2. SRNS: A challenge for paediatric nephrologists.
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 Nephrotic syndrome
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- Mycophenolate Mofetil
5-Levamisole
inhibitor
6- mTOR
7-Therapy for CNI-dependent, resistant SRNS

5. Intensified immunosuppression and
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, histone deacetylase inhibitors
(HDACi) have been greatly explored to treat chronic
kidney diseases because of the anti-fibrotic, anti-
inflammatory, and immunosuppressive effects that
they exhibit. Histone deacetylases (HDACs) are the
class of enzymes that remove the acetyl groups from
the lysine amino acid on histone and thereby promote
chromatin condensation and repression of
transcription. HDACi are 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: Thrombospondin type-1 domain containing 7A;
APOL1: Apolipoprotein 1; 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,
Calcineurin Inhibitors; MMF,
Mycophenolate mofetil;
MAB, Monoclonal antibody.

11. Classification of HDACs. HDAC, Histone Deacetylase.

12. Valproic acid (VPA) Prevented
Proteinuria and Kidney Injury in
Adriamycin (ADR) Nephropathy. A.
Experimental design that was used
by Beneden et 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 <

13. Mechanisms and Pathways Associated with HDACi. HDACi, Histone deacetylases
inhibitor; STAT3, Signal transducer and activator of transcription 3; TGF-β1,
Transforming growth factor β1; EGFR, Epidermal growth factor receptor; ROS,
Reactive oxygen species; MAPK, Mitogen activated protein kinases; JNK: c-Jun N-
terminal kinase; NF-κB, Nuclear factor kappa B; iNOS, inducible Nitric oxide

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, Signal transducer 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, Extracellular matrix; TGF-β, Transforming growth factor beta

15. • Over the past 20 years delineation of the underlying biology
of the target cell in INS - the glomerular podocyte - has
transformed our understanding of the mechanisms that
contribute to breakdown of the glomerular filtration barrier
and the development of INS. It is increasingly clear that
nephrotic syndrome 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. Contribution of molecular signals and soluble factors to podocyte health. The podocyte slit diaphragm complex acts as a key node for
molecular signals to regulate the actin cytoskeleton. Integrins and components of the actin cytoskeleton, which regulate podocyte
adhesion and motility, provide a second node for molecular signals. Soluble circulating or autocrine factors (such as insulin, shigatoxin
(Stx) and proteases) influence both of these signalling nodes, thereby affecting podocyte cell shape, dynamics and attachment. Unknown
circulating factors produced by immune cells such as TH17 cells are likely to mediate some of these pathways in ‘circulating factor
disease’ (CFD). Intermediate gene transcription of intracellular mediators (such as BMF, IGFBP3 and IL-1β) can be used as markers of
active CFD. Podocyte- secreted factors such as vascular endothelial growth factor A (VEGFA) and endothelin (ET-1) can also affect
endothelial cell health in a reciprocal manner through binding to their receptors, VEGFAR and ETA- R or ETB- R, respectively.

20. proposed stratification of steroid- resistant
nephrotic syndrome based on
disease mechanisms and outcomes. Available
evidence suggests that monogenic nephrotic
syndrome is distinct from immune- mediated
nephrotic syndrome, with distinct clinical outcomes.
For instance, patients with monogenic disease are
generally resistant to immunosuppression and show
faster progression to end- stage renal disease (ESRD),
but with little chance of recurrence following
transplantation. Immune- mediated disease 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 of disease. Patients who respond early
to intensified immunosuppression have a high chance
of achieving a good long- term outcome. There are
currently no biomarkers to indicate if a patient has
steroid- sensitive nephrotic syndrome (SSNS). A
subset of these patients will become steroid-
resistant (that is, develop secondary steroid- resistant
nephrotic syndrome (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) apheresis has been used
increasingly in clinical practice for the treatment of renal diseases
with nephrotic syndrome (NS), specifically focal segmental
glomerulosclerosis (FSGS). Persistent hyperlipidemia for
prolonged periods is nephrotoxic and leads to chronic
progressive glomerular and tubulointerstitial injury. Effective
management of hyperlipidemia with HMG-CoA reductase
inhibitors or LDL apheresis in 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 apheresis for NS refractory to drug therapy. Here
we update on the current understanding of lipid nephrotoxicity
and application of LDL apheresis to prevent progression of renal
diseases.

22. Pthophysiological mechanism
involved in liponephrotoxicity,
LDL low-density
lipoprotein, FFAs free fatty acids,
TG triglycerides,
ANGPTL4 angiopoietin-like 4,
RAS renin angiotensin system.
Main mechanism is highlighted in
blue color

23. Idiopathic steroid-resistant nephrotic syndrome (SRNS) is
most frequently characterized by focal segmental
glomerulosclerosis (FSGS) but also other histological lesions,
such as diffuse mesangial sclerosis. 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 proteinuria in
genetic causes of SRNS, such as inhibitors of the renin-
angiotensin-aldosterone system and indomethacin.

24. 1- Supportive non immunologic treatment of genetic causes of
NS:
*Cogenital and infantile NS: albumin infusions,
nephrectomy, RAAS inhibitors with or without
indometacin
*Non immunologic treatment in pediatric and
adolscents genetic 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. ‫ت‬‫س‬‫ا‬‫اری‬‫ک‬‫هن‬،‫رد‬‫م‬‫ن‬‫ی‬‫چن‬‫رگ‬‫م‬ ‫رد‬‫م‬‫ب‬‫ان‬‫س‬‫ا‬‫ر‬‫خ‬‫رد‬‫م‬‫ی‬‫کس‬‫ت‬‫گف‬
‫رد‬‫خ‬
‫رد‬‫سپ‬‫ارد‬‫م‬‫هب‬،‫یک‬‫ن‬‫بد‬‫ل‬‫ا‬‫ک‬ ‫د‬‫ا‬‫د‬‫از‬‫ب‬‫پدر‬‫هب‬،‫ی‬‫م‬‫ا‬‫ر‬‫گ‬‫ان‬‫ج‬
،‫ی‬‫ی‬‫و‬‫گ‬‫و‬‫ت‬‫ه‬‫ک‬،‫شد‬‫ون‬‫ن‬‫ک‬‫نده‬‫ز‬ ‫از‬‫ب‬‫ت‬‫ف‬‫ر‬‫ی‬‫ک‬‫ل‬‫م‬‫ا‬‫ب‬،‫لک‬‫م‬‫ن‬‫آ‬
‫رد؟‬‫م‬‫ب‬
‫ف‬‫ا‬‫م‬‫ر‬‫س‬‫هب‬‫ه‬‫ک‬،‫او‬‫بد‬‫ن‬‫آب‬ ‫رپید‬‫ادی‬‫ب‬‫هب‬‫ه‬‫ک‬،‫او‬‫بد‬‫ن‬‫اه‬‫ک‬
‫رد‬‫س‬
‫رد‬‫م‬‫ش‬‫ی‬‫م‬‫وی‬‫ج‬‫هب‬‫ا‬‫ر‬‫ان‬‫ه‬‫ج‬‫و‬‫د‬‫و‬‫ک‬ ‫ن‬‫ا‬‫د‬‫اک‬‫خ‬‫ن‬‫ی‬‫ا‬‫رد‬‫ود‬‫ب‬‫زری‬‫ج‬‫گن‬
‫وی‬‫س‬‫رد‬‫خ‬‫و‬‫ان‬‫ج‬ ‫ند‬‫ک‬‫ف‬‫ی‬‫ک‬‫ا‬‫خ‬‫وی‬‫س‬،‫ی‬‫ک‬‫ا‬‫خ‬‫ر‬‫ک‬‫ی‬‫پ‬
‫ت‬‫ا‬‫و‬‫ا‬‫م‬‫س‬
‫رب‬
‫د‬
‫سپ‬‫اانن‬‫ج‬‫هب‬‫ه‬‫ک‬‫ند‬‫ی‬‫و‬‫گ‬‫ه‬‫ط‬‫غل‬‫م‬ ‫ق‬‫ل‬‫خ‬‫ند‬‫ن‬‫ا‬‫د‬‫ن‬‫ه‬‫ک‬،‫ا‬‫ر‬‫دوم‬‫ان‬‫ج‬
‫رد‬
‫هب‬‫ت‬‫خ‬‫ی‬‫م‬‫ردآ‬‫اف‬‫ص‬
‫ی‬ّ‫ردد‬
‫د‬‫ز‬‫شد‬‫ا‬‫د‬‫ج‬‫و‬‫ت‬‫ف‬‫ر‬‫م‬‫خ‬‫ر‬‫س‬‫رب‬ ‫ی‬‫م‬
‫ر‬
‫د‬
‫هب‬‫ش‬‫ک‬‫ش‬‫ی‬‫پ‬
‫د‬‫اد‬‫ش‬‫ن‬‫ا‬‫و‬‫ر‬،‫ی‬‫م‬‫ا‬‫ر‬‫گ‬‫ت‬‫س‬‫دو‬
‫ر‬‫کت‬
‫ی‬‫ع‬‫ا‬‫م‬‫س‬‫ا‬‫مد‬‫ح‬‫م‬
‫ی‬‫ل‬
‫ک‬‫ِی‬‫ژ‬‫و‬‫ل‬‫رو‬‫نف‬‫ص‬‫ص‬‫تخ‬
‫وق‬‫ف‬‫و‬‫اد‬‫ت‬‫س‬‫ا‬
‫ان‬‫س‬‫ا‬‫ر‬‫خ‬‫ان‬‫ک‬‫ود‬