| 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
-
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
-
In: Nephrol Dial Transplant. - 1460-2385. ; 24:1, s. 286-92
-
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. |
- 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
-
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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| 9. |
- 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
-
In: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:6, s. 649-58
-
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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| 10. |
- Carlsson, Lena M S, 1957, et al.
(author)
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The incidence of albuminuria after bariatric surgery and usual care in swedish obese subjects (SOS): a prospective controlled intervention trial.
- 2015
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 39:1, s. 169-175
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Journal article (peer-reviewed)abstract
- Background:Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria.Subjects:The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI⩾34 in men and BMI⩾38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30mg per 24h) over up to 15 years.Results:During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P<0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine.Conclusions:Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.International Journal of Obesity advance online publication, 10 June 2014; doi:10.1038/ijo.2014.72.
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| 11. |
- Cederkrantz, Elin, et al.
(author)
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Evaluation of Effects on the Peritoneum After Intraperitoneal α-Radioimmunotherapy with (211)At.
- 2012
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In: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 27:6, s. 353-364
-
Journal article (peer-reviewed)abstract
- Abstract The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70μm) and the short half-life (7.21h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response.
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| 12. |
- Ciarimboli, Giuliano, et al.
(author)
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Dynamic alterations of glomerular charge density in fixed rat kidneys suggest involvement of endothelial cell coat
- 2003
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In: Am J Physiol Renal Physiol.. ; 285:4
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Journal article (peer-reviewed)abstract
- In a previous paper, we found that low ionic strength (I) reversibly reduced the glomerular charge density, suggesting increased volume of the charge-selective barrier. Because glutaraldehyde makes most structures rigid, we considered the isolated, perfusion-fixed rat kidney to be an ideal model for further analysis. The fixed kidneys were perfused with albumin solutions containing FITC-Ficoll at two different Is (I = 151 and 34 mM). At normal I, the fractional clearance () for albumin was 0.0049 (SE -0.0017, +0.0027, n = 6), whereas for neutral Ficoll35.5A of similar size was significantly higher 0.104 (SE 0.010, n = 5, P < 0.001). At low I, for albumin was 0.0030 (SE -0.0011, +0.0018, n = 6, not significant from albumin at normal I) and for Ficoll35.5A was identical to that at normal I, 0.104 (SE 0.015, n = 6, P < 0.01 compared with albumin at low I). According to a heterogeneous charged fiber model, low I reduced the fiber density from 0.056 to 0.0315, suggesting a 78% gel volume expansion. We conclude that 1) there is a significant glomerular charge barrier. 2) Solutions with low I increase the volume of the charge barrier even in kidneys fixed with glutaraldehyde. Our findings suggest that polysaccharide-rich structures, such as the endothelial cell coat, are key components in the glomerular barrier.
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| 13. |
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| 14. |
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| 15. |
- Daehn, I., et al.
(author)
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Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis
- 2014
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In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738. ; 124:4, s. 1608-1621
-
Journal article (peer-reviewed)abstract
- Focal segmental glomerular sclerosis (FSGS) is a primary kidney disease that is commonly associated with proteinuria and progressive loss of glomerular function, leading to development of chronic kidney disease (CKD). FSGS is characterized by podocyte injury and depletion and collapse of glomerular capillary segments. Progression of FSGS is associated with TGF-beta activation in podocytes; however, it is not clear how TGF-beta signaling promotes disease. Here, we determined that podocyte-specific activation of TGF-beta signaling in transgenic mice and BALB/c mice with Adriamycin-induced glomerulosclerosis is associated with endothelin-1 (EDN1) release by podocytes, which mediates mitochondrial oxidative stress and dysfunction in adjacent endothelial cells via paracrine EDN1 receptor type A (EDNRA) activation. Endothelial dysfunction promoted podocyte apoptosis, and inhibition of EDNRA or scavenging of mitochondrial-targeted ROS prevented podocyte loss, albuminuria, glomerulosclerosis, and renal failure. We confirmed reciprocal crosstalk between podocytes and endothelial cells in a coculture system. Biopsies from patients with FSGS exhibited increased mitochondrial DNA damage, consistent with EDNRA-mediated glomerular endothelial mitochondrial oxidative stress. Our studies indicate that segmental glomerulosclerosis develops as a result of podocyte-endothelial crosstalk mediated by EDN1/EDNRA-dependent mitochondrial dysfunction and suggest that targeting the reciprocal interaction between podocytes and endothelia may provide opportunities for therapeutic intervention in FSGS.
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| 16. |
- Davies, Simon, et al.
(author)
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Single-dwell treatment with a low-sodium solution in hypertensive peritoneal dialysis patients
- 2020
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In: Peritoneal Dialysis International. - : SAGE Publications. - 0896-8608 .- 1718-4304. ; 40:5, s. 446-454
-
Journal article (peer-reviewed)abstract
- © The Author(s) 2020. Background: Patients on peritoneal dialysis (PD) may suffer from sodium (Na) and fluid overload, hypertension and increased cardiovascular risk. Low-Na dialysis solution, by increasing the diffusive removal of Na, might improve blood pressure (BP) management. Methods: A glucose-compensated, low-Na PD solution (112 mmol/L Na and 2% glucose) was compared to a standard-Na solution (133 mmol/L Na and 1.5% glucose) in a prospective, randomised, single-blind study in hypertensive patients on PD. One daily exchange of the standard dialysis regimen was substituted by either of the study solutions for 6 months. The primary outcome (response) was defined as either a decrease of 24-h systolic BP (SBP) by ≥6 mmHg or a fall in BP requiring a medical intervention (e.g. a reduction of antihypertensive medication) at 8 weeks. Results: One hundred twenty-three patients were assessed for efficacy. Response criteria were achieved in 34.5% and 29.1% of patients using low- and standard-Na solutions, respectively (p = 0.51). Small reductions in 24 h, office, and self-measured BP were observed, more marked with low-Na than with standard-Na solution, but only the between-group difference for self-measured SBP and diastolic BP was significant (p = 0.002 and p = 0.003). Total body water decreased in the low-Na group and increased in the control group, but between-group differences were not significant. Hypotension and dizziness occurred in 27.0% and in 11.1% of patients in the low-Na group and in 16.9% and 4.6% in the control group, respectively. Conclusions: Superiority of low-Na PD solution over standard-Na solution for control of BP could not be shown. The once daily use of a low-Na PD solution was associated with more hypotensive episodes, suggesting the need to reassess the overall concept of how Na-reduced solutions might be incorporated within the treatment schedule.
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| 17. |
- Domínguez-Gil, B., et al.
(author)
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The Reality of Inadequate Patient Care and the Need for a Global Action Framework in Organ Donation and Transplantation
- 2022
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In: Transplantation. ; 106:11, s. 2111-2117
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Journal article (peer-reviewed)abstract
- BACKGROUND: Transplant therapy is considered the best and often the only available treatment for thousands of patients with organ failure that results from communicable and noncommunicable diseases. The number of annual organ transplants is insufficient for the worldwide need. METHODS: We elaborate the proceedings of the workshop entitled "The Role of Science in the Development of International Standards of Organ Donation and Transplantation," organized by the Pontifical Academy of Sciences and cosponsored by the World Health Organization in June 2021. RESULTS: We detail the urgency and importance of achieving national self-sufficiency in organ transplantation as a public health priority and an important contributor to reaching relevant targets of the United Nations Agenda for Sustainable Development. It details the elements of a global action framework intended for countries at every level of economic development to facilitate either the establishment or enhancement of transplant activity. It sets forth a proposed plan, by addressing the technical considerations for developing and optimizing organ transplantation from both deceased and living organ donors and the regulatory oversight of practices. CONCLUSIONS: This document can be used in governmental and policy circles as a call to action and as a checklist for actions needed to enable organ transplantation as treatment for organ failure. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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| 18. |
- Dunér, Fredrik, et al.
(author)
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Permeability, ultrastructural changes, and distribution of novel proteins in the glomerular barrier in early puromycin aminonucleoside nephrosis.
- 2010
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In: Nephron. Experimental nephrology. - : S. Karger AG. - 1660-2129. ; 116:2
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Journal article (peer-reviewed)abstract
- BACKGROUND/AIMS: It is still unclear what happens in the glomerulus when proteinuria starts. Using puromycin aminonucleoside nephrosis (PAN) rats, we studied early ultrastructural and permeability changes in relation to the expression of the podocyte-associated molecules nephrin, α-actinin, dendrin, and plekhh2, the last two of which were only recently discovered in podocytes. METHODS: Using immune stainings, semiquantitative measurement was performed under the electron microscope. Permeability was assessed using isolated kidney perfusion with tracers. Possible effects of ACE inhibition were tested. RESULTS: By day 2, some patchy foot process effacement, but no proteinuria, appeared. The amount of nephrin was reduced in both diseased and normal areas. The other proteins showed few changes, which were limited to diseased areas. By day 4, foot process effacement was complete and proteinuria appeared in parallel with signs of size barrier damage. Nephrin decreased further, while dendrin and plekhh2 also decreased but α-actinin remained unchanged. ACE inhibition had no significant protective effect. CONCLUSIONS: PAN glomeruli already showed significant pathology by day 4, despite relatively mild proteinuria. This was preceded by altered nephrin expression, supporting its pivotal role in podocyte morphology. The novel proteins dendrin and plekhh2 were both reduced, suggesting roles in PAN, whereas α-actinin was unchanged.
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| 19. |
- Ebefors, Kerstin, 1977, et al.
(author)
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Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells
- 2019
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In: Kidney International. - : Elsevier BV. - 0085-2538. ; 96:4, s. 957-970
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Journal article (peer-reviewed)abstract
- Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-beta receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondria! reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis.
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| 20. |
- Ebefors, Kerstin, 1977, et al.
(author)
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Mesangial cells from patients with IgA nephropathy have increased susceptibility to galactose-deficient IgA1
- 2016
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In: Bmc Nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 17
-
Journal article (peer-reviewed)abstract
- Background: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people. Circulating galactose-deficient IgA (gd-IgA), present in patients with IgAN, form immune complex deposits in the glomerular mesangium causing local proliferation and matrix expansion. Intriguing though, individuals having gd-IgA deposits in the kidneys do not necessarily have signs of glomerular disease. Recurrence of IgAN only occurs in less than half of transplanted patients with IgAN, indicating that gd-IgA is not the only factor driving the disease. We hypothesize that, in addition to IgA complexes, patients with IgAN possess a subtype of mesangial cells highly susceptible to gd-IgA induced cell proliferation. Methods: To test the hypothesis, we designed a technique to culture primary mesangial cells from renal biopsies obtained from IgAN patients and controls. The cell response to gd-IgA treatment was then measured both on gene and protein level and the proliferation rate of the cells in response to PDGF was investigated. Results: When treated with gd-IgA, mesangial cells from patients with IgAN express and release more PDGF compared to controls. In addition, the mesangial cells from patients with IgAN were more responsive to treatment with PDGF resulting in an increased proliferation rate of the cells compared to control. Mesangial cells cultured from patients with IgAN expressed and released more IL-6 than controls and had a higher expression of matrix genes. Both mesangial cells derived from patients with IgAN and controls increased their expressed TGF beta 1 and CCL5 when treated with gd-IgA. Conclusion: We conclude that mesangial cells derived from IgAN patients have a mesangioproliferative phenotype with increased reactivity to IgA and that these cellular intrinsic properties may be important for the development of IgA nephropathy.
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| 21. |
- Ebefors, Kerstin, 1977, et al.
(author)
-
Role of glomerular proteoglycans in IgA nephropathy
- 2011
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
-
Journal article (peer-reviewed)abstract
- Mesangial matrix expansion is a prominent feature of the most common form of glomerulonephritis, IgA nephropathy (IgAN). To find molecular markers and improve the understanding of the disease, the gene and protein expression of proteoglycans were investigated in biopsies from IgAN patients and correlated to clinical and morphological data. We collected and microdissected renal biopsies from IgAN patients (n = 19) and from healthy kidney donors (n = 14). Patients were followed for an average time of 4 years and blood pressure was according to target guidelines. Distinct patterns of gene expression were seen in glomerular and tubulo-interstitial cells. Three of the proteoglycans investigated were found to be of special interest and upregulated in glomeruli: perlecan, decorin and biglycan. Perlecan gene expression negatively correlated to albumin excretion and progress of the disease. Abundant decorin protein expression was found in sclerotic glomeruli, but not in unaffected glomeruli from IgAN patients or in controls. Transforming growth factor beta (TGF-beta), known to interact with perlecan, decorin and biglycan, were upregulated both on gene and protein level in the glomeruli. This study provides further insight into the molecular mechanisms involved in mesangial matrix expansion in IgAN. We conclude that perlecan is a possible prognostic marker for patients with IgAN. In addition, the up-regulation of biglycan and decorin, as well as TGF-beta itself, indicate that regulation of TGF-beta, and other profibrotic markers plays a role in IgAN pathology.
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| 22. |
- Elvin, Johannes, et al.
(author)
-
Melanocortin 1 Receptor Agonist Protects Podocytes Through Catalase and RhoA Activation.
- 2016
-
In: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 310:9
-
Journal article (peer-reviewed)abstract
- Drugs containing adrenocorticotropic hormone (ACTH) have been used as therapy for patients with nephrotic syndrome. We have previously shown that ACTH and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for the MC1R. The podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside and downstream effects of MC1R activation on podocyte survival; antioxidant defense and cytoskeleton dynamics were studied. To increase the response and enhance the intracellular signals, podocytes were transduced to overexpress MC1R. We show that puromycin promotes MC1R expression in podocytes and that activation of the MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protects against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies.
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| 23. |
- Eyre, Sintra, 1968, et al.
(author)
-
Positive Effects of Protein Restriction in Patients With Chronic Kidney Disease
- 2008
-
In: Journal of Renal Nutrition. - : Elsevier BV. - 1051-2276. ; 18:3, s. 269-280
-
Journal article (peer-reviewed)abstract
- Objectives: The potential benefit or harm of low-protein diets (LPDs) for patients with chronic kidney disease has been debated. This study sought to investigate the effects of treatment with LPDs on nutritional markers, morbidity, and survival during subsequent dialysis. A second objective was to evaluate the effect of LPDs on renal function and the start of dialysis. Design: This was a retrospective study of medical records. Setting: The setting was an outpatient nephrology and dialysis clinic. Patients: One-hundred twenty-two renal patients were recruited from the central dialysis registry of one clinic. The patients had been followed by a nephrologist for $6 months before dialysis. Sixty-one patients were treated with LPDs, and an equal number of control patients not treated with LPDs were matched for sex, age, dialysis modality, diabetes, and start of dialysis. Main Outcome Measures: Main outcome measures included weight and weight change, serum albumin, glomerular filtration rate, morbidity, and mortality. Results: There was less mean weight loss in the LPD group the year before dialysis (0.14 kg/month, compared with the control group at 0.36 kg/month, P , .05). The level of serum albumin was higher in the LPD group at the start of dialysis (P , .01). The mean rate of progression during the 6 months before dialysis was lower in the LPD group (4.1 mL/min/year) than in the control group (13.4 mL/min/year) (P , .001). The LPD group had fewer days of hospitalization at the start of dialysis than the control group (8.2 vs 15.4 days, respectively, P , .01). There was no difference in mortality between groups 1, 2, or 5 years after starting dialysis. Conclusions: Low-protein diets can reduce patient morbidity, preserve renal function, relieve uremic symptoms and improve nutritional status. The results suggest that LPDs can postpone the start of dialysis for 6 months, and entail substantial cost-savings. Low-protein diets should be used more generally in the renal community.
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| 24. |
- Fagerstrom, Peter, et al.
(author)
-
Urinary albumin excretion in healthy adults: a cross sectional study of 24-hour versus timed overnight samples and impact of GFR and other personal characteristics.
- 2015
-
In: BMC nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 16:1
-
Journal article (peer-reviewed)abstract
- Urinary albumin can be measured in 24 h or spot samples. The 24 h urinary albumin excretion rate is considered the gold standard, but is cumbersome to collect. Instead, often an overnight sample is collected, and adjusted for dilution. Proxies for 24 h excretion rate have been studied in diabetics, but seldom in healthy individuals. Our aims were to compare 24 h and overnight albumin excretion, to assess the impact of personal characteristics, and to examine correlations between the 24 h excretion rate and proxies such as the albumin to creatinine ratio (ACR).
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| 25. |
- Fischbach, M., et al.
(author)
-
Effect of peritoneal dialysis fluid composition on peritoneal area available for exchange in children
- 2004
-
In: Nephrol Dial Transplant. - : Oxford University Press (OUP). - 0931-0509. ; 19:4, s. 925-32
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Although conventional peritoneal dialysis fluids (PDFs), such as Dianeal, are non-physiological in composition, new PDFs including Physioneal have a more neutral pH, are at least partially buffered with bicarbonate and, most importantly, contain low concentrations of glucose degradation products (GDPs). METHODS: To evaluate the impact of new PDFs in childcare, we performed a comparative crossover study with Dianeal and Physioneal. We examined both intraperitoneal pressure (IPP), which partly reflects pain induction, and the total pore area available for exchange, which indicates the number of capillaries perfused in the peritoneal membrane at any given moment and therefore partly reflects peritoneal dialysis capacity. The IPP was determined after inflow of 1000 ml/m(2) body surface area (BSA) of dialysate (intraperitoneal volume; IPV). The steady-state unrestricted area over diffusion distance (A(0)/ triangle up x, in cm(2)/cm per 1.73 m(2) BSA) was calculated from the three-pore theory. Six children were enrolled in the study. On the first day, two consecutive peritoneal equilibration tests of 90 min each were performed using first Dianeal and then Physioneal. On the second study day, the procedure was repeated with the fluids given in the opposite order. RESULTS: The mean IPP normalized to IPV (ml/m(2)) was significantly higher for Dianeal (9.5 +/- 0.9 cm/1000 ml/m(2)) than for Physioneal (7.9 +/- 1.2 cm/1000 ml/m(2), P < 0.01). The mean A(0)/ triangle up x was 17 +/- 4% larger with Dianeal (36 095 +/- 2009 cm(2)/cm per 1.73 m(2)) than with Physioneal (31 780 +/- 2185 cm(2)/cm per 1.73 m(2), P < 0.001; based on 24 data pairs). CONCLUSIONS: These pilot study results suggest a higher biocompatibility for Physioneal than for Dianeal. Less inflow pain associated with Physioneal induced a lower IPP reflecting enhanced fill volume tolerance, and the lower A(0)/ triangle up x reflected less capillary recruitment. Taken together, these results suggest that the new more biocompatible PDFs will improve peritoneal dialysis therapy, although this conclusion will require verification in extended clinical trials.
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| 26. |
- Fischbach, M., et al.
(author)
-
Measurement by magnetic resonance imaging of the peritoneal membrane in contact with dialysate in rats
- 2005
-
In: Adv Perit Dial. - 1197-8554. ; 21, s. 17-20
-
Journal article (peer-reviewed)abstract
- To be optimal, a peritoneal dialysis prescription should consider the peritoneal surface area recruitment. In fact, as shown by computed tomography imaging, only a fraction of the available anatomic peritoneum is in contact with the dialysate (PDF). Various factors may dynamically affect the recruitment of the wetted membrane: posture, fill volume, PDF composition (biocompatibility), and pharmacologic agents (phospholipids). To precisely determine the peritoneal membrane recruitment capacity, we developed an animal model. In 5/6 bi-nephrectomized rats on peritoneal dialysis, between week 6 and week 8 post surgery, we used MRI to assess the contact area, with the dialysate acting as the contrast medium (fill volume: 10 mL per 100-g rat body weight). The MRI protocol consisted of axially oriented, turbo spin-echo, 3-mm slice, T2 weighted sequences. The contact area was measured using an adapted three-dimensional MRI reconstruction software based on DICOM (digital imaging and communications in medicine) images. The MRI studies (n=10) were successful. They showed that only a fraction of the presumed anatomic area (30% - 40%) was in contact with the PDF Peritoneal MRI in rats is a method that shows potential for assessing peritoneal contact area and its variation under experimental conditions.
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| 27. |
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| 28. |
- Fischbach, M., et al.
(author)
-
The influence of peritoneal surface area on dialysis adequacy
- 2005
-
In: Perit Dial Int. - 0896-8608. ; 25 Suppl 3
-
Journal article (peer-reviewed)abstract
- In children, the prescription of peritoneal dialysis is based mainly on the choice of the peritoneal dialysis fluid, the intraperitoneal fill volume (mL/m2 body surface area (BSA)], and the contact time. The working mode of the peritoneal membrane as a dialysis membrane is more related to a dynamic complex structure than to a static hemodialyzer. Thus, the peritoneal surface area impacts on dialysis adequacy. In fact, the peritoneal surface area may be viewed as composed of three exchange entities: the anatomic area, the contact area, and the vascular area. First, in infants, the anatomic area appears to be two-fold larger than in adults when expressed per kilogram body weight. On the other hand, the anatomic area becomes independent of age when expressed per square meter BSA. Therefore, scaling of the intraperitoneal fill volume by BSA (m2) is necessary to prevent a too low ratio of fill volume to exchange area, which would result in a functional "hyperpermeable" peritoneal exchange. Second, the contact area, also called the wetted membrane, is only a portion of the anatomic area, representing 30% to 60% of this area in humans, as measured by computed tomography. Both posture and fill volume may affect the extent of recruitment of contact area. Finally, the vascular area is influenced by the availability of both the anatomic area and the recruited contact area. This surface is governed essentially by both peritonealvascular perfusion, represented by the mesenteric vascular flow and, hence, by the number of perfused capillaries available for exchange. This vascular area is dynamically affected by different factors, such as composition of the peritoneal fluid, the fill volume, and the production of inflammatory agents. Peritoneal dialysis fluids that will be developed in the future for children should allow an optimization of the fill volume owing to a better tolerance in terms of lower achieved intraperitoneal pressure for a given fill volume. Moreover, future peritoneal dialysis fluids should protect the peritoneal membrane from hyperperfusion (lower glucose degradation products).
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| 29. |
- Fischbach, M., et al.
(author)
-
The peritoneal membrane: a dynamic dialysis membrane in children
- 2003
-
In: Adv Perit Dial. ; 19, s. 265-8
-
Journal article (peer-reviewed)abstract
- Peritoneal dialysis prescription in children should be individualized--based not only on numerical targets (Kt/Vurea, Kcreat), but also on consideration of the peritoneal membrane, a dynamic dialysis membrane. In fact, the effective peritoneal surface area is at least a triple entity: an anatomic area, a contact area, and an exchange area. The anatomic area appears to be twice as large in infants as in adults if expressed per kilogram of body weight (BW), although the area is independent of age if expressed per square meter of body surface area (BSA). Therefore, scaling of the intraperitoneal fill volume (IPV) by BSA in square meters is necessary to avoid a low IPV/area ratio, which results in a functionally "hyperpermeable" peritoneal exchange. The contact area (the wetted membrane) is only a fraction of the anatomic area--that is, 30%-60% in humans (by computed tomography). Contact area depends on a variety of factors, such as posture and fill volume, that affect the degree of recruitment of membrane contact area. The exchange area is influenced by both the anatomic are and the contact area. However, it is mainly governed by the specific vascular area as determined by the peritoneal vascular perfusion and the capillaries available for exchange. Vascular area is dynamically affected by a variety of factors, such as the composition of the peritoneal dialysis fluid, the fill volume, and possible inflammatory agents.
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| 30. |
- Friberg, Ingrid Osika, et al.
(author)
-
Patients' perceptions and factors affecting dialysis modality decisions
- 2018
-
In: Peritoneal Dialysis International. - : SAGE Publications. - 0896-8608. ; 38:5, s. 334-342
-
Journal article (peer-reviewed)abstract
- Background: Home-based dialysis, including peritoneal dialysis (PD) and home hemodialysis (HHD), has been shown to be associated with tower costs and higher health-related quality of life than in-center HD. However, factors influencing the choice of dialysis modality, including gender, are still not well understood. Methods: A questionnaire was sent out to all dialysis patients in the western region of Sweden in order to investigate factors affecting choice of dialysis modality. Logistic regression was used to analyze the data. Results: Patients were more likelyto have home dialysis if they received predialysis information from 3 or more sources and, to a greater extent, perceived the information as comprehensive and of high quality. In addition, patients had a lower likelihood of receiving home dialysis with increasing age and if they lived closer to a dialysis center. Men had in comparison with women a greater likelihood of receiving home dialysis if they lived with a spouse. In-center dialysis patients more often believed that the social interaction and support provided through in-center HD treatment influenced the choice of dialysis modality. Conclusion: This study highlights the need for increased awareness of various factors that influence the choice of dialysis modality and the importance of giving repeated, comprehensive, high-quality information to dialysis and predialysis patients and their relatives. Information and support must be adapted to the needs of individual patients and their relatives if the intention is to improve patients' well-being and the proportion of patients using home dialysis.
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| 31. |
- Fridén, Vincent, 1975, et al.
(author)
-
The glomerular endothelial cell coat is essential for glomerular filtration
- 2011
-
In: Kidney international. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 79:12, s. 1322-1330
-
Journal article (peer-reviewed)abstract
- The endothelial cell surface layer (ESL) is believed to contribute to the glomerular barrier, and the nature of its molecular structure is still largely unknown. The ESL consists of the membrane-bound glycocalyx and the loosely attached endothelial cell coat (ECC). A brief injection of hypertonic sodium chloride into the left renal artery was used to displace, elute, and collect non-covalently bound components of the renal ESL in rats. This procedure increased the fractional clearance of albumin 12-fold without detectable morphological changes as assessed by electron microscopy compared with the control group injected with isotonic saline. Mathematical modeling suggested a reduced glomerular charge density. Mass spectrometry of the renal eluate identified 17 non-covalently bound proteins normally present in the ECC. One of these proteins, orosomucoid, has previously been shown to be important for capillary permselectivity. Another protein, lumican, is expressed by glomerular endothelial cells and likely contributes to maintaining an intact barrier. Thus, the absence of one or more of these proteins causes proteinuria and illustrates the importance of the ECC in glomerular permselectivity.Kidney International advance online publication, 16 March 2011; doi:10.1038/ki.2011.58.
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| 32. |
- Giglio, Daniel, 1977, et al.
(author)
-
Changes in muscarinic receptors in the toad urothelial cell line TBM-54 following acrolein treatment
- 2008
-
In: Clinical and Experimental Pharmacology and Physiology. - : Wiley. - 0305-1870 .- 1440-1681. ; 35:2, s. 217-222
-
Journal article (peer-reviewed)abstract
- 1. In cyclophosphamide-induced cystitis in the rat, cholinergic function of the bladder and muscarinic receptor expression are altered. In the present study, we investigated whether the toad urothelial cell line TBM-54 expresses functional muscarinic receptors and whether changes in muscarinic receptors can be induced in vitro by treating cells with acrolein, a metabolite of cyclophosphamide causing cystitis. 2. The occurrence of muscarinic receptors on cells was assessed by microphysiometry, a method analysing receptor function by measuring changes in the extracellular acidity rate (ECAR) in response to receptor stimulation. 3. Challenging untreated cells with the muscarinic receptor agonist carbachol gave rise to a concentration-dependent increase in changes in ECAR, with a maximal response at 1 mmol/L carbachol of 51 +/- 6%. Pre-incubating cells with different muscarinic receptor antagonists (i.e. pirenzepine (M(1) receptor selective), methoctramine (M(2)/M(4) receptor selective) and 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP; M(3)/M(1)/M(5) receptor selective)), gave rise to a concentration-dependent decrease in the effects of carbachol (0.5 mmol/L) on changes in ECAR. 4. Western blot analysis was used to determine the expression of all muscarinic receptor subtypes (M(1)-M(5)) by the cell line. Following acrolein treatment, cells were markedly less sensitive to carbachol and the expression of muscarinic M(2) receptors was decreased, whereas the expression of muscarinic M(3) receptors was increased. 5. In conclusion, the urothelial cell line TBM-54 expresses functional muscarinic receptors and exposure to acrolein leads to a modulation in the expression of muscarinic receptors. Consequently, acrolein may have direct effects on muscarinic receptor function and expression that contribute to the pathogenesis of cyclophosphamide-induced cystitis.
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| 33. |
- Granqvist, Anna, et al.
(author)
-
Podocyte proteoglycan synthesis is involved in the development of nephrotic syndrome
- 2006
-
In: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 291
-
Journal article (peer-reviewed)abstract
- Proteoglycans (PG) are important for the glomerular barrier, for cell signaling and for the anchorage of cells to the glomerular basement membrane. They are, however, complex macromolecules, and their production has not yet been thoroughly investigated for podocytes. In the present study, we have studied the biosynthesis of proteoglycans by highly differentiated human podocytes and in rats. The cells were treated with puromycin aminonucleoside (PAN, a nephrosis inducing agent), steroids (used as primary treatment for nephrotic syndrome) or both. Analysis was made by Taqman(R)real-time PCR, Western blot and by metabolic labeling with (35)S and (3)H. We found that podocytes produce versican, syndecan-1, decorin and biglycan together with the previously known PGs syndecan-4, glypican and perlecan. PAN treatment down-regulated the mRNA and the protein expression of both versican (by 24+/-6%, p<0.01, for mRNA and by 50% for protein) and perlecan (by 14+/-5%, p<0.05, for mRNA and by 50% for protein). The decreased expression was confirmed by studying the glomerular gene expression in rats treated with PAN during a time course study. In addition, puromycin decreased the expression of enzymes involved in the glycosaminoglycan (GAG) biosynthesis. Steroid treatment decreased perlecan (by 24+/-3%, p<0.01) and syndecan-1 expression (by 30+/-4%, p<0.01), but increased the expression of decorin 2.5-fold. The observed alterations of proteoglycan synthesis induced by PAN may lead to decreased glomerular anionic charge and disturbed podocyte morphology, factors that are important for the development of a nephrotic syndrome.
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| 34. |
- Granqvist, Anna, et al.
(author)
-
Primary human glomerular endothelial cells produce proteoglycans, and puromycin affects their posttranslational modification
- 2005
-
In: Am J Physiol Renal Physiol. - : American Physiological Society. - 0363-6127 .- 1931-857X .- 1522-1466. ; 288:4
-
Journal article (peer-reviewed)abstract
- This article describes the possible role of the endothelial cell-surface coat, containing proteoglycans (PGs) with connected glycosaminoglycans (GAGs), in maintaining glomerular permselectivity. Primary human glomerular endothelial cells (HGEC) in culture were treated with the nephrosis-inducing agent puromycin aminonucleoside (PAN). Analysis was made by TaqMan real-time PCR, Western blot analysis, and by metabolic labeling with [(35)S]sulfate. The HGECs express several PGs: syndecan, versican, glypican, perlecan, decorin, and biglycan, which may contribute to the glomerular charge barrier. PAN treatment downregulated both the protein expression (by 25%) and the mRNA expression (by 37 +/- 6%, P < 0.001, n = 8) of versican compared with control. Transferases important for chondroitin and heparan sulfate biosynthesis were also significantly downregulated by PAN, resulting in less sulfate groups, shorter GAG chains, and reduced PG net-negative charge. Moreover, analysis of the cell media after PAN treatment revealed a reduced content of [(35)S]sulfate-labeled PGs (40% of control). We conclude that PAN may cause proteinuria by affecting the endothelial cell-surface layer and not only by disrupting the foot process arrangement of the podocytes. Thus the endothelium may be a more important component of the glomerular barrier than hitherto acknowledged.
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| 35. |
- Hanse, Eric, 1962, et al.
(author)
-
[The medical education in Gothenburg is being reformed. Professional development, research and internationalization]
- 2011
-
In: Läkartidningen. - 0023-7205. ; 108:12, s. 669-73
-
Journal article (peer-reviewed)abstract
- The medical education at the Sahlgrenska Academy, University of Gothenburg, is being reformed by an emphasis on professional development, international contacts and research. Students’ professional development consists of five core areas: Communication and self-reflection, Leadership and teamwork, Ethical attitude, Human rights and gender issues, and a Scientific and critical attitude. A learning progression of students’ professional competence is organised by five process leaders, coordinating core learning objectives and examinations within the existing curriculum. By promoting international exchange, more than half of the students in undergraduate medical education have had international contacts. The Sahlgrenska Academy aims to promote medical students’ interest for research and to increase the percentage among medical doctors that have a PhD degree. A program for combining medical education with research and teaching is being launched along with a MD/PhD program for medical basic science and a special PhD/MD program.
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| 36. |
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| 37. |
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| 38. |
- Haraldsson, Börje, 1957, et al.
(author)
-
Glomerular filtration barrier
- 2009
-
In: Curr Opin Nephrol Hyper. ; 18, s. 331-335
-
Research review (peer-reviewed)
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| 39. |
- Haraldsson, Börje, et al.
(author)
-
Glomerular filtration barrier
- 2009
-
In: Current opinion in nephrology and hypertension. - 1062-4821 .- 1473-6543. ; 18:4, s. 331-335
-
Journal article (peer-reviewed)abstract
- PURPOSE OF REVIEW: In 2008, more than 376 papers were published on the glomerular barrier. Most of them dealt with the podocyte and its role in kidney disease.RECENT FINDINGS: There is new information on signaling pathways that are utilized in podocytes during proteinuria. Interestingly, the glomerular endothelium, with its fenestrae and glycocalyx, seems to be important for the maintenance of an intact glomerular barrier. All new advances at the molecular level are compatible with a highly size and charge-selective glomerular membrane and refute the concept of a 'leaky' glomerular barrier with tubular retrieval of intact albumin. Still, the hypothesis has its advocates, keeping a stimulating 'charge debate' alive.SUMMARY: Glomerular diseases account for 90% of chronic kidney disease requiring dialysis and transplantation at an annual cost of $20 billion in the USA. In clinical practice, we lack specific treatment of these diseases, giving us plenty of room for improvement. Future research should be directed toward deeper understanding of the signaling pathways involved in different conditions of proteinuria, the cross-talk between cell types in the glomerulus, and the identification of novel targets for treatment of acquired kidney disease.
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| 40. |
- Haraldsson, Börje, 1957
(author)
-
Microalbuminuria and Insulin Resistance
- 2009
-
In: Microcirculation and Insulin Resistance. - Lyon, France : Bentham Science Publishers Ltd.. - 9781608050574 ; , s. 85-90
-
Book chapter (other academic/artistic)abstract
- The glomerular barrier is highly selective and only minute amounts reaches the urine. Normally, the daily loss of albumin in urine is less than 30 mg and microalbuminuria denotes losses between 30-300 mg per day. Overt proteinuria means daily losses between 300- 3000 mg, whereas larger albumin losses are in the nephritic range. There are a wide variety of conditions that cause microalbuminuria or proteinuria, but recently our understanding of these phenomena has improved considerably. Microalbuminuria is one of the first signs of diabetic nephropathy where it reflects endothelial dysfunction and increased risk of microvascular complications. Microalbuminuria is also an independent predictor of cardiovascular disease in non-diabetic individuals. Insulin resistance is an interesting condition that precedes the development of type II diabetes. Patients with severe kidney disease have insulin resistance without developing diabetes. Insulin resistance is also associated to microalbuminuria, hypertension and obesity. Finally, there is an association between all these conditions and certain inflammatory vascular reactions. In this chapter, I will try to review our current understanding of microalbuminuria and how it is related to insulin resistance.
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| 41. |
- Haraldsson, Börje, 1957, et al.
(author)
-
Properties of the Glomerular Barrier and Mechanisms of Proteinuria
- 2008
-
In: Physiological Reviews. - : American Physiological Society. - 0031-9333 .- 1522-1210. ; 88:2, s. 451-487
-
Journal article (peer-reviewed)abstract
- This review focuses on the intricate properties of the glomerular barrier. Other reviews have focused on podocyte biology, mesangial cells, and the glomerular basement membrane (GBM). However, since all components of the glomerular membrane are important for its function, proteinuria will occur regardless of which layer is affected by disease. We review the properties of endothelial cells and their surface layer, the GBM, and podocytes, discuss various methods of studying glomerular permeability, and analyze data concerning the restriction of solutes by size, charge, and shape. We also review the physical principles of transport across biological or artificial membranes and various theoretical models used to predict the fluxes of solutes and water. The glomerular barrier is highly size and charge selective, in qualitative agreement with the classical studies performed 30 years ago. The small amounts of albumin filtered will be reabsorbed by the megalin-cubulin complex and degraded by the proximal tubular cells. At present, there is no unequivocal evidence for reuptake of intact albumin from urine. The cellular components are the key players in restricting solute transport, while the GBM is responsible for most of the resistance to water flow across the glomerular barrier.
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| 42. |
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| 43. |
- Haraldsson, Börje, 1957
(author)
-
The endothelium as part of the integrative glomerular barrier complex
- 2014
-
In: Kidney International. - : Elsevier BV. - 0085-2538. ; 85, s. 8-11
-
Journal article (peer-reviewed)abstract
- A new study by Xu et al. presents compelling evidence for an important role of the glomerular endothelium in acute kidney injury. They show that lipopolysaccharide reduces the endothelial surface layer, resulting in mild albuminuria, reduced glomerular filtration rate, and fewer endothelial fenestrae. Tumor necrosis factor-α (TNF-α) is identified as instrumental in these lipopolysaccharide effects through the TNF-α type 1 receptor. The study highlights that the glomerular endothelium has a key role in the maintenance of the glomerular filtration barrier.
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| 44. |
- Haraldsson, Börje, 1957, et al.
(author)
-
The glomerular endothelium: new insights on function and structure.
- 2012
-
In: Current opinion in nephrology and hypertension. - 1535-3842. ; 21:3, s. 258-63
-
Journal article (peer-reviewed)abstract
- It is our aim to review the latest findings on the intricate functional and structural properties of the glomerular endothelium. Previously, all focus has been on the podocyte and the glomerular basement membrane (GBM), but it is now clear that the endothelium plays an important part of the glomerular barrier.
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| 45. |
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| 46. |
- Haraldsson, Börje, 1957, et al.
(author)
-
Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier
- 2004
-
In: News Physiol Sci. - 1548-9213. ; 19, s. 7-10
-
Research review (peer-reviewed)abstract
- The key question is not why some patients have proteinuria but rather why not all people have it. In the present review, we will present an update on the glomerular barrier after the recent breakthroughs in podocyte biology. In particular, we will discuss the role of the endothelium, which seems to be a neglected part of the glomerular membrane.
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| 47. |
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| 48. |
- Hedman, Heidi, 1982, et al.
(author)
-
Long-term clinical outcome for patients poisoned by the fungal nephrotoxin orellanine
- 2017
-
In: BMC Nephrology. - : Springer Science and Business Media LLC. - 1471-2369. ; 18
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Journal article (peer-reviewed)abstract
- Background: Accidental intake of mushrooms of the Cortinarius species (deadly webcap) may cause irreversible renal damage and the need for dialysis or transplantation. The species is found in forests of Northern Europe, Scandinavia and North America and may be mistaken for other edible mushrooms. The highly selective nephrotoxic compound of the mushroom is called orellanine. Very little is known about the long-term effects of the nephrotoxin. Methods: We identified patients who ingested deadly webcap in the period of 1979 to 2012. Informed consent and medical records were obtained for 28 of the 39 cases that occurred during the 34-year period. A case control group was also studied based on sex, age and initiation of dialysis or transplantation. Results: The average age at time of the accidental intake was 40 +/- 3 (n = 28) years. 64% of patients were male, and 22 of 28 patients developed acute kidney injury requiring dialysis. Serum creatinine peaked at 1 329 +/- 133 mu mol/l, and serum urea was 31 +/- 3.5 mmol/l. No signs of acute damage were present in any other organ. The average time of follow-up was 16.9 +/- 2.1 years (1.24-34.3 years, n = 28). 15 patients were transplanted and 3 also had a second graft. At follow-up, 23 patients were alive, and five had died at ages of 67 +/- 5 (range 54-84). The outcome was similar in the case control group with 6 deaths in 20 patients. Conclusion: We conclude that the long-term prognosis for patients poisoned by deadly webcap who lost their renal function is not different compared to other patients in active uremic care.
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- Herrmann, A., et al.
(author)
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Analysis of the Mushroom Nephrotoxin Orellanine and Its Glucosides
- 2012
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In: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 75:10, s. 1690-1696
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Journal article (peer-reviewed)abstract
- Orellanine is a nephrotoxin found in various Cortinaceae mushroom species. Unintentional consumption after these species were confused with edible mushrooms such as Cantharellus tubaeformis has caused several casualties. In this work, a quantitative HPLC-ESI-MS/MS method for total orellanine in Cortinarius rubellus, spiked blood plasma, and a mushroom stew prepared from C. tubaeformis with the addition of a single specimen of C. rubellus is presented. The existence of mono- and diglucosylated orellanine in C. rubellus was also proven, although quantitative analysis could not be obtained for the glucosides due to rapid hydrolyzation to orellanine in the extract. Extraction with 3 M HCl or water mainly yielded orellanine, while MeOH or acidified MeOH mainly extracted mono- and diglucosylated orellanine. The highest recovery of total orellanine was obtained with 3 M HCl, which was subsequently used for quantitative analysis. A C-18 HPLC column and low pH in the eluents retained all these toxins. Orellanine could be detected at a 4.9 ng/mL level in all extracts, which is well below the threshold for acute toxic effects. Additionally, the fragmentation pattern of orellanine upon electrospray MS/MS was probed. The method described is useful for two important applications. First, it allows quantitative analysis of processed food products that may be contaminated by orellanine from Cortinaceae mushrooms. Second, orellanine is currently being evaluated as a potential cure of metastatic renal cancer, and this work provides a method for monitoring orellanine at low concentrations within the therapeutic interval in blood serum.
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