Childhood nephrotic syndrome—current and future therapies
1. G R E E N B A U M , L . A . E T A L .
N A T . R E V . N E P H R O L . 8 , 4 4 5 – 4 5 8 ( 2 0 1 2 ) ;
P U B L I S H E D O N L I N E 1 2 J U N E 2 0 1 2 ;
A T U L D E S A I 1 0 / 8 / 1 2
Childhood nephrotic syndrome—
current and future therapies
2. BACKGROUND
Not a single disease
• Genetic mutations
• Circulating factors
• T cell or B cell
abnormality
Podocyte injury
Nephrotic
syndrome
• MCD
• FSGS
• MsGN
• MPGN
• MN
3. Mortality rate
Prior to antibiotics & steroids 67 %
Introduction of sulfonamides 42%
Introduction of Penicillins 35%
Introduction of ACTH 5%
4. Definitions
Nephrotic syndrome: • Edema
• Proteinuria: >40mg/sq m/hr
or > 50mg/kg/day or PCR :
>2 g/g 3+ protein on dipstick
• Hypoalbuminemia : <2.5 g/dl
• Hyperlipdemia
Prednisolone Rx
2mg/kg/day x 6wk
1.5mg/kg alt day x 6wk
• uPCR <200mg/g
• <1+ protein on dipstick
for 3 consecutive days
COMPLETE
REMISSION
• Proteinuria reduction by
> 50 % from presenting
value and
• uPCR 200- 2000 mg/g
PARTIAL REMISSION
Resistance if no CR by 8 wk of Rx
5. Relapse : uPCR > 2g/g or > 3 + proteinuria on
dipstick test for 3 consecutive days.
Infrequent : 1 relapse within 6 months of initial
response, or one to three relapses in any 12-month
period
Frequent : Two or more relapses within 6 months of
initial response, or four or more relapses in any 12-
month period
SDNS: Two consecutive relapses during
corticosteroid therapy, or within 14 days of ceasing
therapy
7. CURRENTLY AVAILABLE Rx FOR
SDNS/FRNS/SRNS
Corticosteroid : low dose for long period in
FRNS/SDNS
IV glucocorticoids :
High dose IV steroid can sometimes induce remission in SRNS
18 month protocol of IV CS +/- CYC in SRNS is effective
Methylprednisolone treatment of patients with SRNS
F. Bryson Waldo, Mark R. Benfield and Edward C. Kohaut
PEDIATRIC NEPHROLOGY
Volume 6, Number 6 (1992), 503-505,
13 pts: 8 blacks, 5 white
10 had FSGS on Bx, 3 nil lesion
Initial response: 5 had complete response; 2 PR
Of responded pts, 5 relapsed while on a;t week MP rx
3 of them received 2nd course of MP+ chlorambucol : 2 responded
Observed for mean of 47 months (6-64 months)
3 pts with nil disease : proteinuria free
6 have ESRD
2 renal; insufficiency
Blacks : no response
MP 20 mg/kg : on Mon, Wed, Fri for 2 weeks
Weekly for 8weeks
Every other week for 8 weeks
Monthly for 10 months
9. CNIS
Cyclosporine & Tacrolimus
prevents T-cell activation through inhibition of
calcineurin-induced IL2 gene expression
Also stabilize podocyte actin cytoskeleton
in a nonrandomized trial, 65 children with SRNS (45
with MCD; 20 with FSGS) were treated with a
combination of ciclosporin and prednisone, with 27
children (41%) achieving complete remission.
In a randomized study published in 2008, ciclosporin
was superior to intravenous cyclophosphamide in
children with SRNS.
10. MMF
IMPDH inhibitor
No salvage pathway in lymphocytes
1200mg/mt sq in 2 divided dose.
Various uncontrolled study : MMF beneficial in
FRNS/SRNS
13. RITUXIMAB
Chimeric monoclonal antibody that
Depletes CD20+ B cells.
Use in Nephrology :
• Microscopic polyangiitis and granulomatosis
with polyangiitis (Wegener) (FDA approval in
2011)
• Posttransplant lymphoproliferative disorder
• Lupus nephritis
• Membranous nephropathy
• Recurrence of nephrotic syndrome in patients
with FSGS following transplantation
• Nephrotic syndrome.
14. RITUXIMAB in SDNS/FRNS
54 children (mean age 11 +/- 4 years) with INS dependent on prednisone
and calcineurin inhibitors for >12 months were randomized.
Rituximab and lower doses of prednisone and calcineurin inhibitors are
noninferior to standard therapy in maintaining short-term remission in
children with INS dependent on both drugs and allow their temporary
withdrawal.
15. In a retrospective comparison of 23 children with
SDNS, rituximab and tacrolimus were similarly
effective in reducing relapse rates and glucocorticoid
exposure
In another retrospective study of 30 children with
SDNS treated with repeated doses of rituximab to
maintain depressed CD19 levels for at least 15
months, long-term remission (~17 months) following
complete CD19 recovery was noted in 19 (63%) of
patients.
16. a retrospective review of long-term outcomes for 37
children with SDNS found that 375 mg/m2 given
weekly for 1–4 courses resulted in a sustained
remission in 26 children (70%) for 12 months and,
among 29 children followed for more than 2 years,
12 (41%) remained in remission
17. RITUXIMAB IN SRNS
• 33 children with SRNS who received 2–4 doses of rituximab.
• At 6 months after the last dose of rituximab: 9 (27%) children had
entered complete remission, 7 (21%) had experienced a partial
remission, and 17 (51%) had had no response.
• The median time to response was 32 days (8–60 days),
18. RITUXIMAB: DOSING
Appropriate dosing not known
375 mg/ sq mt every wk : 1-4 dose – commonly used.
Most have complete B cell depletion after single dose
The total Rituximab dose doesn’t correlate with
clinical outcome
21. Rituximab : relapse
Relapse time : variable. Usually 5-9 month
Often associated with repopulation of CD 20 + B
cells
22.
23. Rituximab : Mode of action in NS
Rituximab binds directly to an acid
sphingomyelinase-like phosphodiesterase 3b
(SMPDL3B) on the surface of podocytes.
The binding of rituximab to this ‘off-target’ podocyte
protein prevented the downregulation of acid
sphingomyelinase activity in cultured podocytes
induced by sera from adults with recurrent FSGS, as
well as restored actin stress fiber formation and
podocyte viability.
24. GALACTOSE
Novel Rx option in NS
Binds permeability factor in pts with FSGS
Alters the glomerular permeability.
27. Thiazolidinediones
Thiazolidinediones reduced proteinuria,
microalbuminuria, podocyte injury, vascular injury,
inflammation and fibrosis in both diabetic
nephropathy and nondiabetic glomerulosclerosis in
mouse and rat models, as well as in humans.
28. The thiazolidinedione pioglitazone protected against
progression of puromycin aminonucleoside (PAN)-
induced glomerulosclerosis in vivo and against injury
of cultured podocytes in vitro.
Thiazolidinediones markedly decreased albuminuria
and proteinuria in patients with diabetes mellitus
29.
30. Future treatments
p38 MAPK, MK2 and PKCα signaling
Notch signaling
Targeting IL-13
Suppressing the unfolded protein response
Maintaining redox homeostasis
31. MAPK: signalling
The major families of
MAPK typically translate
extracellular stimuli to
intracellular responses.
The p38 MAPK pathway
has crucial roles in
inflammation,
differentiation, senescence,
tumorigenesis, and
apoptosis, as well as in a
variety of renal diseases
32. The various forms of protein kinase C (PKC) also
have a role in both glomerular and tubular function
PKC λ deletion : nephrotic syndrome
PKC α deletion : prevents NS
33. NOTCH SIGNALLING
Notch signaling regulates multiple cellular processes
including development, differentiation, proliferation
and apoptosis.
In mammals, there are four Notch (Notch 1–4) and
five ligand (Jagged1, Jagged2, DLL1, DLL3, DLL4)
genes.
all containing transmembrane domains such that
ligand-receptor signaling occurs between adjacent
cells
Play crucial role in nephrogenesis.
34. Notch signaling involves receptors, ligands,
modifiers, and transcription factors.
Following Jagged or Delta-like protein ligand
binding, the intracellular domain of the Notch
receptor is cleaved off by a γ-secretase and
subsequently translocated to the nucleus where it
binds to the transcriptional repressor RBP-J
35. Niranjan and co-workers demonstrated that
transgenic mice conditionally overexpressing Notch-
ICD in mature podocytes developed proteinuria and
glomerulosclerosis, in association with p53
activation and podocyte apoptosis.
Conversely, genetic deletion of downstream Rbpj in
the podocytes of mice with diabetes protected
against glomerular proteinuria, as did pharmacologic
inhibition of the upstream γ-secretase in rats with
PAN-induced proteinuria.
37. Supressing unfolded protein response
Stress induced disturbance of protein folding in ER :
unfolded protein response.
UPR : recognised as the underlying pathologic
mechanism in various diseases.
UPR is a complex signaling program of stress
adaption by maintaining protein folding
homeostasis.
If folding homeostasis cannot be maintained because
of severe stress, programs are activated that initiate
autophagy and/or apoptosis.
38. This cellular stress response has already been recognized
as having a pathogenic role in some forms of nephrotic
syndrome.
In kidney biopsy samples from adults with nephrotic
syndrome associated with FSGS, crescentic
glomerulonephritis, membranous glomerulonephritis,
and membranoproliferative glomerulonephritis,
indicators of the UPR, such as heat shock 70 kDa protein
5 and DNA-damage-inducible transcript 3 are found to
be upregulated when compared with patients with MCD,
whereas the apoptosis regulator Bcl-2 was
downregulated.
39. The UPR was regulated by the mammalian target of
rapamycin (mTOR) complex 1
mTOR inhibitors : reduce proteinuria
40. The UPR has also been suggested to have a role in
some inherited forms of nephrotic syndrome, caused
by mutations in nephrin, podocin and α-actinin-4.
41. Future therapeutic approaches could target
stabilization of folding homeostasis in podocytes.
Approaches might include enhancement of protein
chaperoning or enhancement of degradation
capacities, by increasing the expression of relevant
chaperones or proteasome system activity,
respectively.
42. Alternative approaches might include the use of low-
molecular mass compounds that reduce misfolding
and protein aggregation, such as sodium
4-phenylbutyrate or (–)-epigallocatechin-3-gallate,
which is a secondary plant metabolite.
43. Maintaining redox homeostasis
Oxidative stress occurs in both children and adults
with various kidney diseases.
Reactive oxygen species (ROS) have been suggested
to have a role in the pathogenesis of nephrotic
syndrome through actions such as impairing the
integrity of the glomerular basement membrane or
reducing podocyte proteoglycan de novo synthesis
44. Oxidative injury of podocytes in nephrotic syndrome
might also be caused indirectly through increased
exposure to oxidized serum albumin
Developing improved, or more targeted, strategies to
reduce podocyte oxidative stress and/or regulate
redox homeostasis would be an auspicious approach
to attenuate podocyte injury in nephrotic syndrome
45. the radical scavenger edaravone or dietary
supplementation with the antioxidants probucol and
vitamin E : of modest benefit
