| 1. |
- Eckerbom, Per, 1974-
(författare)
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Assessment of Renal Physiology Using Functional MRI
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Kidney injury is a major cause of morbidity and mortality throughout the world, leading to substantial individual suffering and to a heavy financial burden for the society. A large number of common conditions such as diabetes, hypertension, autoimmune diseases and infections are highly associated with kidney injury. Disturbances in renal perfusion and oxygenation are believed to be involved in the pathogenesis of kidney injury and are therefore of interest to investigate closely. Studies to further the understanding of kidney injury have previously most often involved invasive procedures or ionizing radiation which have limited studies in humans due to ethical reasons. Hence there is a need to explore and implement noninvasive, nonionizing techniques to carry out human studies of renal physiology in health and disease. This thesis aimed to do so using a number of novel, noninvasive magnetic resonance imaging (MRI) techniques. In the first study of this thesis, we scanned the kidneys of healthy volunteers with noninvasive MRI and found significant differences between the renal cortex, inner and outer medulla regarding blood flow, oxygenation, water diffusion and tissue characteristics. In the second study we scanned the kidneys with MRI and collected urine from healthy volunteers every fourth hour for 24 hours and found circadian variations for total renal blood flow as well as for a number of urinary parameters. Renal oxygenation was stable with only small diurnal variations. In the third study we implemented the MRI techniques used in study 1 and 2 and one additional MRI technique in COVID-19 patients admitted to the intensive care unit for severe respiratory failure, with and without acute kidney injury (AKI). We found significantly reduced total renal blood flow as well as cortical and medullary perfusion in patients with AKI compared to patients without AKI. No significant difference was found between the two groups regarding renal oxygenation, water diffusion or tissue characteristics. In the fourth study we used the same MRI techniques as in study 3 to follow up patients previously treated for severe COVID-19 without and with different degrees of AKI. We found significantly reduced apparent diffusion coefficient (ADC) and total renal blood flow in patients that had high grade AKI compared to patients that did not have AKI during hospitalization for COVID-19. No significant difference regarding oxygenation was found between the groups.In conclusion, this thesis shows that it is possible to use multiparametric noninvasive MRI for renal studies in clinical practice.
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| 2. |
- Eckerbom, Per, 1974-, et al.
(författare)
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Circadian variation in renal blood flow and kidney function in healthy volunteers monitored with noninvasive magnetic resonance imaging
- 2020
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 319:6, s. F966-F978
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Hu, Chunyan, et al.
(författare)
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Renomedullary Interstitial Cell Endothelin A Receptors Regulate BP and Renal Function
- 2020
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Ingår i: Journal of the American Society of Nephrology. - : American Society of Nephrology (ASN). - 1046-6673 .- 1533-3450. ; 31:7, s. 1555-1568
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Tidskriftsartikel (refereegranskat)abstract
- Significance Statement The functional significance of renomedullary interstitial cells, which are uniquely and abundantly expressed in the renal inner medulla, is largely unknown. In vitro studies have demonstrated that endothelin A receptors regulate multiple aspects of renomedullary interstitial cell function. Using a novel mouse model with inducible renomedullary interstitial cell?specific endothelin A receptor gene targeting, the authors found that compared with control mice, mice lacking endothelin A receptors in renomedullary interstitial cells exhibited reduced BP, enhanced natriuresis and diuresis, increased endogenous natriuretic and diuretic factor production, and reduced medullary transporter expression. These studies identify a role for renomedullary interstitial cells in vivo in regulating renal function under physiologic conditions. Background The physiologic role of renomedullary interstitial cells, which are uniquely and abundantly found in the renal inner medulla, is largely unknown. Endothelin A receptors regulate multiple aspects of renomedullary interstitial cell function in vitro. Methods To assess the effect of targeting renomedullary interstitial cell endothelin A receptors in vivo, we generated a mouse knockout model with inducible disruption of renomedullary interstitial cell endothelin A receptors at 3 months of age. Results BP and renal function were similar between endothelin A receptor knockout and control mice during normal and reduced sodium or water intake. In contrast, on a high-salt diet, compared with control mice, the knockout mice had reduced BP; increased urinary sodium, potassium, water, and endothelin-1 excretion; increased urinary nitrite/nitrate excretion associated with increased noncollecting duct nitric oxide synthase-1 expression; increased PGE(2) excretion associated with increased collecting duct cyclooxygenase-1 expression; and reduced inner medullary epithelial sodium channel expression. Water-loaded endothelin A receptor knockout mice, compared with control mice, had markedly enhanced urine volume and reduced urine osmolality associated with increased urinary endothelin-1 and PGE(2) excretion, increased cyclooxygenase-2 protein expression, and decreased inner medullary aquaporin-2 protein content. No evidence of endothelin-1?induced renomedullary interstitial cell contraction was observed. Conclusions Disruption of renomedullary interstitial cell endothelin A receptors reduces BP and increases salt and water excretion associated with enhanced production of intrinsic renal natriuretic and diuretic factors. These studies indicate that renomedullary interstitial cells can modulate BP and renal function under physiologic conditions.
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| 4. |
- Karlmark, Bertil, et al.
(författare)
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Hans R Ulfendahl (1927-2021) : Obituary
- 2021
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Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 232:2
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 5. |
- Nensén, Oskar, et al.
(författare)
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Intrarenal oxygenation determines kidney function during the recovery from an ischemic insult
- 2020
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Ingår i: American Journal of Physiology - Renal Physiology. - : American Physiological Society. - 1931-857X .- 1522-1466. ; 319:6, s. F1067-F1072
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Tidskriftsartikel (refereegranskat)abstract
- Acute kidney injury (AKI) is a significant clinical problem associated with poor outcome. The kidney, due to its inhomogeneous blood flow, is particularly susceptible to changes in oxygen delivery, and intrarenal hypoxia is a hallmark of AKI and progression to chronic kidney disease. However, the role of intrarenal hypoxia per se in the recovery from an ischemic insult is presently unclear. The present study was designed to investigate 1) the role of systemic hypoxia in the acute progression and recovery of AKI and 2) whether increased intrarenal oxygenation improves recovery from an ischemic insult. Anesthetized male Sprague-Dawley rats were subjected to unilateral warm renal ischemia for 45 min followed by 2 h of reperfusion under systemic hypoxia (10% inspired oxygen), normoxia (21% inspired oxygen), or hyperoxia (60% inspired oxygen). Intrarenal oxygen tension was successfully manipulated by altering the inspired oxygen. Glomerular filtration rate (GFR) before the ischemic insult was independent of intrarenal oxygen tension. GFR during the recovery from the ischemic insult was significantly lower compared with baseline in all groups (3 ± 1%, 13 ± 1%, and 30 ± 11% of baseline for hypoxia, normoxia, and hyperoxia, respectively). However, GFR was significantly higher in hyperoxia than hypoxia (P < 0.05, hypoxia vs. hyperoxia). During recovery, renal blood flow was only reduced in hyperoxia, as a consequence of increased renal vascular resistance. In conclusion, the present study demonstrates that renal function during the recovery from an ischemic insult is dependent on intrarenal oxygen availability, and normobaric hyperoxia treatment has the potential to protect kidney function.
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| 6. |
- Schnermann, Jurgen, et al.
(författare)
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Erik Persson (1941-2020) : a Remembrance
- 2020
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Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 230:4
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 7. |
- Sivertsson, Ebba, et al.
(författare)
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Dose-dependent regulation of kidney mitochondrial function by angiotensin II
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.
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| 8. |
- Sivertsson, Ebba, 1984-
(författare)
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Oxygen Metabolism in Experimental Kidney Disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tubulointerstitial hypoxia has been proposed a unifying mechanism behind the development of chronic kidney disease (CKD), regardless of primary diagnosis. Important factors that contribute to the development of hypoxia are reduced bioavailability of nitric oxide (NO), oxidative stress and mitochondria uncoupling. Diabetes and hypertension are the leading causes of CKD. Once established, CKD is a progressive disease and there is no curative treatment. This thesis aimed to investigate the in vivo kidney oxygen metabolism and in vitro mitochondria function in animal models of pathological conditions known to cause kidney injury.The immunosuppressant drug rapamycin has been suggested to counteract diabetic nephropathy by reducing kidney hypertrophy and proteinuria. In a rat model of diabetes type 1, we demonstrate that rapamycin induced intrarenal hypoxia, oxidative stress and mitochondria leak respiration. In diabetic animals, these changes, together with diabetes induced tubular injury, were further aggravated by rapamycin. Proteinuria was decreased by rapamycin in diabetic animals, due to altered glomerular permeability of large molecules. When investigating the role of hypoxia in development of nephropathy there are often confounding factors such as concomitant hyperglycemia, hypertension and oxidative stress to consider. In rats, we demonstrate that increased kidney metabolism, induced by increased thyroid hormone signaling, induced kidney hypoxia, proteinuria and mitochondria leak respiration. Importantly blood glucose, blood pressure and oxidative stress was unchanged. This provides further evidence that hypoxia per se can induce kidney injury. The role of mitochondria dysfunction in hypertensive kidney disease is unclear and angiotensin II (Ang II) has been shown to inhibit mitochondria respiration. In a mouse model of hypertension, we demonstrate that Ang II regulation of mitochondria respiration was dose-dependent. Low Ang II signaling increased leak respiration without compromising efficiency of oxidative phosphorylation. In contrast, high Ang II signaling inhibited mitochondria respiration and decreased efficiency of oxidative phosphorylation. Finally, uremic toxins accumulate in patients with CKD and correlate with the degree of decline in kidney function. In a rat model of CKD, we demonstrate that treatment to reduce plasma levels of protein bound uremic toxins improves cardiac output and kidney oxygenation. In summary, the common denominator for pathological conditions investigated in this thesis is the occurrence of intrarenal hypoxia. This thesis demonstrates that increased mitochondria oxygen consumption via leak respiration as an important contributing factor. Further, targeting plasma levels of circulating uremic toxins may be a potential treatment strategy to slow the rate of progression of CKD.
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| 9. |
- Sivertsson, Ebba, et al.
(författare)
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Thyroid hormone increases oxygen metabolism causing intrarenal tissue hypoxia; a pathway to kidney disease
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- The proposed mechanisms for the development of nephropathy are many, complex and often overlapping. Although recent literature strongly supports a role of kidney hypoxia as an independent pathway to nephropathy, the evidence remains inconclusive since the role of hypoxia is difficult to differentiate from confounding factors such as hyperglycemia, hypertension and oxidative stress. By increasing kidney oxygen consumption using triiodothyronine (T-3) and, thus, avoiding these confounding factors, the aim of the present study was to investigate renal hypoxia per se as a causal pathway for the development of nephropathy. Healthy Sprague-Dawley rats were treated with T-3 (10 mu g/kg/day) and the angiotensin II AT(1)-receptor antagonist candesartan (1 mg/kg in drinking water) to eliminate effects of T-3-induced renin release; and compared to a candesartan treated control group. After 7 weeks of treatment in vivo kidney function, oxygen metabolism and mitochondrial function were evaluated. T-3 did not affect glomerular filtration rate or renal blood flow, but increased total kidney oxygen consumption resulting in cortical hypoxia. Nephropathy, demonstrated as albuminuria and tubulointerstitial fibrosis, developed in T-3-treated animals. Mitochondria uncoupling mediated by uncoupling protein 2 and the adenosine nucleotide transporter was demonstrated as a mechanism causing the increased kidney oxygen consumption. Importantly, blood glucose levels, mean arterial blood pressure and oxidative stress levels were not affected by T-3. In conclusion, the present study provides further evidence for increased kidney oxygen consumption causing intrarenal tissue hypoxia, as a causal pathway for development of nephropathy.
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