Diabetic Nephropathy Lance Sloan, MD Stephen Fadem, MD
Objectives • Educate physicians and nurses on practical management tips for diabetes control. • Identify goals for diabetes therapy in patients with CKD with emphasis on prevention and medication side effects
At the end of this online presentation you should • Understand the relationship between diabetes and kidney disease • Know the difference between type 1 and Type 2 diabetes • Be familiar with some of the clinical trials that have shaped our progress • List key management objectives for Diabetes as it relates to progressive CKD • Be familiar with therapy for diabetes
Incidence ESRD due to Diabetes in Network 14 is 206/million Each year in Texas 206/million patients start dialysis because of diabetic nephropathy. Texas has the highest incidence in the nation. Source: USRDS
Predicted and actual cost adjusted by diagnosis Dialysis management of diabetic ESRD patients, particularly with heart failure Source: USRDS
Two Types of Diabetes • Type 1 – onset in youth, destruction of beta cells and a requirement for insulin • Type 2 – onset as adult or young adult, related to insulin resistance. May be treated with lifestyle modification, oral medications, and later may require insulin
Type 1 Diabetes • Insulin-dependent/Juvenile onset • 20 to 30% develop microalbuminuria after 15 years • Amin, R, Widmer, B, Dalton, N & Dunger, DB: Unchanged incidence of Microalbuminuria in Children with Type 1 Diabetes since 1986: A UK based inception cohort. Arch Dis Child:adc.2008.144337, 2009. • Of the ones who develop this less than half progress to diabetic nephropathy • Associated with microvascular disease – retina and kidney. The increased sugar is neurotoxic – hence neuropathy • 2.2 percent will develop ESRD in 20 years and 7.8 percent in 30 years • Finne P, Reunanen A, Stenman S, et al. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 2005; 294: 1782-1787.
Type 1 Diabetes (Continued) • The microalbuminuria can regress – and it is not always related to the use of ACE or ARB therapy • Perkins, BA, Ficociello, LH, Silva, KH, Finkelstein, DM, Warram, JH & Krolewski, AS: Regression of Microalbuminuria in Type 1 Diabetes. N Engl J Med, 348:2285-2293, 2003 • The risk of developing kidney failure after 20 to 25 years in patients who have no proteinuria is low • Labile swings in blood sugar because of autonomic insufficiency • Always requires insulin • If diabetic nephropathy develops, the patient will develop insulin resistance – metabolic syndrome due to kidney disease. Atherosclerosis and hypertension are not primary but secondary events
Type 2 Diabetes • Common in Hispanics, Native Americans and Pima Indians • Incidence of ESRD is lower, but the disease is more frequent – thus it is the most common cause of renal failure • United Kingdom Prospective Diabetes Study • UKPDS – large British study, (predominantly Caucasians) • Adler, AI, Stevens, RJ, Manley, SE, Bilous, RW, Cull, CA & Holman, RR: Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int, 63:225-32, 2003. • Incidence of microalbuminuria 25% but incidence of ESRD only 0.8% • Microlbuminuria patients spent an average of 11 years before progressing to overt proteinuria • Only 2.3% progress from macroalbuminuria to ESRD
Type 2 Diabetes (Continued) • Disease progresses slowly over many years and is associated with proteinuria. The urine should show more than just red cells. • In the elderly, it is impossible to clinically distinguish the hypertensive and atherosclerotic effects from the diabetic effects without a kidney biopsy. • Not associated with labile blood sugar swings • Insulin resistance
Incidence of Type 2 Diabetes • Doubled in past 20 years • Framingham Offspring Study • Related to Lifestyle Change and Obesity • BMI Increase confirmed by NHANES Dataset • Source: American Heart Association • Prevalence of Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2007 • Total: 23.6 million people • 7.8 percent of the population—have diabetes. • Diagnosed: 17.9 million people • Undiagnosed: 5.7 million people • Source: NIDDK
Metabolic Syndrome • Characterized by insulin resistance – 50 to 75 million Americans • High blood pressure • High blood sugars • High levels of triglycerides • Low levels of HDL • Increased waist line • It is associated with • Diabetes, Hypertension, stroke, cardiovascular disease • Dominant Features • Obesity, lack of exercise
Diet Plays a Major Role • The Sugar Fix • High fructose corn syrup • Decreases the ATP in cells – this decreases cell respiration and causes hypoxia in cells • Releases cytokines that impair nitrous oxide synthesis • Releases uric acid which increases blood pressure • Causes leptin resistance (Leptin turns off the appetite) continue to be hungry • Supersized – HFCS is in many soft drinks and other products • Americans eat more sugar, now have an epidemic of obesity, the metabolic syndrome, heart disease and diabetes
Management Objectives • Lifestyle • An aspirin a day • Smoking and Exercise • Weight/cholesterol • Blood Pressure • ACE and ARB • Vitamin D • Diabetes Control
Lifestyle - An aspirin a day - Smoking and Exercise - Weight/cholesterol • Can be a rewarding way to keep diabetes under control. • Requires a lifelong strategy • Diet: Avoid fructose, excess salt, trans fats and excess carbohydrates • Two alcoholic beverages at most/day • 25% incident diabetics are smokers • Potentiates kidney disease • Increases inflammation • Gentle aerobic exercise • Aspirin a day to reduce cardiovascular risk
ACE and ARB Blood Pressure Control
Blood pressure goal in CKD< 130/80 • Any person with abnormal kidneys is at risk for heart disease • Most patients will require two or more medications to control their blood pressure • Lowering the systolic blood pressure to <130 mm Hg is usually associated with a reduction in diastolic blood pressure to <80 mm Hg Adapted from American Journal of Kidney Diseases, Vol 43, No 5, Suppl Suppl 1 (May), 2004: pp S14-S15
Many blood pressures medications may be needed to control severe blood pressure
ACES & ARBS are the two majorclasses of medicationsused to treathigh blood pressure
Effect of ACE Inhibitorson Progression of CKD Maschio. N Engl J Med. 1996;334:939.
Proteinuria is a powerful determinant of renal deterioration. Source: The New England Journal of Medicine -- November 12, 1998 -- Vol. 339, No. 20 Mechanisms of Disease: Pathophysiology of Progressive Nephropathies Giuseppe Remuzzi, Tullio Bertani
Collaborative Study Group – Reduction of proteinuria in Type 1 DM with ACE Placebo Captopril 60 37% 40 22% 20% Percent 20 7% 4% 0 -20 -40 -40% -60 Changes in proteinuria Incidence of ESRD Incidence of mortality Lewis EJ, et al. N Engl J Med. 1993;329:1456-1462.
ARBS in Diabetes – The RENAAL Trial • (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) • Brenner. BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G,Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study InvestigatorsEffects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9. • Randomized, double-blind, multicenter, placebo-controlled • Losartan Vs Placebo and conventional BP medications • 1513 patients • Outcome: Composite of doubling creatinine, ESRD, Death • Followup 3.4 years • RESULT: Reduced doubling of creatinine by 25% and ESRD by 28%
ARBS in Diabetes - IRMA • IRMA (Irbesartan Microalbuminuria) study • Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P;Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):870-8 • multicenter, randomized, double-blind, placebo-controlled trial, randomized • 590 patients with type 2 diabetic nephropathy (albuminuria) • Randomized to irbesartan, 150 mg, 300 mg (Avapro) or placebo • Blood pressure medications allowed • Endpoint was overt nephropathy – a urine albumin at least 30% greater than baseline • 10/194 (300 mg group) – reached endpoint • 19/195 (150 mg group) – reached endpoint • 30/201 (Placebo group) – reached endpoint • Blood pressure unchanged
ARBS in Diabetes IDNT • IDNT (Irbesartan Diabetic Nephropathy Trial) • Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-860. • Randomized, double-blind, placebo-controlled • 1715 patients to irbesartan,amlodipine or placebo • 2.6 years • BP therapy allowed (with exception on study drugs) • Result: • Lowered risk of developing ESRD by 23%
What slows progression? • Proven interventions • Control blood sugar in diabetics • Strict blood pressure control • Certain meds: ACES (Angiotensin-converting enzyme inhibition) and ARBS (angiotensin-2-receptor blockade) • Studied, but inconclusive • Dietary protein restriction • Lipid lowering therapy • Partial correction of anemia • Vitamin D administration
How are we doing? Am J Kidney Dis. 2005 Dec;46(6):1080-7. Elderly diabetic patients Medical insurance claims 65 years and older 30,750 patients studied (58.7% also had high blood pressure and/or protein in the urine) Of these only 50.7% (CI 50.0-51.4) received an ACE or ARB
ACCOMPLISH TRIAL • Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial • Has been stopped early – accomplished its goal • benazepril plus amlodipine better than benazepril plus hydrochlorothiazide • Study group – Hypertensives at risk secondary to previous events or diabetes • 11,464 patients • ≥ 55 years old • BP ≥ 160 • 60.4% with diabetes • Obese • Cardiovascular, renal disease or target damage • 70% treated with two or more agents • Only 37.5% had blood pressure les than 140/90 • Endpoints – cardiovascular morbidity MI, (stroke, unstable angina, bypass) or death • ACE/amlodipine Risk reduced by 20% compared with ACE/diuretic • SOURCE: Presented by KA Jamerson, American College of Cardiology, March 31, 2008
Vitamin D • Type 1 Diabetes in children might be prevented with vitamin D supplements and 5 – 10 minutes of noon sunlight • Epidemiology study • UCSD • SOURCE: University of California - San Diego. "Sun Exposure And Vitamin D Levels May Play Strong Role In Risk Of Type 1 Diabetes In Children." ScienceDaily 5 June 2008. 10 March 2009 <http://www.sciencedaily.com /releases/2008/06/080605073804.htm>.
Diabetes Control • Sulfonylureas • Biguanides • Thiazolidinediones “Glitazones” • Meglitinides • DPP-4 Inhibitors • Incretin Memetics • Insulin
SULFONYUREAS • First category of oral agents for diabetes – now in third generation • Mainly for type 2 diabetes – work on existing beta cells • Increase secretion of insulin by binding to potassium channels and opening calcium channels • Can cause hypoglycemia and weight gain
BIGUANIDES • Metformin used in obese type 2 diabetics • Maximum reduction in HgbA1c after 6 months • Action lasts additional 9 months with thiazolidinedione • With sulfonureas HgbA1C tends to increase • Reduced cardiovascular risks • Pharmacotherapy. 2007 Aug;27(8):1102-10.Loss of glycemic control in patients with type 2 diabetes mellitus who werereceiving initial metformin, sulfonylurea, or thiazolidinedione monotherapy.Riedel AA, Heien H, Wogen J, Plauschinat CA.
ROSIGLITAZONE • Controversy regarding risk of causing MI • Odds ratio 1.43 • ADOPT – increased fractures • Associated with macular edema • Stimulates the PPARγ receptor • Not to be used in heart failure • Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007;356(24):2457-2471.
INCRETIN MIMETICS • Exenatide (Byetta) • From the saliva of the gila monster • Incretin – mimetic • Enhances beta cell insulin • Blocks glucagon • Delays gastric emptying • Injection sub cutaneously 30 to 60 minutes before first and last meal – adjunctive therapy • Side effects – Gastrointestinal symptoms • FDA warning – pancreatitis – may be fatal
WHEN TO START INSULIN • Start with oral agents (metformin) and proceed to insulin if goal is not achieved • May be able to manage for up to 6 years • HgbA1C – use a target • In kidney patients and those who may be operating heavy machinery – because of the risk of hypoglycemia – may want to have a higher goal • Mono-duo-triple therapy – disease has advanced
HgbA1C • American Diabetic Association 7.0% • American Society of Clinical Endocrinologist 6.5% • Many local endocrinologist 6.0% • CONTROVERSY: The lower the HgbA1C the lower the risk of microvascular disease, but the higher the risk of hypoglycemia
INSULIN Adapted from Hirsch IB, Edelman SV Practical Management of Type 1 Diabetes, PCI Book,, West Islip Ny (2005)
INSULIN • Glucose homeostasis declines – • Loss of post prandial glycemic control • Decline in control around breakfast • Nocturnal Hyperglycemia • Consider prandial insulin before starting basal insulin • Basal insulin typically started in type 2
Diabetes and the eye • Type 1 • Almost always have retinopathy and neuropathy by the time they develop nephropathy, but many patients with retinopathy do not have nephropathy • Detected clinically by the doctor or opthalmologist • Type 2 • Retinopathy will likely be accompanied by nephropathy • If no retinopathy is present, they may have something other than diabetic nephropathy
Background Diabetic Retinopathy NORMAL BDR