Top

Published in:

Open Access 01-11-2018 | Review

Deriving and understanding the risk of post-transplant recurrence of nephrotic syndrome in the light of current molecular and genetic advances

Authors: Agnieszka Bierzynska, Moin A. Saleem

Published in: Pediatric Nephrology | Issue 11/2018

Abstract

After renal transplantation, recurrence of the original disease is the second most common cause of graft loss, after rejection. The most dramatic manifestation of this phenomenon is in patients with nephrotic syndrome (NS). NS is a descriptive term describing a clinical picture centred on proteinuria arising from damage to the glomerular filtration barrier (GFB). There are many different drivers of that damage, ranging from immune dysregulation to genetic disorders and chronic disease/infections. The main categories in childhood are “idiopathic” (presumed immune mediated) and genetic NS, with further stratification of the idiopathic group according to steroid responses. A significant proportion of patients with NS progress to established renal failure, requiring transplantation, and one of the most difficult clinical scenarios faced by nephrologists is the recurrence of the original disease in up to 50% of patients, usually rapidly post-transplant. This is thought to be the archetypal “circulating factor” disease, in which as yet unknown circulating plasma “factor(s)” in the recipient target the donor kidney. The ability to predict in advance which patients will suffer recurrence would enhance our ability to counsel patients and families, and potentially identify those patients before transplant for tailored immunosuppressive preparation. Until very recently, stratification based on clinical categorisations has been poor in being able to predict those patients in whom disease will recur, and laboratory biomarkers are yet to be adequately refined. However, by mapping our growing understanding of disease mechanisms to clinical phenotypes, and with greatly improved genetic diagnostics, we have made progress in being able to stratify patients more specifically, and allow better predictive algorithms to be developed. Using our knowledge of podocyte biology, circulating factor-induced specific biomarkers are also being tested. This review is aimed at outlining those advances, and suggesting how we can move further forward in both clinical and biological markers of disease type.

Bierzynska A, McCarthy HJ, Soderquest K, Sen ES, Colby E, Ding WY, Nabhan MM, Kerecuk L, Hegde S, Hughes D, Marks S, Feather S, Jones C, Webb NJ, Ognjanovic M, Christian M, Gilbert RD, Sinha MD, Lord GM, Simpson M, Koziell AB, Welsh GI, Saleem MA (2017) Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 91(4):937–947CrossRef

Santin S, Bullich G, Tazon-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 6:1139–1148CrossRef

Hickson LJ, Gera M, Amer H, Iqbal CW, Moore TB, Milliner DS, Cosio FG, Larson TS, Stegall MD, Ishitani MB, Gloor JM, Griffin MD (2009) Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence. Transplantation 87:1232–1239CrossRef

Ingulli E, Tejani A (1991) Incidence, treatment, and outcome of recurrent focal segmental glomerulosclerosis posttransplantation in 42 allografts in children—a single-center experience. Transplantation 51:401–405CrossRef

Tejani A, Stablein DH (1992) Recurrence of focal segmental glomerulosclerosis posttransplantation: a special report of the North American Pediatric Renal Transplant Cooperative Study. J Am Soc Nephrol 2:S258–S263PubMed

Maas RJ, Deegens JK, van den Brand JA, Cornelissen EA, Wetzels JF (2013) A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation. BMC Nephrol 14:47CrossRef

Odorico JS, Knechtle SJ, Rayhill SC, Pirsch JD, D'Alessandro AM, Belzer FO, Sollinger HW (1996) The influence of native nephrectomy on the incidence of recurrent disease following renal transplantation for primary glomerulonephritis. Transplantation 61:228–234CrossRef

Fujisawa M, Iijima K, Ishimura T, Higuchi A, Isotani S, Yoshiya K, Arakawa S, Hamami G, Matsumoto O, Yoshikawa N, Kamidono S (2002) Long-term outcome of focal segmental glomerulosclerosis after Japanese pediatric renal transplantation. Pediatr Nephrol 17:165–168CrossRef

Dall'Amico R, Ghiggeri G, Carraro M, Artero M, Ghio L, Zamorani E, Zennaro C, Basile G, Montini G, Rivabella L, Cardillo M, Scalamogna M, Ginevri F (1999) Prediction and treatment of recurrent focal segmental glomerulosclerosis after renal transplantation in children. Am J Kidney Dis 34:1048–1055CrossRef

10.

Sener A, Bella AJ, Nguan C, Luke PP, House AA (2009) Focal segmental glomerular sclerosis in renal transplant recipients: predicting early disease recurrence may prolong allograft function. Clin Transplant 23(1):96–100CrossRef

11.

Pinto J, Lacerda G, Cameron JS, Turner DR, Bewick M, Ogg CS (1981) Recurrence of focal segmental glomerulosclerosis in renal allografts. Transplantation 32(2):83–89CrossRef

12.

Artero M, Biava C, Amend W, Tomlanovich S, Vincenti F (1992) Recurrent focal glomerulosclerosis: natural history and response to therapy. Am J Med 92(4):375–383CrossRef

13.

Cheong HI, Han HW, Park HW, Ha IS, Han KS, Lee HS, Kim SJ, Choi Y (2000) Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis. Nephrol Dial Transplant 15(1):78–81CrossRef

14.

Senggutuvan P, Cameron JS, Hartley RB, Rigden S, Chantler C, Haycock G, Williams DG, Ogg C, Koffman G (1990) Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: analysis of incidence and risk factors in 59 allografts. Pediatr Nephrol 4(1):21–28CrossRef

15.

Kim SJ, Ha J, Jung IM, Ahn MS, Kim M, Lee HS, Cheong HI, Choi Y (2001) Recurrent focal segmental glomerulosclerosis following renal transplantation in Korean pediatric patients. Pediatr Transplant 2001 5(2):105–111CrossRef

16.

Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula MK, Dudley JA, Inward CD, Coward RJ, Tizard J, Reid C, Antignac C, Boyer O, Saleem MA (2014) Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol 25:1342–1348CrossRef

17.

Rudnicki M (2016) FSGS recurrence in adults after renal transplantation. Biomed Res Int 2016:3295618CrossRef

18.

Striegel JE, Sibley RK, Fryd DS, Mauer SM (1986) Recurrence of focal segmental sclerosis in children following renal transplantation. Kidney Int Suppl 19:S44–S50PubMed

19.

Stephanian E, Matas AJ, Mauer SM, Chavers B, Nevins T, Kashtan C, Sutherland DE, Gores P, Najarian JS (1992) Recurrence of disease in patients retransplanted for focal segmental glomerulosclerosis. Transplantation 53:755–757CrossRef

20.

Welsh GI, Saleem MA (2012) The podocyte cytoskeleton—key to a functioning glomerulus in health and disease. Nat Rev Nephrol 8:14–21CrossRef

21.

Bierzynska A, Soderquest K, Dean P, Colby E, Rollason R, Jones C, Inward CD, McCarthy HJ, Simpson MA, Lord GM, Williams M, Welsh GI, Koziell AB, Saleem MA; NephroS; UK study of Nephrotic Syndrome (2016) MAGI2 mutations are responsible for congenital nephrotic syndrome. J Am Soc Nephrol 28(5):1614–1621

22.

Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergada I, Cassinelli H, Das U, Krone R, Hacihamdioglu B, Sari E, Yesilkaya E, Storr HL, Clemente M, Fernandez-Cancio M, Camats N, Ram N, Achermann JC, Van Veldhoven PP, Guasti L, Braslavsky D, Guran T, Metherell LA (2017) Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest 27:942–953CrossRef

23.

Sen ES, Dean P, Yarram-Smith L, Bierzynska A, Woodward G, Buxton C, Dennis G, Welsh G, Williams M, Saleem MA (2017) Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations. J Med Genet. https://doi.org/10.1136/jmedgenet-2017-104811 CrossRef

24.

Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, Maiguel D, Karumanchi SA, Yap HK, Saleem M, Zhang Q, Nikolic B, Chaudhuri A, Daftarian P, Salido E, Torres A, Salifu M, Sarwal MM, Schaefer F, Morath C, Schwenger V, Zeier M, Gupta V, Roth D, Rastaldi MP, Burke G, Ruiz P, Reiser J (2011) Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17:952–960CrossRef

25.

Bitzan M, Babayeva S, Vasudevan A, Goodyer P, Torban E (2012) TNF alpha pathway blockade ameliorates toxic effects of FSGS plasma on podocyte cytoskeleton and beta 3 integrin activation. Pediatr Nephrol 27:2217–2226CrossRef

26.

Sgambat K, Banks M, Moudgil A (2013) Effect of galactose on glomerular permeability and proteinuria in steroid-resistant nephrotic syndrome. Pediatr Nephrol 28:2131–2135CrossRef

27.

Bertelli R, Ginevri F, Caridi G, Dagnino M, Sandrini S, Di Duca M, Emma F, Sanna-Cherchi S, Scolari F, Neri TM, Murer L, Massella L, Basile G, Rizzoni G, Perfumo F, Ghiggeri GM (2003) Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin. Am J Kidney Dis 41:1314–1321CrossRef

28.

Billing H, Muller D, Ruf R, Lichtenberger A, Hildebrandt F, August C, Querfeld U, Haffner D (2004) NPHS2 mutation associated with recurrence of proteinuria after transplantation. Pediatr Nephrol 19:561–564CrossRef

29.

Becker-Cohen R, Bruschi M, Rinat C, Feinstein S, Zennaro C, Ghiggeri GM, Frishberg Y (2007) Recurrent nephrotic syndrome in homozygous truncating NPHS2 mutation is not due to anti-podocin antibodies. Am J Transplant 7:256–260CrossRef

30.

Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ, Legendre C, Niaudet P, Antignac C (2004) NPHS2 Mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 66:571–579CrossRef

31.

Hocker B, Knuppel T, Waldherr R, Schaefer F, Weber S, Tonshoff B (2006) Recurrence of proteinuria 10 years post-transplant in NPHS2-associated focal segmental glomerulosclerosis after conversion from cyclosporin a to sirolimus. Pediatr Nephrol 21:1476–1479CrossRef

32.

Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732CrossRef

33.

Caridi G, Bertelli R, Perfumo F, Ghiggeri GM (2004) Heterozygous NPHS1 or NPHS2 mutations in responsive nephrotic syndrome and the multifactorial origin of proteinuria. Kidney Int 66:1715–1716CrossRef

34.

Caridi G, Bertelli R, Di Duca M, Dagnino M, Emma F, Onetti Muda A, Scolari F, Miglietti N, Mazzucco G, Murer L, Carrea A, Massella L, Rizzoni G, Perfumo F, Ghiggeri GM (2003) Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol 14:1278–1286CrossRef

35.

Ghiggeri GM, Aucella F, Caridi G, Bisceglia L, Ghio L, Gigante M, Perfumo F, Carraro M, Gesualdo L (2006) Posttransplant recurrence of proteinuria in a case of focal segmental glomerulosclerosis associated with WT1 mutation. Am J Transplant 6:2208–2211CrossRef

36.

Weins A, Kenlan P, Herbert S, Le TC, Villegas I, Kaplan BS, Appel GB, Pollak MR (2005) Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol 16:3694–3701CrossRef

37.

Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O’Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291CrossRef

38.

Pereira AC, Pereira AB, Mota GF, Cunha RS, Herkenhoff FL, Pollak MR, Mill JG, Krieger JE (2004) NPHS2 R229Q Functional variant is associated with microalbuminuria in the general population. Kidney Int 65:1026–1030CrossRef

39.

Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, Schachter AD, Poch E, Abreu PF, Appel GB, Pereira AB, Kalluri R, Pollak MR (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest 110:1659–1666CrossRef

40.

Tory K, Menyhard DK, Woerner S, Nevo F, Gribouval O, Kerti A, Straner P, Arrondel C, Huynh Cong E, Tulassay T, Mollet G, Perczel A, Antignac C (2014) Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet 46:299–304CrossRef

41.

Baum MA, Stablein DM, Panzarino VM, Tejani A, Harmon WE, Alexander SR (2001) Loss of living donor renal allograft survival advantage in children with focal segmental glomerulosclerosis. Kidney Int 59:328–333CrossRef

42.

Abbott KC, Sawyers ES, Oliver JD 3rd, Ko CW, Kirk AD, Welch PG, Peters TG, Agodoa LY (2001) Graft loss due to recurrent focal segmental glomerulosclerosis in renal transplant recipients in the United States. Am J Kidney Dis 37:366–373CrossRef

43.

Hariharan S, Adams MB, Brennan DC, Davis CL, First MR, Johnson CP, Ouseph R, Peddi VR, Pelz C, Roza AM, Vincenti F, George V (1999) Recurrent and de novo glomerular disease after renal transplantation: a report from renal allograft disease registry. Transplant Proc 31:223–224CrossRef

44.

Francis A, Trnka P, McTaggart SJ (2016) Long-term outcome of kidney transplantation in recipients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 11:2041–2046CrossRef

45.

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 334:878–883CrossRef

46.

Le Berre L, Godfrin Y, Lafond-Puyet L, Perretto S, Le Carrer D, Bouhours JF, Soulillou JP, Dantal J (2000) Effect of plasma fractions from patients with focal and segmental glomerulosclerosis on rat proteinuria. Kidney Int 58:2502–2511CrossRef

47.

Konigshausen E, Sellin L (2016) Circulating permeability factors in primary focal segmental glomerulosclerosis: a review of proposed candidates. Biomed Res Int 2016:3765608CrossRef

48.

Kronbichler A, Saleem MA, Meijers B, Shin JI (2016) Soluble urokinase receptors in focal segmental glomerulosclerosis: a review on the scientific point of view. J Immunol Res 2016:2068691CrossRef

49.

Coward RJ, Foster RR, Patton D, Ni L, Lennon R, Bates DO, Harper SJ, Mathieson PW, Saleem MA (2005) Nephrotic plasma alters slit diaphragm-dependent signaling and translocates nephrin, podocin, and CD2 associated protein in cultured human podocytes. J Am Soc Nephrol 16:629–637CrossRef

50.

Harris JJ, McCarthy HJ, Ni L, Wherlock M, Kang H, Wetzels JF, Welsh GI, Saleem MA (2013) Active proteases in nephrotic plasma lead to a podocin-dependent phosphorylation of VASP in podocytes via protease activated receptor-1. J Pathol 229:660–671CrossRef

51.

Gadegbeku CA, Gipson DS, Holzman LB, Ojo AO, Song PX, Barisoni L, Sampson MG, Kopp JB, Lemley KV, Nelson PJ, Lienczewski CC, Adler SG, Appel GB, Cattran DC, Choi MJ, Contreras G, Dell KM, Fervenza FC, Gibson KL, Greenbaum LA, Hernandez JD, Hewitt SM, Hingorani SR, Hladunewich M, Hogan MC, Hogan SL, Kaskel FJ, Lieske JC, Meyers KE, Nachman PH, Nast CC, Neu AM, Reich HN, Sedor JR, Sethna CB, Trachtman H, Tuttle KR, Zhdanova O, Zilleruelo GE, Kretzler M (2013) Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int 83:749–756CrossRef

Title: Deriving and understanding the risk of post-transplant recurrence of nephrotic syndrome in the light of current molecular and genetic advances
Authors: Agnieszka Bierzynska
Moin A. Saleem
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 11/2018
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-017-3793-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Deriving and understanding the risk of post-transplant recurrence of nephrotic syndrome in the light of current molecular and genetic advances

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 11/2018

Cry of a dying kidney: Questions

Prevalence and predictors of blood transfusion after pediatric kidney transplantation

Clinical parameters, LysoGb3, podocyturia, and kidney biopsy in children with Fabry disease: is a correlation possible?

Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS)

Clinical experience with the use of ferric citrate as a phosphate binder in pediatric dialysis patients

Nephrotoxin exposure and acute kidney injury in critically ill children undergoing congenital cardiac surgery