Recurrence of steroid-resistant nephrotic syndrome in kidney transplants is associated with increased acute renal failure and acute rejection

ABSTRACT. Steroid-resistant nephrotic syndrome (SRNS) represents a heterogeneous group of kidney disorders that are often resistant to other immunosuppressive agents and tend to progress to end-stage renal failure. Mutations in the gene NPHS2 that encode a protein named podocin have recently been found in a recessive form of SRNS. Ten children from two inbred families of Israeli-Arab descent presented with SRNS. Renal histologic findings were of diffuse mesangial proliferation. Six patients reached end-stage renal failure, but nephrotic syndrome did not recur after renal transplantation. Mutation analysis of NPHS2 revealed that they were homozygous for the C412T mutation (R138X). Eighteen children were subsequently analyzed with SRNS due to biopsy-proven focal segmental glomerulosclerosis (FSGS) from unrelated families of Israeli-Arab descent. Analysis disclosed six additional patients (33%) bearing the same mutation in a homozygous pattern. Three of them had no affected relatives, although they came from large families. Taken together, of the 27 patients tested (familial and nonfamilial), 15 patients (55%) were homozygous for the mutation (R138X). They all shared the same haplotype and were homozygous for the A1023G polymorphism, thus pointing to a possible founder effect. Thirteen children of Israeli-Jewish origin with SRNS and biopsy-proven FSGS and 15 children of both ethnic groups with steroid-responsive FSGS were tested, and none was found to have mutations in NPHS2. The results of this study demonstrate that mutations in NPHS2 are a common cause of SRNS in Israeli-Arab children. Mutations in NPHS2 may cause SRNS in nonfamilial cases. The interethnic differences in the occurrence of NPHS2 mutations may explain, in part, the previous observation that Arab patients with FSGS in Israel have a worse prognosis as compared with Jewish patients, despite similar presenting symptoms and medical management. Identifying the causing mutation will enable clinicians to avoid unnecessary immunosuppressive therapeutic trials in newly diagnosed patients and to provide prenatal diagnosis to families at risk.

Download Full-text

Prevalence, Genetics, and Clinical Features of Patients Carrying Podocin Mutations in Steroid-Resistant Nonfamilial Focal Segmental Glomerulosclerosis

Journal of the American Society of Nephrology ◽

10.1681/asn.v12122742 ◽

2001 ◽

Vol 12 (12) ◽

pp. 2742-2746 ◽

Cited By ~ 1

Author(s):

Gianluca Caridi ◽

Roberta Bertelli ◽

Alba Carrea ◽

Marco Di Duca ◽

Paolo Catarsi ◽

...

Keyword(s):

Renal Failure ◽

Nephrotic Syndrome ◽

Focal Segmental Glomerulosclerosis ◽

Founder Effect ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

End Stage Renal Failure ◽

Segmental Glomerulosclerosis ◽

End Stage ◽

Nphs2 Gene

ABSTRACT. Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.

Download Full-text

THE ROLE OF HIPPURAN RENOGRAPHY AS A DIAGNOSTIC TEST TO DETERMINE TRANSIENT ACUTE RENAL FAILURE (ARF) EVENTS IN NEPHROTIC SYNDROME (NS) PATIENTS

Nephrology ◽

10.1046/j.1440-1797.2002.00007-1-154.x ◽

2002 ◽

Vol 7 (1) ◽

pp. A154-A154

Author(s):

E. Sukandar ◽

R. Bandiara

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Nephrotic Syndrome ◽

Diagnostic Test

Download Full-text

Faculty Opinions recommendation of Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104725.560794 ◽

2008 ◽

Author(s):

Neil Turner

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

New Therapy

Download Full-text

A rare cause of steroid-resistant nephrotic syndrome in a child: Answers

Pediatric Nephrology ◽

10.1007/s00467-019-04385-6 ◽

2019 ◽

Vol 35 (4) ◽

pp. 621-623

Author(s):

Lale Guliyeva ◽

Yılmaz Tabel ◽

Ali Düzova ◽

Nusret Akpolat ◽

Seza Özen ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome

Download Full-text

Whole-Exome Sequencing Solved over 2-Decade Kidney Disease Enigma

Nephron ◽

10.1159/000514293 ◽

2021 ◽

pp. 1-6

Author(s):

Suramath Isaranuwatchai ◽

Ankanee Chanakul ◽

Chupong Ittiwut ◽

Chalurmpon Srichomthong ◽

Vorasuk Shotelersuk ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Kidney Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Treatment Plan ◽

Unknown Etiology ◽

Pediatric Case ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Whole Exome

Chronic kidney disease of unknown etiology (CKDu) has been a problem in renal practice as indefinite diagnosis may lead to inappropriate management. Here, we report a 54-year-old father diagnosed with CKDu at 33 years old and his 8-year-old son with steroid-resistant nephrotic syndrome. Using whole-exome sequencing, both were found to be heterozygous for c.737G>A (p.Arg246Gln) in LMX1B. The diagnosis of LMX1B-associated nephropathy has led to changes in the treatment plan with appropriate genetic counseling. The previously reported cases with this particular mutation were also reviewed. Most children with LMX1B-associated nephropathy had nonnephrotic proteinuria with normal renal function. Interestingly, our pediatric case presented with steroid-resistant nephrotic syndrome at 8 years old and progressed to ESRD requiring peritoneal dialysis at the age of 15 years. Our report emphasized the need of genetic testing in CKDu for definite diagnosis leading to precise management.

Download Full-text