Erdmann Seeliger

Contrast-induced kidney injury: mechanisms, risk factors, and prevention

In general, iodinated contrast media (CM) are tolerated well, and CM use is steadily increasing. Acute kidney injury is the leading life-threatening side effect of CM. Here, we highlight endpoints used to assess CM-induced acute kidney injury (CIAKI), CM types, risk factors, and CIAKI prevention. Moreover, we put forward a unifying theory as to how CIAKI comes about; the kidney medullas unique hyperosmolar environment concentrates CM in the tubules and vasculature. Highly concentrated CM in the tubules and vessels increases fluid viscosity. Thus, flow through medullary tubules and vessels decreases. Reducing the flow rate will increase the contact time of cytotoxic CM with the tubular epithelial cells and vascular endothelium, and thereby damage cells and generate oxygen radicals. As a result, medullary vasoconstriction takes place, causing hypoxia. Moreover, the glomerular filtration rate declines due to congestion of highly viscous tubular fluid. Effective prevention aims at reducing the medullary concentration of CM, thereby diminishing fluid viscosity. This is achieved by generous hydration using isotonic electrolyte solutions. Even forced diuresis may prove efficient if accompanied by adequate volume supplementation. Limiting the CM dose is the most effective measure to diminish fluid viscosity and to reduce cytotoxic effects.

Viscosity of contrast media perturbs renal hemodynamics.

Contrast-induced nephropathy is a common cause of acute renal failure, and the mechanisms underlying this injury are not completely understood. We sought to determine how physicochemical properties of contrast media may contribute to kidney damage in rats. We administered contrast media of equivalent iodine concentrations but differing physiocochemical properties: the high-osmolality iopromide was compared to the high-viscosity iodixanol. In addition, the non-iodinated substances mannitol (equivalent osmolality to iopromide) and dextran (equivalent viscosity to iodixanol) were also studied. Both types of contrast media transiently increased renal and hindquarter blood flow. The high-osmolality agents iopromide and mannitol markedly increased urine production whereas iodixanol, which caused less diuresis, significantly enhanced urine viscosity. Only the high-viscosity agents iodixanol and dextran decreased renal medullary blood flux, erythrocyte concentration, and pO2. Moreover, iodixanol prolonged the tubuloglomerular feedback response and increased plasma creatinine levels to a greater extent than iopromide or dextran. Therefore, the viscosity of contrast media may play a significant role in contrast-induced nephropathy.

Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney Injury

BACKGROUND Acute kidney injury (AKI) after cardiac surgery is a common and serious condition carrying significant costs. During cardiopulmonary bypass (CPB) surgery, modifiable factors may contribute to post-operative AKI. Their avoidance might be a potential target for nephroprotection. METHODS The objective of the present study was to identify and determine whether intraoperative hypotension, anaemia, or their combination, red blood cell transfusion or vasopressor use are independent risk factors for post-operative AKI defined by the RIFLE (renal Risk, Injury, Failure, Loss of renal function and End-stage renal disease) classification and other thresholds using a mixed logistic multivariate model. RESULTS We analysed 381 468 mean arterial pressure (MAP) measurements from 920 consecutive on-pump cardiac surgery patients. Overall, 19.5% developed AKI which was associated with an 8.2-fold increase in-hospital mortality. Haemoglobin concentration was an independent risk factor for AKI {odds ratio [OR] 1.16 per g/dL decrease [95% confidence interval (CI) 1.05-1.31]; P = 0.018} with systemic arterial oxygen saturation and pressure values not adding further strength to such an association. MAP alone or vasopressor administration was not independently associated with AKI but volume of red blood cell transfusion was, with its effect being apparent at a haemoglobin level of >8 g/dL (>5 mmol/L). In patients with severe anaemia (<25th percentile of lowest haemoglobin), the independent effect of hypotension (>75th percentile of area under the curve MAP <50 mmHg) on AKI was more pronounced [OR 3.36 (95% CI 1.34-8.41); P = 0.010]. CONCLUSION Intraoperative avoidance of the extremes of anaemia, especially during severe hypotension and avoidance of transfusion in patients with haemoglobin levels >8 g/dL (>5 mmol/L) may help decrease AKI in patients undergoing cardiac surgery and represent targets for future controlled interventions.

Up to 50-fold Increase in Urine Viscosity with Iso-osmolar Contrast Media in the Rat

PURPOSE To compare changes in urinary viscosity in the renal tubules following administration of a high-viscosity iso-osmolar contrast agent (iodixanol) to that observed following administration of a less viscous, higher osmolar contrast agent (iopromide) in anesthetized rats. MATERIALS AND METHODS A total of 43 rats were studied. Experiments were approved by the Berlin, Germany, animal protection administration. A viscometer was developed to measure viscosity in minute samples (7 microL). Urine was collected, viscosity was measured (at 37 degrees C), and glomerular filtration rate (GFR) was determined by means of creatinine clearance. Boluses of 1.5 mL of iodixanol (320 mg iodine per milliliter, iso-osmolar to plasma, high viscosity) or iopromide (370 mg iodine per milliliter, higher osmolality and lower viscosity than iodixanol) were injected into the thoracic aorta. There were five groups (seven rats per group). Groups 1 (iodixanol) and 2 (iopromide) had free access to water prior to the experiment; groups 3 (iodixanol) and 4 (iopromide) received an additional infusion of isotonic saline (4 mL/kg/h). Group 5 was treated as group 1 but received only 0.75 mL of iodixanol. The observation period was 100 minutes. Statistical comparisons were made by means of nonparametric procedures (Friedman test, Kruskal-Wallis test). RESULTS Iodixanol increased urine viscosity from 0.69 to 36.7 mm(2)/sec; thus, urine became threefold more viscous than native iodixanol solution. The increase in urine viscosity after injection of iopromide was from 0.73 to 2.3 mm(2)/sec. While GFR was not significantly affected by iopromide, GFR transiently decreased by 50% after administration of iodixanol. Iopromide had a diuretic effect twofold greater than that of iodixanol. Saline infusion blunted the viscosity rise and transient decline in GFR caused by iodixanol, as did reducing the iodixanol dose by 50%. CONCLUSION Contrast media, in particular iodixanol, increase urine viscosity (which is equal to tubular fluid viscosity in the collecting ducts); in response to iodixanol, GFR markedly decreases. Saline infusion attenuates this response, thus potentially explaining the protective effects of volume expansion in contrast medium-induced nephropathy.

Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury.

20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20-hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies.

How bold is blood oxygenation level-dependent (BOLD) magnetic resonance imaging of the kidney? Opportunities, challenges and future directions.

Renal tissue hypoperfusion and hypoxia are key elements in the pathophysiology of acute kidney injury and its progression to chronic kidney disease. Yet, in vivo assessment of renal haemodynamics and tissue oxygenation remains a challenge. Many of the established approaches are invasive, hence not applicable in humans. Blood oxygenation level‐dependent (BOLD) magnetic resonance imaging (MRI) offers an alternative. BOLD‐MRI is non‐invasive and indicative of renal tissue oxygenation. Nonetheless, recent (pre‐) clinical studies revived the question as to how bold renal BOLD‐MRI really is. This review aimed to deliver some answers. It is designed to inspire the renal physiology, nephrology and imaging communities to foster explorations into the assessment of renal oxygenation and haemodynamics by exploiting the powers of MRI. For this purpose, the specifics of renal oxygenation and perfusion are outlined. The fundamentals of BOLD‐MRI are summarized. The link between tissue oxygenation and the oxygenation‐sensitive MR biomarker T2∗ is outlined. The merits and limitations of renal BOLD‐MRI in animal and human studies are surveyed together with their clinical implications. Explorations into detailing the relation between renal T2∗ and renal tissue partial pressure of oxygen (pO2) are discussed with a focus on factors confounding the T2∗ vs. tissue pO2 relation. Multi‐modality in vivo approaches suitable for detailing the role of the confounding factors that govern T2∗ are considered. A schematic approach describing the link between renal perfusion, oxygenation, tissue compartments and renal T2∗ is proposed. Future directions of MRI assessment of renal oxygenation and perfusion are explored.

Detailing the relation between renal T2* and renal tissue pO2 using an integrated approach of parametric magnetic resonance imaging and invasive physiological measurements.

ObjectivesThis study was designed to detail the relation between renal T2* and renal tissue pO2 using an integrated approach that combines parametric magnetic resonance imaging (MRI) and quantitative physiological measurements (MR-PHYSIOL). Materials and MethodsExperiments were performed in 21 male Wistar rats. In vivo modulation of renal hemodynamics and oxygenation was achieved by brief periods of aortic occlusion, hypoxia, and hyperoxia. Renal perfusion pressure (RPP), renal blood flow (RBF), local cortical and medullary tissue pO2, and blood flux were simultaneously recorded together with T2*, T2 mapping, and magnetic resonance–based kidney size measurements (MR-PHYSIOL). Magnetic resonance imaging was carried out on a 9.4-T small-animal magnetic resonance system. Relative changes in the invasive quantitative parameters were correlated with relative changes in the parameters derived from MRI using Spearman analysis and Pearson analysis. ResultsChanges in T2* qualitatively reflected tissue pO2 changes induced by the interventions. T2* versus pO2 Spearman rank correlations were significant for all interventions, yet quantitative translation of T2*/pO2 correlations obtained for one intervention to another intervention proved not appropriate. The closest T2*/pO2 correlation was found for hypoxia and recovery. The interlayer comparison revealed closest T2*/pO2 correlations for the outer medulla and showed that extrapolation of results obtained for one renal layer to other renal layers must be made with due caution. For T2* to RBF relation, significant Spearman correlations were deduced for all renal layers and for all interventions. T2*/RBF correlations for the cortex and outer medulla were even superior to those between T2* and tissue pO2. The closest T2*/RBF correlation occurred during hypoxia and recovery. Close correlations were observed between T2* and kidney size during hypoxia and recovery and for occlusion and recovery. In both cases, kidney size correlated well with renal vascular conductance, as did renal vascular conductance with T2*. Our findings indicate that changes in T2* qualitatively mirror changes in renal tissue pO2 but are also associated with confounding factors including vascular volume fraction and tubular volume fraction. ConclusionsOur results demonstrate that MR-PHYSIOL is instrumental to detail the link between renal tissue pO2 and T2* in vivo. Unravelling the link between regional renal T2* and tissue pO2, including the role of the T2* confounding parameters vascular and tubular volume fraction and oxy-hemoglobin dissociation curve, requires further research. These explorations are essential before the quantitative capabilities of parametric MRI can be translated from experimental research to improved clinical understanding of hemodynamics/oxygenation in kidney disorders.

High temporal resolution parametric MRI monitoring of the initial ischemia/reperfusion phase in experimental acute kidney injury.

Ischemia/reperfusion (I/R) injury, a consequence of kidney hypoperfusion or temporary interruption of blood flow is a common cause of acute kidney injury (AKI). There is an unmet need to better understand the mechanisms operative during the initial phase of ischemic AKI. Non-invasive in vivo parametric magnetic resonance imaging (MRI) may elucidate spatio-temporal pathophysiological changes in the kidney by monitoring the MR relaxation parameters T2* and T2, which are known to be sensitive to blood oxygenation. The aim of our study was to establish the technical feasibility of fast continuous T2*/T2 mapping throughout renal I/R. MRI was combined with a remotely controlled I/R model and a segmentation model based semi-automated quantitative analysis. This technique enabled the detailed assessment of in vivo changes in all kidney regions during ischemia and early reperfusion. Significant changes in T2* and T2 were observed shortly after induction of renal ischemia and during the initial reperfusion phase. Our study demonstrated for the first time that continuous and high temporal resolution parametric MRI is feasible for in-vivo monitoring and characterization of I/R induced AKI in rats. This technique may help in the identification of the timeline of key events responsible for development of renal damage in hypoperfusion-induced AKI.

Iodinated contrast media cause direct tubular cell damage, leading to oxidative stress, low nitric oxide, and impairment of tubuloglomerular feedback.

Iodinated contrast media (CM) have adverse effects that may result in contrast-induced acute kidney injury. Oxidative stress is believed to play a role in CM-induced kidney injury. We test the hypothesis that oxidative stress and reduced nitric oxide in tubules are consequences of CM-induced direct cell damage and that increased local oxidative stress may increase tubuloglomerular feedback. Rat thick ascending limbs (TAL) were isolated and perfused. Superoxide and nitric oxide were quantified using fluorescence techniques. Cell death rate was estimated using propidium iodide and trypan blue. The function of macula densa and tubuloglomerular feedback responsiveness were measured in isolated, perfused juxtaglomerular apparatuses (JGA) of rabbits. The expression of genes related to oxidative stress and the activity of superoxide dismutase (SOD) were investigated in the renal medulla of rats that received CM. CM increased superoxide concentration and reduced nitric oxide bioavailability in TAL. Propidium iodide fluorescence and trypan blue uptake increased more in CM-perfused TAL than in controls, indicating increased rate of cell death. There were no marked acute changes in the expression of genes related to oxidative stress in medullary segments of Henles loop. SOD activity did not differ between CM and control groups. The tubuloglomerular feedback in isolated JGA was increased by CM. Tubular cell damage and accompanying oxidative stress in our model are consequences of CM-induced direct cell damage, which also modifies the tubulovascular interaction at the macula densa, and may therefore contribute to disturbances of renal perfusion and filtration.

Pressure-dependent renin release: effects of sodium intake and changes of total body sodium

The impact of sodium intake and changes in total body sodium (TBS) for the setting of pressure-dependent renin release (PDRR) was studied in freely moving dogs. An aortic cuff allowed servo control of renal perfusion pressure (RPP) at preset values. Protocols were 1) high sodium intake (HSI), 2) low sodium intake (LSI), 3) TBS moderately increased (+3.1 mmol Na/kg body wt) by 20% reduction of RPP for 2-4 days, 4) large increase of TBS (+8.2) by combining protocol 3 with aldosterone infusion, and 5) TBS reduced (-3.1) by peritoneal dialyses. Twenty-four-hour time courses of arterial plasma renin activity (PRA) revealed that LSI increased PRA for the first 10 h only; afterward PRA did not differ between LSI and HSI. Reduced TBS increased PRA constantly, and the large increase of TBS constantly reduced PRA. PDRR stimulus-response curves (assessed 20 h after last sodium intake) revealed an exponential relationship in each protocol. PDRR was not changed by different sodium intake. Conversely, reduced TBS increased PDRR markedly, whereas the large increase of TBS suppressed it. Thus an inverse relationship between TBS and PRA, i.e., a TBS-dependent renin release, was found. This relationship was enhanced by decreasing RPP. This interplay between TBS-dependent renin release and PDRR allows the organism a differentiated reaction to changes in TBS and arterial pressure.The impact of sodium intake and changes in total body sodium (TBS) for the setting of pressure-dependent renin release (PDRR) was studied in freely moving dogs. An aortic cuff allowed servo control of renal perfusion pressure (RPP) at preset values. Protocols were 1) high sodium intake (HSI), 2) low sodium intake (LSI), 3) TBS moderately increased (+3.1 mmol Na/kg body wt) by 20% reduction of RPP for 2-4 days, 4) large increase of TBS (+8.2) by combining protocol 3 with aldosterone infusion, and 5) TBS reduced (-3.1) by peritoneal dialyses. Twenty-four-hour time courses of arterial plasma renin activity (PRA) revealed that LSI increased PRA for the first 10 h only; afterward PRA did not differ between LSI and HSI. Reduced TBS increased PRA constantly, and the large increase of TBS constantly reduced PRA. PDRR stimulus-response curves (assessed 20 h after last sodium intake) revealed an exponential relationship in each protocol. PDRR was not changed by different sodium intake. Conversely, reduced TBS increased PDRR markedly, whereas the large increase of TBS suppressed it. Thus an inverse relationship between TBS and PRA, i.e., a TBS-dependent renin release, was found. This relationship was enhanced by decreasing RPP. This interplay between TBS-dependent renin release and PDRR allows the organism a differentiated reaction to changes in TBS and arterial pressure.