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      Renal Phenotype in Mitochondrial Diseases: A Multicenter Study


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          Aims: This study aimed to investigate associations between renal and extrarenal manifestations of mitochondrial diseases and their natural history as well as predictors of renal disease severity and overall disease outcome. The secondary aim was to generate a protocol of presymptomatic assessment and monitoring of renal function in patients with a defined mitochondrial disease. Methods: A multicenter, retrospective cohort study was performed by the Mitochondrial Clinical and Research Network (MCRN). Patients of any age with renal manifestations associated with a genetically verified mitochondrial disease were included from 8 expert European centers specializing in mitochondrial diseases: Gothenburg, Oulu, Copenhagen, Bergen, Helsinki, Stockholm, Rotterdam, and Barcelona. Results: Of the 36 patients included, two-thirds had mitochondrial DNA-associated disease. Renal manifestations were the first sign of mitochondrial disease in 19%, and renal involvement was first identified by laboratory tests in 57% of patients. Acute kidney injury occurred in 19% of patients and was the first sign of renal disease in the majority of these. The most common renal manifestation was chronic kidney disease (75% with stage 2 or greater), followed by tubulopathy (44.4%), the latter seen mostly among patients with single large-scale mitochondrial DNA deletions. Acute kidney injury and tubulopathy correlated with worse survival outcome. The most common findings on renal imaging were increased echogenicity and renal dysplasia/hypoplasia. Renal histology revealed focal segmental glomerulosclerosis, nephrocalcinosis, and nephronophthisis. Conclusion: Acute kidney injury is a distinct renal phenotype in patients with mitochondrial disease. Our results highlight the importance to recognize renal disease as a sign of an underlying mitochondrial disease. Acute kidney injury and tubulopathy are 2 distinct indicators of poor survival in patients with mitochondrial diseases.

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          Most cited references24

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          Mitochondrial energetics in the kidney

          Mitochondria provide the kidney with energy to remove waste from the blood and regulate fluid and electrolyte balance. This Review discusses how mitochondrial homeostasis is maintained, the changes in mitochondrial energetics that occur in acute kidney injury and diabetic nephropathy, and how targeting mitochondrial energetics might aid the treatment of renal disease.
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            Apoptosis and acute kidney injury.

            Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the 'perfect storm' for outer mitochondrial membrane injury to release its cellular 'executioners'. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.
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              Measurement and estimation of GFR in children and adolescents.

              GFR is the best indicator of renal function in children and adolescents and is critical for diagnosing acute and chronic kidney impairment, intervening early to prevent end-stage renal failure, prescribing nephrotoxic drugs and drugs cleared by a failing kidney, and monitoring for side effects of medications. Renal inulin clearance was the gold standard for GFR but is compromised by lack of availability, difficult assays, and problems of collecting timed urine samples, especially in children with vesicoureteral reflux or bladder dysfunction. Creatinine clearance-based estimates of GFR are often used in pediatrics. The addition of cimetidine to eliminate creatinine secretion permits accurate measurement of GFR in those who can completely empty their bladders to provide timed urine collections. Radioisotopes are used in plasma disappearance GFR determinations; however, these are not ideal for use in children, especially for repeated studies. The plasma disappearance of iohexol serves as a promising alternative GFR marker, because it is safe and not radioactive, easily measured, not metabolized or transported by the kidney, and excreted primarily by glomerular filtration. GFR estimating equations, based on serum concentrations of creatinine or cystatin C, are popular clinically and in research studies. Efforts are ongoing to improve these estimating equations for children and make the results readily available to clinicians obtaining standard chemistry profiles, as is being done for adults. However, at this time, there is no dependable substitute for an accurately determined GFR, and iohexol plasma disappearance offers the best combination of safety, accuracy, and reproducible precision.

                Author and article information

                Kidney Diseases
                S. Karger AG
                March 2022
                24 January 2022
                : 8
                : 2
                : 148-159
                [_a] aDepartment of Paediatrics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
                [_b] bDepartment of Paediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [_c] cDepartment of Children and Adolescents, Oulu University Hospital, Oulu, Finland
                [_d] dPEDEGO Research Unit, Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Ophthalmology, Otorhinolaryngology, Medical Research Center Oulu (MRC Oulu), University of Oulu, Oulu, Finland
                [_e] eDepartment of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
                [_f] fDepartment of Pediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway
                [_g] gDepartment of Clinical Medicine (K1), University of Bergen, Bergen, Norway
                [_h] hDepartment of Pediatric Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
                [_i] iResearch Programs Unit, Stem Cells and Metabolism, University of Helsinki, Helsinki, Finland
                [_j] jCentre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden
                [_k] kDepartment Toxicogenomics, Faculty of Health, Medicine and Life Sciences, Graduate School MHeNS, Maastricht University, Maastricht, The Netherlands
                [_l] lNeuromuscular Diseases Unit, Hospital Sant Joan de Déu, Barcelona, Spain
                [_m] mDepartment of Neurology, Neuromuscular Centre, Sahlgrenska University Hospital, Gothenburg, Sweden
                [_n] nNeuro-SysMed, Center of Excellence for Clinical Research in Neurological Diseases, Haukeland University Hospital, Bergen, Norway
                521148 Kidney Dis 2022;8:148–159
                © 2022 The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 13 February 2021
                : 23 November 2021
                Page count
                Figures: 3, Tables: 3, Pages: 12
                Research Article

                Cardiovascular Medicine,Nephrology
                Mitochondrial disease,Acute kidney injury,Mitochondrial DNA,Renal manifestations


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