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

BACKGROUND

Not a single disease

• Genetic mutations• Circulating factors• T cell or B cell

abnormality

Podocyte injury

Nephrotic syndrome

• MCD• FSGS• MsGN• MPGN• MN

Mortality rate

Prior to antibiotics & steroids 67 %

Introduction of sulfonamides 42%

Introduction of Penicillins 35%

Introduction of ACTH 5%

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 Rx2mg/kg/day x 6wk1.5mg/kg alt day x 6wk

• uPCR <200mg/g• <1+ protein on dipstick

for 3 consecutive daysCOMPLETE 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

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

Response of NS to Rx

Idiopathic NS

Steroid sensitive

90%

Steroid resistant

10%

40% 60%

Infrequent relapse

FRNSSDNS

• ALKYLATING AGENTS

• CNI• MMF• RITUXIMAB

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 SRNS18 month protocol of IV CS +/- CYC in SRNS is effective

Methylprednisolone treatment of patients with SRNSF. Bryson Waldo, Mark R. Benfield and Edward C. Kohaut

PEDIATRIC NEPHROLOGYVolume 6, Number 6 (1992), 503-505,

13 pts: 8 blacks, 5 white10 had FSGS on Bx, 3 nil lesionInitial response: 5 had complete response; 2 PROf responded pts, 5 relapsed while on a;t week MP rx3 of them received 2nd course of MP+ chlorambucol : 2 respondedObserved for mean of 47 months (6-64 months)3 pts with nil disease : proteinuria free6 have ESRD2 renal; insufficiencyBlacks : no response

MP 20 mg/kg : on Mon, Wed, Fri for 2 weeksWeekly for 8weeks

Every other week for 8 weeksMonthly for 10 months

CYTOTOXIC DRUGS

Cyclophosphamide and chlorambucil

Cyclophosphamide: CD not to exceed 168 mg/kg

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, ciclosporinwas superior to intravenous cyclophosphamide in children with SRNS.

MMF

IMPDH inhibitor

No salvage pathway in lymphocytes

1200mg/mt sq in 2 divided dose.

Various uncontrolled study : MMF beneficial in FRNS/SRNS

Plasmapheresis

Only few case report of its use in native kidney nephrotic syndrome.

NEW APPROACHES

Rituximab

Galactose

Adalimumab

Thiazolidinediones

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.

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.

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.

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

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),

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

Rituximab : repeat dose interval

Rituximab : relapse

Relapse time : variable. Usually 5-9 month

Often associated with repopulation of CD 20 + B cells

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 podocytesinduced by sera from adults with recurrent FSGS, as well as restored actin stress fiber formation and podocyte viability.

GALACTOSE

Novel Rx option in NS

Binds permeability factor in pts with FSGS

Alters the glomerular permeability.

Adalimumab

Monoclonal anti TNF antibody

Binds to TNF, prevents its binding to its receptor.

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.

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

Future treatments

p38 MAPK, MK2 and PKCα signaling

Notch signaling

Targeting IL-13

Suppressing the unfolded protein response

Maintaining redox homeostasis

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

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

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.

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

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.

IL 13

Lebrikizumab = IL 13 antibody

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.

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.

The UPR was regulated by the mammalian target of rapamycin (mTOR) complex 1

mTOR inhibitors : reduce proteinuria

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.

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.

Alternative approaches might include the use of low-molecular mass compounds that reduce misfoldingand protein aggregation, such as sodium 4-phenylbutyrate or (–)-epigallocatechin-3-gallate, which is a secondary plant metabolite.

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

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

the radical scavenger edaravone or dietary supplementation with the antioxidants probucol and vitamin E : of modest benefit

TARGETING GENETIC FORM OF NS

Cyclosporine in NS caused by mutation in TRPC6