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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
Mechanisms of intervention to reduce proteinuria&Biomarkers: beyond proteinuria

Jeffrey Kopp, MD

Kidney Disease Section

NIDDK, NIH

possible mechanisms of proteinuria reduction
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
Hydrostatic mechanisms

Reducing efferent arteriolar tone

- ACEI, ARB

Treating systemic hypertension

- all agents

podocyte injury
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
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
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
Endothelium

Haraldsson, Physiol Rev 2008

injury to endothelial cell and endothelial surface layer
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
Pima diabetics: Macroproteinuria but not microproteinuria is associated with shunt

Macro

Micro

  • Shunt magnitude correlates with FPE

Lemley, JASN 2000

impaired albumin reabsorption by proximal tubule in pan nephrosis
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
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
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

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
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
Biomarkers and CKD
  • Increased interest, increased funding
  • Needed: more systematic searches, validation in prospective observational studies (CRIC, CKID) and interventional trials
biomarker discovery approaches
Biomarker discovery approaches

SELDI-TOF

MALDI-TOF

2D gel

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

PAN

Thy-1

5/6 Nx

Yu JASN 2005

diabetic nephropathy nephrinuria
Diabetic nephropathy: Nephrinuria
  • Increased urine nephrin in diabetes, but unrelated to proteinuria

Men

Women

Pätäri, Diabetes 2003

lupus nephritis urinary cytokines
Lupus nephritis: urinary cytokines

Li Autoimmunity Rev 2006

treatment reduces urinary tgf in diabetic nephropathy
Treatment reduces urinary TGF- in diabetic nephropathy

ACEI + ARB

Ruboxistaurin

Gilbert Diabetes Care 2007

Song NDT 2006

urinary exosomes

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
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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