Predicting and changing the future for people with CKD

Predicting and changing the future for people with CKD I. David Weiner, M.D. Co-holder, C. Craig and Audrae Tisher Chair in Nephrology Professor of Medicine and Physiology and Functional Genomics University of Florida College of Medicine

Pre-modern medicine St. Louis Post-Dispatch, April 13, 1945.

Pre-modern medicine Data from the diary of Dr. Howard G. Bruenn

Three critical functions of modern medicine Predict the natural history Manage natural history s complications Change the natural history

CKD is a rapidly growing problem http://www.usrds.org/2009/view/img_v1_03.htm, accessed 2/8/10

CKD predicts the future 6 Year Rate per 100 18 45 7 45 16 40 6 40 14 35 35 5 12 30 30 10 25 4 25 3820 15 615 2 10 410 1 25 5 0 00 >90 60-89 <60 6.0 15.4 40.0 30.5 10.8 26.5 8.5 15.4 10.8 8.5 0.4 1.0 6.0 0.4 1.0 ESRD CHD Combined CVD Rahman M, et al, Ann Int Med 144:172-80, 2006.

What else predicts the future for people with CKD? Hemmelgarn, et al, JAMA 303:423-9, 2010.

GFR predicts the future Mortality (per 1000 person years) 12 10 8 6 4 2 0 6.7 2.7 2.9 4.0 60+ 45-60 30-44.9 15-29.9 egfr (ml/min/(1.73m 2 ) Hemmelgarn, et al, JAMA 303:423-9, 2010.

Proteinuria predicts the future Mortality (per 1000 person years) 12 10 8 6 4 2 0 7.2 7.2 7.5 5.8 5.2 5.8 2.7 2.9 4.0 10.4 9.1 6.7 Dipstick Proteinuria 2+ Trace or 1+ 60+ 45-60 30-44.9 15-29.9 Negative egfr (ml/min/(1.73m 2 ) Hemmelgarn, et al, JAMA 303:423-9, 2010.

Proteinuria predicts the future Mortality (per 1000 person years) 12 10 8 6 4 2 0 2.7 10.4 Dipstick Proteinuria 2+ Trace or 1+ 60+ 45-60 30-44.9 15-29.9 Negative egfr (ml/min/(1.73m 2 ) Hemmelgarn, et al, JAMA 303:423-9, 2010.

Proteinuria predicts the future Mortality (per 1000 person years) 12 10 8 6 4 2 0 2.7 7.2 6.7 Dipstick Proteinuria 2+ Trace or 1+ 60+ 45-60 30-44.9 15-29.9 Negative egfr (ml/min/(1.73m 2 ) Hemmelgarn, et al, JAMA 303:423-9, 2010.

ACR predicts the future 24.6 Mortality (per 1000 person years) 25 20 15 10 5 0 18.0 18.9 22.0 15.9 14.1 9.9 11.9 16.3 10.0 6.3 7.0 ACR >300 mg/g 30-300 mg/g 60+ 45-60 30-44.9 15-29.9 <30 mg/g egfr (ml/min/(1.73m 2 ) Hemmelgarn, et al, JAMA 303:423-9, 2010.

What to do? Recognize proteinuria predicts CV events Screen and treat modifiable cardiovascular risk factors Are there specific treatments to decrease proteinuria that decrease CV events?

Treatments that decrease proteinuria in CKD patients ACE-I decrease proteinuria Is this beneficial for people with CKD? Pro ACE-I slows CKD progression ACE-I decreases cardiovascular events in most highrisk patient populations Con Association of proteinuria with CVD does not prove causation Homocysteine and CV events ACE-I causes initial decrease in GFR GFR predicts cardiovascular risk

HOPE study Multicenter (267) study of 9297 patients 980 with CKD Serum creatinine 1.4 2.3 mg/dl Placebo, 471 ACE-I (ramipril), 509 No significant baseline differences Follow-up, 3.5 5.5 yrs Mann, et al, Ann Intern Med 134:629-36, 2001.

Effect of ACE-I therapy on mortality in people with CKD Placebo ACE-I 25% 23% 20% 19% 15% 13% 15% 14% 10% 5% 9% 6% 8% 4% 4% 0% Mann, et al, Ann Intern Med 134:629-36, 2001.

The more studies showing the same result, the more likely it s correct PROGRESS Study 6105 participants with previous cerebrovascular disease 1757 with CKD at study entry Randomized to ACE-I vs placebo V Perkovic, et al, JASN 18:2766-72, 2007.

How many events are prevented if you treat 100 people with an ACE-I for 5 years? > 60 ml/min <60 ml/min 10 9.1 9 8 7.1 Events prevented 7 6 5 4 5.3 4.0 3 2 1 0 Major Vascular Event Stroke V Perkovic, et al, JASN 18:2766-72, 2007.

Predictive testing Proteinuria predicts outcome in patients with CKD ACE-I therapy is beneficial in patients with CKD

Treating patients with CKD Proteinuria Predictive test Treat with ACE-I Metabolic acidosis Why worry? Adverse skeletal and skeletal muscle effects Metabolic acidosis may contribute to post-menopausal osteoporosis Treatment is sodium bicarbonate why not treat? Sodium in sodium bicarbonate Might worsen hypertension, edema and proteinuria

Acidosis and CKD

Should you treat mild metabolic acidosis in patients with CKD? Patients studied Stage IV CKD Plasma HCO 3 - > 16 and < 20 Stable medical condition Treatment Excluded Malignancy Morbid obesity Poorly controlled hypertension (> 150/90 despite 4 meds) Overt CHF Oral NaHCO 3, dosed to serum HCO 3-23

Sodium bicarbonate improves metabolic acidosis J Am Soc Nephrol 20:2075-84, 2009.

Sodium bicarbonate does not worsen BP J Am Soc Nephrol 20:2075-84, 2009.

Sodium bicarbonate slows progression of CKD J Am Soc Nephrol 20:2075-84, 2009.

Sodium bicarbonate decreases need for dialysis J Am Soc Nephrol 20:2075-84, 2009.

Sodium bicarbonate therapy improves nutritional markers J Am Soc Nephrol 20:2075-84, 2009.

Treating patients with CKD Proteinuria Predictive test Treat with ACE-I Metabolic acidosis Predictive test Therapeutic target Anemia

Anemia predicts increased mortality in diabetic patients with CKD

TREAT study (Trial to Reduce cv Events with Aranesp Therapy) NEJM 361:2019-32, 2009.

Does correcting the anemia in diabetic patients with CKD improve mortality? TREAT Trial Randomized, placebo-controlled multi-center trial Anemia correction to goal of 13 gm/dl vs no correction as long as > 9 gm/dl Treatment with darbepoietin (Aranesp) >4000 patients enrolled in >600 centers NEJM 361:2019-32, 2009.

Does correcting the anemia in diabetic patients with CKD improve mortality? Characteristic Mean 25-75% range Age 68 60-75 M/F 42.5% M, 57.5% F Race 63% W, 20% AA, 13% H, 3% O Duration DM (yrs) 15 8-22 BMI 30 26-35 Retinopathy 47% Neuropathy 48% History CV disease 65% Creatinine (mg/dl) 1.8 1.5-2.3 egfr 34 27-43 NEJM 361:2019-32, 2009.

Patients reasonably well treated Treatment ACE-I or ARB 80% Beta-blocker 49% Statin 58% ASA 42% NEJM 361:2019-32, 2009.

Treatment of anemia was achieved NEJM 361:2019-32, 2009.

TREATing anemia does NOT alter CV composite end-point NEJM 361:2019-32, 2009.

TREATing anemia does NOT alter mortality NEJM 361:2019-32, 2009.

TREATing anemia does not alter MI or myocardial ischemia NEJM 361:2019-32, 2009.

TREATing anemia does not prevent ESRD NEJM 361:2019-32, 2009.

TREATing anemia may alter patient-reported outcomes 60% 50% 40% 30% 20% 10% FACT-Fatigue Score % with clinically meaningful improvement after 25 wks 55% 50% Short-Form General Health Survey Energy No difference Physical functioning No difference 0% Aranesp Placebo NEJM 361:2019-32, 2009.

TREATing anemia DOES increase number of strokes NEJM 361:2019-32, 2009.

In patients with a HISTORY of cancer, Placebo TREATed 35% 32% 30% 25% 23% 24% 23% Proportion dying during study 20% 15% 10% 7% 5% 0% Deaths 1% Deaths from cancer Non-cancer deaths NEJM 361:2019-32, 2009.

Does the anemia in diabetic patients with CKD cause, or just predict, mortality? TREAT Trial No benefit of ESA therapy on ANY cardiovascular or renal end-point ESA therapy worsened Risk of strokes Mortality in patients with history of cancer Anemia is easily measured tool that predicts mortality in diabetic patients with CKD NEJM 361:2019-32, 2009.

Treating patients with CKD Proteinuria Predictive test Therapeutic target Metabolic acidosis Predictive test Therapeutic target Anemia Predictive test NOT therapeutic target Hypertension How should we measure it?

Which predicts the future better, home or office BP? Niiranen, et al, Hypertension 55(6):1346-51, 2010.

Which predicts the future better, home or office BP? Niiranen, et al, Hypertension 55(6):1346-51, 2010.

If you know the home BP, does the office BP matter? Adjusted Hazards Ratio for Occurrence of Fatal and Nonfatal CV Events With a Systolic/Diastolic BP Increase of 10/5 mm Hg BP Variable HR 95% CI P Value Systolic BP Home 1.22 1.09 1.37 <0.001 Both BP values were included in the Cox proportional hazards model. Data adjusted for gender, age, smoking status, history of cardiovascular events, presence of diabetes mellitus, presence of antihypertensive medication, and presence of hypercholesterolemia. HR indicates hazard ratio; CI, confidence interval. Niiranen, et al, Hypertension 55(6):1346-51, 2010.

If you know the home BP, does the office BP matter? Adjusted Hazards Ratio for Occurrence of Fatal and Nonfatal CV Events With a Systolic/Diastolic BP Increase of 10/5 mm Hg BP Variable HR 95% CI P Value Systolic BP Home 1.22 1.09 1.37 <0.001 Office 1.01 0.92 1.22 0.80 Both BP values were included in the Cox proportional hazards model. Data adjusted for gender, age, smoking status, history of cardiovascular events, presence of diabetes mellitus, presence of antihypertensive medication, and presence of hypercholesterolemia. HR indicates hazard ratio; CI, confidence interval. Niiranen, et al, Hypertension 55(6):1346-51, 2010.

If you know the home BP, does the office BP matter? Adjusted Hazards Ratio for Occurrence of Fatal and Nonfatal CV Events With a Systolic/Diastolic BP Increase of 10/5 mm Hg BP Variable HR 95% CI P Value Systolic BP Home 1.22 1.09 1.37 <0.001 Office 1.01 0.92 1.22 0.80 Diastolic BP Home 1.15 1.05 1.26 0.002 Both BP values were included in the Cox proportional hazards model. Data adjusted for gender, age, smoking status, history of cardiovascular events, presence of diabetes mellitus, presence of antihypertensive medication, and presence of hypercholesterolemia. HR indicates hazard ratio; CI, confidence interval. Niiranen, et al, Hypertension 55(6):1346-51, 2010.

If you know the home BP, does the office BP matter? Adjusted Hazards Ratio for Occurrence of Fatal and Nonfatal CV Events With a Systolic/Diastolic BP Increase of 10/5 mm Hg BP Variable HR 95% CI P Value Systolic BP Home 1.22 1.09 1.37 <0.001 Office 1.01 0.92 1.22 0.80 Diastolic BP Home 1.15 1.05 1.26 0.002 Office 1.06 0.97 1.16 0.19 Both BP values were included in the Cox proportional hazards model. Data adjusted for gender, age, smoking status, history of cardiovascular events, presence of diabetes mellitus, presence of antihypertensive medication, and presence of hypercholesterolemia. HR indicates hazard ratio; CI, confidence interval. Niiranen, et al, Hypertension 55(6):1346-51, 2010.

Treating patients with CKD Proteinuria Predictive test Treat with ACE-I Metabolic acidosis Predictive test Therapeutic goal Anemia Predictive test NOT therapeutic marker Hypertension Measure home BP

A newly recognized side-effect of anabolic steroids J Am Soc Nephrol 21: 163 172, 2010.

A newly recognized side-effect of anabolic steroids J Am Soc Nephrol 21: 163 172, 2010.

What I ve tried to discuss about changing the future for people with CKD Proteinuria is an important predictive marker Treat CKD patients with ACE-I to reduce CV events Acidosis is a predictive marker and treatment goal Anemia is a predictive marker, not treatment goal Use home BP measurements Anabolic steroids are bad