Circadian variation in renal blood flow and kidney function in healthy volunteers monitored with noninvasive magnetic resonance imaging

Circadian regulation of kidney function is involved in maintaining whole body homeostasis, and dysfunctional circadian rhythm can potentially be involved in disease development. Magnetic resonance imaging (MRI) provides reliable and reproducible repetitive estimates of kidney function noninvasively without the risk of adverse events associated with contrast agents and ionizing radiation. The purpose of this study was to estimate circadian variations in kidney function in healthy human subjects with MRI and to relate the findings to urinary excretions of electrolytes and markers of kidney function. Phase-contrast imaging, arterial spin labeling, and blood oxygen level-dependent transverse relaxation rate (R2*) mapping were used to assess total renal blood flow and regional perfusion as well as intrarenal oxygenation in eight female and eight male healthy volunteers every fourth hour during a 24-h period. Parallel with MRI scans, standard urinary and plasma parameters were quantified. Significant circadian variations of total renal blood flow were found over 24 h, with increasing flow from noon to midnight and decreasing flow during the night. In contrast, no circadian variation in intrarenal oxygenation was detected. Urinary excretions of electrolytes, osmotically active particles, creatinine, and urea all displayed circadian variations, peaking during the afternoon and evening hours. In conclusion, total renal blood flow and kidney function, as estimated from excretion of electrolytes and waste products, display profound circadian variations, whereas intrarenal oxygenation displays significantly less circadian variation.

Renal hemodynamics and fatty acid uptake: effects of obesity and weight loss

Human studies of renal hemodynamics and metabolism in obesity are insufficient. We hypothesized that renal perfusion and renal free fatty acid (FFA) uptake are higher in subjects with morbid obesity compared with lean subjects and that they both decrease after bariatric surgery. Cortical and medullary hemodynamics and metabolism were measured in 23 morbidly obese women and 15 age- and sex-matched nonobese controls by PET scanning of [15O]-H2O (perfusion) and 14( R,S)-[18F]fluoro-6-thia-heptadecanoate (FFA uptake). Kidney volume and radiodensity were measured by computed tomography, cardiac output by MRI. Obese subjects were re-studied 6 mo after bariatric surgery. Obese subjects had higher renal volume but lower radiodensity, suggesting accumulation of water and/or lipid. Both cardiac output and estimated glomerular filtration rate (eGFR) were increased by ~25% in the obese. Total renal blood flow was higher in the obese [885 (317) (expressed as median and interquartile range) vs. 749 (300) (expressed as means and SD) ml/min of controls, P = 0.049]. In both groups, regional blood perfusion was higher in the cortex than medulla; in either region, FFA uptake was ~50% higher in the obese as a consequence of higher circulating FFA levels. Following weight loss (26 ± 8 kg), total renal blood flow was reduced ( P = 0.006). Renal volume, eGFR, cortical and medullary FFA uptake were decreased but not fully normalized. Obesity is associated with renal structural, hemodynamic, and metabolic changes. Six months after bariatric surgery, the hemodynamic changes are reversed and the structural changes are improved. On the contrary, renal FFA uptake remains increased, driven by high substrate availability.

Multiparametric assessment of renal physiology in healthy volunteers using noninvasive magnetic resonance imaging

Noninvasive methods of magnetic resonance imaging (MRI) can quantify parameters of kidney function. The main purpose of this study was to determine baseline values of such parameters in healthy volunteers. In 28 healthy volunteers (15 women and 13 men), arterial spin labeling to estimate regional renal perfusion, blood oxygen level-dependent transverse relaxation rate (R2*) to estimate oxygenation, and apparent diffusion coefficient (ADC), true diffusion (D), and longitudinal relaxation time (T1) to estimate tissue properties were determined bilaterally in the cortex and outer and inner medulla. Additionally, phase-contrast MRI was applied in the renal arteries to quantify total renal blood flow. The results demonstrated profound gradients of perfusion, ADC, and D with highest values in the kidney cortex and a decrease towards the inner medulla. R2* and T1 were lowest in kidney cortex and increased towards the inner medulla. Total renal blood flow correlated with body surface area, body mass index, and renal volume. Similar patterns in all investigated parameters were observed in women and men. In conclusion, noninvasive MRI provides useful tools to evaluate intrarenal differences in blood flow, perfusion, diffusion, oxygenation, and structural properties of the kidney tissue. As such, this experimental approach has the potential to advance our present understanding regarding normal physiology and the pathological processes associated with acute and chronic kidney disease.

Tissue oxygen and hemodynamics in renal medulla, cortex, and corticomedullary junction during hemorrhage-reperfusion

Previous studies of intrarenal perfusion and tissue oxygenation have produced a wide range of results and have not matched tissue oxygen tension (tPo2) with concurrent changes in flow in three distinct regions. We thus used an anesthetized rat model of hemorrhage-reperfusion to address this question. Combined tpo2/laser-Doppler fiber-optic probes were simultaneously sited in cortical, corticomedullary (CMJ), and medullary regions of the left kidney. Total renal blood flow was measured in separate experiments. Recordings were made during exsanguination of 10 and 20% of estimated blood volume at 10-min intervals, followed by shed-blood resuscitation after a further 10 min. The decay in tpo2 was then recorded following total cessation of blood flow, allowing estimation of local oxygen consumption. During exsanguination, tPo2 was maintained in all intrarenal regions, despite significant falls in blood pressure and total renal blood flow. However, intrarenal flow was redistributed with reduced cortical, unchanged CMJ, and increased medullary blood flow. After resuscitation, significant rises above baseline were seen in blood pressure and in tpo2 across all regions. Whereas cortical and medullary flows regained baseline values, CMJ flow fell. The ratio of tpo2 to microvascular blood flow increased significantly in all regions during resuscitation, suggesting decreased oxygen consumption. On total cessation of blood flow, the cortex and CMJ showed significant increases in the oxygen decay half-life, consistent with decreased consumption. To our knowledge, this is the first quantitative demonstration of a markedly heterogeneous intrarenal cardiorespiratory response to a hemodynamic insult, with effects most marked at the corticomedullary junction.

Aortic blood flow subtraction: an alternative method for measuring total renal blood flow in conscious dogs

We have measured total renal blood flow (TRBF) as the difference between signals from ultrasound flow probes implanted around the aorta above and below the renal arteries. The repeatability of the method was investigated by repeated, continuous infusions of angiotensin II and endothelin-1 seven times over 8 wk in the same dog. Angiotensin II decreased TRBF (350 ± 16 to 299 ± 15 ml/min), an effect completely blocked by candesartan (TRBF 377 ± 17 ml/min). Subsequent endothelin-1 infusion reduced TRBF to 268 ± 20 ml/min. Bilateral carotid occlusion (8 sessions in 3 dogs) increased arterial blood pressure by 49% and decreased TRBF by 12%, providing an increase in renal vascular resistance of 69%. Dynamic analysis showed autoregulation of renal blood flow in the frequency range <0.06–0.07 Hz, with a peak in the transfer function at 0.03 Hz. It is concluded that continuous measurement of TRBF by aortic blood flow subtraction is a practical and reliable method that allows direct comparison of excretory function and renal blood flow from two kidneys. The method also allows direct comparison between TRBF and flow in the caudal aorta.

Role of the renal medulla in volume and arterial pressure regulation

The original fascination with the medullary circulation of the kidney was driven by the unique structure of vasa recta capillary circulation, which Berliner and colleagues (Berliner, R. W., N. G. Levinsky, D. G. Davidson, and M. Eden. Am. J. Med. 24: 730-744, 1958) demonstrated could provide the economy of countercurrent exchange to concentrate large volumes of blood filtrate and produce small volumes of concentrated urine. We now believe we have found another equally important function of the renal medullary circulation. The data show that it is indeed the forces defined by Starling 100 years ago that are responsible for the pressure-natriuresis mechanisms through the transmission of changes of renal perfusion pressure to the vasa recta circulation. Despite receiving only 5-10% of the total renal blood flow, increases of blood flow to this region of the kidney cause a washout of the medullary urea gradient and a rise of the renal interstitial fluid pressure. These forces reduce tubular reabsorption of sodium and water, leading to a natriuresis and diuresis. Many of Starling's intrinsic chemicals, which he named "hormones," importantly modulate this pressure-natriuresis response by altering both the sensitivity and range of arterial pressure around which these responses occur. The vasculature of the renal medulla is uniquely sensitive to many of these vasoactive agents. Finally, we have found that the renal medullary circulation can play an important role in determining the level of arterial pressure required to achieve long-term fluid and electrolyte homeostasis by establishing the slope and set point of the pressure-natriuresis relationship. Measurable decreases of blood flow to the renal medulla with imperceptible changes of total renal blood flow can lead to the development of hypertension. Many questions remain, and it is now evident that this is a very complex regulatory system. It appears, however, that the medullary blood flow is a potent determinant of both sodium and water excretion and signals changes in blood volume and arterial pressure to the tubules via the physical forces that Professor Starling so clearly defined 100 years ago.

Sensitivity of the renal medullary circulation to plasma vasopressin

Studies were carried out to determine the effects of physiological changes of plasma arginine vasopressin (AVP) on blood flow distribution in the renal cortex and medulla. Acute decerebration was performed so that studies could be carried out within the low physiological range of circulating AVP. Changes of renal cortical and medullary microcirculatory blood flow were measured with implanted optical fibers and laser-Doppler flowmetry, and total renal blood flow was measured with transit-time ultrasonography. During intravenous infusion of increasing doses of AVP, when plasma AVP was increased in steps from 2.9 to 11.2 pg/ml by intravenous infusion, mean arterial pressure (98 +/- 3 mmHg), total renal blood flow (8.2 +/- 0.6 ml. min-1.g kidney-1), and blood flow in the microcirculation of the cortex (2.11 +/- 0.28 V) remained unchanged, whereas that in the renal medulla decreased progressively. Medullary flow was significantly reduced when circulating levels of AVP increased from a control level of 2.8 to 5.0 pg/ml. The reductions of medullary flow were accompanied by parallel increases of urine osmolality. These data indicate that the vessels supplying the renal medullary circulation are sensitive within the range of plasma AVP concentrations observed with moderate water restriction. The medullary circulation exhibits a sensitivity AVP that parallels that found in the medullary collecting ducts.

Response of the avian kidney to acute changes in arterial perfusion pressure and portal blood supply

Domestic fowl kidneys autoregulate total renal blood flow and glomerular filtration rate (GFR) over a wide range of renal arterial perfusion pressure (RAPP). Sustained (approximately 2-4 h) restriction of renal portal blood flow attenuates the autoregulatory responses. The present study was designed to assess the effects of acute (approximately 10 min) alterations of renal portal blood flow on renal function, and to dissociate the renal responses to altered renal portal blood flow from the renal responses to reductions in RAPP. The thermal pulse decay (TPD) technique and p-aminohippuric acid clearance (CPAH) were used to measure blood flow. During acute increases and decreases in renal portal blood flow, regional renal blood flow as measured by the TPD system (RBFTPD) was significantly positively correlated with total kidney blood flow represented by CPAH (RBFPAH). These results indicate that changes in total kidney blood flow induced by alteration of portal perfusion were reflected in the regional measurement of renal blood flow. Changes in renal portal blood flow did not affect the urine flow rate (UFR), GFR, or fractional excretion of sodium (FENa). Reducing RAPP from 120 to 50 mmHg significantly reduced UFR, GFR, and FENa. Overall, these results indicate that large acute changes in renal portal blood flow can significantly alter total renal blood flow without significantly affecting parameters (UFR, GFR, and FENa) primarily influenced by the renal arterial vasculature.