Abstract
Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.
Original language | English |
---|---|
Pages (from-to) | 1112-1123 |
Number of pages | 12 |
Journal | Kidney International |
Volume | 100 |
Issue number | 5 |
DOIs | |
Publication status | Published - Nov 2021 |
Externally published | Yes |
Keywords
- chronic kidney disease
- cysteamine
- end-stage kidney disease
- growth
- leucocyte cystine levels
- renal Fanconi syndrome
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In: Kidney International, Vol. 100, No. 5, 11.2021, p. 1112-1123.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis
AU - Emma, Francesco
AU - Hoff, William van t.
AU - Hohenfellner, Katharina
AU - Topaloglu, Rezan
AU - Greco, Marcella
AU - Ariceta, Gema
AU - Bettini, Chiara
AU - Bockenhauer, Detlef
AU - Veys, Koenraad
AU - Pape, Lars
AU - Hulton, Sally
AU - Collin, Suzanne
AU - Ozaltin, Fatih
AU - Servais, Aude
AU - Deschênes, Georges
AU - Novo, Robert
AU - Bertholet-Thomas, Aurélia
AU - Oh, Jun
AU - Cornelissen, Elisabeth
AU - Janssen, Mirian
AU - Haffner, Dieter
AU - Ravà, Lucilla
AU - Antignac, Corinne
AU - Devuyst, Olivier
AU - Niaudet, Patrick
AU - Levtchenko, Elena
N1 - Funding Information: This work was started with the support of the FP7 European Community Program EUNEFRON (European Network for the Study of Orphan Nephropathies). In the past 36 months, FE, DH, GD, DB, KH, EL, GA, and LP have received consulting fees and/or other honoraria for lectures, presentations, educational events, or participation to advisory boards, from 1 or more of the following for-profit third parties: Recordati Rare Diseases, Chiesi Pharmaceuticals, and Avrobio. FE, MG, EL, DH, OD, CA, AB-T, AS, GA, EC, and LP are members of the European Reference Network for Rare Kidney Diseases (www.ERKNet.org)—project 739532. FE, OD, AS, CA, and KN are supported by the Cystinosis Research Foundation. OD is supported by the University Research Priority Program (UFSP) ITINERARE (Innovative Therapies in Rare Diseases) of the University of Zurich. EL is supported by the Flemish Foundation for Scientific Research (The Research Foundation–Flanders Clinical Investigator grant). AB-T is a member of the French rare diseases healthcare network/rare renal diseases (ORKiD). AS, PN, MG, FE, EL, GA, GD, RN, and AB-T contribute to the RaDiCo-European Cystinosis Cohort (ECYSCO) that is part of the Rare Disease Cohort program supported by Inserm and funded by the French National Research Agency through the Investissements d'Avenir program (ANR-10-COHO-0003). It uses the Research Electronic Data Capture tool REDCap. RT and FO were supported by grant 01301101001 from Hacettepe University Scientific Research and Development Office. The authors would like to thank Dominik Müller, Christoph Aufricht, Sylvie Cloarec, Jérôme Harambat, Stéphane Decramer, Denis Morin, Maurice Savage, Mary MvGraw, Judith van der Voort, Denis Gill, T. James Beattie, Sue Rigden, Maggie Fitzpatrick, David Hughes, Robert J Postlewaite, Malcolm Coulthard, Alan Watson, Robert Jones, and Gail Moss for contributing patient data, and Alessandra Geraci for assembling the initial database. The study was designed by FE, WvH, PN, EL, and OD. FE, WvH, KH, RT, MG, GA, DB, KV, LP, SH, SC, FO, AS, GD, RN, AB-T, JO, MC, MJ, DH, PN, and EL took care of patients and collected data. CB and FE created the final database and verified all data entry. FE, KV, and CA reviewed and classified the genetic data. Data analysis and interpretation was performed by FE, EL, and OD. Statistical analysis was performed by FE and LR. The manuscript was drafted by FE and EL and reviewed by all authors. All authors provided significant intellectual contributions to the manuscript and approved the final version. Funding Information: This work was started with the support of the FP7 European Community Program EUNEFRON (European Network for the Study of Orphan Nephropathies). In the past 36 months, FE, DH, GD, DB, KH, EL, GA, and LP have received consulting fees and/or other honoraria for lectures, presentations, educational events, or participation to advisory boards, from 1 or more of the following for-profit third parties: Recordati Rare Diseases, Chiesi Pharmaceuticals , and Avrobio. FE, MG, EL, DH, OD, CA, AB-T, AS, GA, EC, and LP are members of the European Reference Network for Rare Kidney Diseases ( www.ERKNet.org )—project 739532. FE, OD, AS, CA, and KN are supported by the Cystinosis Research Foundation . OD is supported by the University Research Priority Program (UFSP) ITINERARE (Innovative Therapies in Rare Diseases) of the University of Zurich . EL is supported by the Flemish Foundation for Scientific Research (The Research Foundation–Flanders Clinical Investigator grant). AB-T is a member of the French rare diseases healthcare network / rare renal diseases (ORKiD). AS, PN, MG, FE, EL, GA, GD, RN, and AB-T contribute to the RaDiCo-European Cystinosis Cohort (ECYSCO) that is part of the Rare Disease Cohort program supported by Inserm and funded by the French National Research Agency through the Investissements d'Avenir program (ANR-10-COHO-0003). It uses the Research Electronic Data Capture tool REDCap. RT and FO were supported by grant 01301101001 from Hacettepe University Scientific Research and Development Office. Publisher Copyright: © 2021 International Society of Nephrology
PY - 2021/11
Y1 - 2021/11
N2 - Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.
AB - Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.
KW - chronic kidney disease
KW - cysteamine
KW - end-stage kidney disease
KW - growth
KW - leucocyte cystine levels
KW - renal Fanconi syndrome
UR - http://www.scopus.com/inward/record.url?scp=85115949021&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.kint.2021.06.019
DO - https://doi.org/10.1016/j.kint.2021.06.019
M3 - Article
C2 - 34237326
SN - 0085-2538
VL - 100
SP - 1112
EP - 1123
JO - Kidney International
JF - Kidney International
IS - 5
ER -