Diabetic Nephropathy 2009

Diabetic Nephropathy Joel Michels Topf, MD Clinical Nephrologist

Year Capacity 1926 84,401 85,753 97,239 101,001 1991 102,501 107,501 107,501 2006 107,501 2009 106,201 Incident ESRD 0 0 0 0 56,103 87,179 91,275 110,854 117,632

Diabetes, diabetic nephropathy and the epidemic raging in the U.S.

Diabetics on Dialysis: 183,706 USRDS Atlas 2005 http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7 Total no of Diabetics: 23,600,000 0.78%

Finne, P. JAMA 2005; 294:1782-87.

Diabetic nephropathy Progressive renal damage as a result of diabetis mellitus type I or II Initially, patients have increased GFR (2x normal) Followed by proteinuria Followed by progressively deteriorating GFR

5-10 years 15-20 years 20 years

Ritz E, et al. N Engl J Med 1999;341 :1127-33.

220 g 240 g Size Matters Normal kidney weight is 150 g Diseases with large kidneys: Multiple Myeloma • Hydronephrosis Amyloidosis • Renal Cell Cancer ADPKD/ARPKD • Not HIVAN

nodular glomerulosclerosis Kimmelstiel-Wilson lesions

One in five diabetic patients on dialysis do not have this “classic” pathology. They have ischemic nephropathy, with non-specific vascular and interstitial lesions Ritz E, Orth SR. N Eng J Med 1999; 341:1127-33.

Type I Diabetes Type II Diabetes No difference in glycemic control between people who get nephropathy and those who don’t Ritz E, et al. N Engl J Med 1999;341 :1127-33. Incidence of proteinuria at 25 years after diagnosis

Genetics Familial clustering Diabetic family members of patients with diabetic nephropathy have an OR of 4.0 Race ESRD is 5 times more likely in African Americans with family members on dialysis from DN Pima indians have very high rates of diabetic nephropathy

Transforming Growth Factor Beta Angiotensin II Hyperglycemia Extracellular matrix Fibrosis Scientific studies on TGFß and renal disease Huang Y, Et al. Kidney International 2006; 69: 1713-4. TGFß

Hyperfiltration Early finding Renal vasodilation Causes early increases in GFR Later Nephron loss results in compensatory hyperfiltration No increase in GFR

A B C 0 years 5 years 10 years

What is microalbuminuria? Any albumin in the urine Trace protein on dipstick in a first morning specimen 20-200 µg/min on a timed specimen 30-300 mg albumin/g creatinine 30-300 mg/L What is macroalbuminuria? 1+ protein on a dipstick in a first morning specimen 1+ protein on a dipstick at any time >250 mg in 24 hours >3.5 g per 24 hours Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Diabetes

Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Diabetes Microalbuminuria Dipstick negative Macroalbuminuria Dipstick positive 30 300 mg/d 0  MI, CVA, CV Death  All-cause mortality  CHF hospitalization Gerstein, H. C. et al. JAMA 2001;286:421-426. Albuminuria (mg/d)

Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Cholesterol < 198 Triglycerides < 145 Glycemic control (hgb a1c <8) Blood pressure (sbp<115) ACEi Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I

Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type II Diagnosis Diagnosis Diagnosis

U/A at Diagnosis (Type 2 patients) Random spot collection Albumin:creatinine Repeat 3x in 3-6 months 2 of 3 ≥ 30mg/g creatinine Microalbuminuria, begin treatment Nephropathy Quantify µalb:Cr Consider referral Modified from the American Diabetes Association. Diabetes Care. 2002; 25 Suppl 1: S85-S89. No microalbuminuria Re-screen yearly Negative Positive No Yes Differential of microalbuminuria Early diabetic nephropathy Obesity Hypertension Endothelial dysfunction Metabolic syndrome Atherosclerosis

When is proteinuria not diabetic nephropathy? When does a diabetic need a biopsy?

Suspicious for non-diabetic nephropathy Onset within 5 years of dx of diabetes Acute onset Active sediment Unusual review of systems Serologies ANA, Hep B, Hep C, HIV Absence of retinopathy or neuropathy

TREATMENT Blood pressure control Glycemic control Angiotensin 2 control Proteinuria control Cholesterol control

Intensive therapy Low fat (<30%) diet 30 minutes exercise 3-5 days/week Smoking cessation ACEi regardless of blood pressure Vitamin Aspirin A1c <6.5 Blood pressure control Cholesterol control Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.

Primary end point CV Death Non fatal MI CABG/PCI Nonfatal stroke Amputation Peripheral revascularization Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.

Treatment Blood pressure control Glycemic control Angiotensin 2 control Proteinuria control Cholesterol control

Randomized prospective trial of treatment strategies in type two diabetes Protocol written in 1976 Recruitment from 1977-1991 End of study 1997 Type 2 diabetic patients 5,102 Person years follow-up 53,000 ukpds

Primary Endpoint: Any Diabetes Related Endpoint 1401 of 3867 patients (36%) First occurrence of any one of: diabetes related death non fatal myocardial infarction, heart failure or angina non fatal stroke amputation renal failure retinal photocoagulation or vitreous haemorrhage cataract extraction or blind in one eye

Microvascular Endpoints Any Diabetes Related Endpoint Favors conventional 0.5 1 2 0.88 0.90 0.94 0.84 1.11 0.75 0.029 0.34 0.44 0.052 0.52 0.0099 Any diabetes related endpoint Diabetes related deaths All cause mortality Myocardial infarction Stroke Microvascular RR p Favors intensive Relative Risk 0 10 20 30 40 50 0 3 6 9 12 15 Proportion of patients (%) Years from randomisation Hypoglycemia: any episode 0 1 2 3 4 5 0 3 6 9 12 15 Hypoglycemia: major episodes Proportion of patients (%)

Blood pressure: Tight vs less tight control 60 80 100 140 160 180 0 2 4 6 8 mmHg Years from randomisation 144 154 87 82 Blood pressure: Bad vs worse control

Any diabetes-related endpoints 0% 10% 20% 30% 40% 50% 0 3 6 9 % of patients with events Tight blood pressure control (758) Less tight blood pressure control (390) risk reduction 24% p=0.0046 Years from randomisation risk reduction 32% p=0.019 Diabetes-related deaths Stroke 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 44% p=0.013 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 37% p=0.0092 Microvascular endpoints

UK Prospective Diabetes Study An intensive glucose control policy HbA 1c 7.0 % vs 7.9 % reduces risk of any diabetes-related endpoints 12% p=0.030 microvascular endpoints 25% p=0.010 myocardial infarction 16% p=0.052 A tight blood pressure control policy 144/82 vs 154/87 mmHg reduces risk of any diabetes-related endpoint 24% p=0.005 microvascular endpoint 37% p=0.009 stroke 44% p=0.013 The benefit from tight glycemic control is less than the benefit from lousy blood pressure control

Hypertension Optimal Treatment trial (HOT Trial) randomized 18,790 patients to one of three diastolic blood pressure goals 8% of the original cohort was diabetic The first line agent was felodipine Harrison L, Et al. Lancet 1998; 351: 1755-1762. HOT Diabetics

Home blood pressure is the hemoglobin A1c of blood pressure management. Dr Whitey routinely checks Hgb A1c to make sure my diabetes is on track. Dr Whitey asks me check my home BP to verify my BP is on track.

Lewis, E. J. et al. N Engl J Med 1993;329:1456-1462 Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups

RENAAL Trial 1513 type II DM with nephropathy Cr 1.9 Randomized to placebo or losartan Primary outcome: composite of doubling serum Cr, ESRD, or death Brenner BM, Et al. NEJM 2001; 343: 861-9.

Picture of world with/without electricity

ACEi are good, ARB are good… in patients with albuminuria. What about in normotensive patients without albuminuria?

Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

Multicenter, randomized, double blind controlled trial 285 normotensive patients with type I dm and albuminuria < 20 µg/min Randomized to placebo, enalepril 10/20 mg or losartan 50/100 mg Primary endpoint was change in mesangial volume on renal biopsy Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51. Progression of diabetic retinopathy (2 steps) Odds ratio vs placebo Placebo 38% 1 Enalepril 25% 0.35 (65% reduction) Losartan 21% 0.30 (70% reduction)

ACEi are good ARB are good What about both together?

CALM Study N= 200 Type II DM with microalbuminuria Randomized to: Lisinopril 20 mg qd Candesartan 16 mg qd Combination of lisinopril 20 mg and candesartan 16 mg Mogensen CE, Et al. BMJ 2000; 321: 1440-4.

Combination ACEi & ARB: the Meta analysis 10 studies of patients with diabetic nephropathy 315 patients randomized to ACEi or ACEi and ARB Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007

Problem: Too short Wrong target

Studies use change in proteinuria as the primary endpoint Most were 8-12 weeks in duration Significant reduction in proteinuria compared to ACEi (p=0.01) Reduced GFR (3.9 ml/min, p=0.03) Increase in potassium (0.2 mmol/L, p<0.01) Reduction in BP (5.2/5.3, p<0.01) Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007

STUDIES OF ACEI + ARB IN NON-DIABETICS What about the data of dual therapy in non-diabetics

On Target Telmisartan + ramipril vs ramipril vs telmisartan Outcome: CV death, MI, CVA, hospitalization for CHF 25,620 patients were randomized Study population: age >55, coronary, peripheral or cerebrovascular disease or diabetes with end-organ damage ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

37% had diabetes 13% had microalbuminuria 50% had prior MI 22%had prior CABG 68% had history of hypertension 56 months of follow-up ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

Primary outcome ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

Renal outcomes Renal impairment: 13.5% with combo tx 10.2% ramipril 10.6% telmisartan RR 1.33 for combination tx (p=<0.001) Initiation of dialysis 0.8% with combination therapy 0.6% with monotherapy RR 1.37 (p=0.1) ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

Renal outcomes Second publication with data focused on renal outcomes Primary outcome for this publication was dialysis, death or doubling of serum creatinine Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008

Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008 0.037 0.038 0.020

Increased renal outcomes despite better proteinuria

Cooperate Trial: ACEi+ARB in non-diabetics 263 patients with non-diabetic renal disease Average GFR 37.5 mL/min Average protein excretion 2.5 g/day Randomized to losartan 100mg, trandolapril 3mg, or both Nakao N, Et al. Lancet 2003; 361: 117-24. Endpoint: doubling of serum creatinine or dialysis

RESOLVD 768 patients with heart failure (NYHA II to IV) Potassium rose 0.11 mmol/L (p<0.05 vs Candesartan alone and enalepril alone) ValHeFT 5010 patients with heart failure (NYHA II to IV and EF<40%) Potassium rose 0.12 mmol/L (p<0.001) CHARM-Added trial 2548 patients with heart failure (NYHA II to IV and EF<40%) No significant change in potassium McKelvie RS, Et al. Circulation 1999; 100: 1056-64. Cohn JN, Et al. N Eng J Med 2001; 345: 1667-75. McMurray JJ, Et al. Lancet 2003; 362: 767-71.

Any addition of ACEi ARB Aldosterone antagonist Diuretic Must check electrolytes one week later High potassium Stop the drug Low potassium diet Loop diuretic Thiazide diuretic Liberalize sodium restriction

Theory: reduce proteinuria, reduce cardiovascular events High  High | High  Low | Low  High | Low  Low Ibsen H, Et al. Hypertension 2005; 45: 198-202. Pre-specified subanalysis of the LIFE trial 8206 men and women ages 55-80 with hypertension and LVH 13% were diabetics Primary analysis was Atenolol vs Losartan Composite endpoint (CEP) was CV death, non-fatal stroke, or non-fatal MI … Reduction in albuminuria during treatment translates to a reduction in cardiovascular events…

Theory: reduce proteinuria, reduce cardiovascular events and renal end-points Reanalysis of the RENAAL trial. Instead of the intension to treat analysis, patients were analyzed by baseline proteinuria or reduction in proteinuria. The reduction in albuminuria at 6 months predicted outcomes at 42 months … Interestingly, suppression of albuminuria was the strongest predictor of long-term protection from cardiovascular events… De Zeeuw D, Et al. Circulation 2004; 110: 921-927.

Conclusion: reduction in proteinuria reduces CV complications and renal complications Implications: reduction in proteinuria can be used as an intermediate end-point, i.e. interventions which reduce proteinuria are good.

Calcium channel blockers Verapamil does not delay development of microalbuminuria Verapamil does reduce proteinuria in diabetics independent of changes in blood pressure Aldosterone antagonists Spironolactone reduces proteinuria in diabetics Change in proteinuria is independent of blood pressure All patients were treated with an ACEi or ARB 24-Hr ambulatory BP fell 6/2 Carvedilol RCT of metoprolol vs. carvedilol, improved A1c and albuminuria Bakris GL, Et al. JAMA 2004; 292: 2227-36. Ruggenenti P, Et al. N Eng J Med 2004; 351: 1941-51. % Change in Proteinuria Blood pressure Bakris GL, Et al. Kidney Int 1998; 58: 1283-9. Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.

Aliskiren in addition to losartan in DM2 and nephropathy RCT double blind, multicenter N=599 Placebo vs 150 mg aliskiren for 3 months Followed by doubling of the dose of the placebo and aliskiren (300 mg) Study duration 6 months

Use of aliskiren 150 mg for 3 months and 300 mg for 3 months lowered albuminuria 20% compared to placebo 150 mg 300 mg

Run-in ACEi or ARB ACEi + ARB Atorvastatin Group A Placebo Group B Randomization Bianchi S, Et al. Am J Kidney Dis 2003; 41:565-570. A Controlled, Prospective Study of the Effects of Atorvastatin on Proteinuria and Progression of Kidney Disease 56 men and women with non-diabetic GN CrCl 53 mL/min and proteinuria = 2.5 g/d

GREACE Study 1541Greek men and women Age < 75, LDL > 100 and hx CHD 20% DM 3 year follow-up CHD events: Study:12% vs control: 24.5% Athyros VG, Et al. J Clin Pathol 2004; 57: 728-34.

Endothelin antagonists Avosentan is an endothelin A antagonist Endothelin A receptors stimulate matrix production in animal models of diabetic nephropathy Avosentan proof of concept 286 diabetics with 1.0-1.5 g proteinuria on ACEi/ARB reduced the urinary albumin excretion rate by about 50% No change in BP, HR, CrCl Slight decrease in Hct

Ascend trial, Phase III trial of Avosentan International multi-center, double-blind, placebo-controlled trial. Randomization is 1:1:1 25 mg avosentan 50 mg avosentan Placebo End-point is doubling of serum creatinine, ESRD or death Enrollment criteria Type II diabetics age 21-80 Diabetes at least 3 yrs ago Albuminuria > 300 mg/day Cr 1.0-1.4 for men Cr 1.0-1.3 for women All patients must be on ACEi/ARB or intolerant

Conclusions Diabetic nephropathy is the most common cause of ESRD in the world ESRD is a rare out-come among diabetics Just over half of diabetics will develop nephropathy Blood pressure control Glycemic control Angiotensin 2 reduction Proteinuria reduction ACEi + ARB Statins Aldosterone antagonists Dihydropyridine calcium channel blockers Endothelin antagonists

Incidence of ESRD due to diabetic nephropathy IDNT RENALL

Diabetic Nephropathy 2009

In this document