High urinary ferritin reflects myoglobin iron evacuation in DMD patients.

[en] Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the dystrophin gene leading to the absence of the normal dystrophin protein. The efforts of many laboratories brought new treatments of DMD to the reality, but ongoing and forthcoming clinical trials suffer from absence of valuable biomarkers permitting to follow the outcome of the treatment day by day and to adjust the treatment if needed. In the present study the levels of 128 urinary proteins including growth factors, cytokines and chemokines were compared in urine of DMD patients and age related control subjects by antibody array approach. Surprisingly, statistically significant difference was observed only for urinary ferritin whose level was 50 times higher in young DMD patients. To explain the observed high urinary ferritin content we analysed the levels of iron, iron containing proteins and proteins involved in regulation of iron metabolism in serum and urine of DMD patients and their age-matched healthy controls. Obtained data strongly suggest that elevated level of urinary ferritin is functionally linked to the renal management of myoglobin iron derived from leaky muscles of DMD patients. This first observation of the high level of ferritin in urine of DMD patients permits to consider this protein as a new urinary biomarker in muscular dystrophies and sheds light on the mechanisms of iron metabolism and kidney functioning in DMD.

Disciplines :

Neurology
Pediatrics

Author, co-author :

Rouillon, Jeremy

Lefebvre, Thibaud

Denard, Jerome

Puy, Vincent

Daher, Raed

Ausseil, Jerome

Zocevic, Aleksandar

Fogel, Paul

Peoc'h, Katell

Wong, Brenda

More authors (5 more)

Language :

English

Title :

High urinary ferritin reflects myoglobin iron evacuation in DMD patients.

Publication date :

March 2018

Journal title :

Neuromuscular Disorders

ISSN :

0960-8966

eISSN :

1873-2364

Publisher :

Elsevier, Netherlands

Pages :

1-8

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 13 February 2019

Statistics

Number of views

65 (1 by ULiège)

Number of downloads

0 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Ervasti, J.M., Ohlendieck, K., Kahl, S.D., Gaver, M.G., Campbell, K.P., Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle. Nature 345 (1990), 315–319.
Cullen, M.J., Mastaglia, F.L., Morphological changes in dystrophic muscle. Br Med Bull, 36, 1980 145–22.
Ricotti, V., Ridout, D.A., Scott, E., Quinlivan, R., Robb, S.A., Manzur, A.Y., et al. Long-term benefits and adverse effects of intermittent versus daily glucocorticoids in boys with Duchenne muscular dystrophy. J Neurol Neurosurg Psychiatry 84 (2013), 698–705.
Poysky, J., Behavior patterns in Duchenne muscular dystrophy: report on the Parent Project Muscular Dystrophy behavior workshop 8–9 of December 2006, Philadelphia, USA. Neuromuscul Disord 17 (2007), 986–994.
Ishikawa, Y., Miura, T., Ishikawa, Y., Aoyagi, T., Ogata, H., Hamada, S., et al. Duchenne muscular dystrophy: survival by cardio-respiratory interventions. Neuromuscul Disord 21 (2011), 47–51.
Howard, R.L., Buddington, B., Alfrey, A.C., Urinary albumin, transferrin and iron excretion in diabetic patients. Kidney Int 40 (1991), 923–926.
Delanaye, P., Schaeffner, E., Ebert, N., Cavalier, E., Mariat, C., Krzesinski, J.M., et al. Normal reference values for glomerular filtration rate: what do we really know?. Nephrol Dial Transplant 27 (2012), 2664–2672.
Wassell, J., Haptoglobin: function and polymorphism. Clin Lab 46 (2000), 547–552.
Adornato, B.T., Corash, L., Engel, W.K., Erythrocyte survival in Duchenne muscular dystrophy. Neurology 27 (1977), 1093–1094.
Fervenza, F.C., Croatt, A.J., Bittar, C.M., Rosenthal, D.W., Lager, D.J., Leung, N., et al. Induction of heme oxygenase-1 and ferritin in the kidney in warm antibody hemolytic anemia. Am J Kidney Dis 52 (2008), 972–977.
Kagen, L.J., Moussavi, S., Miller, S.L., Tsairis, P., Serum myoglobin in muscular dystrophy. Muscle Nerve 3 (1980), 221–226.
Rouillon, J., Zocevic, A., Leger, T., Garcia, C., Camadro, J.M., Udd, B., et al. Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy. Neuromuscul Disord 24 (2014), 563–573.
Ishikawa, K., Narita, O., Saito, H., Kato, K., Determination of ferritin in urine and in serum of normal adults with a sensitive enzyme immunoassay. Clin Chim Acta 123 (1982), 73–81.
Lipschitz, D.A., Allegre, A., Cook, J.D., The clinical significance of ferritinuria. Blood 55 (1980), 260–264.
Sears, D.A., Anderson, P.R., Foy, A.L., Williams, H.L., Crosby, W.H., Urinary iron excretion and renal metabolism of hemoglobin in hemolytic diseases. Blood 28 (1966), 708–725.
Kell, D.B., Pretorius, E., Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 6 (2014), 748–773.
Lefebvre, T., Dessendier, N., Houamel, D., Ialy-Radio, N., Kannengiesser, C., Manceau, H., et al. LC-MS/MS method for hepcidin-25 measurement in human and mouse serum: clinical and research implications in iron disorders. Clin Chem Lab Med 53 (2015), 1557–1567.
Daher, R., Kannengiesser, C., Houamel, D., Lefebvre, T., Bardou-Jacquet, E., Ducrot, N., et al. Heterozygous mutations in BMP6 pro-peptide lead to inappropriate hepcidin synthesis and moderate iron overload in humans. Gastroenterology 150 (2016), 672–683 e4.
Smith, F.E., Herbert, J., Gaudin, J., Hennessy, D.J., Reid, G.R., Serum iron determination using ferene triazine. Clin Biochem 17 (1984), 306–310.
Filler, G., Lepage, N., Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula?. Pediatr Nephrol 18 (2003), 981–985.
Viollet, L., Gailey, S., Thornton, D.J., Friedman, N.R., Flanigan, K.M., Mahan, J.D., et al. Utility of cystatin C to monitor renal function in Duchenne muscular dystrophy. Muscle Nerve 40 (2009), 438–442.
Braat, E., Hoste, L., De Waele, L., Gheysens, O., Vermeersch, P., Goffin, K., et al. Renal function in children and adolescents with Duchenne muscular dystrophy. Neuromuscul Disord 25 (2015), 381–387.
Anders, S., Huber, W., Differential expression analysis for sequence count data. Genome Biol, 11, 2010, R106.
Moulouel, B., Houamel, D., Delaby, C., Tchernitchko, D., Vaulont, S., Letteron, P., et al. Hepcidin regulates intrarenal iron handling at the distal nephron. Kidney Int 84 (2013), 756–766.
Kiessling, W.R., Beckmann, R., Serum levels of myoglobin and creatine kinase in Duchenne muscular dystrophy. Klin Wochenschr 59 (1981), 347–348.
Konagaya, M., Takayanagi, T., Konagaya, Y., Sobue, I., The fluctuation of serum myoglobin levels in Duchenne muscular dystrophy and the carrier. J Neurol Sci 55 (1982), 259–265.
Wang, W., Knovich, M.A., Coffman, L.G., Torti, F.M., Torti, S.V., Serum ferritin: past, present and future. Biochim Biophys Acta 1800 (2010), 760–769.
Rouillon, J., Poupiot, J., Zocevic, A., Amor, F., Leger, T., Garcia, C., et al. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies. Hum Mol Genet 24 (2015), 4916–4932.
Miller, F., Hemoglobin absorption by the cells of the proximal convoluted tubule in mouse kidney. J Biophys Biochem Cytol 8 (1960), 689–718.
Vanholder, R., Sever, M.S., Erek, E., Lameire, N., Rhabdomyolysis. J Am Soc Nephrol 11 (2000), 1553–1561.
El-Abdellati, E., Eyselbergs, M., Sirimsi, H., Hoof, V.V., Wouters, K., Verbrugghe, W., et al. An observational study on rhabdomyolysis in the intensive care unit. Exploring its risk factors and main complication: acute kidney injury. J Am Soc Nephrol, 3, 2013, 8.
Barstow, L., Small, R.E., Liver function assessment by drug metabolism. Pharmacotherapy 10 (1990), 280–288.
Holt, S., Moore, K., Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol 8 (2000), 72–76.
Zorova, L.D., Pevzner, I.B., Chupyrkina, A.A., Zorov, S.D., Silachev, D.N., Plotnikov, E.Y., et al. The role of myoglobin degradation in nephrotoxicity after rhabdomyolysis. Chem Biol Interact 256 (2016), 64–70.
Demos, M.A., Gitin, E.L., Kagen, L.J., Exercise myoglobinemia and acute exertional rhabdomyolysis. Arch Intern Med 134 (1974), 669–673.
Hamilton, R.W., Hopkins, M.B. 3rd, Shihabi, Z.K., Myoglobinuria, hemoglobinuria, and acute renal failure. Clin Chem 35 (1989), 1713–1720.
Koskelo, P., Kekki, M., Wager, O., Kinetic behaviour of 131-I-labelled myoglobin in human beings. Clin Chim Acta 17 (1967), 339–347.
Palatini, P., Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension. Nephrol Dial Transplant 27 (2012), 1708–1714.
Helal, I., Fick-Brosnahan, G.M., Reed-Gitomer, B., Schrier, R.W., Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol 8 (2012), 293–300.
Matsumura, T., Saito, T., Fujimura, H., Sakoda, S., Renal dysfunction is a frequent complication in patients with advanced stage of Duchenne muscular dystrophy. Rinsho Shinkeigaku 52 (2012), 211–217.
Motoki, T., Shimizu-Motohashi, Y., Komaki, H., Mori-Yoshimura, M., Oya, Y., Takeshita, E., et al. Treatable renal failure found in non-ambulatory Duchenne muscular dystrophy patients. Neuromuscul Disord 25 (2015), 754–757.
Zhang, A., Uaesoontrachoon, K., Shaughnessy, C., Das, J.R., Rayavarapu, S., Brown, K.J., et al. The use of urinary and kidney SILAM proteomics to monitor kidney response to high dose morpholino oligonucleotides in the mdx mouse. Toxicol Rep 2 (2015), 838–849.
Cirak, S., Arechavala-Gomeza, V., Guglieri, M., Feng, L., Torelli, S., Anthony, K., et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378 (2011), 595–605.
Goemans, N.M., Tulinius, M., van den Akker, J.T., Burm, B.E., Ekhart, P.F., Heuvelmans, N., et al. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N Engl J Med 364 (2011), 1513–1522.
Bowles, D.E., McPhee, S.W., Li, C., Gray, S.J., Samulski, J.J., Camp, A.S., et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther 20 (2012), 443–455.
Price, F.D., Kuroda, K., Rudnicki, M.A., Stem cell based therapies to treat muscular dystrophy. Biochim Biophys Acta 1772 (2007), 272–283.