Recurrence of Nephrotic Syndrome after Transplantation in CNF Is due to Autoantibodies to Nephrin

Wang, S.; Ahola, Heikki; Palmén, Tuula; Solin, Marja Liisa; Luimula, Pauliina; Holthöfer, Harry

doi:10.1159/000052628

Cited by 34 publications

(18 citation statements)

References 17 publications

(32 reference statements)

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“…Approximately 20% of these young patients develop a post-transplant nephrosis from the first day after transplantation (38) to 33 months (39). A recent publication suggests a role for an immunization against the normal nephrin protein presented by the graft in these patients (40). Clinically, the most informative observation suggesting the involvement of (an) albuminuric factor(s) in FSGS is the recurrence of albuminuria after renal transplantation (from a few hours to a few days later) in 30% of patients with primary FSGS.…”

Section: Discussionmentioning

confidence: 99%

Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Berre¹,

Godfrin²,

Günther³

et al. 2002

J. Clin. Invest.

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Buffalo/Mna rats spontaneously develop a focal segmental glomerulosclerosis with a histological pattern similar to the human disease. In this study, we investigated the potential of recurrence of the disease by transplantation of normal kidneys into Buffalo/Mna recipients. Kidneys from healthy LEW.1W rats were grafted into proteinuric 6-month-old Buffalo/Mna rats without or with specific tolerance induction following donor-specific transfusion (DST) aimed at controlling host anti-donor immune responses. The inverse combination was carried out to determine whether a proteinuric Buffalo/Mna kidney can recover its permselectivity in a normal environment. As a control, LEW.1W kidneys were grafted into Wistar Furth recipients. After transplantation without DST, recurrence of proteinuria in LEW.1W kidneys appeared at approximately 10 days, possibly associated with rejection of the graft. In the same combination with DST, proteinuria occurred after 20 days, and the attendant glomerular damage suggested that the initial kidney disease had recurred. Transplanted control animals remained free of proteinuria. In the opposite combination, the proteinuria and the lesions of Buffalo/Mna kidneys regressed after transplantation into healthy LEW.1W rats. The recurrence of proteinuria after transplantation in Buffalo/Mna and the remission of lesions in Buffalo/Mna kidneys transplanted into normal hosts suggests that Buffalo/Mna rats express circulating albuminuric factors, which may be relevant to the relapse of idiopathic nephrotic syndrome in humans.

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Section: Discussionmentioning

confidence: 99%

Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Berre¹,

Godfrin²,

Günther³

et al. 2002

J. Clin. Invest.

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“…24,25 It has been suggested that nephrin deficiency causes podocyte injury in vivo, but this has not been directly confirmed. Development of glomerular dysfunction in rodents injected with an antinephrin antibody, 26,27 as well as recurrence of nephropathy due to alloimmunization against nephrin after kidney transplantation in individuals with congenital nephropathy of the Finnish type, 28,29 suggests that antinephrin antibody is detrimental to glomerular function. The mechanism of antinephrin antibody causing glomerular dysfunction in these cases, however, is not known.…”

mentioning

confidence: 99%

Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys

Chuang

D’Agati

et al. 2015

Journal of the American Society of Nephrology

102

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Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference-mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm-mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm-mediated signaling to preserve glomerular function and podocyte viability in adult mice.

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“…Recurrence of CNF occurs in 20%25% of the patients after renal transplantation [61,62]. The recurrence of NS in CNF children appears only in patients with a Fin major /Fin major homozygous genotype and in patients with high levels of serum anti-Nephrin antibodies, suggesting an autoimmune reaction against Nephrin.…”

Section: Nephrin In Congenital Nephrotic Syndrome Of Finnish Typementioning

confidence: 99%

An update: the role of Nephrin inside and outside the kidney

2015

Sci. China Life Sci.

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Nephrin is a key molecule in podocytes to maintain normal slit diaphragm structure. Nephin interacts with many other podocyte and slit diaphragm protein and also mediates important cell signaling pathways in podocytes. Loss of nephrin during the development leads to the congenital nephrotic syndrome in children. Reduction of nephrin expression is often observed in adult kidney diseases including diabetic nephropathy and HIV-associated nephropathy. The critical role of nephrin has been confirmed by different animal models with nephrin knockout and knockdown. Recent studies demonstrate that knockdown of nephrin expression in adult mice aggravates the progression of unilateral nephrectomy and Adriamycin-induced kidney disease. In addition to its critical role in maintaining normal glomerular filtration unit in the kidney, nephrin is also expressed in other organs. However, the exact role of nephrin in kidney and extra-renal organs has not been well characterized. Future studies are required to determine whether nephrin could be developed as a drug target to treat patients with kidney disease.

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Recurrence of Nephrotic Syndrome after Transplantation in CNF Is due to Autoantibodies to Nephrin

Cited by 34 publications

References 17 publications

Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Extrarenal effects on the pathogenesis and relapse of idiopathic nephrotic syndrome in Buffalo/Mna rats

Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys

An update: the role of Nephrin inside and outside the kidney

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