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Timing of renal replacement therapy does not influence survival and growth in children with congenital nephrotic syndrome caused by mutations in NPHS1: data from the ESPN/ERA-EDTA Registry



Congenital nephrotic syndrome (CNS) of the Finnish type, NPHS1, is the most severe form of CNS. Outcomes of renal replacement therapy (RRT) in NPHS1 patients in Europe were analysed using data from the ESPN/ERA-EDTA Registry. As NPHS1 is most prevalent in Finland and the therapeutic approach differs from that in many other countries, we compared outcomes in Finnish and other European patients.


NPHS1 mutations were confirmed in 170 children with CNS who initiated RRT (dialysis or renal transplantation) between 1991 and 2012. Finnish (n = 66) and non-Finnish NPHS1 patients (n = 104) were compared with respect to treatment policy, age at first RRT and renal transplantation (RTX), patient and graft survival, estimated glomerular filtration rate (eGFR) and growth. Age-matched patients with congenital anomalies of the kidney and urinary tract (CAKUT) served as controls.


Finnish NPHS1 patients were significantly younger than non-Finnish patients, both at the start of RRT and at the time of RTX. We found similar overall 5-year patient survival on RRT (91 %) and graft survival (89 %) in both NPHS1 groups and CAKUT controls. At the start of RRT, height standard deviation score (SDS) was higher in Finnish patients than in non-Finnish patients (mean [95 % CI]: −1.31 [−2.13 to −0.49] and −3.0 [−4.22 to −1.91], p < 0.01 respectively), but not at 5 years of age. At 5 years of age height and body mass index (BMI) SDS were similar to those of CAKUT controls.


Overall, 5-year patient and graft survival of both Finnish and non-Finnish NPHS1 patients on RRT were excellent and comparable with CAKUT patients with equally early RRT onset and was independent of the timing of RRT initiation and RTX.

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  1. 1.

    Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein -Nephrin- is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582

    Article  PubMed  Google Scholar 

  2. 2.

    Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler M, Niaudet P, Antigmac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Jalanko H (2009) Congenital nephrotic syndrome. Pediatr Nephrol 24:2121–2128

    Article  PubMed  Google Scholar 

  4. 4.

    Hinkes BG, Mucha B, Vlangos CN et al (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119:e907–e919

    Article  PubMed  Google Scholar 

  5. 5.

    Patrakka J, Kestilä M, Wartiovaara J, Ruotsalainen V, Tissari P, Lenkkeri U, Männikkö M, Visapää I, Holmberg C, Rapola J, Tryggvason K, Jalanko H (2000) Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int 58:972–980

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Holmberg C, Antikainen M, Rönnholm K, Ala-Houhala M, Jalanko H (1995) Management of congenital nephrotic syndrome of the Finnish type. Pediatr Nephrol 9:87–93

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Ismaili K, Wissing KM, Janssen F, Hall M (2009) Genetic forms of nephrotic syndrome: a single-center experience in Brussels. Pediatr Nephrol 24:287–294

    Article  PubMed  Google Scholar 

  8. 8.

    Santin S, Bullich G, Tazón-Vega B, Garcia-Maset R, Gimenez I, Silva I, Ruiz P, Ballarin J, Torra R, Ars E (2011) Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6:1139–1148

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Philippe A, Nevo F, Esquivel EL, Reklaityte D, Gribouval O, Tête MJ, Loirat C, Dantal J, Fischbach M, Pouteil-Noble C, Decramer S, Hoehne M, Benzing T, Charbit M, Niaudet P, Antignac C (2008) Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19:1871–1878

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Wong W, Morris MC, Kara T (2013) Congenital nephrotic syndrome with prolonged renal survival without renal replacement therapy. Pediatr Nephrol 28:2313–2321

    Article  PubMed  Google Scholar 

  11. 11.

    Licht C, Eifinger F, Gharib M, Offner G, Michalk DV, Querfeld U (2000) A stepwise approach to the treatment of early onset nephrotic syndrome. Pediatr Nephrol 14:1077–1082

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Coulthard MG (1989) Management of Finnish congenital nephrotic syndrome by unilateral nephrectomy. Pediatr Nephrol 3:451–453

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Mattoo TK, al-Sowailem AM, al-Harbi MS, Mahmood MA, Katawee Y, Hassab MH (1992) Nephrotic syndrome in 1st year of life and the role of unilateral nephrectomy. Pediatr Nephrol 6:16–18

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Kovacevic L, Reid CJ, Rigden SPA (2003) Management of congenital nephrotic syndrome. Pediatr Nephrol 18:426–430

    Article  PubMed  Google Scholar 

  15. 15.

    Kim MS, Stablein D, Harmon WE (1998) Renal transplantation in children with congenital nephrotic syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 2:305–308

    CAS  PubMed  Google Scholar 

  16. 16.

    Tizard EJ, Verrina E, van Stralen KJ, Jager KJ (2009) Progress with the European society for paediatric nephrology (ESPN)/ERA-EDTA Registry for children with established renal failure (ERF). Nephrol Dial Transplant 24:2615–2617

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Van Dijk PC, Jager KJ, de Charro F, Collart F, Cornet R, Dekker FW, Grönhagen-Riska C, Kramar R, Leivestad T, Simpson K, Briggs JD, ERA-EDTA registry (2001) Renal replacement therapy in Europe: the results of a collaborative effort by the ERA-EDTA registry and six national or regional registries. Nephrol Dial Transplant 16:1120–1129

    Article  PubMed  Google Scholar 

  18. 18.

    Bonthuis M, van Stralen KJ, Verrina E, Edefonti A, Molchanova EA, Hokken-Koelega A, Schaefer F, Jager KJ (2012) Use of national and international growth charts for studying height in European children: development of up-to-date European height-for-age charts. PLoS One 7(8):e42506

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Bonthuis M, van Stralen KJ, Verrina E, Groothoff JW, Alonso Melgar A, Edefonti A, Fischbach M, Mendes P, Molchanova EA, Paripović D, Peco-Antic A, Printza N, Rees L, Rubik J, Stefanidis CJ, Sinha MD, Zagożdżon I, Jager KJ, Schaefer F (2013) Underweight, overweight and obesity in paediatric dialysis and renal transplant patients. Nephrol Dial Transplant 28:iv195–iv204

    Article  PubMed  Google Scholar 

  20. 20.

    WHO multicenter growth reference study group (2006) WHO child growth standards: length/height-for -age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-height. Methods and development. World Health Organization, Geneva

    Google Scholar 

  21. 21.

    De Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J (2007) Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 85:660–667

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Noordzij M, Leffondré K, van Stralen KJ, Zoccali C, Dekker FW, Jager KJ (2013) When do we need competing risks methods for survival analysis in nephrology? Nephrol Dial Transplant 28:2670–2677

    Article  PubMed  Google Scholar 

  24. 24.

    Mekahli D, Shaw V, Lederman SE, Rees L (2010) Long-term outcome of infants with severe chronic kidney disease. Clin J Am Soc Nephrol 5:10–17

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Alexander RT, Foster BJ, Tonelli MA, Soo A, Nettel. Aguirre A, Hemmelgarn BR, Samuel SM (2012) Survival and transplantation outcomes of children less than 2 years of age with end-stage renal disease. Pediatr Nephrol 27:1975–1983

    Article  PubMed  Google Scholar 

  26. 26.

    Vidal E, Edefonti A, Murer L, Gianoglio B, Maringhini S, Pecoraro C, Sorino P, Leozappa G, Lavoratti G, Ratsch IM, Chimenz R, Verrina E, Italian Registry of Paediatric Chronic Dialysis (2012) Peritoneal dialysis in infants: the experience of the Italian Registry of paediatric chronic dialysis. Nephrol Dial Transplant 27:388–395

    Article  PubMed  Google Scholar 

  27. 27.

    Laakkonen H, Hölttä T, Lönnqvist T, Holmberg C, Rönnholm K (2008) Peritoneal dialysis in children under two years of age. Nephrol Dial Transplant 23:1747–1753

    Article  PubMed  Google Scholar 

  28. 28.

    Laakkonen H, Happonen J-M, Marttinen E, Paganus A, Hölttä T, Holmberg C, Rönnholm K (2010) Normal growth and intravascular volume status with good metabolic control during peritoneal dialysis. Pediatr Nephrol 25:1529–1538

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Chesnaye N, Bonthuis M, Shaefer F, Groothoff JW, Verrina E, Heaf JG, Jankauskiene A, Lukosiene V, Molchanova EA, Mota C, Peco-Antić A, Ratsch IM, Bjerre A, Roussinov DL, Sukalo A, Topaloglu R, Van Hoeck K, Zagozdzon I, Jager KJ, Van Stralen KJ, ESPN/ERA–EDTA registry (2014) Demographics of paediatric renal replacement therapy in Europe: a report of the ESNP/ERA-EDTA registry. Pediatr Nephrol 29:2403–2410

    Article  PubMed  Google Scholar 

  30. 30.

    US Renal Data System USRDS 2012 annual data report: atlas of CKD & ESRD (2012) Volume 2 atlas ESRD. Pediatric ESRD. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda MD. Available at:

  31. 31.

    Shroff R, Rees L, Trompeter R, Hutchinson C, Ledermann S (2006) Long-term outcome of chronic dialysis in children. Pediatr Nephrol 21:257–264

    Article  PubMed  Google Scholar 

  32. 32.

    Verrina E, Edefonti A, Gianoglio B, Rinaldi S, Sorino P, Zacchello G, Lavoratti G, Maringhini S, Pecoraro C, Calevo MG, Turrini Dertenois L, Perfumo F (2004) A multicenter experience on patient and technique survival in children on chronic dialysis. Pediatr Nephrol 19:82–90

    Article  PubMed  Google Scholar 

  33. 33.

    Seikaly M, Ho PL, Emmett L, Tejani A (2001) The 12th annual report of the North American Pediatric Renal Transplant Cooperative Study: renal transplantation from 1987 through 1998. Pediatr Transplant 5:215–231

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    US Renal Data System (2012) USRDS 2012 annual data report: atlas of CKD & ESRD, ADR 2012 reference tables, transplantation: outcomes. Available at:

  35. 35.

    Laine J, Holmberg C, Salmela K, Jalanko H, Sairanen H, Peltola K, Rönnholm K, Eklund B, Wikström S, Leijala M (1994) Renal transplantation in children with emphasis on young patients. Pediatr Nephrol 8:313–319

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Holmberg C, Laine J, Rönnholm K, Ala-Houhala M, Jalanko H (1996) Congenital nephrotic syndrome. Kidney Int 53:S51–S56

    CAS  Google Scholar 

  37. 37.

    Van Arendonk KJ, Boyarsky BJ, Orandi BJ, James NT, Smith JM, Colombani PM, Segev DL (2014) National trends over 25 years in pediatric kidney transplant outcomes. Pediatrics 133:594–601

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Rees L, Azocar M, Borzych D, Watson AR, Büscher A, Edefonti A, Bilge I, Askenazi D, Leozappa G, Gonzales C, van Hoeck K, Secker D, Zurowska A, Rönnholm K, Bouts AH, Stewart H, Ariceta G, Ranchin B, Warady BA, Schaefer F; International Pediatric Peritoneal Dialysis Network (IPPN) registry (2011) Growth in very young children undergoing chronic peritoneal dialysis. J Am Soc Nephrol 22:2303–2312

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We would like to thank the patients, their parents and the staff of all the dialysis and transplant units who have contributed data via their national registries and contact persons. We also would like to thank E Levtchenko, D Haffner, Z Massy and C Stefanidis for being members of the ESPN/ERA-EDTA Registry Committee; D Shitza, R Kramar, G Mayer, S Baiko, A Sukalo, K van Hoeck, F Collart, JM des Grottes, D Pokrajac, D Roussinov, D Batinić, M Lemac, J Slavicek, D Milosevic, A Elia, T Seeman, K Vondrak, JG Heaf, U Toots, P Finne, C Grönhagen-Riska, C Couchoud, M Lassalle, E Sahpazova, N Abazi, T Davitaia, B Tönshoff, K Krupka, B Höcker, L Pape, G von Gersdorff, C Scholz, N Afentakis, A Kapogiannis, N Printza, G Reusz, CS Berecki, A Szabó, T Szabó, ZS Györke, E Kis, R Palsson, V Edvardsson, B Gianoglio, S Maringhini, C Pecoraro, S Picca, S Testa, E Vidal, E Verrina, S Rudaitis, A Jankauskiene, V Said-Conti, S Gatcan, O Berbeca, N Zaikova, S Pavićević, T Leivestad, A Bjerre, A Zurowska, I Zagozdzon, C Mota, M Almeida, C Afonso, G Mircescu, L Garneata, EA Molchanova, NA Tomilina, BT Bikbov, M Kostic, A Peco-Antic, B Spasojevic-Dimitrijeva, G Milosecski-Lomic, D Paripovic, S Puric, D Kruscic, L Podracka, G Kolvek, N Battelino, G Novljan, J Buturovic-Ponikvar, A Alonso Melgar and the Spanish Pediatric Registry; S Schön, KG Prütz, L Backmän, M Evans, M Stendahl, B Rippe, CE Kuenhi, E Maurer, GF Laube, S Tschumi, P Parvex, M Hemmelder, A Hemke, and all centres participating in the RichQ study; R Topaloglu, A Duzova, D Ivanov, A Hamilton, R Pruthi, F Braddon, A Casula, MD Sinha, for contributing data to the ESPN/ERA-EDTA Registry.

The ESPN/ERA-EDTA Registry is funded by the European Society of Pediatric Nephrology (ESPN), the European Renal Association and European Dialysis and Transplant Association (ERA-EDTA) and the European Commission.

This article was written by Tuula Hölttä, Marjolein Bonthuis, Karlijn J van Stralen, Anna Bjerre, Rezan Topaloglu, Fatih Ozaltin, Christer Holmberg, Jerome Harambat, Kitty J Jager, Franz Schaefer, Jaap W Groothoff on behalf of the ESPN/ERA-EDTA Registry and the ERA-EDTA registry, which is an official body of the ERA-EDTA (European Renal Association/European Dialysis and Transplant Association).

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Correspondence to Marjolein Bonthuis.

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Tuula Hölttä, Marjolein Bonthuis, Franz Schaefer and Jaap W. Groothoff contributed equally to this work

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Hölttä, T., Bonthuis, M., Van Stralen, K.J. et al. Timing of renal replacement therapy does not influence survival and growth in children with congenital nephrotic syndrome caused by mutations in NPHS1: data from the ESPN/ERA-EDTA Registry. Pediatr Nephrol 31, 2317–2325 (2016).

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  • Congenital nephrotic syndrome
  • NPHS1
  • Kidney transplantation
  • Graft survival
  • Dialysis
  • Pediatrics