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.

Early effects of an x-ray contrast medium on renal T(2) */T(2) MRI as compared to short-term hyperoxia, hypoxia and aortic occlusion in rats.

AIM: X-ray contrast media (CM) can cause acute kidney injury (AKI). Medullary hypoxia is pivotal in CM-induced AKI, as indicated by invasively and pin-point measured tissue oxygenation. MRI provides spatially resolved blood oxygenation level-dependent data using T2 * and T2 mapping. We studied CM effects on renal T2 */T2 and benchmarked them against short periods of hyperoxia, hypoxia and aortic occlusion (AO). METHODS: Rats were equipped with carotid artery catheters (tip towards aorta) and supra-renal aortic occluders. T2 */T2 mapping was performed using a 9.4-T animal scanner. CM (1.5 mL iodixanol) was injected into the thoracic aorta with the animal in the scanner followed by 2 h of T2 */T2 mapping. For T2 */T2 assessment, regions of interest in the cortex (C), outer medulla (OM), inner medulla (IM) and papilla (P) were determined according to morphological features. RESULTS: Hyperoxia increased T2 * in C (by 17%) and all medullary layers (25-35%). Hypoxia decreased T2 * in C (40%) and all medullary layers (55-60%). AO decreased T2 * in C (18%) and all medullary layers (30-40%). Upon injection of CM, T2 * increased transiently, then decreased, reaching values 10-20% below baseline in C and OM and 30-40% below baseline in IM and P. CONCLUSION: T2 * mapping corroborates data previously obtained with invasive methods and demonstrates that CM injection affects renal medullary oxygenation. CM-induced T2 * decrease in OM was small vs. hypoxia and aortic occlusion. T2 * decrease obtained for hypoxia was more pronounced than for AO. This indicates that T2 * may not accurately reflect blood oxygenation under certain conditions.

Linking non-invasive parametric MRI with invasive physiological measurements (MR-PHYSIOL): towards a hybrid and integrated approach for investigation of acute kidney injury in rats.

Acute kidney injury of various origins shares a common link in the pathophysiological chain of events: imbalance between renal medullary oxygen delivery and oxygen demand. For in vivo assessment of kidney haemodynamics and oxygenation in animals, quantitative but invasive physiological methods are established. A very limited number of studies attempted to link these invasive methods with parametric Magnetic Resonance Imaging (MRI) of the kidney. Moreover, the validity of parametric MRI (pMRI) as a surrogate marker for renal tissue perfusion and renal oxygenation has not been systematically examined yet. For this reason, we set out to combine invasive techniques and non-invasive MRI in an integrated hybrid setup (MR-PHYSIOL) with the ultimate goal to calibrate, monitor and interpret parametric MR and physiological parameters by means of standardized interventions. Here we present a first report on the current status of this multi-modality approach. For this purpose, we first highlight key characteristics of renal perfusion and oxygenation. Second, concepts for in vivo characterization of renal perfusion and oxygenation are surveyed together with the capabilities of MRI for probing blood oxygenation-dependent tissue stages. Practical concerns evoked by the use of strong magnetic fields in MRI and interferences between MRI and invasive physiological probes are discussed. Technical solutions that balance the needs of in vivo physiological measurements together with the constraints dictated by small bore MR scanners are presented. An early implementation of the integrated MR-PHYSIOL approach is demonstrated including brief interventions of hypoxia and hyperoxia.

The step response: a method to characterize mechanisms of renal blood flow autoregulation.

Response of renal vasculature to changes in renal perfusion pressure (RPP) involves mechanisms with different frequency characteristics. Autoregulation of renal blood flow (RBF) is mediated by the rapid myogenic response, by the slower tubuloglomerular feedback (TGF) mechanism, and, possibly, by an even slower third mechanism. To evaluate the individual contribution of these mechanisms to RBF autoregulation, we analyzed the response of RBF to a step increase in RPP. In anesthetized rats, the suprarenal aorta was occluded for 30 s, and then the occlusion was released to induce a step increase in RPP. Three dampened oscillations were observed; their oscillation periods ranged from 9.5 to 13 s, from 34.2 to 38.6 s, and from 100.5 to 132.2 s, respectively. The two faster oscillations correspond with previously reported data on the myogenic mechanism and the TGF. In accordance, after furosemide, the amplitude of the intermediate oscillation was significantly reduced. Inhibition of nitric oxide synthesis by Nomega-nitro-l-arginine methyl ester significantly increased the amplitude of the 10-s oscillation. It is concluded that the parameters of the dampened oscillations induced by the step increase in RPP reflect properties of autoregulatory mechanisms. The oscillation period characterizes the individual mechanism, the dampening is a measure for the stability of the regulation, and the square of the amplitudes characterizes the power of the respective mechanism. In addition to the myogenic response and the TGF, a third rather slow mechanism of RBF autoregulation exists.

Influence of baroreflex on volume elasticity of heart and aorta in the rabbit.

Optimal ventriculoaortic coupling includes tuning of elastic properties. The ratio of effective arterial elastance and left ventricular endsystolic elastance is often taken as a measure for mechanical and energetical efficiency. The present study determined the time course of ventricular and aortic volume elasticity (VE = dp/dV) throughout a complete heartbeat. This was achieved by using changes of eigenfrequency of two catheter-transducer systems under closed chest conditions in rabbits. Short-term VE modulation was studied by a baroreflex response, as induced by pressure changes applied to the carotid sinus. Long-term changes were studied in atherosclerotic rabbits (12 wk of high-cholesterol feeding). The time course and mean values of ventricular and aortic VE were changed by the baroreflex stimulus. Cholesterol feeding diminished the response. The degree of ventriculoaortic coupling, as quantified by VE(Aorta)/VE(Ventricle) ratio, varied during a single ejection period. The large span allows either maximal energetical efficiency or maximal stroke work. Although normal rabbits adjusted their ventriculoaortic coupling during baroreflex input, the cholesterol-fed rabbits failed to do so.

Contribution of pressure natriuresis to control of total body sodium: balance studies in freely moving dogs.

1. This study aims at determining whether elevation of renal perfusion pressure (RPP) may correct for increased total body sodium (TBS), via pressure natriuresis. 2. Freely moving dogs were studied on four consecutive days. During day 1, low-dose angiotensin II and aldosterone were infused. Pressure natriuresis was prevented by servo-controlling RPP to 20 % below the control level. Sodium and water retention increased TBS and total body water. Mean arterial blood pressure rose by approximately 25 mmHg. 3. In protocol 1, infusions and control of RPP were maintained over three more days. Sodium was retained on all days, resulting in a continuous increase in TBS. 4. In protocol 2, control of RPP was stopped after day 1. Thus, pressure natriuresis could exert its effect beginning with day 2. Angiotensin II and aldosterone infusions were continued. This prevented the effects of endogenous suppression of the renin-angiotensin-aldosterone system (RAAS), which is caused by increased TBS. No further sodium retention occurred, i.e. TBS remained at the elevated level gained on day 1. 5. In protocol 3, control of RPP and the infusions were stopped. Thus, pressure natriuresis and RAAS suppression could exert their combined effects. Sodium excretion exceeded sodium intake on day 2. Control level of TBS was regained within 24 h. 6. It was concluded that when RPP is considerably elevated, pressure natriuresis prevents further increase of TBS in the face of elevated angiotensin II and aldosterone levels. However, pressure natriuresis does not suffice to restore TBS to control. This requires additional endogenous suppression of RAAS.

Nitric oxide and the role of blood pressure variability to the kidney.

Blood pressure variability is buffered by at least two mechanisms: the arterial baroreceptor reflex and nitric oxide (NO). Only recently is the importance of blood pressure variations on cardiovascular control being investigated. Here we report of a study performed in conscious dogs, in which renovascular hypertension was induced. Reduction of renal arterial pressure (RAP) to 85 mmHg for 24 h elicited profound hypertension by 60 mmHg (vs. control: 110 +/- 3 mmHg; P < 0.01). This was accompanied by reduced volume and sodium excretion (-48% of control, P < 0.01 and -80% of control, P < 0.01, respectively) and augmented renin release by more than two-fold (P < 0.01). This intervention was compared with a protocol in which RAP was reduced to the same mean value, however, RAP oscillated by +/-10 mmHg at 0.1 Hz. This manoeuvre led to a transient increase in NO3 excretion in urine (P < 0.01), blunted antidiuresis (-14% of control) as well as antinatriuresis (-40% of control) and attenuated the increased renin release by 30% (P < 0.05). In consequence, the magnitude of blood pressure increase was only half as high as that observed during static reduction of RAP (P < 0.01). It is concluded that blood pressure oscillations to the kidney have a profound influence on water and electrolyte balance and on renin release, which alleviates the onset of Goldblatt hypertension.

Coupling of left ventricular and aortic volume elasticity in the rabbit.

Changes in volume elasticity (VE) of the left ventricle and aorta could be important for blood flow. A procedure is presented to rapidly assess VE of the left ventricle and aorta by analyzing changes in the eigenfrequency. Six control rabbits and 11 rabbits with atheromatosis (12 wk of high-cholesterol feeding) were studied. In control rabbits, during the first half of the systole, left ventricular VE continuously increased to +43% (P < 0.05). Then VE gradually declined to an end-diastolic minimum (20% of the average systolic levels, P < 0.05). Aortic VE changes were in the opposite direction to the ventricle. Aortic VE continuously decreased throughout the systole; the last value was 20% lower than at the beginning of the systole (P < 0.05). Conversely, diastolic VE of the aorta took on greater values. This inverse time course between ventricle and aorta may reduce energy requirements for conveying blood. High cholesterol-fed rabbits did not reveal the inverse behavior of ventricular and aortic VE, e.g., aortic VE increased during the systole (119%, P < 0.05).

Antihypertensive effect of 0.1-Hz blood pressure oscillations to the kidney.

BACKGROUND: Physiological blood pressure (BP) fluctuations with frequencies >0.1 Hz can override renal blood flow autoregulation. The influence of such immediate changes in renal perfusion pressure (RPP) on daily BP regulation, eg, via shear stress-stimulated liberation of renal endothelial NO, however, is unknown. Thus, we studied the effects of such RPP oscillations on renal function and on systemic BP during the onset of renal hypertension. METHODS AND RESULTS: Seven beagles (randomly assigned to each of the following protocols) were chronically instrumented for the measurement of systemic BP, RPP, and renal excretory function. An inflatable cuff was used to reduce and to oscillate RPP over 24 hours in the freely moving dog. Reducing RPP to 87+/-2 mm Hg diminished excretion of sodium and water and doubled plasma renin activity (PRA, n=7, P<0. 01) but had no significant effect on urinary nitrate excretion (n=6), a marker of NO generation. Superimposing 0.1-Hz oscillations (+/-10 mm Hg) onto the reduced RPP blunted hypertension, returned fluid excretion almost to control levels, and doubled renal sodium elimination. Nitrate excretion peaked at 8 hours, only to return to control values shortly thereafter. PRA, conversely, was significantly reduced during the last third of the experimental protocols. CONCLUSIONS: BP fluctuations transiently stimulate NO liberation and induce a reduction in PRA, which enhances 24-hour sodium and water excretion and markedly attenuates the acute development of renovascular hypertension.

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.

Mechanisms compensating Na and water retention induced by long-term reduction of renal perfusion pressure.

Endogenous downregulation of plasma aldosterone (Aldo) concentration, despite increased plasma renin activity (PRA), has been suggested to compensate Na and water retention, which is induced by long-term reduction of renal perfusion pressure (rRPP). To determine whether fixed plasma Aldo concentration would prevent equilibration of 24-h Na and water balances during rRPP, chronically instrumented, freely moving beagle dogs were kept under standardized conditions (daily intake 5.5 mmol Na/kg body wt) and studied for 4 consecutive days under the following conditions: control without rRPP (protocol 1) and rRPP + infusion of Aldo (rRPP + Aldo, protocol 2). Because Aldo administration reduces PRA and, thereby, angiotensin II (ANG II) levels ANG II was additionally infused in protocol 3 (rRPP + ANG II + Aldo). During rRPP + Aldo, 24-h Na balances were never equilibrated. Daily Na retention was approximately 3.5 mmol/kg body wt on day 1 and decreased to approximately 1.6 mmol/kg body wt on day 4; 24-h water balances changed in a similar manner. PRA decreased stepwise. On all rRPP + ANG II + Aldo days, Na and water retentions were more extensive than during rRPP + Aldo. Daily Na retention decreased from approximately 4.4 mmol/kg body wt on day 1 to approximately 3.0 mmol/kg body wt on day 4. Plasma atrial natriuretic peptide increased during both protocols. It is concluded that 1) endogenous downregulation of components of the renin-angiotensin-aldosterone system is a pivotal compensatory mechanism to reduce Na and water retention and 2) natriuretic and diuretic factors seem to be of minor potency, because not even the sum of all could counterbalances the Na- and water-retaining effects of Aldo and ANG II.

Changes of blood pressure, sodium excretion and sodium balance due to variations of the renin-angiotensin-aldosterone system.

UNLABELLED: Studies were performed in partly free moving Beagle dogs, kept under standardized environmental and dietetic conditions (food intake: once daily at 8:30 a.m., 5.5 mmol Na/kg body weight per 24 h). The dogs were chronically instrumented with an inflatable cuff around the aorta above the renal arteries, two aortic catheters above and below the cuff, and a bladder catheter. Three protocols were performed in 7 dogs each: (i) CONTROL: urine collection in 20-min intervals and measurement of Na excretion, continuous registration of mean arterial blood pressure (MABP) and heart rate for 4 consecutive days. (ii) As (i), but additional servocontrolled reduction of the renal perfusion pressure (rRPP) to stimulate renin secretion and the formation of angiotensin II and aldosterone. (iii) As (ii), but additional constant infusion of the angiotensin converting enzyme inhibitor Captopril. Despite rRPP Na is only transiently retained (pressure escape). MABP level is elevated, as long as total-body Na is augmented. In protocol iii no Na retention occurs, indicating that rRPP per se causes no Na retention. MABP level remained unchanged. Independent of the preset MABP level similar diurnal variation in MABP are present in all protocols. During control days major amounts of Na are excreted postprandially. Up to 5:00 p.m. 65% of the daily Na intake is excreted. After disturbance of Na control (protocols ii and iii) the Na excretion is shifted to the evening and night. Probably due to this shift Na retention can be prevented. Furthermore, these results demonstrate that rRPP-induced increases of total body Na and MABP are solely mediated by the activation of the renin-angiotensin-aldosterone system.

Diurnal pattern of sodium excretion in dogs with and without chronically reduced renal perfusion pressure.

In 5 conscious dogs the diurnal patterns of urinary sodium excretion (UNaV) were investigated, initially during 1 control day and, thereafter, during 4 days of servo-controlled reduction of renal perfusion pressure (rRPP). The individual dog's mean arterial blood pressure was reduced to 80% of the blood pressure on the control day. This value was always found to be below the threshold for the pressure-dependent renin release. During the entire study period urine was collected in 4-hour intervals and blood samples were taken every 4 h. The dogs were kept on a standardized high sodium and high water intake and were fed once daily at 8.30 h. On the control day, UNaV, urinary flow rate (UV), fractional lithium excretion (FELi) and fractional sodium excretion (FENa) had similar diurnal patterns. They peaked 4-8 h after food intake and decreased to low values during the night. On day 1 of rRPP, UNaV and FENa were maintained at very low levels in all collection periods, whereas the patterns of UV and FELi were unaltered compared with the patterns on the control day. On days 2-4 of rRPP, a clear-cut maximum in the patterns of UNaV and FENa recurred, comparable with the patterns on the control day. However, compared with the control day this maximum was shifted by 4 h towards the night. In contrast, the patterns of UV and FELi remained unchanged compared with the control day. The results indicate that UNaV has a typical time course in conscious, sodium- and water-replete dogs fed once daily. Endogenous stimulation of sodium reabsorption by means of rRPP results in a characteristic 4-hour shift of UNaV and FENa towards the night during rRPP days 2-4. This delay in UNaV seems to be evoked by processes in the distal tubule.

ACE inhibition prevents Na and water retention and MABP increase during reduction of renal perfusion pressure.

Two groups of six dogs were studied during 4 control days and 4 days of reduced renal perfusion pressure (rRPP) servo controlled at 20% below the individual dog's 24-h mean arterial blood pressure (MABP) during control days, i.e., below the threshold for renin release. On rRPP days, endogenous activation of plasma aldosterone and angiotensin II was inhibited by the angiotensin-converting enzyme inhibitor captopril. The dogs were kept on a high-Na and high-water intake. Unlike studies during rRPP alone, there was no Na and water retention during rRPP+captopril. Glomerular filtration rate dropped by approximately 9%, and MABP remained in the range of control days. Plasma renin activity rose to values 14 times greater than control, whereas plasma aldosterone decreased by approximately 60%. Atrial natriuretic peptide remained in the range of controls. In conclusion, angiotensin-converting enzyme inhibition can prevent the otherwise obligatory Na and water retention and systemic MABP increase during a 20% reduction in renal perfusion pressure. This is achieved most likely via the captopril-induced fall in angiotensin II and plasma aldosterone levels.

Influence of captopril on 24-hour balances and the diurnal patterns of urinary output, blood pressure, aldosterone and atrial natriuretic peptide in conscious dogs.

The diurnal time course of urinary flow rate (UV), urinary sodium (UNaV), and potassium (UKV) excretion, and of hormones such as atrial natriuretic peptide (ANP) and aldosterone, was investigated during 5 days of continuous captopril infusion (15 micrograms.kg body weight-1.min-1) in 4 conscious dogs on a high sodium diet (14.5 mmol Na.kg body weight-1.24 h-1). All food and water was given once daily at 8.30 a.m. On the control day and on days 1, 3, and 5 of captopril infusion, urine was collected by an automated system at 20-min intervals over 24 h, blood was taken every 4 h. Mean arterial blood pressure (MABP) and heart rate were evaluated as 5-min averages. Time courses of UNaV, UV, and UKV were compared with the individual control day without captopril. With captopril, 24-hour balances for Na and H2O were slightly negative, while the K balance was slightly positive for 2-3 days. Thereafter, all 24-hour balances were restored. MABP continued to decrease even after Na and water intake and output had come into balance again. Captopril treatment changed the diurnal excretion pattern for UNaV and UV characteristically. In the postprandial period until 5 p.m., less Na and urine were excreted than on the control day, whereas during the evening and night more Na and urine were excreted. The changes in the excretion pattern persisted for the entire observation period. The results indicate that disturbances in the regulating systems, induced by converting-enzyme blockade, bring about complex reactions of, e.g., MABP, ANP and aldosterone that finally restore Na and water 24-hour input/output balances.

Endogenous variations and sodium intake-dependent components of diurnal sodium excretion patterns in dogs.

1. Automated, sequential, 20 min urine collections were made to provide a record of diurnal variations of urinary sodium excretion (UNaV) in seven dogs, in which the same daily intake of sodium, potassium and water was administered, at first orally (between 08.30 and 08.50 h) on day 1 and then by i.v. infusion at a constant rate on days 2 and 3. This basic protocol was employed for two different levels of sodium intake: normal (NSI; 2.5 mmol (kg body wt)-1 (24 h)-1) and high (HSI; 14.5 mmol (kg body wt)-1 (24 h)-1). 2. The aims were: firstly, to establish the diurnal pattern of UNaV under these circumstances; secondly, to find out whether the quantity of sodium administered influences this diurnal pattern; and thirdly, to distinguish endogenous fluctuations from intake-dependent components in the UNaV excretion patterns. 3. On day 1 (oral intake) all dogs exhibited a similar excretion pattern, which peaked between 13.00 and 15.00 h on both diets and then diminished again over the remainder of the 24 h period. 4. On days 2 and 3 (infusion) UNaV fluctuated within a considerable range. 5. On HSI, the maximal UNaV rates on day 1 were about double those observed on infusion days. On HSI, UNaV during infusion days seems to consist of a constant basal component of about 5-6 mumol (kg body wt)-1 min-1 upon which a fluctuating component is superimposed. The basal component may be a reactive homeostatic response to the high sodium intake, whereas the superimposed fluctuating component may reflect endogenous variations.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of obstetrical manipulations on the prostaglandin content of the uterus]. / Der Einflu geburtshilflicher Manipulationen auf den uterinen Prostaglandingehalt.

It is reported about the concentration of PG F2 alpha, PG E2, TxB2 and 6-keto-PG F1 alpha in amniotic fluid after obstetrical manipulations without rupture of amniotic membranes. Only digital distension of the cervix was followed by a rise of PG F2 alpha values. On the other side there was no increase in PG-concentration after application of a transabdominal catheter or after amniotomy.