Syndrome d`Alport

Quels progrès dans la recherche
sur les maladies rénales
génétiques en pédiatrie ?
Denis Morin
Montpellier
Recherche clinique en pédiatrie
• Faibles nombres de patients parfois
– Études multicentriques +++
• Considérations éthiques
– Recherche qu’on ne peut pas faire chez des
patients adultes
• Importances des protocoles (PHRC, autres,..)
Néphrologie Pédiatrique
Basalopathies
SHU atypique
Maladies kystiques
Glomérulopathies
Tubulopathies
Autres…
Maladies rénales kystiques
• Polykystose dominante
• Polykystose récessive
• Maladie kystique liée à TCF2
Polykystose dominante
• Diagnostic anténatal possible
– Echographie / IRM
• Questions concernant la prise
en charge
– Surveillance simple de loin
en loin ?
– Possibilités d’attitudes
thérapeutiques préventives
à l’image de ce qui existe
pour les adultes ?
Polykystose récessive
• Maladie rare 1/25 000 naissances
• Transmission autosomique
récessive
• Expression anténatale fréquente
– Mise en évidence de gros reins
hyperéchogènes
– Parfois retentissement fœtal
• Oligoamnios
• Diagnostic génétique possible
– Etude de corrélations
génotype/phénotype
• Pas de résultats probants en
terme de conseil génétique
(CJASN 2010)
Polykystose récessive
• Grande variabilité d’expression clinique
– Atteinte rénale
– Atteinte hépatique
• Prise en charge symptomatique
– Traitement anti-HTA
– Prise en charge insuffisance rénale chronique
• Place d’une approche thérapeutique
spécifique visant à limiter le développement
des kystes ?
Pathologie kystique liée à des
mutations du gène TCF2/HNF1b
Syndrome d’Alport
Syndrome d’Alport
• Basalopathie héréditaire
-
Forme liée à l’X
Forme autosomique récessive
Forme autosomique dominante
Anomalie chaines a du collagène
• Evolution
⁻ Protéinurie
⁻ HTA
⁻ Insuffisance rénale
Syndrome d’Alport
Heidet L , Gubler M JASN 2009;20:1210-1215
©2009 by American Society of Nephrology
Figure 2. Schematic algorithm in case of Alport syndrome suspicion because of hematuria {+/-} proteinuria
Heidet, L. et al. J Am Soc Nephrol 2009;20:1210-1215
Copyright ©2009 American Society of Nephrology
Syndrome d’Alport
Cyclosporine A treatment in patients with
Alport syndrome: a single-center experience.
Massela et al Ped Nephrology 2010
“Our data do not support the use of CsA therapy for proteinuric
patients with AS, particularly if they have chronic renal
failure”
Syndrome d’Alport
•
Efficacy and safety of losartan in children with Alport
syndrome results from a subgroup analysis of a prospective,
randomized, placebo- or amlodipine-controlled trial.
Webb J and col. Nephrol Dial Transplant. 2011 Aug;26(8):2521-6
• Inhibition du système rénine angiotensine
– Effet anti-protéinurique
– Anti-cytokine
– Inhibition de la production de collagène
– Inhibition de la fibrose tubulo-interstitielle
Syndrome d’Alport
• Nephroprotective effect of the HMG-CoAreductase inhibitor cerivastatin in a mouse
model of progressive renal fibrosis in Alport
syndrome
• Koepke ML et al . NDT 2007
– Action antio-fibrotique
– Moindre infiltrat de cellules inflammatoires
– Intérêt d’un traitement précoce en pédiatrie ?
Syndrome d’Alport
• Modèle animal de souris COL4A3 -/• Intérêt de la transplantation médullaire ?
– Recrutement de cellules aptes à devenir des
podocytes et des cellules mésangiales
– A confirmer
Syndrome hémolytique et
urémique
Syndrome hémolytique et urémique
• Forme post-diarrhéique : typique
– Nourrisson avant 2 ans
– Infection à E.Coli entéropathogène
– Anémie, thrombopénie, IRA
– Dialyse dans 50% des cas
– Pronostic dominé par atteinte neurologique
– Présence schizocytes
Syndrome hémolytique et
urémique
• Forme atypique
– Age de début variable
• Formes néonatales
– Pas de contexte infectieux
• SHU D-
– Début plus insidieux
• HTA plus fréquente
– Risque de rechute
SHU atypique
• Déficit en ADAMTS 13
• Anomalie du métabolisme Vitamine B12
• Anomalie de la régulation de protéines du
système du complément
Système du complément
Système du complément
SHU atypique et anomalies du complément
• Différents facteurs en cause
– MCP ,
– C3, H, I, B
• Etude de l’expression de MCP
• Dosages du C3 et des facteurs H, I, B
• Anticorps anti-H ?
• Génotypage même si taux plasmatiques normaux
– anomalies qualitatives ?
SHU atypique et anomalies du complément
Prise en charge
• Traitement symptomatique : HTA, IRA, Anémie,…
• Traitement « spécifique » récent
– Plasmathérapie débutée dès que possible
• Perfusion de plasma
• Echanges plasmatiques +++
• Questions :
– Combien de temps ?
– Problèmes abords vasculaires
SHU atypique et anomalies du complément
Prise en charge
•
–
–
–
A long terme ?
Echanges plasmatiques
Anticorps monoclonal anti-C5
Concentré de facteur H
• Si insuffisance rénale terminale
–
–
–
–
Transplantation rénale + EP
Transplantation combinée foie – rein
Concentré de facteur H
Anticorps monoclonal anti-C5
SHU atypique et anomalies du complément
Prise en charge
• Actuellement
• Protocole de prise en charge des SHU
atypique de l’enfant par Eculizumab
SHU typique et activation du
système du complément
• « Epidémie » de SHU post-diarrhéique en
2011 (Allemagne, Bordeaux, Lille)
• Formes avec atteinte neurologique
– Intérêt du traitement par Eculizumab dans les
formes sévère de SHU typique
Cystinose
PHYSIOPATHOLOGIE
• Défaut du transporteur
lysosomal de cystine:
CYSTINOSINE
• Gène CTNS (23 kb)
• Transmission autosomique
récessive: 1/200 000
naissances vivantes
• Accumulation et cristallisation
intralysosomiale de cystine =
Maladie systémique
W Gahl, 2002
Cystinose - Traitement
• Cystagon = chlorydrate de cystéamine
– 10-50 mg/Kg/jour sans dépasser 1300 mg/m2
– En 4 prises dont une nocturne +++
– Cible thérapeutique
– Cystine intraleucocytaire < 1 nmole/mg protéine
– Collyre cystéamine
• Traitement symptomatique du syndrome de
Fanconi
Cystinose - Evolution
Age distribution of patients starting renal replacement therapy (RRT) in different eras.
Van Stralen K J et al. CJASN 2011;6:2485-2491
©2011 by American Society of Nephrology
Cystinose - Traitement
• Etude « Raptor »
– Vise à étudier la tolérance et l’efficacité d’une
forme galénique nouvelle de cystéamine qui
permettra une prise toutes les 12 heures
– Etude qui s’est déroulé aux USA et en Europe
– Doit permettre une diminution des prises de
médicaments, source d’une meilleure observance
• Equivalence entre Raptor et Cystagon
– Démarche en vue d’obtenir l’AMM en cours
Syndromes néphrotiques
Syndromes néphrotiques
Machuca E et al. Hum. Mol. Genet. 2009;18:R185-R194
© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions,
please email: journals.permissions@oxfordjournals.org
Syndromes néphrotiques
• SN génétiquement déterminés
• Néphrose lipoïdique
Syndromes néphrotiques
• SN génétiquement déterminés
• Néphrose lipoïdique
Syndromes néphrotiques
• Début précoce, parfois néonatal, peut être
tardif
• ATCD familiaux
• Transmission AD ou AR
• Corticorésistance
• Pas de récidive après transplantation rénale
• Etude génétique nécessaire pour affirmer le
diagnostic
Diaphragme de fente / Podocytes
Machuca E et al. Hum. Mol. Genet. 2009;18:R185-R194
© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions,
please email: journals.permissions@oxfordjournals.org
Age de début du SN selon le type d’anomalie génétique
Machuca E et al. Hum. Mol. Genet. 2009;18:R185-R194
© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions,
please email: journals.permissions@oxfordjournals.org
Syndromes néphrotiques
• SN génétiquement déterminés
• Néphrose lipoïdique
Néphrose lipoïdique
•
•
•
•
1 an à 12 ans
Protéinurie / rechutes
Lésion glomérulaires minimes
Pronostic dominé par évolution
– Corticosensibilité ?
– Corticodépendance ?
– Corticorésistance ?
• Probablement « polygénique »
Néphrose
Néphrose
Néphrose
Traitement
Etude Néphromycy (V Baudoin)
• Vise à comparer l’efficacité et la tolérance de deux
thérapeutiques utilisées dans la néphrose corticodépendante
– Cyclophosphamide
– Mycophénolate mophétil
• Débutée début 2011
Néphrose
Traitement
• Etude NEPHRUTIX
– Vise à mesure l’efficacité et la tolérance du
Rituximab dans certains cas de néphrose corticodépendante et antiocalcineurine dépendante
– Rituximab :
• antiCD20
• Action sur les B lymphocytes
• Efficacité / risques
Conclusion
• Beaucoup d’autres sujets
– Tubulopathies
– Oxalose
– Cystinurie
–…
Diabète Insipide Néphrogénique
congénital
DINc
• Pathologie rare ++
• Expression néonatale précoce
– Polyurie – perte de poids – déshydratation
– Hypernatrémie – trouble de concentration des
urines
– Résistance du tubule rénal à l’action de la
vasopressine
DINc
DINc - Génétique
Récépteur V2 de la vasopressine
Sexe masculin
Femme transmettrice
Aquaporine 2
Expression dans les deux sexes
Diabète insipide néphrogénique
congénital
• Traitement symptomatique
– Hydratation : NEDC parfois
– AINS
– Hydrochlorothiazide
• Traitement spécifique en cas de mutation du
RV2 : molécules chaperonnes ?
Molécule Chaperonne
Bouvier et al 2006
Effets chez les patients ?
Mais….
Efficacité fonction de la nature des mutations en cause
Bouvier et al 2006
Recherche de pharmacochaperones agonistes
Expression à la surface cellulaire-Microscopie confocale
Contrôle
MCF57 18H
V2
A294P
L44P
R337X
JASN 2009
Effet agoniste des MCF sur les récepteurs DNIc
MCF = Pharmacochaperones Agonistes pour A294P et L44P
Pas d’effet sur le mutant R337X malgré une restauration à la membrane
JASN 2009
Autre pathologie lié à une
mutation du Récepteur V2 de la
vasopressine :
Syndrome d’antidiurèse d’origine
néphrogénique
NSIAD décrit en 2005
L
e2
C
TM3
125
NSIAD
C
L
R
A
V K
Y
L
Q M
V
G M
120
Y
A
S S
Y
M
I
L A
M T
L
135
D
i2
R
H
H
R
A
I
DINc
NSIAD
• Signes cliniques: variabilité phénotypique
– Crises convulsives ++, âge d’apparition variable
– Mais aussi patients asymptomatiques
• Signes biologiques:
–
–
–
–
–
Hyponatrémie
Baisse de l’osmolalité plasmatique
Osmolalité urinaire inadaptée anormalement élevée
Absence ou faible sécrétion de vasopressine
Réponse anormale à une épreuve de charge hydrique
• Principal diagnostic différentiel: SIADH
NSIAD
• Possibilité d’évolution neurologique péjorative si
absence de diagnostic et récidive des convulsions
• Circonstance déclenchant la symptomatologie:
ingestion excessive d’eau (chaleur, relais de
l’allaitement maternel)
• Traitement:
– Restriction hydrique +/- urée
– Inefficacité des antagonistes non peptidiques du récepteur
V2
• Femmes transmettrices:
– Souvent antidiurèse inappropriée
– Parfois signes cliniques ou biologiques
NSIAD
• Pathologie de description récente
• Variabilité phénotypique patients et femmes
transmettrices
• Fréquence probablement sous-estimée
• Nécessité d’une information médicale ciblée pour
permettre le diagnostic
• Avancées dans la compréhension des mécanismes
physiopathologiques
• Meilleure appréhension de la structure du récepteur
V2
OMIM
Gene/locus
601678
SLC12A1/15q2
Type I
1.1
241200
KCNJ1/11q24 Type II
602522
CLCNKB/1p36 Type III
Antenatal
Bartter
607364
syndrome with
SNHL
BSND/1p31 or
CLCNKA–
Type IV
CLCNKB/1p36
Classic Bartter
602522
syndrome
CLCNKB/1p36
SLC12A3/16q1 Type III
3
Gitelman
Syndrome
SLC12A3/16q1
3
CLCNKB/1p36
Antenatal
Bartter
syndrome
263800
Genetic
Protein
Principal
expression in
Other features
featuresa
renal tubule
Polyhydramnio
s, prematurity,
Na-K-2Cl
nephrocalcinos
TAL
cotransporter
is, polyuria,
failure to
thrive
Transitory
Kir 1.1
hyperkalaemia
potassium
TAL and CCD
in neonatal
channel
period in most
patients
ClC-Kb
Nephrocalcino
chloride
TAL and DCT
sis in some
channel
patients
Barttin ClC-Ka
TAL and DCT
CRI with some
and ClC-Kb
tAL, TAL, DCT
Barttin
chloride
and CCD
mutations
channels
Severe to mild
ClC-Kb
salt wasting
Sometimes
chloride
TAL and DCT with or
hypomagnesae
channel Na-Cl DCT
without
mia
cotransporter
nephrocalcinos
is
Sometimes
Na-Cl
polyuria,
cotransporter
Hypomagnesa failure to
DCT TAL and
ClC-Kb
emia,
thrive or
DCT
chloride
hypocalciuria growth
channel
hormone
deficiency
Implicated
molecule
Plasma potassium, chloride and bicarbonate concentration at diagnosis in patients with
antenatal and neonatal Bartter syndrome according to the gene involved.
Brochard K et al. Nephrol. Dial. Transplant. 2009;24:14551464
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Growth under treatment (water and electrolyte + indomethacin) according to the gene
involved.
Brochard K et al. Nephrol. Dial. Transplant. 2009;24:14551464
© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
The kidney diseases discussed above can be life-threatening and most have limited, often unsuccessful, treatment options. Many
patients with MPGN and aHUS experience recurrent episodes that eventually lead to end-stage renal failure.40,57,84 Even when kidney
transplants are successful, diseases that are caused by systemic factors such as mutated fH, C3 and fB can present again and the
outcome is often fatal.72,103 In such situations, combined kidney and liver transplantation may be the only way to correct the underlying
defects, and success with such an approach has been described in the literature but the high risk for adverse events in such procedures
makes this a less desirable option.104,105 By the same principle, kidney transplantation may be an acceptable option for end-stage aHUS
patients whose diseases are attributable to mutations in the membrane regulator MCP.91,106 Given the well-established role of
complement in the pathogenesis of these kidney diseases, it is envisioned that systemic or targeted local complement inhibition may
represent a promising therapeutic strategy. In this context, the recent approval and successful clinical application of a first-in-class
complement inhibitor Eculizumab, a humanized anti-C5 monoclonal antibody,107 for treatment of the complement-mediated disease
paroxysmal nocturnal haemaglobinuria108–110 is particularly encouraging. Based on a number of animal studies in which C5 deficiency or
C5-blocking antibodies reduced renal injury,59,69,111 it may be anticipated that Eculizumab will prove to be efficacious for some, if not all,
complement-mediated kidney disorders as well. Indeed, two case reports on the successful treatments of paediatric aHUS patients
with Eculizumab have already appeared in the literature112,113 and clinical trials on the use of Eculizumab in aHUS are currently
underway.114
Other complement-based therapeutic strategies include chemical and biological agents that target additional complement
components. A chemical inhibitor for C3aR and two antagonists for C5aR, a cyclic hexapeptide and a recombinant C5a analogue, have
been developed and shown to effectively block anaphylatoxin-mediated inflammatory injury in a variety in vitro and in vivo studies
including models of renal IRI and transplantation.115–118 A synthetic peptide, named Compstatin, with potent human C3-inhibiting
activity has also been developed by phage display and shown to effectively shut down human complement activation in several
experiments including an ex vivo model of hyperacute rejection of kidney xenotransplantation model.119–121 Compstatin is currently
being evaluated in clinical trials for the treatment of AMD, a disease that also implicates abnormal AP complement activation.122 One of
the concerns of targeting C3 with agents like Compstatin is that they obliterate the complement system completely, potentially
compromising host defence and leaving the patients susceptible to infection. Because the AP complement is principally involved in
many of the complement-mediated diseases, efforts have also been made to develop inhibitors that target the AP only. For example,
two anti-C3b mAbs that specifically inhibit the AP C3 convertase with no activity on classical and lectin pathway complement activation
have been described recently.123,124
A third area of promising research for treating complement-mediated kidney injury is the creation of soluble recombinant forms of
complement regulatory proteins. Several studies have shown that administering a soluble form of CR1 or Crry can reduce renal
injury125,126 and such proteins have an extended half-life when fused to an Ig Fc domain.127 More recently, strategies have been
developed to target the recombinant protein to sites of injury. He et al. targeted recombinant regulatory proteins to the kidney using an
Ag-specific single chain Ab fragment.128 In other efforts, the inhibitors were directed to sites of complement activation with the design
of a fusion protein consisting the C3d-binding domain of CR2 and a regulatory protein partner, either Crry (CR2-Crry) or the SCR1-5
region of fH (CR2-fH).129 In one study of MRL/lpr mice, which are prone to autoimmune glomerulonephritis and vasculitis, CR2-Crry
ameliorated disease symptoms compared with untreated mice.130 Studies with these recombinant proteins have also been performed
The basic defect in Alport syndrome is either the lack, in the mature GBM, of the 3- 4- 5(IV) network and its failure to replace the 1- 2 network,
which is known to be less resistant to proteolysis, or the presence of a defective 3- 4- 5(IV) network. There are several animal models for AS, in
dogs and mice that faithfully recapitulate autosomal and X-linked forms of the disease. They have brought novel data to the understanding of the
mechanisms responsible for the progression of AS nephropathy and in the elaboration of future therapies. The re-expression of the 3(IV) chain in
Col4a3-/- mice, for example, was shown to restore the expression of 4 and 5 (IV), thus demonstrating that the expression of all three 3- 4- 5(IV)
chains is required for network assembly.12 The downstream mechanisms responsible for progressive alteration of the GBM and renal failure are not
fully understood. In young Alport mice, the ultrastructurally normal GBM is known to already be abnormally permeable.13 The concomitant
accumulation of mRNAs encoding TGFβ1 and extracellular matrix components in human and mouse Alport podocytes are thought to reflect key
events in renal disease progression.14 Blocking the TGFβ1 pathway prevents GBM thickening in Alport mice.15
The role of metalloproteinases in Alport disease has been underlined by recent studies. Increased expression of MMP2, MMP3, and MMP9 has
been described, both at the transcriptional and the protein level, in AS kidneys in humans, mice, and dogs.16,17 Such MMP up-regulation is not
unique to Alport nephropathy. However, AS kidney basement membranes were shown to be more readily degradable in vitro by collagenase,
elastase, and cathepsins, compared with normal kidney basement membranes,18 and this is thought to be due to the lack of the highly cross linked
3- 4- 5(IV) network. Blocking simultaneously at least MMP2, MMP3, and MMP9 in Col4a3-/- mice delays the progression of the disease if treatment
is given before development of GBM injury and occurrence of proteinuria in a C57BL6 genetic background.16 In addition, a recent study found an
increase of MMP12 expression in podocytes of humans, mice, or dogs affected with AS, possibly linked to MCP1-mediated activation of the
podocyte CCR2 receptor.19 Either MMP12 inhibitor or CCR2 receptor antagonist attenuates the GBM thickening in Col4a3-/- mice.19
Pharmacologic therapeutic approaches have been tested in animal models and in humans. Cyclosporine A was found to delay progression of renal
failure in humans and dogs in initial studies.20,21 However, cyclosporine is also found to be rapidly associated with nephrotoxicity, thereby precluding
its long-term use.22 Angiotensin-converting enzyme inhibitors and/or angiotensin 2 type 1 receptor antagonists reduce urinary protein excretion and
preserve glomerular filtration in dogs affected with X-linked AS, in Col4a3-/- mice,23 and in a few pediatric patients.24 Larger controlled studies are
necessary in humans to clarify the long-term benefit of the treatment and the nature and doses of drugs that are effective. Also, criteria for micro- or
macroalbuminuria for starting renoprotective treatment by blockade of the renin-angiotensin system remain to be precisely determined. In Alport
mice, chemokine receptor-1 blockade as well as statin treatment improves survival and renal lesions.25 Finally, bone marrow transplantation of
Col4a3-/- mice shows recruitment of bone marrow cells as future podocytes and mesangial cells, partial restoration of the expression of the 3- 45(IV) network, and clinical and histologic improvement.26–28 However, a recent study suggested that irradiation, which preceded bone marrow
transplantation, may improve the survival of Col4a3-/- mice by itself, through as yet unidentified mechanisms.29
Overt anti-GBM nephritis occurs in only 3 to 5% of transplanted Alport patients.30 The risk of graft loss is very high, and treatment with
plasmapheresis and cyclophosphamide has shown limited benefit. The risk of recurrence on subsequent transplantation is very high. This
complication is more likely to occur in patients with deletions or frameshift mutations, who do not express the 3 4 5(IV) GBM network. However,
many patients with COL4A5 deletion have been successfully transplanted, without developing anti GBM nephritis, and predictive factors for
developing the disease are currently unknown.
Cemara
1.
2.
3.
4.
5.
6.
7.
Determination of C3, CFH, CFI and CFB levels, expression of MCP and screening
for anti-CFH antibodies is indicated for all patients with aHUS. Normal C3 level
does not eliminate the presence of CFH or CFI mutation or of anti-CFH
antibodies.
Genotyping of CFH, CFI and MCP, and if possible CFB and C3, is indicated for all
patients with aHUS, even if plasma levels are normal.
The identified mutation has to be regarded as a risk factor for HUS, not as the
direct cause. The association of mutations in several genes is not exceptional.
Penetrance of the disease is 50% in patients with a mutation in complement.
Therefore, the risk of developing HUS is difficult to predict in family members
with the mutation. Intrafamilial genetic heterogeneity exists, suggesting that
unknown genetic factors are present.
A post-diarrheal onset of HUS can be observed in all groups. Therefore,
genotyping must be performed for patients with uncertain diagnosis of D +
/STEC + HUS, especially before transplantation. The worst prognosis is in
patients with CFH mutation, who are at high risk of ESRD as soon as at first flare
or within the year of onset.
Plasmatherapy (PE with FFP) should be started as early as possible. Although
evidence is lacking, benefit is expected mainly in CFH-mutated patients and in
patients with anti-CFH antibodies. Benefit is likely in all other subgroups of
aHUS, except the MCP subgroup, where spontaneous remission generally
occurs.
The risk of graft loss due to HUS recurrence or graft thrombosis is high in
patients with CFH and CFI mutations, while it is very low in patients with MCP
mutations. Family living donor transplantation is contraindicated, because of
the risk of graft loss due to recurrence and the risk that donors themselves
might have HUS after donation, due to unknown genetic factors shared with
the recipient.
Kidney transplantation under pre-, intra- and post-operative intensive
plasmatherapy may be successful in some patients.
Combined liver and kidney transplantation under pre- and intra-operative
plasmatherapy, and post-operative anticoagulation, has been successful in a
few patients with CFH mutation. This option will now have to be considered on
an individual basis for patients with mutations in other factors synthesized in
the liver.
Hope for the future relies on therapies which could prevent ESRD, such as CFH
concentrate or anti-C5 monoclonal antibodies.
Figure 1. Clinical course and laboratory findings
Mache, C. J. et al. Clin J Am Soc Nephrol 2009;4:1312-1316
Copyright ©2009 American Society of Nephrology
Infiltration of CD3-positive T-cells (A–D), F4/80-positive macrophages (E–F) and α-SMApositive activated fibroblasts (H–J).
Koepke M et al. Nephrol. Dial. Transplant. 2007;22:10621069
© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Figure 2. Representative human B1R expression in normal and pathologic human kidney biopsies
Klein, J. et al. J Am Soc Nephrol 2010;21:1157-1164
Copyright ©2010 American Society of Nephrology
Figure 4. Delayed B1Ra treatment reduces renal lesions and improves renal function
Klein, J. et al. J Am Soc Nephrol 2010;21:1157-1164
Copyright ©2010 American Society of Nephrology
Figure 5. B1R blockade inhibits the development of renal fibrosis
Klein, J. et al. J Am Soc Nephrol 2010;21:1157-1164
Copyright ©2010 American Society of Nephrology
Recherche plus fondamentale
Gene
Locus
Inheritance
Protein
Functiona
Phenotype or
Syndrome
Slit-Diaphragm protein complex
NPHS1
19q13.1
AR
Nephrin
NPHS2
1q25–31
AR
Podocin
PLCE1
10q23
AR
Phospholipase Cε1
CD2AP
6p12.3
AR (?)
CD2 associated protein
TRPC6
11q21–22
AD
TRPC6
Main component of the
SD. Anchors the SD to the
CNS of the Finnish type.
actin cytoskeleton.
Early-onset SRNS in cases
Modulate signalling
carrying at least one mild
events related with actin
mutation
cytoskeleton dynamics,
cell polarity and survival
CNS. Early and late onset
Scaffold protein linking AR SRNS. Juvenile and
plasma membrane to the adult SRNS in cases
actin cytoskeleton.
bearing the R229Q
Modulates
variant in compound
mechanosensation
heterozygous state with a
pathogenic mutation
Involved in cell junction
Early-onset SRNS with
signalling and glomerular
DMS and FSGS
development
Not precisely defined in
humans, may cause earlyAdapter protein, may
onset SRNS and FSGS.
anchor the SD to the
Mice model exhibits a
actin cytoskeleton
severe phenotype
resembling CNS in
humans
Receptor-activated nonselective calcium
Adult-onset SRNS with
permeant cation channel.
FSGS
Involved in
mechanosensation
Actin cytoskeleton components
ACTN4
19q13
AD
α-actinin-4
F-actin crosslinking protein
Late-onset SRNS
with incomplete
penetrance and
slow progression
to ESRD
MYH9
22q12.3
complex
NMMHC-A
Cellular myosin
that appears to
play a role in
cytokinesis and
cell shape
High risk
haplotypes
associated with
increased risk of
FSGS and ESKD in
African-Americans
LMX1B
9q34.1
AD
LIM/homeobox
protein LMX1B
Podocyte and
GBM development
and maintenance
Nail-patella
syndrome. NS in
40% of cases
SMARCAL1
2q35
AR
hHARP
ATP-dependent
annealing helicase
that rewind stably
unwound DNA
Schimke immunoosseus dysplasia
WT1
11p13
AD
Wilms’ tumour 1
Zinc finger
transcription
factor that
functions both as a
tumour suppressor
and as a critical
regulator of kidney
and gonadal
development
Denys–Drash
syndrome, Frasier
syndrome, WAGR
syndrome, isolated
FSGS and DMS
Nuclear proteins
Glomerular basement membrane proteins
LAMB2
3p21
AR
Laminin-β2
GBM component,
scaffold for type IV
collagen assembly.
Interactions with
integrin α3β1 links the
GBM to the actin
cytoskeleton
Pierson syndrome
ITGB4
17q25.1
AR
Integrin-β4
Cell-matrix adhesion,
critical structural role
in the
hemidesmosome of
epithelial cells
Epidermolysis bullosa.
Anecdotic cases
presenting with NS
and FSGS
COQ2
4q21–q22
AR
Polyprenyltransferase
CoQ10 biosynthesis,
which transfers
electrons from the
mitochondrial
respiratory chain
COQ10 deficiency,
early-onset SRNS, with
or without
encephalomyopathy
PDSS2
6q21
AR
Decaprenyl
diphosphate synthase2
CoQ10 biosynthesis,
which transfers
electrons from the
mitochondrial
respiratory chain
COQ10 deficiency,
Leigh syndrome and
SRNS
MTTL1
mtDNA
tRNA-LEU
Mitochondrial tRNA for
leucine
MELAS syndrome.
Mitochondrial
diabetes, deafness and
FSGS, with or without
nephrotic syndrome
LIMP II
May act as a lysosomal
receptor
Action myoclonus
renal failure
Mitochondrial proteins
Lysosomal proteins
SCARB2
4q13–21
AR
Light and electron microscopy.
Koepke M et al. Nephrol. Dial. Transplant. 2007;22:10621069
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