Childhood nephrotic syndromecurrent and future therapies

Greenbaum, L. A. et al. Nat. Rev. Nephrol. 8, 445458 (2012); published online 12 June 2012;

Atul desai 10/8/12Childhood nephrotic syndromecurrent and future therapiesBACKGROUNDNot a single disease

Genetic mutationsCirculating factorsT cell or B cell abnormalityPodocyte injuryNephrotic syndromeMCDFSGSMsGNMPGNMNMortality ratePrior to antibiotics & steroids67 %Introduction of sulfonamides42%Introduction of Penicillins35%Introduction of ACTH5%DefinitionsNephrotic syndrome: EdemaProteinuria: >40mg/sq m/hr or > 50mg/kg/day or PCR : >2 g/g 3+ protein on dipstickHypoalbuminemia : 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 periodFrequent : Two or more relapses within 6 months of initial response, or four or more relapses in any 12-month periodSDNS: Two consecutive relapses during corticosteroid therapy, or within 14 days of ceasing therapyResponse of NS to RxIdiopathic NSSteroid sensitive90%Steroid resistant10%40%60%Infrequent relapseFRNSSDNSALKYLATING AGENTSCNIMMFRITUXIMAB

CURRENTLY AVAILABLE Rx FOR SDNS/FRNS/SRNSCorticosteroid : low dose for long period in FRNS/SDNSIV glucocorticoids :

High dose IV steroid can sometimes induce remission in SRNS18 month protocol of IV CS +/- CYC in SRNS is effectiveMethylprednisolone treatment of patients with SRNSF. Bryson Waldo, Mark R. Benfield and Edward C. KohautPEDIATRIC 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 responseMP 20 mg/kg : on Mon, Wed, Fri for 2 weeksWeekly for 8weeksEvery other week for 8 weeksMonthly for 10 monthsCYTOTOXIC DRUGSCyclophosphamide and chlorambucilCyclophosphamide: CD not to exceed 168 mg/kgCNISCyclosporine & Tacrolimusprevents Tcell activation through inhibition of calcineurin-induced IL2 gene expressionAlso stabilize podocyte actin cytoskeletonin 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.

MMFIMPDH inhibitorNo salvage pathway in lymphocytes1200mg/mt sq in 2 divided dose.Various uncontrolled study : MMF beneficial in FRNS/SRNSPlasmapheresisOnly few case report of its use in native kidney nephrotic syndrome.NEW APPROACHESRituximabGalactose AdalimumabThiazolidinedionesRITUXIMABChimeric monoclonal antibody thatDepletes CD20+ B cells.Use in Nephrology :

Microscopic polyangiitis and granulomatosis with polyangiitis (Wegener) (FDA approval in 2011) Posttransplant lymphoproliferative disorderLupus nephritisMembranous nephropathyRecurrence of nephrotic syndrome in patients with FSGS following transplantationNephrotic 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 exposureIn 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 remissionRITUXIMAB 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: DOSINGAppropriate dosing not known375 mg/ sq mt every wk : 1-4 dose commonly used.Most have complete B cell depletion after single doseThe total Rituximab dose doesnt correlate with clinical outcome

Rituximab : repeat dose interval

Rituximab : relapseRelapse time : variable. Usually 5-9 monthOften associated with repopulation of CD 20 + B cells

Rituximab : Mode of action in NSRituximab 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.GALACTOSENovel Rx option in NSBinds permeability factor in pts with FSGSAlters the glomerular permeability.

Adalimumab Monoclonal anti TNF antibodyBinds to TNF, prevents its binding to its receptor.

ThiazolidinedionesThiazolidinediones 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 treatmentsp38 MAPK, MK2 and PKC signalingNotch signalingTargeting IL13Suppressing the unfolded protein responseMaintaining redox homeostasisMAPK: signallingThe 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 functionPKC deletion : nephrotic syndromePKC deletion : prevents NSNOTCH SIGNALLINGNotch 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 cellsPlay 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 RBPJNiranjan 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 secretase in rats with PAN-induced proteinuria.IL 13Lebrikizumab = IL 13 antibodySupressing unfolded protein responseStress 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 Bcl2 was downregulated.The UPR was regulated by the mammalian target of rapamycin (mTOR) complex 1 mTOR inhibitors : reduce proteinuriaThe UPR has also been suggested to have a role in some inherited forms of nephrotic syndrome, caused by mutations in nephrin, podocin and actinin4.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 4phenylbutyrate or ()-epigallocatechin3-gallate, which is a secondary plant metabolite.

Maintaining redox homeostasisOxidative 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 synthesisOxidative 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 syndromethe radical scavenger edaravone or dietary supplementation with the antioxidants probucol and vitamin E : of modest benefitTARGETING GENETIC FORM OF NSCyclosporine in NS caused by mutation in TRPC6