Advertisement

Pediatric Nephrology

, Volume 21, Issue 5, pp 711–718 | Cite as

Recurrence of proteinuria following renal transplantation in congenital nephrotic syndrome of the Finnish type

  • Tarak SrivastavaEmail author
  • Robert E. Garola
  • Marjo Kestila
  • Karl Tryggvason
  • Vesa Ruotsalainen
  • Mukut Sharma
  • Virginia J. Savin
  • Hannu Jalanko
  • Bradley A. Warady
Original Article

Abstract

We report a Caucasian boy of Italian descent with congenital nephrotic syndrome of the Finnish type (NPHS1, CNF, MIM 256300) who developed recurrence of proteinuria and hypoalbuminemia on the seventh post-operative day following living related renal transplantation from his paternal aunt. The allograft biopsy was normal except for effacement of podocyte foot processes on electron microscopy. He was treated by the substitution of mycophenolate mofetil with cyclophosphamide for 12 weeks, in addition to cyclosporine, prednisone and daclizumab. His proteinuria resolved quickly following the initiation of cyclophosphamide treatment, and he remains in remission 4 years after receiving his transplant. His native and allograft kidneys were evaluated for nephrin expression by immunohistochemistry, DNA analysis for the NPHS1 mutation, serum for the presence of auto-antibodies to nephrin by both enzyme-linked immunosorbent assay (ELISA) and fetal glomeruli immunofluorescence assay, and serum for glomerular permeability to albumin (Palb) activity using a functional in vitro assay for Palb. Nephrin expression was completely absent in the native kidney, while it was decreased in the allograft compared with normal. DNA analysis of the NPHS1 gene revealed mutations 3248G>T and 3250delG in exon 24, causing G1083V and 1084Vfs, respectively, inherited from his father, and 3478C>T in exon 27, that leads to R1160X, inherited from his mother. Serum was negative for auto-antibodies to nephrin. Interestingly, the Palb activity was increased at the time of recurrence of proteinuria following transplantation (Palb 0.73±0.10) and remained elevated when retested more than 3 years later (Palb 0.54±0.09). This is the first report of increased Palb activity in recurrence of proteinuria following transplantation in NPHS1. We speculate the role of increased Palb activity in the recurrence of proteinuria following transplantation in NPHS1.

Keywords

Congenital nephrotic syndrome of the Finnish type NPHS1 Renal transplantation Proteinuria Post-transplant nephrosis Glomerular albumin permeability Palb 

Notes

Acknowledgment

We acknowledge the help of Ms Maija Suvanto for her technical assistance in the DNA analysis. The study was approved by our institutional review board (03 07-075).

References

  1. 1.
    Kestila M, Lenkkeri U, Mannikko 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 1:575–582CrossRefGoogle Scholar
  2. 2.
    Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestila M, Jalanko H, Holmberg C, Tryggvason K (1999) Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci U S A 96:7962–7967CrossRefGoogle Scholar
  3. 3.
    Holmberg C, Antikainen M, Ronnholm K, Ala Houhala M, Jalanko H (1995) Management of congenital nephrotic syndrome of the Finnish type. Pediatr Nephrol 9:87–93CrossRefGoogle Scholar
  4. 4.
    Patrakka J, Ruotsalainen V, Reponen P, Qvist E, Laine J, Holmberg C, Tryggvason K, Jalanko H (2002) Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 73:394–403CrossRefGoogle Scholar
  5. 5.
    Barayan SS, Al-Akash SI, Malekzadeh M, Marik JL, Cohen AH, Ettenger RB, Yadin O (2001) Immediate post-transplantation nephrosis in a patient with congenital nephrotic syndrome. Pediatr Nephrol 16:547–549CrossRefGoogle Scholar
  6. 6.
    Lane PH, Schnaper HW, Vernier RL, Bunchman TE (1991) Steroid-dependent nephrotic syndrome following renal transplantation for congenital nephrotic syndrome. Pediatr Nephrol 5:300–303CrossRefGoogle Scholar
  7. 7.
    Flynn JT, Schulman SL, Dechadarevian JP, Dunn SP, Kaiser BA, Polinsky MS, Baluarte HJ (1992) Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome. Pediatr Nephrol 6:553–555CrossRefGoogle Scholar
  8. 8.
    Laine J, Jalanko H, Holthofer H, Krogerus L, Rapola J, Von Willebrand E, Lautenschlager I, Salmela K, Holmberg C (1993) Post-transplantation nephrosis in congenital nephrotic syndrome of the Finnish type. Kidney Int 44:867–874CrossRefGoogle Scholar
  9. 9.
    Carraro M, Caridi G, Bruschi M, Artero M, Bertelli R, Zennaro C, Musante L, Candiano G, Perfumo F, Ghiggeri GM (2002) Serum glomerular permeability activity in patients with podocin mutations (NPHS2) and steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13:1946–1952CrossRefGoogle Scholar
  10. 10.
    Ruotsalainen V, Patrakka J, Tissari P, Reponen P, Hess M, Kestila M, Holmberg C, Salonen R, Heikinheimo M, Wartiovaara J, Tryggvason K, Jalanko H (2000) Role of nephrin in cell junction formation in human nephrogenesis. Am J Pathol 157:1905–1916CrossRefGoogle Scholar
  11. 11.
    Srivastava T, Whiting JM, Garola RE, Dasouki MJ, Ruotsalainen V, Tryggvason K, Hamed R, Alon US (2001) Podocyte proteins in Galloway–Mowat syndrome. Pediatr Nephrol 16:1022–1029CrossRefGoogle Scholar
  12. 12.
    Sharma M, Sharma R, McCarthy ET, Savin VJ (2004) The focal segmental glomerulosclerosis permeability factor: biochemical characteristics and biological effects. Exp Biol Med 229:85–98CrossRefGoogle Scholar
  13. 13.
    Savin VJ, Sharma R, Lovell HB, Welling DJ (1992) Measurement of albumin reflection coefficient with isolated rat glomeruli. J Am Soc Nephrol 3:1260–1269PubMedGoogle Scholar
  14. 14.
    Doyle SM, Savin V, Winn M, Conlon P (1999) Circulating permeability factor in familial focal segmental glomerulosclerosis (FSGS). J Am Soc Nephrol 10:115AGoogle Scholar
  15. 15.
    Savin VJ, Sharma R, Sharma M, McCarthy ET, Swan SK, Ellis E, Lovell H, Warady B, Gunwar S, Chonko AM, Artero M, Vincenti F (1996) Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878–883CrossRefGoogle Scholar
  16. 16.
    Fasola CG, Gillingham KJ, Troppmann C, Gruessner RW, Gores PF, Dunn DL, Payne WD, Sutherland DE, Matas AJ, Najarian JS (1994) Kidney transplant or retransplant can effectively treat congenital nephrotic syndrome: a single-center experience. Transplant Proc 26:9PubMedGoogle Scholar
  17. 17.
    Kari JA, Romagnoli J, Duffy P, Fernando ON, Rees L, Trompeter RS (1999) Renal transplantation in children under 5 years of age. Pediatr Nephrol 13:730–736CrossRefGoogle Scholar
  18. 18.
    Patrakka J, Ruotsalainen V, Holmberg C, Tryggvason K, Jalanko H (2000) Nephrin and post-transplantation nephrosis in congenital nephrotic syndrome (NPHS1). J Am Soc Nephrol 11:702AGoogle Scholar
  19. 19.
    Lenkkeri U, Mannikko M, McCready P, Lamerdin J, Gribouval O, Niaudet PM, Antignac CK, Kashtan CE, Homberg C, Olsen A, Kestila M, Tryggvason K (1999) Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 64:51–61CrossRefGoogle Scholar
  20. 20.
    Kawachi H, Koike H, Kurihara H, Yaoita E, Orikasa M, Shia MA, Sakai T, Yamamoto T, Salant DJ, Shimizu F (2000) Cloning of rat nephrin: expression in developing glomeruli and in proteinuric states. Kidney Int 57:1949–1961CrossRefGoogle Scholar
  21. 21.
    Luimula P, Ahola H, Wang SX, Solin ML, Aaltonen P, Tikkanen I, Kerjaschki D, Holthofer H (2000) Nephrin in experimental glomerular disease. Kidney Int 58:1461–1468CrossRefGoogle Scholar
  22. 22.
    Kalluri R, Torre A, Shield CF 3rd, Zamborsky ED, Werner MC, Suchin E, Wolf G, Helmchen UM, Van Den Heuvel LP, Grossman R, Aradhye S, Neilson EG (2000) Identification of alpha3, alpha4, and alpha5 chains of type IV collagen as alloantigens for Alport posttransplant anti-glomerular basement membrane antibodies. Transplantation 69:679–683CrossRefGoogle Scholar
  23. 23.
    Sharma M, Sharma R, McCarthy ET, Savin VJ (1999) The FSGS factor: enrichment and in vivo effect of activity from focal segmental glomerulosclerosis plasma. J Am Soc Nephrol 10:552–561PubMedGoogle Scholar
  24. 24.
    Candiano G, Musante L, Carraro M, Faccini L, Campanacci L, Zenanro C, Artero M, Ginevri F, Perfumo F, Gusmano R, Ghiggeri GM (2001) Apolipoproteins prevent glomerular albumin permeability induced in vitro by serum from patients with focal segmental glomerulosclerosis. J Am Soc Nephrol 12:143–150PubMedGoogle Scholar
  25. 25.
    Sharma R, Sharma M, McCarthy ET, Ge XL, Savin VJ (2000) Components of normal serum block the focal segmental glomerulosclerosis factor activity in vitro. Kidney Int 58:1973–1979CrossRefGoogle Scholar
  26. 26.
    Sharma R, Sharma M, Datta PK, Savin VJ (2002) Induction of metallothionein-I protects glomeruli from superoxide-mediated increase in albumin permeability. Exp Biol Med 227:26–31CrossRefGoogle Scholar
  27. 27.
    Adler S, Sharma R, Savin VJ, Abbi R, Eng B (1996) Alteration of glomerular permeability to macromolecules induced by cross-linking of beta 1 integrin receptors. Am J Pathol 149:987–996PubMedPubMedCentralGoogle Scholar
  28. 28.
    Dileepan KN, Sharma R, Stechschulte DJ, Savin VJ (1993) Effect of superoxide exposure on albumin permeability of isolated rat glomeruli. J Lab Clin Med 121:797–804PubMedGoogle Scholar
  29. 29.
    Cattran D, Neogi T, Sharma R, McCarthy ET, Savin VJ (2003) Serial estimates of serum permeability activity and clinical correlates in patients with native kidney focal segmental glomerulosclerosis. J Am Soc Nephrol 14:448–453CrossRefGoogle Scholar
  30. 30.
    Sharma R, Lovell HB, Wiegmann TB, Savin V (1992) Vasoactive substances induce cytoskeletal changes in cultured rat glomerular epithelial cells. J Am Soc Nephrol 3:1131–1138PubMedGoogle Scholar
  31. 31.
    Sharma R, Sharma M, Ge X, McCarthy ET, Savin VJ (1996) Cyclosporine protects glomeruli from FSGS factor via an increase in glomerular cAMP. Transplantation 62:1916–1920CrossRefGoogle Scholar
  32. 32.
    Li B, Yao J, Morioka T, Oite T (2001) Nitric oxide increases albumin permeability of isolated rat glomeruli via a phosphorylation-dependent mechanism. J Am Soc Nephrol 12:2616–2624PubMedGoogle Scholar
  33. 33.
    Winn MP, Rosenberg P, Conlon RJ, Lynn KL, Farrington MK, Kwan SY, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM (2004) A mutation in TRPC6 causes familial focal segmental glomerulosclerosis. J Am Soc Nephrol 15:33ACrossRefGoogle Scholar

Copyright information

© IPNA 2006

Authors and Affiliations

  • Tarak Srivastava
    • 1
    Email author
  • Robert E. Garola
    • 2
  • Marjo Kestila
    • 3
  • Karl Tryggvason
    • 4
  • Vesa Ruotsalainen
    • 5
  • Mukut Sharma
    • 6
  • Virginia J. Savin
    • 6
  • Hannu Jalanko
    • 7
  • Bradley A. Warady
    • 1
  1. 1.Section of NephrologyThe Children’s Mercy HospitalKansas CityUSA
  2. 2.Department of PathologyDuPont Hospital for ChildrenWilmingtonUSA
  3. 3.Department of Molecular MedicineNational Public Health InstituteHelsinkiFinland
  4. 4.Division of Matrix Biology and Medical Biochemistry and BiophysicsKarolinska InstituteStockholmSweden
  5. 5.Department of BiochemistryUniversity of OuluOuluFinland
  6. 6.Department of Medicine, Division of NephrologyMedical College of WisconsinMilwaukeeUSA
  7. 7.Section of Nephrology, Hospital for Children and AdolescentsUniversity of HelsinkiHelsinkiFinland

Personalised recommendations