Progressive nephropathy is one of the main features of Fabry disease. Although some clinical signs of Fabry nephropathy are already present in childhood, patients are often diagnosed relatively late in the course of the disease due to the absence of specific clinical markers, while a timely diagnosis and the prompt start of enzyme replacement therapy may be beneficial in stabilizing renal function or slowing its decline. Proteinuria/albuminuria has been accepted as the most important marker for Fabry nephropathy; however, a large proportion of renal impairment occurs in nonalbuminuric state. Therefore, early biomarkers may be useful for early identification of kidney involvement. The aim of this article is to review the current available literature on all biomarkers of Fabry nephropathy, with a comprehensive and critical description of their utilization in early recognition of renal damage.

1.
Desnick RJ, Ioannou Y, Eng CM. Fabry disease: α-galactosidase A deficiency.
Scriver CH, Beaudet AL, Sly WS, et al: The Metabolic and Molecular Basis of Inherited Disease
. New York: Mc Graw Hill; 1995. pp. 2741–84.
2.
Pisani A, Visciano B, Imbriaco M, Di Nuzzi A, Mancini A, Marchetiello C, et al. The kidney in Fabry’s disease.
Clin Genet
. 2014 Oct;86(4):301–9.
3.
Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course.
Medicine (Baltimore)
. 2002 Mar;81(2):122–38.
4.
Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso B, Wanner C; Fabry Registry. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy.
Nephrol Dial Transplant
. 2008 May;23(5):1600–7.
5.
Schiffmann R, Warnock DG, Banikazemi M, Bultas J, Linthorst GE, Packman S, et al. Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy.
Nephrol Dial Transplant
. 2009 Jul;24(7):2102–11.
6.
Beirão I, Cabrita A, Torres M, Silva F, Aguiar P, Laranjeira F, et al. Biomarkers and imaging findings of Anderson-Fabry disease – what we know now.
Diseases
. 2017 Jun;5(2):E15.
7.
Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf MG, Hollak CE. Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain.
Orphanet J Rare Dis
. 2013 Mar;8(1):47.
8.
Pisani A, Visciano B, Roux GD, Sabbatini M, Porto C, Parenti G, et al. Enzyme replacement therapy in patients with Fabry disease: state of the art and review of the literature.
Mol Genet Metab
. 2012 Nov;107(3):267–75.
9.
Cox TM. Biomarkers in lysosomal storage diseases. In: Metha A, Beck M, Sunder-Plassmann G, editors.
Fabry disease: Perspectives from 5 years of FOS
. Oxford: Oxford PharmaGenesis; 2006.
10.
Sirrs S, Bichet DG, Iwanochko M, et al. Canadian Fabry Disease Treatment Guidelines, 2018. https://www.garrod.ca/wp-conent/uploads/2019/04/Canadian-Fabry-Treatment-Guidelines-2018-final.pdf
11.
Pisani A, Petruzzelli Annicchiarico L, Pellegrino A, Bruzzese D, Feriozzi S, Imbriaco M, et al. Parapelvic cysts, a distinguishing feature of renal Fabry disease.
Nephrol Dial Transplant
. 2018 Feb;33(2):318–23.
12.
Biegstraaten M, Arngrímsson R, Barbey F, Boks L, Cecchi F, Deegan PB, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.
Orphanet J Rare Dis
. 2015 Mar;10(1):36.
13.
Pisani A, Spinelli L, Visciano B, Capuano I, Sabbatini M, Riccio E, et al. Effects of switching from agalsidase Beta to agalsidase alfa in 10 patients with anderson-fabry disease.
JIMD Rep
. 2013;9:41–8.
14.
Desnick RJ, Dawson G, Desnick SJ, Sweeley CC, Krivit W. Diagnosis of glycosphingolipidoses by urinary-sediment analysis.
N Engl J Med
. 1971 Apr;284(14):739–44.
15.
Nagao S, Satoh N, Inaba S, Iijima S. Concentric lamellar spheres in urine from a female carrier of and patients with Fabry’s disease—with special reference to polarization and electron microscopic comparison with nephrotic syndrome.
J Dermatol
. 1985 Feb;12(1):70–8.
16.
Birch DF, Fairley KF, Becker GJ, et al.
A Color Atlas of Urine Microscopy
. London: Chapman & Hall Medical; 1994. pp. 76–7938.
17.
Selvarajah M, Nicholls K, Hewitson TD, Becker GJ. Targeted urine microscopy in Anderson-Fabry disease: a cheap, sensitive and specific diagnostic technique.
Nephrol Dial Transplant
. 2011 Oct;26(10):3195–202.
18.
Pabico RC, Atancio BC, McKenna BA, Pamukcoglu T, Yodaiken R. Renal pathologic lesions and functional alterations in a man with Fabry’s disease.
Am J Med
. 1973 Sep;55(3):415–25.
19.
Nakamichi T, Miyazaki M, Nakayama K, Sato M, Akiu N, Sato T, et al. Fabry’s disease discovered with chance urinary mulberry cells: a case report.
CEN Case Rep
. 2013 May;2(1):49–52.
20.
Chong PF, Nakamura K, Kira R. Mulberries in the urine: a tell-tale sign of Fabry disease.
J Inherit Metab Dis
. 2018 Jul;41(4):745–6.
21.
Shimohata H, Maruyama H, Miyamoto Y, Takayasu M, Hirayama K, Kobayashi M. Urinary mulberry cells and mulberry bodies are useful tool to detect late-onset Fabry -disease.
CEN Case Rep
. 2017 Nov;6(2):148–51.
22.
Trimarchi H, Canzonieri R, Muryan A, Schiel A, Araoz A, Forrester M, et al. Copious podocyturia without proteinuria and with normal renal function in a young adult with Fabry disease.
Case Rep Nephrol
. 2015;2015:257628.
23.
Tøndel C, Kanai T, Larsen KK, Ito S, Politei JM, Warnock DG, et al. Foot process effacement is an early marker of nephropathy in young classic Fabry patients without albuminuria.
Nephron
. 2015;129(1):16–21.
24.
Vogelmann SU, Nelson WJ, Myers BD, Lemley KV. Urinary excretion of viable podocytes in health and renal disease.
Am J Physiol Renal Physiol
. 2003 Jul;285(1):F40–8.
25.
Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.
J Am Soc Nephrol
. 2005 Oct;16(10):2941–52.
26.
Trimarchi H. The kidney in Fabry disease: more than mere sphingolipids overload.
J Inborn Errors Metab Screen
. 2016;4:1–5.
27.
Trimarchi H, Canzonieri R, Schiel A, Politei J, Stern A, Andrews J, et al. Podocyturia is significantly elevated in untreated vs treated Fabry adult patients.
J Nephrol
. 2016 Dec;29(6):791–7.
28.
Sanchez-Niño MD, Perez-Gomez MV, Valiño-Rivas L, Torra R, Ortiz A. Podocyturia: why it may have added value in rare diseases.
Clin Kidney J
. 2018 Oct;12(1):49–52.
29.
Trimarchi H, Canzonieri R, Costales--Collaguazo C, Politei J, Stern A, Paulero M, et al. Early decrease in the podocalyxin to synaptopodin ratio in urinary Fabry -podocytes.
Clin Kidney J
. 2019 Feb;12(1):53–60.
30.
Fall B, Scott CR, Mauer M, Shankland S, Pippin J, Jefferson JA, et al. Urinary podocyte loss is increased in patients with Fabry disease and correlated with clinical severity of Fabry nephropathy.
PLoS One
. 2016 Dec;11(12):e0168346.
31.
Trimarchi H. Podocyturia: potential applications and current limitations.
World J Nephrol
. 2017 Sep;6(5):221–8.
32.
Ortiz A, Oliveira JP, Wanner C, Brenner BM, Waldek S, Warnock DG. Recommendations and guidelines for the diagnosis and treatment of Fabry nephropathy in adults.
Nat Clin Pract Nephrol
. 2008 Jun;4(6):327–36.
33.
Wanner C, Oliveira JP, Ortiz A, Mauer M, Germain DP, Linthorst GE, et al. Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry.
Clin J Am Soc Nephrol
. 2010 Dec;5(12):2220–8.
34.
Tøndel C, Bostad L, Larsen KK, Hirth A, Vikse BE, Houge G, et al. Agalsidase benefits renal histology in young patients with Fabry disease.
J Am Soc Nephrol
. 2013 Jan;24(1):137–48.
35.
Aguiar P, Azevedo O, Pinto R, Marino J, Baker R, Cardoso C, et al. New biomarkers defining a novel early stage of Fabry nephropathy: A diagnostic test study.
Mol Genet Metab
. 2017 Jun;121(2):162–9.
36.
West M, Nicholls K, Mehta A, Clarke JT, Steiner R, Beck M, et al. Agalsidase alfa and kidney dysfunction in Fabry disease.
J Am Soc Nephrol
. 2009 May;20(5):1132–9.
37.
Rombach SM, Baas MC, ten Berge IJ, Krediet RT, Bemelman FJ, Hollak CE. The value of estimated GFR in comparison to measured GFR for the assessment of renal function in adult patients with Fabry disease.
Nephrol Dial Transplant
. 2010 Aug;25(8):2549–56.
38.
Vedder AC, Linthorst GE, van Breemen MJ, Groener JE, Bemelman FJ, Strijland A, et al. The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels.
J Inherit Metab Dis
. 2007 Feb;30(1):68–78.
39.
Riccio E, Sabbatini M, Bruzzese D, Annicchiarico Petruzzelli L, Pellegrino A, Spinelli L, et al.; on behalf of AFFIINITY Group. Glomerular hyperfiltration: an early marker of nephropathy in Fabry disease.
Nephron
. 2019;141(1):10–7.
40.
Palatini P. Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension.
Nephrol Dial Transplant
. 2012 May;27(5):1708–14.
41.
Helal I, Reed B, McFann K, Yan XD, Fick-Brosnahan GM, Cadnapaphornchai M, et al. Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease.
Clin J Am Soc Nephrol
. 2011 Oct;6(10):2439–43.
42.
Haymann JP, Stankovic K, Levy P, Avellino V, Tharaux PL, Letavernier E, et al. Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature.
Clin J Am Soc Nephrol
. 2010 May;5(5):756–61.
43.
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.
Ann Intern Med
. 2004 Dec;141(12):929–37.
44.
Agarwal R. Estimating GFR from serum creatinine concentration: pitfalls of GFR-estimating equations.
Am J Kidney Dis
. 2005 Mar;45(3):610–3.
45.
Bicik Z, Bahcebasi T, Kulaksizoglu S, Yavuz O. The efficacy of cystatin C assay in the prediction of glomerular filtration rate. Is it a more reliable marker for renal failure?
Clin Chem Lab Med
. 2005;43(8):855–61.
46.
Torralba-Cabeza MA, Olivera S, Hughes DA, Pastores GM, Mateo RN, Pérez-Calvo JI. Cystatin C and NT-proBNP as prognostic biomarkers in Fabry disease.
Mol Genet Metab
. 2011 Nov;104(3):301–7.
47.
Perkins BA, Nelson RG, Ostrander BE, Blouch KL, Krolewski AS, Myers BD, et al. Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study.
J Am Soc Nephrol
. 2005 May;16(5):1404–12.
48.
Feriozzi S, Germain DP, Di Vito R, Legrand A, Ricci R, Barbey F. Cystatin C as a marker of early changes of renal function in Fabry nephropathy.
J Nephrol
. 2007 Jul-Aug;20(4):437–43.
49.
Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients.
Kidney Int
. 1985 Nov;28(5):830–8.
50.
Tenstad O, Roald AB, Grubb A, Aukland K. Renal handling of radiolabelled human cystatin C in the rat.
Scand J Clin Lab Invest
. 1996 Aug;56(5):409–14.
51.
Sweeley CC, Klionsky B. Fabry’s Disease: Classification as a Sphingolipidosis and Partial Characterization of a Novel Glycolipid.
J Biol Chem
. 1963 Sep;238:3148–50.
52.
Young E, Mills K, Morris P, Vellodi A, Lee P, Waldek S, et al. Is globotriaosylceramide a useful biomarker in Fabry disease?
Acta Paediatr Suppl
. 2005 Mar;94(447):51–4.
53.
Auray-Blais C, Ntwari A, Clarke JT, Warnock DG, Oliveira JP, Young SP, et al. How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?
Clin Chim Acta
. 2010 Dec;411(23-24):1906–14.
54.
Auray-Blais C, Cyr D, Ntwari A, West ML, Cox-Brinkman J, Bichet DG, et al. Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease.
Mol Genet Metab
. 2008 Mar;93(3):331–40.
55.
Schiffmann R, Waldek S, Benigni A, Auray-Blais C. Biomarkers of Fabry disease nephropathy.
Clin J Am Soc Nephrol
. 2010 Feb;5(2):360–4.
56.
Rombach SM, Dekker N, Bouwman MG, Linthorst GE, Zwinderman AH, Wijburg FA, et al. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease.
Biochim Biophys Acta
. 2010 Sep;1802(9):741–8.
57.
Nowak A, Mechtler TP, Desnick RJ, Kasper DC. Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes.
Mol Genet Metab
. 2017 Jan - Feb;120(1-2):57–61.
58.
Nowak A, Mechtler TP, Hornemann T, Gawinecka J, Theswet E, Hilz MJ, et al. Genotype, phenotype and disease severity reflected by serum LysoGb3 levels in patients with Fabry disease.
Mol Genet Metab
. 2018 Feb;123(2):148–53.
59.
Vylet’al P, Hůlková H, Zivná M, Berná L, Novák P, Elleder M, et al. Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy.
J Inherit Metab Dis
. 2008 Aug;31(4):508–17.
60.
Prabakaran T, Birn H, Bibby BM, Regeniter A, Sørensen SS, Feldt-Rasmussen U, et al. Long-term enzyme replacement therapy is associated with reduced proteinuria and preserved proximal tubular function in women with Fabry disease.
Nephrol Dial Transplant
. 2014 Mar;29(3):619–25.
61.
Lepedda AJ, Fancellu L, Zinellu E, De Muro P, Nieddu G, Deiana GA, et al. Urine bikunin as a marker of renal impairment in Fabry’s disease.
BioMed Res Int
. 2013;2013:205948.
62.
Cigna D, D’Anna C, Zizzo C, Francofonte D, Sorrentino I, Colomba P, et al. Alteration of proteomic profiles in PBMC isolated from patients with Fabry disease: preliminary findings.
Mol Biosyst
. 2013 Jun;9(6):1162–8.
63.
Vojtová L, Zima T, Tesař V, Michalová J, Přikryl P, Dostálová G, et al. Study of urinary proteomes in Anderson-Fabry disease.
Ren Fail
. 2010;32(10):1202–9.
64.
Manwaring V, Heywood WE, Clayton R, Lachmann RH, Keutzer J, Hindmarsh P, et al. The identification of new biomarkers for identifying and monitoring kidney disease and their translation into a rapid mass spectrometry-based test: evidence of presymptomatic kidney disease in pediatric Fabry and type-I diabetic patients.
J Proteome Res
. 2013 May;12(5):2013–21.
65.
Hollander Z, Dai DL, Putko BN, Yogasundaram H, Wilson-McManus JE, Thompson RB, et al. Gender-specific plasma proteomic biomarkers in patients with Anderson-Fabry disease.
Eur J Heart Fail
. 2015 Mar;17(3):291–300.
66.
Weidemann F, Breunig F, Beer M, Sandstede J, Störk S, Voelker W, et al. The variation of morphological and functional cardiac manifestation in Fabry disease: potential implications for the time course of the disease.
Eur Heart J
. 2005 Jun;26(12):1221–7.
67.
Niemann M, Herrmann S, Hu K, Breunig F, Strotmann J, Beer M, et al. Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment.
JACC Cardiovasc Imaging
. 2011 Jun;4(6):592–601.
68.
MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females.
J Med Genet
. 2001 Nov;38(11):769–75.
69.
Feldt-Rasmussen U, Dobrovolny R, Nazarenko I, Ballegaard M, Hasholt L, Rasmussen AK, et al. Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a “sequencing cryptic” α-galactosidase a large deletion.
Mol Genet Metab
. 2011 Nov;104(3):314–8.
70.
Matafora V, Cuccurullo M, Beneduci A, Petrazzuolo O, Simeone A, Anastasio P, et al. Early markers of Fabry disease revealed by proteomics.
Mol Biosyst
. 2015 Jun;11(6):1543–51.
71.
Bleyer AJ, Zivná M, Kmoch S. Uromodulin-associated kidney disease.
Nephron Clin Pract
. 2011;118(1):c31–6.
72.
Rampoldi L, Scolari F, Amoroso A, Ghiggeri G, Devuyst O. The rediscovery of uromodulin (Tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease.
Kidney Int
. 2011 Aug;80(4):338–47.
73.
Ries M, Bettis KE, Choyke P, Kopp JB, Austin HA 3rd, Brady RO, et al. Parapelvic kidney cysts: a distinguishing feature with high prevalence in Fabry disease.
Kidney Int
. 2004 Sep;66(3):978–82.
74.
Glass RB, Astrin KH, Norton KI, Parsons R, Eng CM, Banikazemi M, et al. Fabry disease: renal sonographic and magnetic resonance imaging findings in affected males and carrier females with the classic and cardiac variant phenotypes.
J Comput Assist Tomogr
. 2004 Mar-Apr;28(2):158–68.
75.
Sayer JA, Haslam P, Brennan P. Parapelvic cysts leading to a diagnosis of Fabry disease.
Kidney Int
. 2008 Nov;74(10):1366.
76.
Pisani A, Daniele A, Di Domenico C, Nigro E, Salvatore F, Riccio E. Late diagnosis of Fabry disease caused by a de novo mutation in a patient with end stage renal disease.
BMC Res Notes
. 2015 Nov;8(1):711.
77.
Pisani A, Riccio E, Cianciaruso B, Imbriaco M. Simultaneous multicystic kidney and Anderson-Fabry disease: 2 separate entities or same side of the coin.
J Nephrol
. 2011 Nov-Dec;24(6):806–8.
78.
Keyl MJ, Bell RD, Parry WL. Summary of renal lymphatic studies.
J Urol
. 1973 Mar;109(3):325–9.
79.
Chatterjee S, Shi WY, Wilson P, Mazumdar A. Role of lactosylceramide and MAP -kinase in the proliferation of proximal -tubular cells in human polycystic kidney disease.
J Lipid Res
. 1996 Jun;37(6):1334–44.
80.
Deshmukh GD, Radin NS, Gattone VH 2nd, Shayman JA. Abnormalities of glycosphingolipid, sulfatide, and ceramide in the polycystic (cpk/cpk) mouse.
J Lipid Res
. 1994 Sep;35(9):1611–8.
81.
Janich P, Corbeil D. GM1 and GM3 gangliosides highlight distinct lipid microdomains within the apical domain of epithelial cells.
FEBS Lett
. 2007 May;581(9):1783–7.
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