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Background The non-ionic agent iohexol is increasingly used as the marker of choice for glomerular filtration rate (GFR) measurement. Estimates of GFR in children have low accuracy and limiting the number of blood-draws in this patient population is especially relevant. We have performed a study to evaluate different formulas for calculating measured GFR based on plasma iohexol clearance with blood sampling at only one time point (GFR1p) and to determine the optimal sampling time point. Methods Ninety-six children with chronic kidney disease (CKD) stage 1-5 (median age 9.2 years; range 3 months to 17.5 years) were examined in a cross-sectional study using iohexol clearance and blood sampling at seven time points within 5 h (GFR7p) as the reference method. Median GFR7p was 66 (range 6-153) mL/min/1.73 m.sup.2. The performances of six different single time-point formulas (Fleming, Ham and Piepsz, Groth and Aasted, Stake, Jacobsson- and Jacobsson-modified) were validated against the reference. The two-point GFR (GFR2p) was calculated according to the Jødal and Brøchner-Mortensen formula. Results The GFR1p calculated according to Fleming with sampling at 3 h (GFR1p.sub.3h-Fleming) had the best overall performance, with 82% of measures within 10% of the reference value (P10). In children with a GFR [greater than or equal to] 30 mL/min/1.73 m.sup.2 (n = 78), the GFR1p.sub.3h-Fleming had a P10 of 92.3%, which is not significantly different (p = 0.29) from that of GFR2p (P10 = 96.2%). Considerable differences within and between the different formulas were found for different CKD stages and different time points for blood sampling. Conclusions For determination of mGFR in children with CKD and an assumed GFR of [greater than or equal to] 30 mL/min/1.73 m.sup.2 we recommend GFR1p.sub.3h-Fleming as the preferred single-point method as an alternative to GFR2p. For children with a GFR < 30 mL/min/1.73 m.sup.2, we recommend the slope-GFR with at least two blood samples. Clinical Trial Registration: http://clinicaltrials.gov http://clinicaltrials.gov , Identifier NCT01092260, https://clinicaltrials.gov/ct2/show/NCT01092260?term=tondel&rank=2, Author(s): Camilla Tøndel [sup.1] [sup.2] , Cathrin Lytomt Salvador [sup.3] [sup.4] , Karl Ove Hufthammer [sup.5] , Bjørn Bolann [sup.6] [sup.7] , Damien Brackman [sup.1] , Anna Bjerre [sup.8] , [...]

Background In children, estimated glomerular filtration rate (eGFR) methods are hampered by inaccuracy, hence there is an obvious need for safe, simplified, and accurate measured GFR (mGFR) methods. The aim of this study was to evaluate different formulas and determine the optimal sampling points for calculating mGFR based on iohexol clearance measurements on blood samples drawn at two time points (GFR2p). Methods The GFR of 96 children with different stages of chronic kidney disease (CKD) (median age 9.2 years, range 3 months to 17.5 years) was determined using the iohexol plasma clearance, with blood sampling at seven time points within 5 h (GFR7p) as the reference method. Median GFR7p was 65.9 (range 6.3-153) mL/min/1.73 m.sup.2. The performance of seven different formulas with early and late normalization to body surface area (BSA) was validated against the reference. Results The highest percentage (95.8 %) of GFR2p within 10 % of the reference was calculated using the formula of Jødal and Brøchner-Mortensen (JBM) from 2009, with sampling at 2 and 5 h. Normalization to BSA before correction of the distribution phase improved the performance of the original Brøchner-Mortensen method from 1972; P10 of 92.7 % compared to P10 of 82.3 % with late normalization, and a similar result was obtained with other formulas. Conclusions GFR2p performed well across a wide spectrum of GFR levels with the JBM formula. Several other formulas tested performed well provided that early BSA normalization was performed. Blood sampling at 2 and 5 h is recommended for an optimal GFR2p assessment., Author(s): Camilla Tøndel[sup.1] [sup.2] , Bjørn Bolann[sup.3] [sup.4] , Cathrin Lytomt Salvador[sup.5] , Damien Brackman[sup.6] , Anna Bjerre[sup.5] , Einar Svarstad[sup.2] [sup.7] , Atle Brun[sup.3] [sup.4] Author Affiliations: (1) Department [...]

Background: Fabry disease (FD) is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or lack of α-galactosidase A activity. This results in the accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes causing cellular impairment and organ failures. While current therapies focus on reversing Gb3 accumulation, they do not address the altered cellular signaling in FD. Therefore, this study aims to explore Gb3-independent mechanisms of kidney damage in Fabry disease and identify potential biomarkers. Methods: To investigate these mechanisms, we utilized a zebrafish (ZF) gla−/− mutant (MU) model. ZF naturally lack A4GALT gene and, therefore, cannot synthesize Gb3. We obtained kidney samples from both wild-type (WT) (n = 8) and MU (n = 8) ZF and conducted proteome profiling using untargeted mass spectrometry. Additionally, we examined mitochondria morphology and cristae morphology using electron microscopy. To assess oxidative stress, we measured total antioxidant activity. Finally, immunohistochemistry was conducted on kidney samples to validate specific proteins. Results: Our proteomics analysis of renal tissues from zebrafish revealed downregulation of lysosome and mitochondrial-related proteins in gla−/− MU renal tissues, while energy-related pathways including carbon, glycolysis, and galactose metabolisms were disturbed. Moreover, we observed abnormal mitochondrial shape, disrupted cristae morphology, altered mitochondrial volume and lower antioxidant activity in gla−/− MU ZF. Conclusions: These results suggest that the alterations observed at the proteome and mitochondrial level closely resemble well-known GLA mutation-related alterations in humans. Importantly, they also unveil novel Gb3-independent pathogenic mechanisms in Fabry disease. Understanding these mechanisms could potentially lead to the development of innovative drug screening approaches. Furthermore, the findings pave the way for identifying new clinical targets, offering new avenues for therapeutic interventions in Fabry disease. The zebrafish gla−/− mutant model proves valuable in elucidating these mechanisms and may contribute significantly to advancing our knowledge of this disorder. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is an X-linked inborn metabolic disorder due to partial or complete lysosomal α-galactosidase A deficiency. FD is characterized by progressive renal insufficiency and cardio- and cerebrovascular involvement. Restricted access on Gb3-independent tissue injury experimental models has limited the understanding of FD pathophysiology and delayed the development of new therapies. Accumulating glycosphingolipids, mainly Gb3 and lysoGb3, are Fabry specific markers used in clinical follow up. However, recent studies suggest there is a need for additional markers to monitor FD clinical course or response to treatment. We used a gla-knockout zebrafish (ZF) to investigate alternative biomarkers in Gb3-free-conditions. RNA sequencing was used to identify transcriptomic signatures in kidney tissues discriminating gla-mutant (M) from wild type (WT) ZF. Gene Ontology (GO) and KEGG pathways analysis showed upregulation of immune system activation and downregulation of oxidative phosphorylation pathways in kidneys from M ZF. In addition, upregulation of the Ca2+ signaling pathway was also detectable in M ZF kidneys. Importantly, disruption of mitochondrial and lysosome-related pathways observed in M ZF was validated by immunohistochemistry. Thus, this ZF model expands the pathophysiological understanding of FD, the Gb3-independent effects of gla mutations could be used to explore new therapeutic targets for FD. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked α-galactosidase A deficiency, resulting in accumulation of glycosphingolipids, especially globotriaosylceramide, in cells in different organs in the body. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive noninvasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. Recent studies support the value of renal biopsy in providing histological information relevant to kidney function and prognosis, and renal biopsy could potentially be used to guide treatment decisions in young Fabry patients. This review aims to provide an update of the current understanding, challenges, and needs to better approach renal complications of Fabry disease in children. Keywords Fabry * Fabry nephropathy * Pediatrics * Kidney biopsy * Enzyme replacement therapy, Introduction Fabry disease, first described by Johannes Fabry and William Anderson in 1898, is an X-linked α-galactosidase A deficiency which results in the failure to breakdown glycosphingolipids, particularly globotriaosylceramide (abbreviated [...]

Objective: Chronic kidney disease (CKD) is a serious medical condition characterized by gradual loss of kidney function. Early detection and diagnosis is mandatory for adequate therapy and prognostic improvement. Hence, in the current pilot study we explore the use of image registration methods for detecting renal morphologic changes in patients with CKD. Methods: Ten healthy volunteers and nine patients with presumed CKD underwent dynamic T1 weighted imaging without contrast agent. From real and simulated dynamic time series, kidney deformation fields were estimated using a poroelastic deformation model. From the deformation fields several quantitative parameters reflecting pressure gradients, and volumetric and shear deformations were computed. Eight of the patients also underwent a kidney biopsy as a gold standard. Results: We found that the absolute deformation, normalized volume changes, as well as pressure gradients correlated significantly with arteriosclerosis from biopsy assessments. Furthermore, our results indicate that current image registration methodologies are lacking sensitivity to recover mild changes in tissue stiffness. Conclusion: Image registration applied to dynamic time series correlated with structural renal changes and should be further explored as a tool for invasive measurements of arteriosclerosis. Significance: Under the assumption that the proposed framework can be further developed in terms of sensitivity and specificity, it can provide clinicians with a non-invasive tool of high spatial coverage available for characterization of arteriosclerosis and potentially other pathological changes observed in chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background High repeatability, accuracy, and precision for renal function measurements need to be achieved to establish renal dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a clinically useful diagnostic tool. Purpose To investigate the repeatability, accuracy, and precision of DCE-MRI measured renal perfusion and glomerular filtration rate (GFR) using iohexol-GFR as the reference method. Material and Methods Twenty healthy non-smoking volunteers underwent repeated DCE-MRI and an iohexol-GFR within a period of 10 days. Single-kidney (SK) MRI measurements of perfusion (blood flow, Fb) and filtration (GFR) were derived from parenchymal intensity time curves fitted to a two-compartment filtration model. The repeatability of the SK-MRI measurements was assessed using coefficient of variation (CV). Using iohexol-GFR as reference method, the accuracy of total MR-GFR was determined by mean difference (MD) and precision by limits of agreement (LoA). Results SK-Fb (MR1, 345 ± 84; MR2, 371 ± 103 mL/100 mL/min) and SK-GFR (MR1, 52 ± 14; MR2, 54 ± 10 mL/min/1.73 m2) measurements achieved a repeatability (CV) in the range of 15-22%. With reference to iohexol-GFR, MR-GFR was determined with a low mean difference but high LoA (MR1, MD 1.5 mL/min/1.73 m2, LoA [-42, 45]; MR2, MD 6.1 mL/min/1.73 m2, LoA [-26, 38]). Eighty percent and 90% of MR-GFR measurements were determined within ± 30% of the iohexol-GFR for MR1 and MR2, respectively. Conclusion Good repeatability of SK-MRI measurements and good agreement between MR-GFR and iohexol-GFR provide a high clinical potential of DCE-MRI for renal function assessment. A moderate precision in MR-derived estimates indicates that the method cannot yet be used in clinical routine. [ABSTRACT FROM AUTHOR]

Background: Agalsidase-α 0.2 mg/kg every other week (eow) and agalsidase-β 1.0 mg/kg/eow are licensed in Europe as equipotent treatment of the α-galactosidase deficiency in Fabry disease. This case series describes the effects of agalsidase dose adjustments in serial kidney biopsies in switch patients. Methods: All treatment-naïve patients with classical Fabry disease in our centre started on agalsidase-β 1.0 mg/kg/eow and subsequently switched to agalsidase-α 0.2 mg/kg/eow were included (n= 3). The median age at enzyme replacement therapy start was 11 (range 7-18) years. Kidney biopsies were performed at baseline, after 5 years of agalsidase-β 1.0 mg/kg/eow and after 3 subsequent years of agalsidase-α 0.2 mg/kg/eow. One patient was re-biopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. The scoring system of the International Scoring Group of Fabry Nephropathy was used. Results: The patients completely cleared globotriaosylceramide (GL3) from mesangial and endothelial cells and partly cleared podocytes on agalsidase-β 1.0 mg/kg/eow. Reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium, occurred after 3 years of agalsidase-α 0.2 mg/kg/eow. Subsequent reduction of podocyte GL3 was observed in the single patient rebiopsied 2 years after reswitch to agalsidase-β 1.0 mg/kg/eow. Conclusion: Partial clearance, reaccumulation and renewed partial clearance of podocyte GL3 deposits in serial kidney biopsies over 8-10 years were seen in parallel with agalsidase dose adjustments. Repeated kidney biopsies may impact therapeutic choices in Fabry disease. [ABSTRACT FROM AUTHOR]