Genetic Basis of Congenital and Infantile Nephrotic Syndromes

Correspondence

Acknowledgements Financial Disclosure: The author declares that he has no relevant financial interests.

Reference 1. Geara AS, El-Imad T. Prolonged immobilization as a potential etiology of metabolic alkalosis in hemodialysis patients. Am J Kidney Dis. 2011;58(6):1040-1041. © 2011 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2011.10.006

Genetic Basis of Congenital and Infantile Nephrotic Syndromes To the Editor: We conducted a nationwide multicenter study to analyze phenotype and genotype of 30 unrelated Korean children with nephrotic syndrome in the first year of life, including 15

patients with congenital and 15 with infantile nephrotic syndrome.1 Mutations were detected in 17 individuals (56.7% overall; 93.3% and 20.0% of patients with congenital and infantile nephrotic syndrome, respectively), in the WT1 (n ⫽ 8), NPHS1 (n ⫽ 6), LAMB2 (n ⫽ 2), and NPHS2 (n ⫽ 1) genes; no polymorphisms were detected in the PLCE1 gene2-5 (Table 1). The frequency of mutations in patients with congenital nephrotic syndrome was similar to those of 2 large studies of European7 (84.8%) and multiethnic8 (81.3%) cohorts. However, in our study, mutations in NPHS2 had the lowest frequency and WT1 mutations were most frequent. Although NPHS1 mutations were detected in only patients with congenital nephrotic syndrome, WT1 mutations were detected in patients from both groups of nephrotic syndrome. WT1 mutations frequently were accompanied by diffuse mesangial sclerosis, genitalia anomalies, or diaphragmatic defects. Of 17 patients with mutations, 11 developed an estimated glomerular filtration rate ⬍60 mL/min/1.73 m2 or end-stage renal disease, 3 died, and 3 had persistent active nephrotic syndrome. Immunosuppressive drugs were administered to 8 patients with infantile ne-

Table 1. Phenotypic and Genotypic Features of Patients With Identified Mutations 1 wk Pt/Sex

Onset of NS

Mutation

Kidney Biopsy

Status at Most Recent Follow-up Age

Patients With a WT1 Mutation 1/M (SR) 2/F 3/F 4/M (GA) 5/F 6/M (SR) 7/M (GA) 8/M (GA)

2 wk 1 wk 8 wk 3 wk 1 wk 1 wk 12 mo 12 mo

p.R366H p.R366H p.R366H p.R366P p.D396Y p.R366C p.R394W c.1228⫹5G⬎A

DMS FSGS DMS ND DMS ND DMS FSGS

5 y 11 mo: functioning kidney transplant (Died at 1 mo of age) (Died at 13 mo of age) 2 y 10 mo: receiving peritoneal dialysis (Died at 6 mo of age) 2 mo: receiving peritoneal dialysis 2 y 6 mo: receiving peritoneal dialysis 18 y: SCr, 2.6 mg/dL; eGFR, 35

Patients With NPHS1 Mutations 9/M

At birth

10/F 11/F 12/M 13/M

At birth 10 wk 5 wk 1 wk

14/M

3 wk

a

p.L719Pfsⴱ4 /p.V1084Gfsⴱ12 p. Y1009ⴱa/p.R1160ⴱ p.Y814ⴱa/p.R460Q p.E629ⴱa/p.Q63Ra p.L719Pfsⴱ4a/p.R1160ⴱ p.A922Da/c.3287⫺11G⬎Aa

MesPGN ND CNF FSGS

2 y 5 mo: SCr, 1.8 mg/dL; eGFR, 26 1 y 7 mo: SCr, 1.6 mg/dL; eGFR, 22 2 y 3 mo: receiving peritoneal dialysis 12 y 3 mo: functioning kidney transplant

ND CNF

2 mo: SCr, 0.2 mg/dL; eGFR, 128 5 y 7 mo: SCr, 0.1 mg/dL; eGFR, 583

Patients With LAMB2 Mutationsb 15/F 16/F

2 wk 8 mo

p.S762Rfsⴱ29/p.S179F p.G502ⴱ/p.C1423Vfsⴱ29

FSGS MCL

1 y 7 mo: SCr, 3.0 mg/dL; eGFR, 16 7 y 6 mo: SCr, 0.7 mg/dL; eGFR, 90

Patient With NPHS2 Mutations 17/M

5 wk

a

p.S120P /p.R168H

FSGS

17 y: functioning kidney transplant

Note: Mutations are designated in terms of protein (p) or cDNA (c) sequence; fsⴱn indicates a frameshift in which the new reading frame ends in a stop codon (ⴱ) n amino acids from the first affected residue; single-letter amino acid abbreviations are used for brevity. Conversion factors for units: SCr in mg/dL to ␮mol/L, ⫻88.4; eGFR in mL/min/1.73 m2 to mL/s/1.63 m2, ⫻0.01667. Abbreviations and definitions: CNF, congenital nephrotic syndrome of Finnish type; DMS, diffuse mesangial sclerosis; eGFR, estimated glomerular filtration rate (calculated using the Schwartz formula and expressed in mL/min/1.73 m2); F, female; FSGS, focal segmental glomerulosclerosis; GA, genitalia anomaly; LAMB2, laminin, beta 2 (laminin S); M, male; MCL, minimal change lesion; MesPGN, mesangial proliferative glomerulonephritis; ND, not done; NPHS1, nephrosis 1, congenital, Finnish type (nephrin); NPHS2, nephrosis 2, idiopathic, steroid-resistant (podocin); NS, nephrotic syndrome; Pt, patient; SCr, serum creatinine; SR, sexual reversal (having female-type external genitalia and a 46,XY karyotype); WT1, Wilms tumor 1. a Novel mutations. b These 2 cases have been reported previously.6 1042

Am J Kidney Dis. 2011;58(6):1037-1045

Correspondence phrotic syndrome without identifiable genetic cause, of which 5 responded to treatment. A genetic testing algorithm for congenital and infantile nephrotic syndrome should be designed on the basis of clinical features9,10 (age at onset, extrarenal manifestations, and renal pathologic findings) and ethnic origin of patients. Immunosuppressive treatment may be attempted, especially in patients with later infantile onset and no detectable genetic cause. Joo Hoon Lee, MD, PhD,12 Kyoung Hee Han, MD1 HyunKyung Lee, MD,1 Hee Gyung Kang, MD, PhD1,3 Kyung Chul Moon, MD, PhD,3,4 Jae Il Shin, MD, PhD5 Hyewon Hahn, MD, PhD,6 Young Seo Park, MD, PhD2 Ki Soo Pai, MD, PhD,7 Byoung-Soo Cho, MD, PhD8 Su-Yung Kim, MD, PhD,9 Seung Joo Lee, MD, PhD10 Il Soo Ha, MD, PhD,13 Yong Choi, MD, PhD11 Hae Il Cheong, MD, PhD1,3 1 Seoul National University Children’s Hospital, Seoul, Korea 2 University of Ulsan College of Medicine, Seoul, Korea 3 Seoul National University Hospital, Seoul, Korea 4 Seoul National University College of Medicine, Seoul, Korea 5 Severance Children’s Hospital, Seoul, Korea 6 Nowon Eulji Hospital, Seoul, Korea 7 Ajou University Hospital, Suwon, Korea 8 Kyung Hee University Hospital, Seoul, Korea 9 Pusan National University, Yangsan, Korea 10 Ehwa University Mokdong Hospital, Seoul, Korea 11 Haeundae Paik Hospital, Busan, Korea Corresponding author (H.I. Cheong): [email protected]

9. Santín S, Bullich G, Tazón-Vega B, et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2011;6:1139-1148. 10. Benoit G, Machuca E, Antignac C. Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol. 2010;25: 1621-1632. © 2011 by the National Kidney Foundation, Inc. doi:10.1053/j.ajkd.2011.09.007

RESEARCH LETTER Comparisons of Technetium-99m Diethylenetriaminepentaacetic Acid Plasma Clearance and Renal Dynamic Imaging With Inulin Clearance To the Editor: Inulin clearance (Cin) has been considered the reference standard for measuring glomerular filtration rate (GFR). Because of the inconvenience of Cin in clinical practice, in some countries, technetium-99m diethylenetriaminepentaacetic acid

Acknowledgements Support: This study was supported by a grant (A080588) from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, and a grant (2008-452) from the Asan Institute for Life Sciences. Financial Disclosure: The authors declare that they have no other relevant financial interests.

References 1. Habib R. Nephrotic syndrome in the 1st year of life. Pediatr Nephrol. 1993;7:347-353. 2. Kestilä M, Lenkkeri U, Männikkö M, et al. Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1:575-582. 3. Boute N, Gribouval O, Roselli S, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet. 2000;24:349354. 4. Jeanpierre C, Denamur E, Henry I, et al. Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am J Hum Genet. 1998;62:824-833. 5. Zenker M, Aigner T, Wendler O, et al. Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet. 2004;13:26252632. 6. Choi HJ, Lee BH, Kang JH, et al. Variable phenotype of Pierson syndrome. Pediatr Nephrol. 2008;23:995-1000. 7. Hinkes BG, Mucha B, Vlangos CN, et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics. 2007;119:e907-e919. 8. Machuca E, Benoit G, Nevo F, et al. Genotype–phenotype correlations in non-Finnish congenital nephrotic syndrome. J Am Soc Nephrol. 2010;21:1209-1217. Am J Kidney Dis. 2011;58(6):1037-1045

Figure 1. Correlation between inulin clearance and (A) 99mTcDTPA plasma clearance (CDTPA-P) and (B) 99mTc-DTPA renal dynamic imaging by the modified Gates method (CDTPA-G). Solid line indicates regression line; dotted lines indicate 95% confidence limits. 1043