NPHS2 mutation associated with recurrence of proteinuria after transplantation

Billing, Heiko; Müller, Dominik; Ruf, Rainer; Lichtenberger, Anne; Hildebrandt, Friedhelm; August, Christian; Querfeld, Uwe; Haffner, Dieter

doi:10.1007/s00467-003-1408-6

Cited by 45 publications

(37 citation statements)

References 12 publications

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“…In addition, this individual developed recurrent proteinuria after transplantation, which responded to plasmapheresis. Although it is not clear why disease should recur in this individual's renal allograft (with a normal ACTN4 genotype), this is consistent with previously reported findings of posttransplantation disease recurrence in podocin-defective patients (17). We are not aware of the development of recurrent proteinuria or FSGS in any other case of ACTN4-associated disease.…”

Section: Discussionsupporting

confidence: 88%

Mutational and Biological Analysis of α-Actinin-4 in Focal Segmental Glomerulosclerosis

Weins

Kenlan

Herbert

et al. 2005

Journal of the American Society of Nephrology

150

133

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Mutations in the ␣-actinin-4 gene (ACTN4) cause an autosomal dominant form of focal segmental glomerulosclerosis (FSGS).A mutational analysis was performed of ACTN4 in DNA from probands with a family history of FSGS as well as in individuals with nonfamilial FSGS. The possible contribution of noncoding variation in ACTN4 to the development of FSGS also was assessed. Multiple nucleotide variants were identified in coding and noncoding sequence. The segregation of nonsynonymous coding sequence variants was examined in the relevant families. Only a small number of nucleotide changes that seemed likely to be causing (or contributing to) disease were identified. Sequence changes that predicted I149del, W59R, V801M, R348Q, R837Q, and R310Q changes were identified. For studying their biologic relevance and their potential roles in the pathogenesis of FSGS, these variants were expressed as GFP-fusion proteins in cultured podocytes. F-actin binding assays also were performed. Three of these variants (W59R, I149del, and V801M) showed clear cellular mislocalization in the form of aggregates adjacent to the nucleus. Two of these mislocalized variants (W59R and I149del) also showed an increased actin-binding activity. The I149del mutation segregated with disease; W59R was found to be a de novo mutation in the proband. A total of five ACTN4 mutations that are believed to be disease causing (three reported previously and two novel) as well as a number of variants with unclear contribution to disease now have been identified. The possibility that some of these other variants increase the susceptibility to FSGS cannot be excluded. ACTN4 mutations seem to account for approximately 4% of familial FSGS.

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Section: Discussionsupporting

confidence: 88%

Mutational and Biological Analysis of α-Actinin-4 in Focal Segmental Glomerulosclerosis

Weins

Kenlan

Herbert

et al. 2005

Journal of the American Society of Nephrology

150

133

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“…The clinical differences in pathogenesis, response to treatment, and recurrence of disease after transplantation between genetic and nongenetic cases of primary FSGS have been a steady topic of discussion. 22,23 Carraro et al analyzed five patients with autosomal recessive steroid-resistant nephrotic syndrome (SRNS) (NPHS2) for serum glomerular permeability activity (Palb), and found high pretransplant Palb in all cases, equivalent to values observed in idiopathic FSGS. 24 In the PodoNet cohort, circulating suPAR levels were higher in familial FSGS and FSGS with documented NPHS2 mutations, and the difference remained significant after adjustment for other covariates.…”

Section: Discussionmentioning

confidence: 99%

Circulating suPAR in Two Cohorts of Primary FSGS

Wei¹,

Trachtman

Li³

et al. 2012

Journal of the American Society of Nephrology

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202

183

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Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsyproven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P,0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

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“…As in our patient, attempts to demonstrate anti-podocin antibodies in both patients have not been successful. Billing et al [50] recently reported a 4.5-year-old girl with infantile steroid-resistant FSGS and a homozygous deletion in exon 8 of the NPHS2 gene who was transplanted with her mother's kidney. Significant proteinuria developed 1 week after transplantation and disappeared following methylprednisolone pulses, increased cyclosporine dosage, and ramipril.…”

Section: Recurrence Of Proteinuria Following Renal Transplantationmentioning

confidence: 97%

Genetic forms of nephrotic syndrome

Niaudet

2004

Pediatr Nephrol

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Mutations of NPHS1, NPHS2, or WT1 may be responsible for severe forms of nephrotic syndrome in children, progressing to end-stage renal failure. Recent studies have shown that congenital nephrotic syndrome may be secondary to mutations of one of these three genes and that some patients have a digenic inheritance of NPHS1 and NPHS2 mutations. The clinical spectrum of NPHS2 mutations has broadened, with the demonstration that mutations in the respective gene podocin may be responsible for nephrotic syndrome occurring at birth, in childhood, or in adulthood. It is now well recognized that podocin mutations are found in 10%-30% of sporadic cases of steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis. Data from large cohorts indicate that the risk of recurrence of nephrotic syndrome after renal transplantation in patients with podocin mutations is very low.

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NPHS2 mutation associated with recurrence of proteinuria after transplantation

Cited by 45 publications

References 12 publications

Mutational and Biological Analysis of α-Actinin-4 in Focal Segmental Glomerulosclerosis

Mutational and Biological Analysis of α-Actinin-4 in Focal Segmental Glomerulosclerosis

Circulating suPAR in Two Cohorts of Primary FSGS

Genetic forms of nephrotic syndrome

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