Friedhelm Hildebrandt, Saskia F. Heeringa  Kidney International 

Slides:



Advertisements
Similar presentations
Figure 1 Schematic representation of idiopathic nephrotic syndrome,
Advertisements

Prof. Dr. Ban A. AbdulMajeed
Volume 74, Issue 8, Pages (October 2008)
Clinical Features. This disorder usually presents either with the
Volume 66, Issue 2, Pages (August 2004)
Volume 70, Issue 10, Pages (November 2006)
Volume 83, Issue 3, Pages (March 2013)
Volume 74, Issue 8, Pages (October 2008)
Steroid-resistant nephrotic syndrome
Volume 91, Issue 4, Pages (April 2017)
Retinal atrophy associated with FSGS in a patient with MELAS syndrome
Morphometric study of arterioles and glomeruli in the aging kidney suggests focal loss of autoregulation1  Gary S. Hill, Didier Heudes, Jean Bariéty 
Volume 86, Issue 6, Pages (December 2014)
Volume 76, Issue 5, Pages (September 2009)
Genotype–phenotype associations in WT1 glomerulopathy
Volume 93, Issue 4, Pages (April 2018)
Volume 86, Issue 6, Pages (December 2014)
John P. Middleton, Patrick H. Pun  Kidney International 
Volume 84, Issue 2, Pages (August 2013)
Kumar Sharma, Ljiljana Paša-Tolić  Kidney International 
Rutger J.H. Maas, Jack F.M. Wetzels, Jeroen K.J. Deegens
A familial childhood-onset relapsing nephrotic syndrome
Immunosuppressive treatment of focal segmental glomerulosclerosis: lessons from a randomized controlled trial  Jeroen K.J. Deegens, Jack F.M. Wetzels 
Peripheral microvascular parameters in the nephrotic syndrome
End-stage renal disease in living kidney donors
Volume 77, Issue 1, Pages 5-6 (January 2010)
Serum-soluble urokinase receptor concentration in primary FSGS
Comorbidity and confounding in end-stage renal disease
Volume 70, Issue 11, Pages (December 2006)
Manjula Kurella Tamura, Kristine Yaffe  Kidney International 
Volume 89, Issue 5, Pages (May 2016)
Tarak Srivastava, Robert E. Garola, Joan M. Whiting, Uri S. Alon 
Volume 70, Issue 12, Pages (December 2006)
Volume 85, Issue 3, Pages (March 2014)
Ferruh Artunc, Friedhelm Hildebrandt, Kerstin Amann 
Volume 73, Issue 10, Pages (May 2008)
Synaptopodin expression in idiopathic nephrotic syndrome of childhood
Obesity-related glomerulopathy: An emerging epidemic
Volume 69, Issue 12, Pages (June 2006)
The glomerular filter: Biologic and genetic complexity
Volume 87, Issue 1, Pages (January 2015)
Volume 69, Issue 5, Pages (March 2006)
Volume 72, Issue 12, Pages (December 2007)
Volume 71, Issue 12, Pages (June 2007)
Racial disparities in access to transplantation: a tough nut to crack
Simvastatin in nephrotic syndrome
Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease  Isabel Ottlewski, Johannes.
Novel mutation in the nephrin gene of a Japanese patient with congenital nephrotic syndrome of the Finnish type  Kunihiko Aya, Hiroyuki Tanaka, Yoshiki.
Volume 71, Issue 4, Pages (February 2007)
Volume 81, Issue 9, Pages (May 2012)
Prehypertension: is it relevant for nephrologists?
Volume 70, Issue 6, Pages (September 2006)
Volume 73, Issue 9, Pages (May 2008)
Cardio-Kidney-Damage: a unifying concept
World Kidney Day 2016: Kidney Disease & Children
Volume 73, Issue 9, Pages (May 2008)
Volume 74, Issue 9, Pages (November 2008)
Volume 87, Issue 1, Pages (January 2015)
Volume 80, Issue 10, Pages (November 2011)
Volume 67, Issue 4, Pages (April 2005)
The Case ∣ The eyes have it!
Volume 65, Issue 5, Pages (May 2004)
Distribution of podocyte gene mutations in patients with genetic congenital nephrotic syndrome (CNS) and steroid–resistant nephrotic syndrome (SRNS). Distribution.
Inhibition of the renin–angiotensin system: is more better?
Volume 75, Issue 7, Pages (April 2009)
The changing face of childhood nephrotic syndrome
Dana V. Rizk, David G. Warnock  Kidney International 
Prediction in idiopathic membranous nephropathy
Daniel L. Roden, Shane T. Grey  Kidney International 
The Ebf1 knockout mouse and glomerular maturation
Presentation transcript:

Specific podocin mutations determine age of onset of nephrotic syndrome all the way into adult life  Friedhelm Hildebrandt, Saskia F. Heeringa  Kidney International  Volume 75, Issue 7, Pages 669-671 (April 2009) DOI: 10.1038/ki.2008.693 Copyright © 2009 International Society of Nephrology Terms and Conditions

Figure 1 Steroid-resistant nephrotic syndrome may be caused by single-gene mutations in up to 25% of patients, depending on age group. (a and b) The younger the patient, the more likely it is that steroid-resistant nephrotic syndrome (SRNS) is caused by a single-gene (‘monogenic’) defect. The age of onset of SRNS and end-stage kidney disease depends on two parameters: (1) The causative gene itself determines onset. As a rule, recessive genes (LAMB2, nephrin, PLCE1, and podocin) cause early onset of nephrotic syndrome (NS) during fetal development, during the first 3 months of life, or during early childhood (see the red to yellow part of the spectrum). In contrast, dominant gene mutations (ACTN4, TRPC6, CD2AP) usually lead to adult-onset SRNS (see the purple part of the spectrum), with the exception of WT1 mutations, which cover a broad age range. (2) The specific mutation of a gene (‘allelic differences’) determines onset. In podocin (NPHS2), a truncation mutation in a compound heterozygous state with any other podocin mutation, or the presence of two R138Q mutations, leads to early onset (mean 1.75 years), whereas the presence of at least one missense mutation (other than R138Q) leads to onset in later childhood (mean 4.17 years). Machuca et al.15 now demonstrate that the variant R229Q together with another podocin mutation may cause adult onset of SRNS (>18 years) (a and b). Both parameters, the specific mutated gene and the specific mutation within that gene, determine the age of onset of SRNS. (c and d) The specific phase of development at which a gene mutation becomes operative determines the resulting renal histology. Typically, early loss of gene function causes early, congenital onset (<3 months of life) with a developmental, morphogenic defect that interferes with glomerulogenesis and that will manifest histologically as diffuse mesangial sclerosis (DMS) or congenital nephrotic syndrome of the Finnish type (CNS-FT). In contrast, later loss of gene function causes onset in childhood or adult life with a defect of tissue maintenance and repair that manifests histologically as focal segmental glomerulosclerosis (FSGS). For example, LAMB2 mutations always cause severe DMS or congenital nephrotic syndrome (CNS) (a and b). Nephrin causes CNS-FT in most cases but occasionally may cause childhood-onset SRNS on the basis of ‘mild’ mutations.21 PLCE1 mutations represent the most frequent cause of DMS; however, a missense mutation can ‘rescue’ toward an FSGS phenotype.5 Podocin mutations typically cause childhood NS but can cause up to 50% of CNS, if R138Q or two truncating mutations are present8 (a and b). WT1 and PLCE1 may cause both the developmental defect of DMS and the degenerative defect of FSGS. It seems that in FSGS the repair of glomerular tufts requires reinitiation of developmental programs involving WT1 and PLCE1. If these mechanisms go awry, scarring or FSGS will result. Kidney International 2009 75, 669-671DOI: (10.1038/ki.2008.693) Copyright © 2009 International Society of Nephrology Terms and Conditions