steroid resistant nephrotic syndrome

management SRNS - updated

2. SRNS: A challenge for paediatricnephrologists.
SRNS: A heterogeneous rare disease entity including
immune-based and monogenic etiologies.
SRNS: treatment strategies are individualized and vary
among centers of expertise.
CNI: have been effectively used to induce remission in
patients with immune-based SRNS, but no consensus on
treating children who become either CNI-dependent or
CNI-resistant, role of RTX as a steroid sparing agent.
Recently, monoclonal antibodies are emerging as
treatment options

3. Recent perspectives on the
stratification of Nephroticsyndrome
Treatment based on: the response to steroid,
histological results, genetic studies.
Treatment based on a novel molecular stratification
based on disease mechanisms as monogenic
immune mediated with circulating factors and
immune mediated without circulating factors.

4. Intensified immunosuppression and
adjuvant agents for SRNS (1)
1-Intravenous methylprednisolone pulse
2-CNIs: CSA, TAC
3-Cyclophosphamide
4-MycophenolateMofetil
5-Levamisole
inhibitor6-mTOR
7-Therapy for CNI-dependent, resistant SRNS

5. Intensified immunosuppressionand
adjuvant agents for SRNS (2)
8-Anti-CD20 monoclonal antibodies: RTX and novel
CD20-blocking agents, Ofatumumab
9-Other monoclonal antibodies:
Abatacept/Belatacept, Adalimumab, Fresolimumab
10-Non-immunologic therapies: RAS inhibitors,
Sparsentan, Galactose, ACTH analog, Mesengimal
stem cells, Retinoids
11-Treating monogenic SRNS

6. Efficacy of treatment options used in the management of cases with SRNS

8. •In the recent past, histonedeacetylaseinhibitors
(HDACi) have been greatly explored to treat chronic
kidney diseases because of the anti-fibrotic, anti-
inflammatory, and immunosuppressive effects that
they exhibit. Histonedeacetylases(HDACs) are the
class of enzymes that remove the acetyl groups from
the lysine amino acid on histoneand thereby promote
chromatin condensation and repression of
transcription. HDACiare the chemical compounds that
inhibit HDAC and alter gene transcription by inducing
changes in the structure of proteins in transcription
factor complexes.

9. Types and Causes of Nephrotic syndrome. Abbreviations-PLA2R: Phospholipase
A2 receptor; THSD7A: Thrombospondintype-1 domain containing 7A;
APOL1: Apolipoprotein1; suPAR: Soluble urokinase-type plasminogen activator
receptor

10. Basic Therapeutic Approach
Followed in Patients with
Nephrotic Syndrome. ACE,
Angiotensin Converting
Enzyme; BP, Blood pressure;
ARBs, Angiotensin
Receptor Blockers; SSNS,
Steroid sensitive nephrotic
syndrome; SDNS, Steroid
dependent nephrotic
syndrome; FRNS, Frequently
relapsing nephrotic
syndrome;
SRNS, Steroid resistant
nephrotic syndrome; CNI,
CalcineurinInhibitors; MMF,
Mycophenolatemofetil;
MAB, Monoclonal antibody.

11. Classification of HDACs. HDAC, Histone Deacetylase.

12. Valproicacid (VPA) Prevented
Proteinuria and Kidney Injury in
Adriamycin (ADR) Nephropathy. A.
Experimental design that was used
by Benedenet al.
for pre-VPA treatment in mice. B.
Proteinuria was prevented when VPA
treatment was started 3 days prior
(pre-VPA) to ADR injection. C. In
the ADR group, serum
cholesterol (mg/dl) was increased
significantly as compared to control
and pre–VPA group. D. Blinded
quantitative histologic evaluation of
glomerulosclerosis. E.
Periodic acid Schiff stained kidney
sections representing kidney injury
at the end of the experiment in the
different groups (control, ADR and
pre-VPA) of mice.
Kidney sections were subjected to
PAS staining. (#P < 0.001; **P <
0.01; *P < 0.05). (Figure reused with

13. Mechanisms and Pathways Associated with HDACi. HDACi, Histonedeacetylases
inhibitor; STAT3, Signal transducer and activator of transcription3; TGF-β1,
Transforming growth factor β1; EGFR, Epidermal growth factorreceptor; ROS,
Reactive oxygen species; MAPK, Mitogen activated proteinkinases; JNK: c-Jun N-
terminal kinase; NF-κB, Nuclear factor kappa B; iNOS,inducible Nitric oxide
synthase.

14. Effect of HDAC inhibitors on Renal Pathologies. HDAC, Histone Deacetylase; ip, intraperotoneal; po, per oral; sc, subcutaneous; MRL/lpr. Murphy Roths
large/ lymphoproliferation; Npr1, Natriuretic peptide receptor A;UUO, unilateral ureteral obstruction; α-SMA, α-smooth muscle actin; AKI, acute kidney
injury; SLE, systemic lupus erythematosus; NZB/W, New Zealand Black/White; GFB, Glomerular filtration barrier; STAT, Signaltransducer and activator of
transcription; NF-κB, Nuclear factor kappa B; RPTEC, renal proximal tubular epithelial cells; EMT: Epithelial-to-mesenchymal transition; ROS, Reactive
oxygen species; ECM, Extracellularmatrix; TGF-β, Transforming growth factor beta

15. •Over the past 20 years delineation of the underlying biology
of the target cell in INS -the glomerularpodocyte-has
transformed our understanding of the mechanisms that
contribute to breakdown of the glomerularfiltration barrier
and the development of INS. It is increasingly clear that
nephroticsyndrome caused by monogenic mutations is
distinct from immune-driven disease, which in some cases is
mediated by circulating factors that target the podocyte.
The combination of systems biology and bioinformatics
approaches, together with powerful laboratory models and
ever-growing patient registries has potential to identify
disease 'signatures' that reflect the underlying molecular
mechanism of INS on an individual basis. Understanding of
such processes could lead to the development of targeted
therapies.

16. Contributionofmolecularsignalsandsolublefactorstopodocytehealth.Thepodocyteslitdiaphragmcomplexactsasakeynodefor
molecularsignalstoregulatetheactincytoskeleton.Integrinsandcomponentsoftheactincytoskeleton,whichregulatepodocyte
adhesionandmotility,provideasecondnodeformolecularsignals.Solublecirculatingorautocrinefactors(suchasinsulin,shigatoxin
(Stx)andproteases)influencebothofthesesignallingnodes,therebyaffectingpodocytecellshape,dynamicsandattachment.Unknown
circulatingfactorsproducedbyimmunecellssuchasTH17cellsarelikelytomediatesomeofthesepathwaysin‘circulatingfactor
disease’(CFD).Intermediategenetranscriptionofintracellularmediators(suchasBMF,IGFBP3andIL-1β)canbeusedasmarkersof
activeCFD.Podocyte-secretedfactorssuchasvascularendothelialgrowthfactorA(VEGFA)andendothelin(ET-1)canalsoaffect
endothelialcellhealthinareciprocalmannerthroughbindingtotheirreceptors,VEGFARandETA-RorETB-R,respectively.

20. proposed stratification of steroid-resistant
nephrotic syndrome based on
disease mechanisms and outcomes. Available
evidence suggests that monogenicnephrotic
syndrome is distinct from immune-mediated
nephroticsyndrome, withdistinct clinical outcomes.
For instance, patients with monogenic disease are
generallyresistant to immunosuppressionand show
faster progression to end-stage renal disease(ESRD),
but with little chance of recurrence following
transplantation. Immune-mediateddisease can be
further stratified according to the presence of certain
clinical clues.A subset of patients with immune-
mediated disease will have circulating factor disease
(CFD), which is most readily identified by post-
transplantation disease recurrence.These patients
tend to be multidrug resistant, and have no known
genetic cause ofdisease. Patients who respond early
to intensified immunosuppressionhave a high chance
of achieving a good long-term outcome. There are
currently no biomarkers to indicateif a patient has
steroid-sensitive nephroticsyndrome (SSNS). A
subset of these patientswill become steroid-
resistant (that is, develop secondary steroid-resistant
nephroticsyndrome (SRNS)), and have a high
likelihood of developing post-transplantation
recurrence. Association with HL A class II alleles or
the rare familial cases of SSNS could
also indicate immune-mediated CFD.

21. Low-density lipoprotein (LDL) apheresishas been used
increasingly in clinical practice for the treatment of renal diseases
with nephroticsyndrome (NS), specifically focal segmental
glomerulosclerosis(FSGS). Persistent hyperlipidemiafor
prolonged periods is nephrotoxicand leads to chronic
progressive glomerularand tubulointerstitialinjury. Effective
management of hyperlipidemiawith HMG-CoAreductase
inhibitors or LDL apheresisin drug-resistant NS patients may
prevent the progression of renal disease and, in some patients,
resolution of NS symptoms.Available literature reveals beneficial
effects of LDL apheresisfor NS refractory to drug therapy. Here
we update on the current understanding of lipid nephrotoxicity
and application of LDL apheresisto prevent progression of renal
diseases.

22. Pthophysiologicalmechanism
involved in liponephrotoxicity,
LDLlow-density
lipoprotein,FFAsfree fatty acids,
TGtriglycerides,
ANGPTL4angiopoietin-like 4,
RASrenin angiotensin system.
Main mechanism is highlighted in
blue color

23. Idiopathic steroid-resistant nephroticsyndrome (SRNS) is
most frequently characterized by focal segmental
glomerulosclerosis(FSGS) but also other histological lesions,
such as diffuse mesangialsclerosis. In the past two decades,
a multitude of genetic causes of SRNS have been discovered
raising the question of effective treatment in this cohort.
Although no controlled studies are available, this review will
discuss treatment options including pharmacologic
interventions aiming at the attenuation of proteinuriain
genetic causes of SRNS, such as inhibitors of the renin-
angiotensin-aldosteronesystem and indomethacin.

24. 1-Supportive non immunologic treatment of genetic causes of
NS:
*Cogenitaland infantile NS: albumin infusions,
nephrectomy, RAAS inhibitors with or without
indometacin
*Non immunologic treatment in pediatric and
adolscentsgenetic SRNS
2-Other options: Galactose, TNF-a inhibitors, vitamin D analog
and cinacalcet
3-Immunosuppressant in genetic SRNS
4-CoQ10 deficiency
5-gene therapy in genetic forms of SRNS

25. Suggestion of an algorithm for
treatment in genetic nephrotic
syndrome (NS). (A) Congenital
and infantile NS with positive
testing results. (B) Pediatric
steroid-resistant nephrotic
syndrome, where often, results
of genetic testing are not
available immediately.

26. تسا یراک نه ، درم نینچ
گرم درمب ناسارخ درم ی
سک
تفگدرخ
درپس درام به ، کین دبلاک داد زاب ردپ به ،یمارگ ناج
،ییوگ وت هک ،دش نونک هدنز زاب تفر یکلم
اب ،کلم نآ؟درمب

ف
امرس به هک ،وا دبن بآ دیپر یداب به هک، وا دبن هاکدر
س
درمشیم
یوج به ار ناهج و د وک نادکاخ نیا در دوب یرز ج
نگ
یوس درخ و ناج دنکف یکاخ یوس ،یکاخ رکیپ
تاوامسبرد
پس ننااج به هک دنیوگ هطلغم قلخ دننادن هک ،ار مود ناجدر
به ت
خیم
آدر فاصی
ّ
ددرد ز دش ادج و تفر م
خ
رس بر یمرد
به ش
کشیپ
د داش ناور ،یمارگ تسود رتک یع
امسا دم
حم
یل
ک یِژولورفن ص
صخت
قوف و داتساناسارخ ناکدو