Steroid resistant nephrotic syndrome remains a therapeutic challenge. Calcineurin inhibitors such as cyclosporine are recommended as initial therapy, continuing for at least 6 months if a partial or complete remission is achieved, or 12 months if remission is seen by 6 months. For children who do not respond to calcineurin inhibitors, mycophenolate mofetil or high-dose corticosteroids may be considered. Cyclophosphamide is not recommended. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are recommended for all children with steroid resistant nephrotic syndrome. Emerging therapies targeting B cells, such as rituximab, show
Door Prof. Dr. Hans Bijlsma wordt ingegaan op de balans tussen effectiviteit en veiligheid bij Glucocorticoїden (GC): leiden GC altijd tot botverlies, of kan het ontstekingsremmend effect sterker zijn dan de direct negatieve effecten op het bot? Zijn de bijwerkingen dosis-afhankelijk? Hoe kijken patiënten tegen bijwerkingen aan? Zijn er nieuwe medicamenten in aantocht met minder bijwerkingen?
Door Prof. Dr. Hans Bijlsma wordt ingegaan op de balans tussen effectiviteit en veiligheid bij Glucocorticoїden (GC): leiden GC altijd tot botverlies, of kan het ontstekingsremmend effect sterker zijn dan de direct negatieve effecten op het bot? Zijn de bijwerkingen dosis-afhankelijk? Hoe kijken patiënten tegen bijwerkingen aan? Zijn er nieuwe medicamenten in aantocht met minder bijwerkingen?
Statins are highly effective LDL-c lowering agents that actually reduce clinical cardiovascular events. The 2013 ACC/AHA guidelines on the management of blood cholesterol recommend high-intensity statin therapy in individuals with high cardiovascular risk as assessed by the 10-year atherosclerotic cardiovascular disease risk calculator. However, a significant number of individuals do not tolerate or respond adequately to statins, and continue to have residual risk in spite of high intensity statin therapy.
There are some exciting developments in the field of lipidology. This decade has been labeled “The PCSK9 decade”. A new class of monoclonal antibodies directed against the PCSK9 glycoproteins appears very promising in further lowering LDL cholesterol and thereby cardiovascular risk. Evolocumab and alirucomab are novel PCSK9 inhibitors that can be given subcutaneously once or twice in a month, and have the potential to reduce LDL-cholesterol to very low levels without any major adverse effects.
Other classes of drugs like Apo-B antisense oligonucleotides (mipomersen), CETP inhibitors (especially anacetrapib), microsomal transfer protein inhibitors (lomitapide) also hold some promise. The future of lipid lowering therapy looks reassuring with these new developments.
Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).
Antibody Aducanumab Reduces Αβ Plaques in Alzheimer’s DiseaseRiaz Rahman
Journal Club presentation prepared for Stony Brook University, Department of Psychiatry. Explains findings of "The Antibody Aducanumab Reduces Αβ Plaques in Alzheimer’s Disease," Sevigny et al, Nature, Vol 537, 1 September 2016.
Place of Mineralocorticoid replacement in CAH : ESICON2018: Mohan T Shenoy MD DMMohan Shenoy
Namasthe. These are my powerpoint slides at the just concluded ESICON 2018 in Bhubaneshwar. I thought of sharing my effort to my medical colleagues.
Topic: Place of Mineralocorticoid replacement in CAH
Alternate Link : https://uploadfiles.io/ba0cw
Valid till Jan 4, 2019
Hope you find it useful for clinical purpose.
Regards
Mohan Shenoy
Ponencia realizada por el Dr. José Ramón González-Juanatey del Hospital Clínico Universitario de Santiago de Compostela en la sesión 'Diabetes 2021. Cardiólogos y endocrinólogos: ¿matrimonio o divorcio?' del 13 de mayo de 2021
An update on the treatment of glomerulonephritisaApollo Hospitals
Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of these entities are responsive to immunosuppressive agents and other therapies. There have been recent advances in the treatment options, notably the benefit shown with the use of rituximab in some forms of GN. Moreover, the KDIGO guideline on the management of glomerulonephritis has recently been published which has consolidated the available evidence on the management of this heterogeneous group of disorders. Though there are significant risks and side-effects involved, the treatment of some of the forms of GN can be very gratifying while others progress relentlessly to ESRD. This review summarizes some of the key recommendations from the KDIGO guideline along with a brief discussion of the supporting evidence.
Statins are highly effective LDL-c lowering agents that actually reduce clinical cardiovascular events. The 2013 ACC/AHA guidelines on the management of blood cholesterol recommend high-intensity statin therapy in individuals with high cardiovascular risk as assessed by the 10-year atherosclerotic cardiovascular disease risk calculator. However, a significant number of individuals do not tolerate or respond adequately to statins, and continue to have residual risk in spite of high intensity statin therapy.
There are some exciting developments in the field of lipidology. This decade has been labeled “The PCSK9 decade”. A new class of monoclonal antibodies directed against the PCSK9 glycoproteins appears very promising in further lowering LDL cholesterol and thereby cardiovascular risk. Evolocumab and alirucomab are novel PCSK9 inhibitors that can be given subcutaneously once or twice in a month, and have the potential to reduce LDL-cholesterol to very low levels without any major adverse effects.
Other classes of drugs like Apo-B antisense oligonucleotides (mipomersen), CETP inhibitors (especially anacetrapib), microsomal transfer protein inhibitors (lomitapide) also hold some promise. The future of lipid lowering therapy looks reassuring with these new developments.
Shashikiran Umakanth presented this at the Egyptian Association of Endocrinology, Diabetes & Atherosclerosis (EAEDA) 2014 conference at Alexandria, Egypt. This conference was help in association with Endocrine Society, USA and the European Association for the Study of Diabetes (EASD).
Antibody Aducanumab Reduces Αβ Plaques in Alzheimer’s DiseaseRiaz Rahman
Journal Club presentation prepared for Stony Brook University, Department of Psychiatry. Explains findings of "The Antibody Aducanumab Reduces Αβ Plaques in Alzheimer’s Disease," Sevigny et al, Nature, Vol 537, 1 September 2016.
Place of Mineralocorticoid replacement in CAH : ESICON2018: Mohan T Shenoy MD DMMohan Shenoy
Namasthe. These are my powerpoint slides at the just concluded ESICON 2018 in Bhubaneshwar. I thought of sharing my effort to my medical colleagues.
Topic: Place of Mineralocorticoid replacement in CAH
Alternate Link : https://uploadfiles.io/ba0cw
Valid till Jan 4, 2019
Hope you find it useful for clinical purpose.
Regards
Mohan Shenoy
Ponencia realizada por el Dr. José Ramón González-Juanatey del Hospital Clínico Universitario de Santiago de Compostela en la sesión 'Diabetes 2021. Cardiólogos y endocrinólogos: ¿matrimonio o divorcio?' del 13 de mayo de 2021
An update on the treatment of glomerulonephritisaApollo Hospitals
Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of these entities are responsive to immunosuppressive agents and other therapies. There have been recent advances in the treatment options, notably the benefit shown with the use of rituximab in some forms of GN. Moreover, the KDIGO guideline on the management of glomerulonephritis has recently been published which has consolidated the available evidence on the management of this heterogeneous group of disorders. Though there are significant risks and side-effects involved, the treatment of some of the forms of GN can be very gratifying while others progress relentlessly to ESRD. This review summarizes some of the key recommendations from the KDIGO guideline along with a brief discussion of the supporting evidence.
A review of literature about Stiripentol and Rufinamide and their role in Dravets and Lennox Gastaut Syndrome respectively. It also looks at off label indications of these two orphan drugs.
This was a review of different guidelines on lupus nephritis from ACR, EULAR, and KDIGO. Goal is appreciate similarities and differences between the different guidelines.
Всемирный день почки 2016 в НИКИ им. академика Ю.Е. ВельтищеваKidneyOrgRu
9 марта 2016 г в конференц-зале Научно-Исследовательского Клинического Института имени академика Ю.Е. Вельтищева проведено праздничное мероприятие, посвященное Всемирному Дню Почки, который отмечается во всем мире с 2006 года по инициативе Международного Общества Нефрологов (http://www.worldkidneyday.org). Впервые в этом году Всемирный День Почки был посвящен детям с акцентом на ранней профилактике развития заболеваний почек.
Сотрудники отделения наследственных и приобретенных болезней почек представили для детей презентации об истории проведения праздника, распространенности заболеваний почек с рекомендациями здорового образа жизни для сохранения функций почек.
Было организовано праздничное веселое интерактивное представление для детей с участием Центра детского и юношеского творчества "Бибирево", театра-студии «Рампа», танцевально-акробатических студий «Овация» и «Альфа». Все дети получили праздничные подарки с символом Всемирного Дня Почки.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
2. Idiopathic Nephrotic Syndrome
minimal change
GN
IgMGN
mesangial
proliferative GN
focal segmental glomerulosclerosis
In all these cases
steroid resistance is the most strong predictor
of progression
5. CHAPTER 4: STEROID-RESISTANT
NEPHROTIC SYNDROME IN
CHILDREN
4.1: EVALUATION OF CHILDREN WITH SRNS
4.1.1: We suggest a minimum of 8 weeks treatment with
corticosteroids to define steroid resistance. (2D)
4.1.2: The following are required to evaluate the child with SRNS
(Not Graded):
• a diagnostic kidney biopsy;
• evaluation of kidney function by GFR or eGFR;
• quantitation of urine protein excretion.
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
11. Cochrane Database Syst Rev 2010
Alkylating agents in idiopathic
steroid-resistant NS in children
9 RCTs involving 449 children: RR of persistent NS
• Oral Cyclophosphamide+P
vs Prednisone
RR 1.01 (0.74-1.36)
• IV CPA vs oral CPA
RR 0.09 (0.01-1.39)
• Azathioprine+P
vs Prednisone
RR 1.01 (0.77-1.32)
no significant effect of alkylating drugs
on RR of persistent NS
12. Treatment and outcome
of children and adults with
idiopathic steroid-resistant NS
ALKYLATING AGENTS
CYCLOSPORIN
13. CHAPTER 4: STEROID-RESISTANT
NEPHROTIC SYNDROME IN
CHILDREN
4.2: TREATMENT RECOMMENDATIONS FOR SRNS
4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for
children with SRNS. (1B)
4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6
months and then stopped if a partial or complete remission of proteinuria
is not achieved. (2C)
4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when
at least a partial remission is achieved by 6 months. (2C)
4.2.1.3: We suggest that low-dose corticosteroid therapy be combined
with CNI therapy. (2D)
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
18. Synaptopodin is instable and undergoes lysis due to cathepsin
with disappearance of cytoskeleton actin stress fibers
19. The interaction between synaptopodin and serine/treonine
binding protein maintains F-actin stability, normal cytoskeleton
structure and absence of proteinuria
F
actin
ser / treo BP
Dephosphorylation
synactopodin
synactopodin
P
ser / treo binding protein
sin
Cyclosporin
sin
sin
20. Cochrane Database Syst Rev 2010
Cyclosporin in idiopathic
steroid-resistant NS in children
3 RCTs: 49 children:
RR of persistent NS
Cyclosporin (CyA) vs PL
RR 0.64 (0.47-0.88)
21. Treatment of steroid-resistant NS
Cyclosporin A
Evidence-based recommendations
Treatment
MCGL
Level of
evidence
Grade
Comments
4
D
Possible benefit from
pooled case series; no
significant benefit in RCT
– small numbers
1
A
Beneficial
Cyclosporin (at
least 6 months)
FSGS
Cyclosporin (at
least 6 months)
22. An example of CyA nephrotoxicity.
Francois H, et al
Am J Kidney Dis. 2007;49:158-61.
Renal tolerability of CyA is reasonably good
when the dosage is low
Meyrier A, Expert Opin Pharm 2005
23. Long Term CyA treatment in SRNS
GE-ITALIAN STUDY Adult and Children
Ghiggeri 2004
• 55 steroid –resistant
NS treated with CyA
NS remission (partial or total): 20 patients
Mean follow-up: 81 months
Renal biopsy after 5 years of treatment:
no tubular or interstitial fibrosis
24. CHAPTER 4: STEROID-RESISTANT
NEPHROTIC SYNDROME IN
CHILDREN
4.2: TREATMENT RECOMMENDATIONS FOR SRNS
4.2.1: We recommend using a calcineurin inhibitor (CNI) as initial therapy for
children with SRNS. (1B)
4.2.1.1: We suggest that CNI therapy be continued for a minimum of 6
months and then stopped if a partial or complete remission of proteinuria
is not achieved. (2C)
4.2.1.2: We suggest CNIs be continued for a minimum of 12 months when
at least a partial remission is achieved by 6 months. (2C)
4.2.1.3: We suggest that low-dose corticosteroid therapy be combined
with CNI therapy. (2D)
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
25. CHAPTER 4: STEROID-RESISTANT
NEPHROTIC SYNDROME IN
CHILDREN
4.2.2: We recommend treatment with ACE-I or ARBs for children with
SRNS. (1B)
4.2.3: In children who fail to achieve remission with CNI therapy:
4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose
corticosteroids (2D), or a combination of these agents (2D) be
considered in children who fail to achieve complete or partial
remission with CNIs and corticosteroids.
4.2.3.2: We suggest that cyclophosphamide not be given to
children with SRNS. (2B)
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
26. Steroid-, cytotoxic- and cyclosporin-resistant
desperate NS:
rescue therapy
Steroid therapy : different doses,
different forms
Cyclosporin late response late and
sustained effect,
cyclosporin dependancy, risk of toxicity
Other calcineurin-inhibitors:
Tacrolimus
27. 22 children with steroid-resistant NS
(9 MCD, 11 FSGS, 2 MP)
TAC 0.1 mg/Kg/day (5-10 μg/ml TL)
Total remission10/13 resistant also to Cyclophosphamide(CP)
2/4 resistant also to Cyclosporine (CyA)
Side effects:diarrhea and hypertension (3 withdrawn)
TAC is an effective therapeutic modality for SRNS,
including children non responsive to CP and CyA
29. Long-term outcome of children with steroid-resistant
nephrotic syndrome treated with tacrolimus
Roberti I, Vyas S. Pediatr Nephrol 2010, 25: 1117-24
19 children with steroid-resistant NS
(10 FSGS, 5 other forms)
Complete remission:11/19 (58%) , partial in 6
Mean time to remission : 8 weeks
Remission sustained during follow-up in 58%.
Among FSGF remission 50% ,
in 40% non responders, ESRF.
30. 41 children with steroid-resistant NS
TAC 0.1-0.2 mg/Kg or CsA 5-6 mg/Kg for 1 year
Alternative day steroids and ACE-i
(10 FSGS, 5 other forms)
At 6 mo Complete remission:TAC 85%, CsA 80%
RR for relapse after 1 year : OR 4.5 (TAC better)
Cosmetic negative effects in CsA only
31. Steroid-, cytotoxic- and cyclosporin-resistant
desperate NS:
rescue therapy
Steroid therapy : different doses, different forms
Cyclosporin late response late and sustained
effect,
cyclosporin dependancy, risk of toxicity
Other calcineurin-inhibitors:
Tacrolimus
Purine synthesis inhibitors:
Mycophenolate
32. MMF and prednisone in steroid-dependent NS
Bagga A Am J Kidney Dis 2003
19 Children previously treated with P, oral CP,
and still cortico-dependent NS:
MMF 30 mg/Kg/day for 2 years associated with low tapering
doses of Prednisone. FU: 18 months
Frequency of relapses from 6.6 to 2 each year p<0.0001:
MMF was effective as steroid-sparing agent
75% reduction of relapses
After withdrawal relapse in 68% of the cases
33. MMF in steroid-resistant NS
Author
N
cases
Regimen
Efficacy
Day CJ
(Wolverhampt,
UK, NDT 2002)
7
adults
MMF (1 gx2)
Complete
remission 6/7
1/7 partial r.
MP pulses (15 mg/kg/week x 4-8)
ACE-i/ARB
MMF (250-500 mg/m2)
Proteinuria
(6-24 months)
72% below
baseline
p<0.01
Montané (Miami,
9
US, Ped Nephrol childr.
2003)
Mendizabal S
(Spain, Ped
Nephrol 2005)
Ulinski (Lyon,
Ped Nephrol
2005)
no response to CP and CyA
27
5 SRNS MMF (1200 mg/m2)
1/5 remission
Relapse after
withdrawal.
CyA with GFR impairment:
2g/1.73 m2
0/4 remissions
9
4SRNS
34. In FSGS
MMF should be used for > 6 months,
No RCT is available.
The rate of relapse is high.
35. CHAPTER 4: STEROID-RESISTANT
NEPHROTIC SYNDROME IN
CHILDREN
4.2.2: We recommend treatment with ACE-I or ARBs for children with
SRNS. (1B)
4.2.3: In children who fail to achieve remission with CNI therapy:
4.2.3.1: We suggest that mycophenolate mofetil (2D), high-dose
corticosteroids (2D), or a combination of these agents (2D) be
considered in children who fail to achieve complete or partial
remission with CNIs and corticosteroids.
4.2.3.2: We suggest that cyclophosphamide not be given to
children with SRNS. (2B)
Kidney Disease: Improving Global Outcomes
WWW.KDIGO.ORG
36. Steroid-, cytotoxic- and cyclosporin-resistant
desperate NS:
rescue therapy
sporadic case reports
Permeability factor (PF)
V.Savin 1993
PF is a small anionic protein
that binds to Prot A and
has analogies with
Immunoglobulins
Plasmapheresis
37. Plasmapheresis and protein A
immunoadsorption
Dantal et al (N Engl, 1994)
In native and in recurrent FSGS in grafted kidneys:
• Effect often limited in time, with relapse at withdrawal
• High cost / often limited benefits
• In cases with antiproteinuric response the
progression to ESRF is only partially limited
38. Recurrence of FSGS
on transplanted kidney
Plasmapheresis or
Immunoadsorbance
on A Protein
+ cyclophosfamide:
70% reduction in proteinuria
Lyon and Miami Protocol
39. Steroid-, cytotoxic- and cyclosporin- resistant NS:
sporadic case reports of
rescue therapy
B cells
as new target
for NS treatment?
Anti-CD 20
chimeric MoAb
Rituximab
40. Rituximab is a
Chimeric Monoclonal Ab:
Mouse IgG variable region
directed against CD20 Ag
+
Human IgG1 constant
region
41. A review of the current use of rituximab in autoimmune diseases
Gurvan HM Int Immunopharmacol 2008 Nov
Pharmacological effects:
B lymphocytes depletion
Reduced expression of
activated T cell markers
42. B and T
collaboration
T lymphocytes and NS
Hodgkin’s disease
Allergy
Viral infections
In vitro evidences
Shaloub’s hypothesis:
permeabilizing
T lymphokine
Permeability Factor (Ig part?)
B cells activated in relapse
43. Francois H, Daugas E, Bensman A, Ronco P.
Unexpected efficacy of rituximab in multirelapsing minimal
change nephrotic syndrome in the adult
Am J Kidney Dis. 2007;49:158-61.
Rituximab
375 mg/m2 x4
persistent
remission
44.
45. Results
• Always effective in 15/15 proteinuria-free
patients
• Remission was induced in 3/7 NS
• In 19/22( 85%) one or more concomitant
immunosuppressive treatment was stopped
46. RTX was repeated in 12 patients who responded,
when CD19 count was >1% of total lymphocytes
47.
48. Collaborative study (London, Tokyo, Toronto, Turin)
G1) steroid-dependent NS : (28 cases)
Complete remission: 61%
G 2) steroid-resistant NS (27 cases)
Complete remission: 22%
G3 post transplant recurrrence (15 cases)
Complete remission: 40%
Side effects 26%
Skin rash,bronchospasm, hypotension
51. Rituximab toxicity and adverse events:
progressive multifocal leukoencephalopathy (PML)
in 2 cases of SLE and one of RA
treated with multiple drugs , including Rituximab
54. The interaction between synaptopodin and serine/treonine
binding protein maintains F-actin stability, normal cytoskeleton
structure and absence of proteinuria
F
actin
ser / treo BP
Dephosphorylation
synactopodin
synactopodin
P
ser / treo binding protein
sin
sin
sin
59. 8 patients in treatment with saquinavir 30 mg/Kg/day
• 6 males, 2 females
• Previous history of NS: 7.2 4.2 years
3 primary SRNS, 3 secondary SRNS
2 SDNS
• Previous treatments:
– Steroids, ACTH (8/8)
– Cyclophosphamide (4/8)
– Cyclosporine A (7/8), Tacrolimus (5/8), MMF (3/8)
– Plasma exchange (3/8)
– Rituximab (4/8)
• Median age at SAQ start-up : 13.5 (7-38) years
• Median duration of treatment: 14.7 (6-68) months
60. drug interaction
between saquinavir and calcineurin inhibitors
Pharmacokinetic
interactions
pGp
MDR2/3
CyP450
SAQ is substrate and inhibitor
Increase in
Cyclosporine A
and
tacrolimus
blood levels
SAQ is metabolyzed by
isoenzyme CYP3A4: modifies
CyA and TAC metabolism
61. Medium dosage of calcineurin inhibitors
administered together with saquinavir
• Cyclosporine A:
2 mg/kg/day
(vs 5 mg/kg/day before SAQ)
to maintain a blood levels of 100 ng/ml
• Tacrolimus:
0.01-0.06 (median 0.018) mg/kg/day
(vs 0.1 mg/kg/day before SAQ)
to maintain a blood levels of 3-5
62.
63. Significant decrease in
cumulative steroid dosage
Medium dosage
of prednisone:
25.2 mg/kg/month
Prednisone mg/kg/month
35
Pre-saquinavir
Mean
mean
reduction
reduction
of 63%
of 56%
Post-saquinavir
100
30
75
25
p=0.03
20
50 %
15
10
25
5
0
0
12 months before SAQ
Last 12 months with SAQ
Medium dosage
of prednisone:
8.4mg/kg/month
Pre-SAQ
Post-SAQ
64. Nuclear binding of NF-kB p50- p65
in immortalized human podocytes
activated by LPS
without or with addition
of SAQ 10 and 20 µM.
Nuclear binding of NF-kB p50, p65
in immortalized human podocytes
activated by TNFα
with or without addition
of SAQ10 and 20 µM.
65. Conclusions
• The protease inhibitor SAQUINAVIR
provided with proteasome inhibitor activity:
1/2 primary SRNS
5/5 SDNS or secondary SRNS
Infrequent
relapsers
• This drug was active when associated with
calcineurin inhibitors, which had to be
reduced to less than one third of the original
dose to obtain safe blood levels.
66. saquinavir benefits:
hypotheses
Proteasome-inhibitor activity:
NF-kB hyperactivity inhibition of in circulating mononuclear cells
with decrease synthesis of a permeability factor (IPS downregulation)
Proteasome-inhibitor activity:
NF-kB hyperactivity inhibition in podocytes with
foot process rearrangement.
Direct impact on podocyte protein synthesis
67. saquinavir benefits:
hypotheses
Combined effect with low doses
of CNI and prednisone
NF-kB target for
Saquinavir (protease inhibitor)
Glucocorticoids (GCR binding to p65)
CNI (non competitive inhibitors of proteasome
& ubiquitinylation)