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Mechanisms of intervention to reduce proteinuria & Biomarkers: beyond proteinuria. Jeffrey Kopp, MD Kidney Disease Section NIDDK, NIH. Possible mechanisms of proteinuria reduction. Reduction in glomerular capillary hydrostatic pressure Restoring glomerular filtration barrier

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Mechanisms of intervention to reduce proteinuria & Biomarkers: beyond proteinuria

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Mechanisms of intervention to reduce proteinuria biomarkers beyond proteinuria l.jpg

Mechanisms of intervention to reduce proteinuria&Biomarkers: beyond proteinuria

Jeffrey Kopp, MD

Kidney Disease Section

NIDDK, NIH


Possible mechanisms of proteinuria reduction l.jpg

Possible mechanisms of proteinuria reduction

  • Reduction in glomerular capillary hydrostatic pressure

  • Restoring glomerular filtration barrier

    - Cytoprotection: podocyte, endothelium

    - Restoration of glomerular basement membrane pore size distribution

  • Restoring proximal tubule protein reabsorption: cytoprotection


Hydrostatic mechanisms l.jpg

Hydrostatic mechanisms

Reducing efferent arteriolar tone

- ACEI, ARB

Treating systemic hypertension

- all agents


Podocyte injury l.jpg

Podocyte injury

Mitochondrial dysfunction

  • Loss of filtration slits and slit diaphragms

  • - Mutations

  • Transcription

  • - ER processing

  • Signaling

  • Actin cytoskeleton

Detachment, loss of adhesion

Apoptosis

Loss of anionic charge: podocalyxin (glucose)

Replenishment failure (?)

Dysregulation (collapsing glomerulopathy)

IC, C5b-9


Protecting and restoring podocyte phenotype l.jpg

Protecting and restoring podocyte phenotype

Preventing IC deposition

  • Glucocorticoids

  • Transcription

  • Actin stabilization

  • Ransom KI 2005

  • Anti-apoptotic

  • Wada JASN 2005

  • Transport from ER

  • Fuji KI 2006

Mizoribine

- Transport from ER via energetics

Nakajo JASN 2007

  • Retinoids

  • reverse FPE

  • nephrin, podocin

  • Vaughan KI 2005

Cyclosporine


Glomerular basement membrane l.jpg

Glomerular basement membrane

  • Collagen IV

  • Mutations

  • - Isoform shift

  •  synthesis by glucose, Ang 2

  • degradation

  • Loss of heparan sulfate (?) and HSPG agrin:

  • production,

  •  degradation

  • Glucose, Ang2

Jefferson, KI 2008


Endothelium l.jpg

Endothelium

Haraldsson, Physiol Rev 2008


Injury to endothelial cell and endothelial surface layer l.jpg

Injury to endothelial cell and endothelial surface layer

Hyperglycemia, AGE

Free fatty acids

ROS, oxidative stress, mitochondrial dysfunction

Proinflammatory cytokines (TNF)

Adiponectin

VEGF antagonism

Haraldsson, Physiol Rev 2008

Rask- Madsen, Nature Clin Pract 2007


Pima diabetics macroproteinuria but not microproteinuria is associated with shunt l.jpg

Pima diabetics: Macroproteinuria but not microproteinuria is associated with shunt

Macro

Micro

  • Shunt magnitude correlates with FPE

Lemley, JASN 2000


Proximal tubule albumin reabsorption l.jpg

Proximal tubule albumin reabsorption

Birn, KI 2006


Impaired albumin reabsorption by proximal tubule in pan nephrosis l.jpg

Impaired albumin reabsorption by proximal tubule in PAN nephrosis

0

40 s

14 min

CON

PAN

Russo, KI 2007


Gene therapy reduces tubulointerstitial injury in rat overload proteinuria model l.jpg

Gene therapy reduces tubulointerstitial injury in rat overload proteinuria model

MCP-1 antagonist

(7ND)

IB

Shimizu, JASN 2003

Takase, KI 2005


Does macroalbuminuria cause tubulointerstitial damage l.jpg

Does macroalbuminuria cause tubulointerstitial damage?

Pro

  • Overload albuminuria models

  • Exposure to albumin (or cytokines of FA on albumin) induces RANTES, MCP-1, IL8, fractalkine, TNF-, ET, TGF-; alters integrins, may induce apoptosis

  • Other proteins: iron carriers, complement, Ig, growth factors

  • Gene therapy to PTC (MCP-1 reduction, IB) protects

Con

  • Minimal change nephropathy: proteinuria for years without progression

  • Role of selectivity


Biomarkers l.jpg

B

B

S

I

Biomarkers

  • Biomarkers: measures that predict clinical outcome

    NIH biomarker working group: “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses”

  • Clinical end point: a variable that reflects how a patient feels or functions or how long a patient survives

  • Surrogate end point: a biomarker that can substitute for an observed clinically meaningful end point

  • Intermediate end point: a characteristic that is intermediate in the causal pathway between an intervention and the clinical endpoint

Clinical end point

Treatment

Stevens, CJASN 2006


Biomarkers in drug development and use l.jpg

Biomarkers in drug development and use

  • Pre-clinical/animal

    Clinical studies: identify pathways

    Animal studies: screening for leads, rank candidates

  • Clinical studies

    Identify pathways

    Early detection

    Differential diagnosis, identify subpopulations

    Prognosis

  • Surrogate end point for trials

    Assess drug effect, dose-ranging, more efficient trial design

  • Clinical therapy: drug dosing

Hewitt, JASN 2004


Biomarkers and ckd l.jpg

Biomarkers and CKD

  • Increased interest, increased funding

  • Needed: more systematic searches, validation in prospective observational studies (CRIC, CKID) and interventional trials


Biomarkers can address different issues across the course of disease l.jpg

Biomarkers can address different issues across the course of disease

Hewitt, JASN 2004


Biomarker discovery approaches l.jpg

Biomarker discovery approaches

SELDI-TOF

MALDI-TOF

2D gel


Two biomarkers are better than one l.jpg

Two biomarkers are better than one

Hewitt, JASN 2004


Cystatin c l.jpg

Cystatin C

  • Cystatin C: 13.3 kDa, product of all nucleated cells, freely filtered and readily reabsorbed

  • May have advantages over serum creatinine (MDRD eGFR) in monitoring GFR over time: vs iothalamate r=0.77, 0.31) (Perkins JASN 2005)


Podocyturia l.jpg

Podocyturia

  • Evidence that podocyte depletion characterizes most progressive CKD

  • Direct counting of urinary podocytes is impractical

  • Enumeration with FACS has proven difficult

  • Podocyte proteins: total, exosomes

Kuusniemi, KI


Podocyturia correlates more closely than proteinuria with disease activity in animal models l.jpg

Podocyturia correlates more closely than proteinuria with disease activity in animal models

PAN

Thy-1

5/6 Nx

Yu JASN 2005


Diabetic nephropathy nephrinuria l.jpg

Diabetic nephropathy: Nephrinuria

  • Increased urine nephrin in diabetes, but unrelated to proteinuria

Men

Women

Pätäri, Diabetes 2003


Lupus nephritis urinary cytokines l.jpg

Lupus nephritis: urinary cytokines

Li Autoimmunity Rev 2006


Treatment reduces urinary tgf in diabetic nephropathy l.jpg

Treatment reduces urinary TGF- in diabetic nephropathy

ACEI + ARB

Ruboxistaurin

Gilbert Diabetes Care 2007

Song NDT 2006


Urinary exosomes l.jpg

Normal FSGS

WT-1

WT-1

Female

6.1 8.4 10.9 15.0 g/day proteinuria

Normal FSGS

Male

2.2 2.8 4.0 6.4 8.4 20 g/day proteinuria

Urinary exosomes

  • Derived from podocytes, RTEC, and lower tract cells

  • Sample various cellular compartments, including nucleus

Zhou KI in press


Conclusions l.jpg

Conclusions

  • Diverse mechanisms of proteinuria and of proteinuria reduction

  • Non-albumin protein biomarkers are not yet validated surrogates, demonstrated to lie within the causal pathway to CKD across multiple diseases and multiple interventions

Strength of association

Glomerular microalbuminuria

diabetic vs metabolic

Glomerular hypertension

Endothelial injury

Glomerular macroalbuminuria

GBM abnormalities

CKD progression

Podocyte injury

Tubular microalbuminuria

Proximal tubule dysfunction

Tubular macroproteinnuria


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