Childhood nephrotic syndrome current and future therapies

GREENBAUM, L. A. ET AL. NAT. REV. NEPHROL. 8, 445458 (2012); PUBLISHED ONLINE 12 JUNE 2012;

ATUL DESAI 10/8/12

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
Introduction of Penicillins Introduction of ACTH

42%
35% 5%

Definitions
Nephrotic syndrome:
Prednisolone Rx 2mg/kg/day x 6wk 1.5mg/kg alt day x 6wk Edema Proteinuria: >40mg/sq m/hr or > 50mg/kg/day or PCR : >2 g/gResistance 3+ protein ifon nodipstick CR by 8 wk of Rx Hypoalbuminemia : <2.5 g/dl Hyperlipdemia

uPCR <200mg/g <1+ protein on dipstick for 3 consecutive days Proteinuria reduction by > 50 % from presenting value and uPCR 200- 2000 mg/g

COMPLETE REMISSION

PARTIAL REMISSION

 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 12month period SDNS: Two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapy

Response of NS to Rx
Idiopathic NS 90% 10%

Steroid sensitive 40% 60%

Steroid resistant

Infrequent relapse

FRNS SDNS

ALKYLATING AGENTS CNI MMF RITUXIMAB

CURRENTLY AVAILABLE Rx FOR SDNS/FRNS/SRNS

Corticosteroid : low dose for long period in

FRNS/SDNS MP 20 mg/kg : on Mon, Wed, Fri for 2 weeks Weekly for 8weeks IV glucocorticoids :

Every other week for 8 weeks in SRNS High dose IV steroid can sometimes induce remission Monthly for 10 months 18 month protocol of IV CS +/- CYC in SRNS is effective 13 pts: 8 blacks, 5 white 10 had FSGS on Bx, 3 nil lesion Methylprednisolone treatment of patients with SRNS InitialF. response: 5 had complete 2 PR Bryson Waldo, Mark R. response; Benfield and Edward C. Kohaut Of responded pts, 5 relapsed while on a;t week MP rx PEDIATRIC NEPHROLOGY 3 of them received 2nd course of MP+ chlorambucol : 2 responded Volume 6, Number 6 (1992), 503-505, 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

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, ciclosporin was 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 14 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 24 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 (860 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 doesnt 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 podocytes induced 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 PKC 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 deletion : nephrotic syndrome PKC deletion : prevents NS

NOTCH SIGNALLING
Notch signaling regulates multiple cellular processes

including development, differentiation, proliferation and apoptosis. In mammals, there are four Notch (Notch 14) 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 -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 NotchICD 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 -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 -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 misfolding and 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