This document discusses a new taxonomy for classifying podocytopathies, diseases involving injury to podocytes. It proposes organizing podocytopathies based on their histopathology (morphological pattern of glomerular injury and podocyte number) and etiology (idiopathic, genetic, reactive). Four main morphological patterns are described: minimal change nephropathy (MCN), focal segmental glomerulosclerosis (FSGS), diffuse mesangial sclerosis (DMS), and collapsing glomerulopathy (CG). Each pattern is defined and their etiologies and clinical associations are discussed. The taxonomy aims to integrate morphological diagnoses with etiology based on current understanding of podocyte biology and
Lymphoma is a cancer of lymphocytes. The most common place for abnormal lymphocytes is in lymph nodes (glands) particularly
under the arms, in the neck and in the groin.
Lymphoma is solid tumors of the immune system arising from cells of lymphoid tissues; lymphocytes, histiocytes, and reticulum cells. It can happen anywhere in the immune system, but usually in lymph nodes, spleen, marrow, and tonsils. Location and the behavior of lymphomas separate them from leukemia.The malignancy starts and restricted to lymphoid tissues and progress to involve the BM and appears in PB, at this stage it may be named, “lymphosarcoma cell leukemia.
ROLE OF NEUTROPHILS IN HEALTH & DISEASE.pptxjasmine918783
The slide contains information about neutrophils, its basic structure, formation, trafficking, functions, the role of neutrophils in acute inflammation, various disorders of neutrophils, etc.
Lymphoma is a cancer of lymphocytes. The most common place for abnormal lymphocytes is in lymph nodes (glands) particularly
under the arms, in the neck and in the groin.
Lymphoma is solid tumors of the immune system arising from cells of lymphoid tissues; lymphocytes, histiocytes, and reticulum cells. It can happen anywhere in the immune system, but usually in lymph nodes, spleen, marrow, and tonsils. Location and the behavior of lymphomas separate them from leukemia.The malignancy starts and restricted to lymphoid tissues and progress to involve the BM and appears in PB, at this stage it may be named, “lymphosarcoma cell leukemia.
ROLE OF NEUTROPHILS IN HEALTH & DISEASE.pptxjasmine918783
The slide contains information about neutrophils, its basic structure, formation, trafficking, functions, the role of neutrophils in acute inflammation, various disorders of neutrophils, etc.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
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
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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- 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
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...
2009 Convegno Malattie Rare Barisoni [23 01]
1. A NEW TAXONOMY FOR THE
PODOCYTOPATHIES
Laura Barisoni
Department of Pathology and
Medicine, Division of Nephrology
New York University
2. Old classification schemes:
Proteinuria and
nephrotic syndrome
MCD FSGS
Poor prognosis and
Good prognosis and
Poor Response to
Response to steroid
Steroid therapy
Therapy
3. Nephrotic syndrome - the 80’s and 90’s
• While the definition of minimal change disease did not change over the years, in the mid
80’s other patterns of glomerular damage have became part of the FSGS spectrum.
• Collapsing glomerulopathy:
- first description in 1978 “ malignant FSGS”
- 1980’s frequent diagnosis during HIV pandemic (HIV-AN)
- first described in non-HIV pts in 1986 (Weiss et al AJKD 1986) – “collapsing
glomerulopathy” – new clinical-pathologic entity.
- in mid 90’s became “idiopathic collapsing FSGS”
• Cellular lesion:
- Term used first by Schwarz and colleagues to indicate a group of lesions with
endocapillary and/or extracapillary increased cellularity.
- Other authors used the term cellular to indicate intracapillary cellularity only.
• Tip lesion:
- Howie et al described tip lesion as a well-defined and specific pathological entity
with clinical similarity to MCD. (J Pathol 1984)
- Tip lesions are also seen in associations with other glomerular diseases such as
diabetic nephropathy or membranous glomerulopathy.
5. Limitations of the morphologic classification
• Various morphologic entities are called “focal segmental
glomerulosclerosis” regardless the presence or absence of
segmental sclerosis.
• Exclusive of diffuse mesangial sclerosis.
• But inclusive of forms of “proliferative” forms of glomerular
damage with nephrotic syndrome.
• Lack of correlation with pathogenetic mechanisms and etiology.
• Based on opinions – no data in the literature to justify the
rational behind it.
6. Morphologic heterogeneity and clinical
heterogeneity
• Collapsing:
– Severe proteinuria with bad prognosis
– High predilection for AA
• Cellular
– Bad prognosis (but better than collapsing)
– High predilection for AA
• Tip
– Severe proteinuria with good prognosis
– High predilection for Caucasian
• FSGS perihilar & NOS
– Intermediate prognosis
7. Proteinuria and nephrotic syndrome in
the 21st century
• The attention of scientists, nephrologists and pathologists
has been recently focused on the role of podocytes as
cause of proteinuria
• In the last 10 years lot of progress has been made in the
understanding the biology of podocytes, how they function
and how they are injured.
• “Taxonomy of the podocytopathies” where morphologic
diagnosis are integrated with etiology
(Barisoni, Schnaper, Kopp, CJASN 2007)
8. Taxonomy
The word “taxonomy” was coined by Carl Linnaeus, the 18th century
Swedish scientist from the Greek roots
taxis meaning arrangement or division, and
nomia meaning law or method.
A taxonomy is organized into multiple levels, each of which represents
a taxon with one or more elements.
The ideal taxonomy separates the elements of each taxon, taxa, into
mutually exclusive, unambiguous, and all-encompassing categories.
A good taxonomy should be simple, easy to remember and to use.
Taxonomies provide classification but also a conceptual framework for
analysis, discussion, and hypothesis generation.
10. The Taxonomy of Podocytopathies
Based on our current knowledge, the taxonomy of the podocytopathies is
organized along two axes (taxon):
• HISTOPATHOLOGY
- Morphologic pattern of glomerular injury
- Podocyte number
• ETIOLOGY
- Idiopathic
- Genetic
- Reactive
Laura Barisoni, Jeffrey Kopp & William Schnaper
C-JASN 2007
12. The Podocyte
A post-mitotic cell with highly
specialized structure and
function specific to the
glomerulus.
• Regulate permselectivity
• Structural support for capillary
• Remodeling GBM
• Endocytosis of filtered proteins
• Counteract hydrostatic pressure
14. Causes of foot process effacement
1. Impaired formation of the slit
diaphragm complex
2. Abnormalities of the adhesive
interaction between podocytes
and GBM
3. Alterations of transcription factors
4. Abnormalities of the actin-based
cytoskeleton
5. Alterations of the apical domain of
podocytes
6. Mitochondria abnormalities
7. Abnormalities of cell metabolism
8. Mechanical stress
9. Viral infection
10. Acute ischemic injury
11. Toxic / metabolic effect
12. Immunologic stimuli
15. How do we translate this large
variety of insults into four
morphologic patterns of
glomerular injury?
16. Injured podocytes may take
distinct pathways
Podocyte injury
Altered Engagement of Developmental De-differentiation
phenotype apoptotic pathways arrest
Proliferation
Proliferation
No change in Cell death (high)
(low)
podocyte number
Segmental Mesangial
No change Collapse
sclerosis sclerosis
MCN FSGS DMS CG
18. Minimal Change Nephropathy
DEFINITION
Normal histology.
Extensive foot process effacement, but preserved number of
podocytes.
ETIOLOGY AND CLINICAL ASSOCIATION
• Idiopathic
• Inherited
- Non-Syndromic (NPHS1, NPHS2)
- Syndromic (DYSF)
• Reactive
- drug-induced
(NSAID, pamidronate, interferon, others)
- dysregulation of the immune system
- hematologic malignancy
21. Glomerular expression of dystroglycans is
reduced in MCD but not in FSGS
Regele JASN11:403-412, 2000
β-dystroglycan
α-dystroglycan β1-integrin
Normal
kidney
FSGS
MCD
22. DG staining in steroid sensitive and steroid resistant MCN
Laura De Petris, David Thomas, Helen Liapis, Laura Barisoni
IHC staining
C
Fig 1
negative positive
SR-MCN SS-MCN MCN (no f-up)
FSGS Ctrl
23. a b
Podocin: control Podocin: steroid-resistant MCN
d
c
25. FSGS
DEFINITION
Segmental solidification of the tuft accompanied by sinechiae.
Hyalinosis and foam cells can also be present. Low number of
podocytes (podocytopenia).
ETIOLOGY AND CLINICAL ASSOCIATION
• Idiopathic
• Inherited
- syndromic
- non-syndromic
• Reactive
- hyperfiltration-mediated
normal renal mass
reduced renal mass
- medication-induced
- permeability factor (?)
26. Idiopathic FSGS
Is idiopathic really idiopathic?
MYH9 is a major-effect risk gene for FSGS.
(Kopp et al. Nat Genet. 2008)
MYH9 risk alleles are more frequent in AA. MYH9 protective alleles are more frequent in EA.
27. Reactive forms:
Hyperfiltration-
Hyperfiltration-mediated FSGS
glomerulomegaly in pt with single kidney
Segmental sclerosis large non-sclerotic glomerulus
28. Which is the relationship
between glomerulomegaly
and FSGS?
29. FSGS: From podocyte hypertrophy to podocytopenia.
Wiggins et al JASN 2005.
In response to increased glomerular volume, podocytes undergo hypertrophy
though 5 stages.
•Stage 1, normal podocyte;
•Stage 2, non-stressed hypertrophy;
•Stage 3, quot;adaptivequot; hypertrophy: changes in synthesis of structural components
but maintenance of normal function;
•Stage 4, quot;de-compensatedquot; hypertrophy
- reduced production of proteins necessary for normal podocyte function.
- widened foot processes and decreased filter efficiency (proteinuria);
•Stage 5, podocyte numbers decrease.
Dr Kriz’s model
32. DMS
DEFINITION:
Diffuse increase of mesangial matrix accompanied
by mild proliferation of hypertrophic podocytes.
ETIOLOGY:
• Idiopathic
• Genetic
- Non-syndromic
- WT1
- NPHS1
- NPHS2
- NPHS3
- COQ6
- Syndromic
- LAMB2 (Pierson S.)
- WT-1 (Denys-Drash S.)
33. WT-1 associated DMS
WT-
•Reduced or dysfunctional expression of WT-1, a podocyte transcription factor.
•Increased expression of growth-promoting molecules (Pax-2, Ki-67).
•Podocyte entry into the cell cycle.
•Preservation of other podocyte markers (nephrin, synaptopodin, a-actinin-4).
34. CNS Finnish type
•Massive proteinuria in utero and NS at birth.
•Rapid progression to renal failure probably due to presence of atubular glomeruli.
•Patients first have DMS with mild proliferation which rapidly evolves into sclerosis.
•Low proliferative and apoptotic index has been demonstrated in the DMS phase.
(Patrakka KI 2000)
(Kuusniemi KI 2006)
35. NPHS3-PLCE1
ε
Chromosome 10q23.32-q24.1 = phospholipase Cε1.
non-truncating missense
Truncating mutations
mutations
Podocytopenia
Developmental arrest
FSGS
DMS
Later onset of NS and slower
early onset of severe NS and
progression to renal failure.
rapid progression to renal failure.
Of Note: 2 pts responded to
steroid and Cyclosporin A. Hinkes et al. Nat Genetic 2006
39. CG is a proliferative disease:
Dedifferentiated podocytes re-enter the
cell cycle and proliferate
Early phase Late phase
40. Degree of dedifferentiation is variable
among different subcategories of CG
Non collapsed glomeruli Collapsed glomeruli
HIV - CG
Pamidronate-
associated CG
TMA-
Associated CG
Barisoni, Thomas et al. ASN 2004
41. In idiopathic and HIV-associated CG
dedifferentiated podocytes have a
dysregulated phenotype
42. In inherited CG (COQ2-NP)
(COQ2-
podocyte phenotype is dedifferentiated
but not dysregulated
Synpo Ki67 WT1
44. Conclusions
MCN, FSGS, DMS and CG are pattern of glomerular damage where the common
denominator is podocyte injury and therefore they should be grouped under the
umbrella of podocytopathies.
Morphologic classifications alone are insufficient to capture the complexity and
heterogeneity of diseases presenting with NS.
- multiple specific disease processes can present with indistinguishable histopatholology
- a specific monogenetic disorder can present with more than one form of histopathologic pattern of
glomerular damage.
We propose that the final diagnosis of the podocytopathies should occur in 3
steps:
a. clinical evaluation
b. morphologic evaluation
c. additional clinical tests, such as genetic or serology for evidence of infections,
or others, when indicated.
It is expected that in the future other variables (proteomics, transcriptomics) will
be added to the present criteria to better define each category and their
prognosis.
The taxonomy should serve as a base structure to classify diseases and guide
therapeutic approach.
45.
46. Specific
genetic
mutations
Medications
Podocyte Dysregulation
Activation of Proliferation of mitochondrial
the immune activity
system
CG
Ischemic
insult
Environmental
Infections
factors
47. Conclusions
MCN, FSGS, DMS and CG are pattern of glomerular injury rather than
single entities. The common denominator is podocyte injury and
therefore they should be grouped under the umbrella of
podocytopathies.
We propose that final diagnosis of the podocytopathies should occur in
3 steps:
a. clinical evaluation
b. morphologic evaluation
c. additional clinical tests, such as genetic or serology for evidence of
infections, or others, when indicated.
It is expected that in the future other variables (proteomics,
transcriptomics) will be added to the present criteria to better define
each category, their prognosis and identify the potential response to
specific therapy (personalized medicine).
48. α-actinine - 4 - associated FSGS
• Adult onset of FSGS
• Variable degree of foot process effacement.
• Rapid degradation and “second hit theory”
Kaplan, Nat Gen 2000
49. Podocin (NPHS2)
Childhood onset of steroid resistant NS
Boute et al Nat Gen 2000
• Onset between 3 months and 5 years of age
• Familial and sporadic forms - variable pathological findings
• Clinical course similar to idiopathic FSGS
• Resistant to steroid therapy
• Progresses to ESRD
• Most of mutations are clustered in N-terminal domain
Adult onset of steroid resistant NS
Tsukaguchi et al., JASN 2000
• Adolescent and adult-onset familial FSGS locus located on
Chromosome 1q25-31.
• Most of mutations are clustered in C-terminal domain
• Rapid progression to renal failure
50. The Podocyte
A post-mitotic cell with highly
specialized structure and
function specific to the
glomerulus.
• Regulate permselectivity
• Structural support for capillary
• Remodeling GBM
• Endocytosis of filtered proteins
• Counteract hydrostatic pressure
53. Summary
• MCN, FSGS, DMS and CG are pattern of glomerular injury rather
than single entities. The common denominator is podocyte injury
and therefore they should be grouped under the umbrella of
podocytopathies.
• The common denominator is podocyte injury and therefore they
should be grouped under the umbrella of podocytopathies.
• Each morphologic category is associated with (or the result of) a
specific pathway that injured podocyte may take, from altered
phenotype and no change in number, to podocytopenia, or
proliferation, when developmental arrest or dedifferentiation occur.
• Criteria for the classification of podocytopathies should include, in
addition to morphologic analysis, clinical associations and
podocyte phenotype.
54. Specific
genetic
mutations
Medications
Dysregulation
Activation of of mitochondrial
the immune Collapsing activity
system glomerulopathy
Ischemic
insult
Environmental
Infections
factors
55. In inherited CG (COQ2-NP)
(COQ2-
Podocyte phenotype is not dysregulated
Ki67
Synpo WT1
56. Nephrotic syndrome – historical background
• Historically nephrotic syndrome was at first associated with the term
“lipoid nephrosis” a renal disease where glomeruli have minimal lesions.
In the early 20th century, the histologic features of FSGS were first
•
described as degenerative changes of glomeruli in lipoid nephrosis.
(Fahr T. “Pathologische Anatomie des morbus brightii” Berlin: Springer; 1925).
It was not until the mid 20th century that it was reported there was a
•
different clinical course between patients with NS and minimal glomerular
changes versus those with juxtamedullary glomerular hyaline or
sclerosing lesions without cellular proliferation.
(Rich A. “A hitherto underscribed vulnerability of the juxtamedullary glomeruli in lipoid
nephrosis” Bull Johns Hopkins Hosp. 1957).
• Other authors began to report progressive renal disease in nephrotic
patients coinciding with progressive glomerular sclerosis and increased
interstitial scarring.
(Hayslett JP Kl et al “Progression of quot;lipoid nephrosisquot; to renal insuffienciency” N Engl J
Med. 1969)
57. THE TAXONOMY OF PODOCYTEPATHIES
Based on our current knowledge, the taxonomy of the podocytopathies is
organized along two axes (taxon):
• HISTOPATHOLOGY
- Morphologic pattern of glomerular injury
- Podocyte number
• ETIOLOGY
- Idiopathic
- Genetic
- Reactive
Laura Barisoni, Jeffrey Kopp & William Schnaper
C-JASN 2007