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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 - Cytoprotection: podocyte, endothelium - Restoration of glomerular basement membrane pore size distribution Restoring proximal tubule protein reabsorption: cytoprotection Hydrostatic mechanisms Reducing efferent arteriolar tone - ACEI, ARB Treating systemic hypertension - all agents 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) Dysregulation (collapsing glomerulopathy) IC, C5b-9 Replenishment failure (?) Protecting and restoring podocyte phenotype Glucocorticoids -Transcription - Actin stabilization Ransom KI 2005 - Anti-apoptotic Preventing IC deposition Mizoribine - Transport from ER via energetics Nakajo JASN 2007 Wada JASN 2005 - Transport from ER Fuji KI 2006 Cyclosporine Retinoids -reverse FPE - nephrin, podocin Vaughan KI 2005 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 Haraldsson, Physiol Rev 2008 Injury to endothelial cell and endothelial surface layer Hyperglycemia, AGE ROS, oxidative stress, mitochondrial dysfunction Free fatty acids 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 Macro Micro Shunt magnitude correlates with FPE Lemley, JASN 2000 Proximal tubule albumin reabsorption Birn, KI 2006 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 MCP-1 antagonist (7ND) IB Takase, KI 2005 Shimizu, JASN 2003 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, IB) protects Con Minimal change nephropathy: proteinuria for years without progression Role of selectivity 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 Treatment B I B S Clinical end point Stevens, CJASN 2006 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 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 Hewitt, JASN 2004 Biomarker discovery approaches SELDI-TOF MALDI-TOF 2D gel Two biomarkers are better than one Hewitt, JASN 2004 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 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 PAN Thy-1 5/6 Nx Yu JASN 2005 Diabetic nephropathy: Nephrinuria Men Women Increased urine nephrin in diabetes, but unrelated to proteinuria Pätäri, Diabetes 2003 Lupus nephritis: urinary cytokines Li Autoimmunity Rev 2006 Treatment reduces urinary TGF- in diabetic nephropathy ACEI + ARB Song NDT 2006 Ruboxistaurin Gilbert Diabetes Care 2007 Urinary exosomes Derived from podocytes, RTEC, and lower tract cells Sample various cellular compartments, including nucleus Normal FSGS WT-1 Male 2.2 2.8 Normal 4.0 6.4 8.4 20 g/day proteinuria FSGS Female 6.1 WT-1 8.4 10.9 15.0 g/day proteinuria Zhou KI in press 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 Glomerular hypertension Glomerular microalbuminuria diabetic vs metabolic Strength of association Endothelial injury GBM abnormalities Glomerular macroalbuminuria Podocyte injury Proximal tubule dysfunction Tubular microalbuminuria Tubular macroproteinnuria CKD progression