The new, expensive, nonionic, low-osmolar radiocontrast agents do not offer apparent benefits in patients with normal or slightly decreased renal function. However, use of such agents may decrease the incidence of radiocontrast-induced renal failure in diabetic patients with severe renal failure. The prognosis for patients with renal vasculitis has improved greatly in the past decade. The discovery of antibodies directed against antigenic targets in the cytoplasm of neutrophils has facilitated the diagnosis of renal vasculitides, has improved our knowledge of the pathogenesis of these diseases, and may guide rational treatment.

Uninephrectomy Does Not Potentiate Contrast Media Nephrotoxicity in the Streptozotocin-Induced Diabetic Rat

We studied the effect of radiographic contrast media on renal function in both streptozotocin-induced diabetic rats and normoglycemic rats with reduced renal functional mass. Male Sprague-Dawley induced-diabetic rats and weight-matched controls were divided into unilaterally nephrectomized and intact groups prior to an intravenous challenge with sodium diatrizoate (Urografin) at two dose levels, 1,300 and 2,600 mg iodine/kg. Serum creatinine concentration did not change on the 1st and 3rd day after a dose of 1,300 mg/kg of iodine in normal or induced-diabetic rats. Consequent to a dose of 2,600 mg/kg of iodine, induced-diabetic rats had a significant increase in serum creatinine levels to 0.9 +/- 0.45 mg/dl (control 0.68 +/- 0.11 mg/dl). The observed increase in serum creatinine concentration after treatment with sodium diatrizoate was significantly correlated with the degree of hyperglycemia, but not with prior unilateral nephrectomy. Unilateral nephrectomy, prior to administration of sodium diatrizoate did not potentiate the risk of radiocontrast agent injury in induced-diabetic rats. From these findings, we infer that: (1) streptozotocin-induced diabetes in the rat confers a risk for the development of radiocontrast-induced acute renal failure and (2) as judged by the rise in serum creatinine concentration after exposure, there is an increased risk of acute renal failure associated with a higher dose of radiocontrast material.

Protective role of furosemide and saline in radiocontrast-induced acute renal failure in the rat.

Acute renal failure (ARF) can be produced in rats by a combination of insults which augment transport activity and blunt regulatory mechanisms designed to maintain medullary oxygen sufficiency. This type of ARF is characterized by necrosis of medullary thick ascending limbs (mTALs). Uninephrectomized, salt-depleted rats injected with indomethacin (10 mg/kg) develop ARF following the administration of the radiocontrast agent, iothalamate. Furosemide (20 mg/kg, intravenous), administered immediately before the contrast material, attenuated the severity of ARF and reduced mTAL necrosis. Treatment with furosemide and/or normal saline prevented both the decline in renal function and mTAL injury. It is concluded that furosemide and normal saline may ameliorate the course of ARF if administered before radiocontrast.

Low Incidence of Renal Failure After Angiography

One hundred consecutive patients with serious illnesses that required angiography were studied prospectively for the development of radiocontrast-induced acute renal failure. The study included 24 diabetics (six diabetics had chronic renal insufficiency), 19 patients with chronic renal insufficiency of other causes, 15 patients with concentrated urine, and 56 patients who received 100 mL or more of a contrast agent. Acute renal failure developed in only one patient. Previous series that indicated much higher incidences were retrospective and not inclusive of all patients, or these studies were composed mainly of patients with diabetic nephropathy and chronic renal failure to whom high doses of a contrast agent were given. Angiography is unlikely to produce acute renal failure except in an occasional patient with well-defined risk factors.

Low incidence of renal failure after angiography

• One hundred consecutive patients with serious illnesses that required angiography were studied prospectively for the development of radiocontrast-induced acute renal failure. The study included 24 diabetics (six diabetics had chronic renal insufficiency), 19 patients with chronic renal insufficiency of other causes, 15 patients with concentrated urine, and 56 patients who received 100 mL or more of a contrast agent. Acute renal failure developed in only one patient. Previous series that indicated much higher incidences were retrospective and not inclusive of all patients, or these studies were composed mainly of patients with diabetic nephropathy and chronic renal failure to whom high doses of a contrast agent were given. Angiography is unlikely to produce acute renal failure except in an occasional patient with well-defined risk factors. (<i>Arch Intern Med</i>1981;141:1268-1270)

Radiocontrast-Induced Acute Renal Failure

Radiocontrast-Induced Acute Renal Failure