| 1. |
- Andelin, M., et al.
(author)
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Assessing the Accuracy of Continuous Glucose Monitoring (CGM) Calibrated With Capillary Values Using Capillary or Venous Glucose Levels as a Reference.
- 2016
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In: Journal of Diabetes Science and Technology. - : Diabetes Technology Society. - 1932-2968. ; 10:4, s. 876-884
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Journal article (peer-reviewed)abstract
- Background: Using the standard venous reference for the evaluation of continuous glucose monitoring (CGM) systems could possibly negatively affect measured CGM accuracy since CGM are generally calibrated with capillary glucose and venous and capillary glucose concentrations differ. We therefore aimed to quantify the effect of using capillary versus venous glucose reference samples on estimated accuracy in capillary calibrated CGM.less thanbr /greater thanMethods: We evaluated 41 individuals with type 1 diabetes mellitus (T1DM) using the Dexcom G4 CGM system over 6 days. Patients calibrated their CGM devices with capillary glucose by means of the HemoCue system. During 2 visits, capillary and venous samples were simultaneously measured by HemoCue and compared to concomitantly obtained CGM readings. The mean absolute relative difference (MARD) was calculated using capillary and venous reference samples.less thanbr /greater thanResults: Venous glucose values were 0.83 mmol/L (15.0 mg/dl) lower than capillary values over all glycemic ranges, P less than .0001. Below 4 mmol/l (72 mg/dl), the difference was 1.25 mmol/l (22.5 mg/dl), P = .0001, at 4-10 mmol/l (72-180 mg/dl), 0.67 mmol/l (12.0 mg/dl), P less than .0001 and above 10 mmol/l (180 mg/dl), 0.95 mmol/l (17.1 mg/dl), P less than .0001. MARD was 11.7% using capillary values as reference compared to 13.7% using venous samples, P = .037. Below 4 mmol/l (72 mg/dl) MARD was 16.6% and 31.8%, P = .048, at 4-10 mmol/l (72-180 mg/dl) 12.1% and 12.6%, P = .32, above 10 mmol/l (180 mg/dl) 8.7% and 9.2%, P = .82.less thanbr /greater thanConclusion: Using capillary glucose concentrations as reference to evaluate the accuracy of CGM calibrated with capillary samples is associated with a lower MARD than using venous glucose as the reference. Capillary glucose concentrations were significantly higher than venous in all glycemic ranges.less thanbr /greater than (© 2016 Diabetes Technology Society.)
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| 2. |
- Andersson, Lena, 1980, et al.
(author)
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Methodological issues on the use of urinary alpha-1-microglobuline in epidemiological studies.
- 2008
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In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 23:4, s. 1252-1256
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Journal article (peer-reviewed)abstract
- Background. Alpha-1-microglobulin (A1M) is a low molecular weight protein that can be measured in urine and used as a marker for tubular function, assuming that the normal variability within and between individuals is known. The aims of this study were to investigate this variability, to find the optimal way of sampling and quantifying A1M in spot urine samples to reflect the 24 h excretion and to examine storage stability. Method. Timed urine specimens were collected from 29 healthy volunteers at fixed time points over 24 h on two separate days. Volumes, creatinine and specific gravity were determined. All samples were analysed with a commercial ELISA for A1M. Results. We found a clear diurnal variation in A1M excretion rate and a gender effect (higher in males). The excretion rate was higher in the daytime, with high urinary flow, compared to overnight values. A1M excretion in spot urine samples was highly correlated with the 24 h excretion at all times except 22:00 in male subjects. Urinary A1M adjusted for creatinine concentration correlated well with the 24 h excretion. Variability within individuals was only 20% of the total variability in 24 h A1M excretion, but 43% in first morning urine. Expressed as CV, the intra-individual variability (between days) was 29% in 24 h excretion. Conclusion. We conclude that diurnal variation and gender should be taken into account when comparing groups. Moreover, in spot samples (e.g. first morning samples) adjustment of A1M for creatinine or specific gravity is a reliable alternative to 24 h urine.
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| 3. |
- Andersson, Maria, 1976, et al.
(author)
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Mild renal ischemia-reperfusion reduces charge and size selectivity of the glomerular barrier
- 2007
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In: American Journal of Physiology Renal Physiology. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 292:6
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Journal article (peer-reviewed)abstract
- Despite recent discoveries of molecules in podocytes, the mechanisms behind most conditions of proteinuria are still poorly understood. To understand more about this delicate barrier, we studied the functional and morphological effects of mild (15 min) renal ischemia-reperfusion injury (IRI). Renal function was studied in rats in vivo, followed by a more detailed analysis of the glomerular barrier in cooled (8 degrees C) isolated perfused kidneys (cIPK). Renal blood flow was quickly restored, whereas the glomerular filtration rate remained halved 30 min after IRI. Tubular cell activity was intact as judged from the unaffected Cr-EDTA U/P concentration ratio. In vivo, the fractional clearance (theta) for albumin increased 16 times. In rats subjected to cIPK starting 30 min after in vivo IRI, theta(albumin) was 15 times and theta(Ficoll_36angstroms) 1.8 times higher than in control cIPKs. According to the heterogeneous charged fiber model, IRI reduced the fiber charge density to 38% of control (P < 0.01, n = 7). Morphometric analysis with electron microscopy did not reveal any changes in the podocytes or the glomerular basement membrane (GBM) after IRI, suggesting more subtle changes of the GBM and/or the endothelial glycocalyx. We conclude that mild renal IRI induces formation of reactive oxygen species, massive proteinuria, and loss of charged fibers with no apparent change in morphology. These novel findings stress the importance of other components of the barrier, such as proteoglycans produced by the glomerular cells, and provide a tentative explanation for the mechanisms behind proteinuria in glomerulonephritis, for example.
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| 4. |
- Ballermann, B. J., et al.
(author)
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The Glomerular Endothelium Restricts Albumin Filtration
- 2021
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In: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 8
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Journal article (peer-reviewed)abstract
- Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.
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| 5. |
- Bergwall, Lovisa, et al.
(author)
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Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Identifies a Target for Podocyte Cytoskeleton Stabilization
- 2018
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Journal article (peer-reviewed)abstract
- The melanocortin-1 receptor (MC1R) in podocytes has been suggested as the mediator of the ACTH renoprotective effect in patients with nephrotic syndrome with the mechanism of action beeing stabilization of the podocyte actin cytoskeleton. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and a rat model of nephrotic syndrome in combination with cell culture analysis. Phosphoproteomics was applied and identified MC1R pathways confirmed using biochemical analysis. We found that glomerular MC1R expression was increased in nephrotic syndrome, both in humans and in a rat model. A MC1R agonist protected podocytes from protamine sulfate induced stress fiber loss with the top ranked phoshoproteomic MC1R activated pathway beeing actin cytoskeleton signaling. Actin stabilization through the MC1R consisted of ERK1/2 dependent phosphorylation and inactivation of EGFR signaling with stabilization of synaptopodin and stressfibers in podocytes. These results further explain how patients with nephrotic syndrome show responsiveness to MC1R receptor activation by decreasing EGFR signaling and as a consequence restore filtration barrier function by stabilizing the podocyte actin cytoskeleton.
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| 6. |
- Björnson Granqvist, Anna, 1974, et al.
(author)
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Impaired glomerular and tubular antioxidative defense mechanisms in nephrotic syndrome.
- 2010
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In: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 299:4
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Journal article (peer-reviewed)abstract
- The molecular mechanisms behind acquired nephrotic syndrome (NS) are still largely unknown. One possible explanation for the development of proteinuria is oxidative damage to the glomerular cells. Our hypothesis was that the oxidative defense is weakened in NS, and we focused on measurements of the oxidative-antioxidative status in the glomerular and tubular parts of the nephron. Gene expression was analyzed in renal biopsies from patients with NS. In addition, to compare the acute and chronic phases of the disease, we studied puromycin-treated rats. In the biopsy material, the expression of enzymes involved in the antioxidative defense was higher in the tubulointerstitial compartment than in the glomerular cells. Real-time PCR analysis revealed a decreased glomerular expression in nephrotic kidneys for the antioxidant enzymes catalase and glutathione peroxidase-3, and -4. The tubular gene expression was downregulated for catalase, glutathione peroxidase-3, and thioredoxin reductase-1 and -2. The altered gene expression was accompanied by increased lipid peroxidation in urine. In rats, serum concentrations of ascorbyl-free radicals, measured with electron spin resonance, were elevated in the acute phase of the disease, suggesting increased oxidative stress in the circulation. In addition, we saw an increase in the plasma antioxidant capacity combined with a decreased oxidation of proteins in sera from nephrotic rats, but not from humans. In conclusion, there is a marked downregulation of several antioxidative enzymes in nephrotic kidneys, especially in glomerular structures. Our data suggest that oxidative damage to glomerular cells may contribute significantly to the course and prognosis of nephrotic syndrome.
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| 7. |
- Braide, Magnus, 1955, et al.
(author)
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Citrate supplementation of PD fluid: effects on net ultrafiltration and clearance of small solutes in single dwells
- 2009
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In: Nephrol Dial Transplant. - 1460-2385. ; 24:1, s. 286-92
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Journal article (peer-reviewed)abstract
- BACKGROUND: Inflammatory reactions affect the general performance as well as the technique survival of peritoneal dialysis (PD). Anti-inflammatory additives like heparin and sodium citrate have shown favourable results in these respects. The present study is the first to evaluate citrate-supplemented PD fluids (PDFs) in humans. METHODS: Crossover design was used to evaluate sodium citrate and heparin-supplemented Gambrosol Trio (2.5% glucose) in 28 stable outpatients from the PD unit. Comparisons were made between single dwells of each fluid. Citrate supplementation at 5 mM/L was compared with standard PDF, and citrate supplementation at 10 mM/L was compared with low-molecular-weight heparin (4500 units of tinzaparin) supplementation and standard PDF. The initial osmolarity of the fluids was equalized by adding sodium chloride. RESULTS: Citrate supplementation at 5 mM/L significantly increased net ultrafiltration, measured as drained volume gain, by 126 mL. Creatinine and phosphate clearance, but not glucose clearance, was significantly improved by supplementation with citrate or heparin. Heparin supplementation created an insignificant trend towards an increased ultrafiltration (P = 0.08). No negative side effects were reported for any of the treatments; however, citrate supplementation led to a small calcium loss by the drained PD fluid (0.4 mmol) and a transient fall in the plasma concentration (0.04 mM/L) of free calcium ions at 5 mM/L citrate. Effects on plasma bicarbonate concentration were insignificant. CONCLUSIONS: Citrate supplementation of PD fluid improved ultrafiltration and clearance of small solutes with only minor effects on calcium turnover. The mechanism is unknown and, according to the results, not related to complement inhibition.
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| 8. |
- Bülow Anderberg, Sara
(author)
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Inflammatory aspects of acute kidney injury development during severe infections
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Acute kidney injury is common in intensive care. In this setting sepsis, by definition a dysregulated inflammatory response secondary to infection, is the most common cause. Sepsis associated acute kidney injury is in turn linked to worse outcome. The syndrome is considered to be the result of multiple mechanisms elicited by the inflammatory response and not merely hypoperfusion. COVID-19 has become an additional cause of acute kidney injury in critically ill patients. The present thesis focused on investigating contributing aspects of the inflammatory response in regard to acute kidney injury development in sepsis and COVID-19.The innate immune response recognizes invading pathogens through preserved molecular structures. When detected small and short-acting immunomodulatory molecules, cytokines, are produced shaping the reaction. Neutrophils are quickly mobilized. They engage in degranulation and expulsion of extracellular traps aiming at eradicating pathogens but may in doing so cause collateral tissue damage. Neutrophils are proposed contributors to renal dysfunction during sepsis and COVID-19.We investigated the effect of hydrocortisone, a glucocorticoid, on renal function and neutrophil infiltration in an ovine sepsis model with associated renal impairment. The observed reduction in glomerular filtration and tubular sodium transport efficiency during sepsis was ameliorated. Neutrophil infiltration which was observed post mortem in renal tissue was not reduced by hydrocortisone.The progression of organ dysfunction and by extension also acute kidney injury during severe COVID-19 was early on considered caused by a hyperinflammatory state. We analysed plasma cytokine concentrations in patients admitted to intensive care because of respiratory failure secondary to COVID-19. Only a moderate increase of theses mediators was found. The majority of the cytokines analysed were in turn associated with acute kidney injury development.Human neutrophil lipocalin is a neutrophil granular protein. It was used to first evaluate neutrophil reactivity by measuring its concentration after ex vivo stimulation and second systemic activity by estimating its concentration in plasma. In turn the association with renal dysfunction in severe COVID-19 was explored. Increased concentrations in both instances were linked to a greater risk of developing severe acute kidney injury.Lastly, the effect of dexamethasone, another glucocorticoid, on AKI development and neutrophil extracellular markers including histones and myeloperoxidase-DNA in critical COVID-19 was investigated. Dexamethasone was associated with lower AKI incidence and reduced extracellular trap formation.
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| 9. |
- Buvall, Lisa, 1976, et al.
(author)
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Orellanine specifically targets renal clear cell carcinoma
- 2017
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:53, s. 91085-91098
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Journal article (peer-reviewed)abstract
- Renal cell carcinoma (RCC), arising from the proximal tubule in the kidney, accounts for approximately 85% of kidney cancers and causes over 140,000 annual deaths worldwide. In the last decade, several new therapies have been identified for treatment of metastatic RCC. Although these therapies increase survival time compared to standard care, none of them has curative properties. The nephrotoxin orellanine specifically targets proximal tubular epithelial cells, leaving other organs unaffected. We therefore hypothesized that the selective toxicity of orellanine extends to clear cell RCC (ccRCC) cells since they emanate from proximal tubular cells. Orellanine would thus target both primary and metastatic ccRCC in vitro and in vivo. We found that orellanine induces dose-dependent cell death in proximal tubular cells and in all ccRCC cells tested, both primary and cell lines, with no toxicity detected in control cells. The toxic action of orellanine involve decreased protein synthesis, disrupted cell metabolism and induction of apoptosis. In nude rats carrying human ccRCC xenografts, brief orellanine treatment eliminated more than 90% of viable tumor mass compared to control rats. This identifies orellanine as a potential treatment concept for ccRCC patients on dialysis, due to its unique selective toxicity towards ccRCC.
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| 10. |
- Bäck, Tom, 1964, et al.
(author)
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Glomerular filtration rate after alpha-radioimmunotherapy with 211At-MX35-F(ab')2: a long-term study of renal function in nude mice.
- 2009
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In: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:6, s. 649-58
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Journal article (peer-reviewed)abstract
- Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, (211)At, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2 MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of (51)Cr-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor- and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following alpha-RIT with (211)At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10 Gy is acceptable, and that the kidneys would not be the primary dose-limiting organ in systemic alpha-RIT when using (211)At-MX35-F(ab')(2).
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