Proteinuria as a Surrogate Outcome in Chronic Kidney Disease Andrew S. Levey, MD Thomas Hostetter, MD Co-Chairs May 1-2, 2008

–Acknowledgements –Summarize the strength of evidence for proteinuria as a surrogate outcome in CKD –Conclusions –Framing the issues –Mechanics of the conference Agenda Format for presentations Goals

Acknowledgements A workshop co-sponsored by the National Kidney Foundation and U.S. Food and Drug Administration Planning Committee: Daniel Cattran MD, Aaron Friedman MD, Federico Goodsaid PhD, Bertram Kasiske MD, Aliza Thompson MD, Greg Miller PhD, John Sedor MD, Katherine Tuttle, MD NKF: Kerry Willis, Tom Manley, Heather McCown, Maggie Goldstein FDA: Norman Stockbridge MD PhD, Shirley Murphy MD, ShaAvhree Buckman MD PhD, Cassandra Pusey, Doug Throckmorton MD

Summarizing the Strength of Evidence What we will be doing: Review of concepts Review of background information Review of primary data What we will not be doing: Systematic review Meta-analysis Guidelines FDA Policy

1.Strengths and limitations of criteria for surrogacy 2.Strengths and limitations of available data for assessment of surrogacy 3.Application to specific clinical circumstances/ therapeutic agents 4.What more needs to be done: additional analyses of existing data vs. additional studies Possible Conclusions from Conference

Importance of Proteinuria Marker of kidney damage Clue to the diagnosis of CKD Risk factor for progression (causal in animal models) Modifier for efficacy of ACE inhibitor therapy in non- diabetic kidney disease Hypothesized marker of vascular permeability (“generalized endothelial dysfunction”) Risk factor for CVD at lower levels than defined as CKD Hypothesized surrogate outcome for kidney disease progression and CVD risk reduction Biomarker

Definitions Biomaker: a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. (Biomarkers Definitions Working Group. Clin Pharmacol Ther 2001; 69: ) Clinical end point: a direct measure of how a patient feels, functions or survives Intermediate Endpoint: a biomarker which is intermediate in the causal pathway between an intervention and a clinical endpoint Surrogate: a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful end point … and is expected to predict the effect of the therapy (Temple R. JAMA 1999; 282: )

Biomarkers Surrogate Endpoints Intermediate Endpoints Relationships Among Biomarkers, Intermediate Endpoints and Surrogate Endpoints

Conceptual Model for CKD DeathDeath ComplicationsComplications NormalNormal Increased risk Kidney failure DamageDamage  GFR

Operational Definition of CKD for Epidemiologic Studies and Public Health Programs DeathDeath ComplicationsComplications NormalNormal Increased risk Kidney failure DamageDamage  GFR 7.7 m eGFR <60 eGFR <15 or dialysis Urine alb/creat >30

Stevens LA, Greene T, Levey AS. Clin J Am Soc Nephrol 1: 874–884, 2006

Criteria for Surrogacy Desai M, Stockbridge N, Temple R The AAPS Journal 2006; 8 (1) Article 17 ( Biologic plausibility - sometimes intuitive, sometimes supported by animal data or by favorable responses in extreme cases. Epidemiologic data - increases (or decreases) in the putative surrogate are correlated with unfavorable (or favorable) clinical outcomes. Clinical trials - changes in the putative surrogate resulting from at least 1 type of intervention, and preferably many types, working by different mechanisms, affect clinical outcomes in a predictable manner that is fully accounted for by the effect on the surrogate (Prentice).

Other issues Measurement –Which proteins? –How to collect the urine? –Measurement methods? –How to express the result? –Cut-off (threshold) values? Context –Which diseases and interventions? –What amount (baseline and change)? –How long?

Proteinuria and Other Markers of Chronic Kidney Disease: A Position Statement of the NKF and NIDDK Eknoyan G, Hostetter T, Bakris GL, Hebert L, Levey AS, Parving HH, Steffes MW, Toto R. Am J Kidney Dis 42: , 2003 Albuminuria Measurement and Terminology For screening, albumin preferred in adults, total protein in children. Untimed samples, indexed to creatinine (random “spot” in adults, first-morning preferred in children). Report as mg/g; reference range <30 mg/g Immunoassays for albumin have “sufficient precision.” There is a need for standardization among laboratories. For monitoring at high levels, can substitute total protein, report as mg/g; reference range <200 mg/g.

Proteinuria and Other Markers of Chronic Kidney Disease: A Position Statement of the NKF and NIDDK Eknoyan G, Hostetter T, Bakris GL, Hebert L, Levey AS, Parving HH, Steffes MW, Toto R. Am J Kidney Dis 42: , 2003 Albuminuria as a Surrogate Marker for Clinical Trials Development of albuminuria in diabetes Remission of nephrotic syndrome Progression of CKD Research recommendations Compile data from existing RCTs to assess relationship of change in proteinuria with clinical endpoints: –Baseline levels of albuminuria –Relative or absolute changes during follow-up –Specific kidney diseases New clinical trials, designed to assess New markers of kidney damage

Agenda Session 1General concepts Session 2Early diabetic kidney disease (microalbuminuria) Session 3Nephrotic syndrome Session 4CKD progression (ACEI/ARB) Session 5CKD progression (others)

Clinical trials Obser- vational studies Baseline proteinuria vs. CKD progressionXX Early change in proteinuria (6-12 months) vs. later CKD progression (after early change) XX Effect of treatment on CKD progression (comparison of randomized groups) after adjustment for baseline and early change in proteinuria XNA Analyses

1.Strengths and limitations of criteria for surrogacy 2.Strengths and limitations of available data for assessment of surrogacy 3.Application to specific clinical circumstances/ therapeutic agents 4.What more needs to be done: additional analyses of existing data vs. additional studies Possible Conclusions from Conference

Rationale Spot urine albumin to creatinine ratio >30 mg/g (some consider sex- specific cut-off values) 2-3 times greater than the normal value Infrequent in general population Earliest marker of kidney damage due to diabetes, glomerular diseases, and hypertension Associated with adverse outcomes Albuminuria (“microalbuminuria”) NHANES III

Simplified Classification of Chronic Kidney Disease by Diagnosis

Risk of Developing Clinical Proteinuria by Baseline Microalbuminuria (MA) in HOPE Mann et al, J Am Soc Nephrol 14: , 2003 OR (95% CI) MA+MA-UnadjustedAdjusted 1 Adjusted 2 All N= % (271/1619) 0.8% (46/6055) 26.3 ( ) 26.2 ( ) 17.5 ( ) DM N= % (231/1013) 1.5% (33/2210) 19.5 ( ) 19.4 ( ) 18.2 ( ) No DM N= % (40/606) 0.34% (13/3845) 20.8 ( ) 20.9 ( ) 16.7 ( ) MA defined as >2 mg/mmol (22.6 mg/g). 1 Adjusted for randomized group (ramipril vs. placebo). 2 In all, adjusted for age, gender, smoking, hypertension, dyslipidemia, DM, abdominal obesity, and renal insufficiency. For DM, adjusted for DM duration, use of oral hypoglycemic agents or insulin, and for glycated hemoglobin level.

NKF-K/DOQI Definition of CKD (2002) KDIGO Modifications (2004) Structural or functional abnormalities of the kidneys for >3 months, as manifested by either: 1. Kidney damage, with or without decreased GFR, as defined by pathologic abnormalities markers of kidney damage –urinary abnormalities (albuminuria) –blood abnormalities (renal tubular syndromes) –imaging abnormalities kidney transplantation 2. GFR <60 ml/min/1.73 m 2, with or without kidney damage

Example Slide 1 (for observational studies and clinical trials) Baseline Participants (N) Urine P-C ratio (mean, SD) Six Months Participants (N) Early change (50% decline in Urine P-C ratio) (N) Study End Outcome (50% decline in eGFR, N) Outcome (50% decline in eGFR after six months, N)

Example Slide 2 (for observational studies and clinical trials) Regression of Outcome vs. BaselineHR (CI) Baseline urine P-C ratio Regression of Outcome vs. Baseline and Early ChangeHR (CI) Baseline urine P-C ratio 50% decline in Urine P-C ratio Note: If proteinuria is a surrogate marker of kidney disease progression, HR for baseline proteinuria will be >1.0 and HR for early change will be <1.0

Example Slide 3 (for clinical trials) Regression of Outcome vs. TreatmentHR (CI) Treatment Regression of Outcome vs. Treatment Adjusted for Baseline HR (CI) Treatment Baseline urine P-C ratio Regression of Outcome vs. Treatment Adjusted for Baseline and Early Change HR (CI) Treatment Baseline urine P-C ratio 50% decline in urine P-C ratio Note: If treatment is effective, HR for treatment will be <1.0. If proteinuria is a surrogate marker for treatment effect, HR for treatment effect will increase from <1.0 to closer to 1.0 in adjusted models.